Trial Outcomes & Findings for Efficacy, Safety and Tolerability of Two Fixed Dose Combinations of Aclidinium Bromide/Formoterol Fumarate, Aclidinium Bromide, Formoterol Fumarate and Placebo for 28-Weeks Treatment in Patients With Moderate to Severe, Stable Chronic Obstructive Pulmonary Disease (COPD) (NCT NCT01572792)

Last Updated: 2017-04-21

Results Overview

For each safety parameter, the last assessment made before the first dose of investigational product in the lead-in study (LAC MD-31) was used as the baseline for all analyses of that safety parameter in this extension study

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

921 participants

Primary outcome timeframe

Baseline of lead-in study to follow-up call 14±3 days after last dose of investigational product (up to Week 52)

Results posted on

2017-04-21

Participant Flow

This study was conducted at 169 study centers, 160 in the United States, and 9 in Canada. The first patient was screened in April 2012 and the last patient visit was in June 2013

This was a double-blind, placebo- and active-controlled, 28-week treatment, extension study of the lead-in study, Study LAC-MD-31 Those patients who chose to continue the treatment in the extension study and met the eligibility for the extension study remained on the same treatment as they were randomized to in the lead-in study

Participant milestones

Participant milestones
Measure	Placebo Placebo administered BID by inhalation	Aclidinium/Formoterol 400/12 μg Aclidinium bromide 400 μg + formoterol fumurate 12 μg fixed dose combination (FDC) administered BID by inhalation	Aclidinium/Formoterol 400/6 μg Aclidinium bromide 400 μg + formoterol fumurate 6 μg fixed dose combination (FDC) administered BID by inhalation	Aclidinium 400 μg Aclidinium bromide 400 μg administered BID by inhalation	Formoterol 12 μg Formoterol fumurate 12 μg administered BID by inhalation
Lead-in Study STARTED	337	338	338	340	339
Lead-in Study COMPLETED	236	272	276	268	270
Lead-in Study NOT COMPLETED	101	66	62	72	69
Extension Study STARTED	146	184	205	194	192
Extension Study COMPLETED	121	155	179	165	160
Extension Study NOT COMPLETED	25	29	26	29	32

Reasons for withdrawal

Reasons for withdrawal
Measure	Placebo Placebo administered BID by inhalation	Aclidinium/Formoterol 400/12 μg Aclidinium bromide 400 μg + formoterol fumurate 12 μg fixed dose combination (FDC) administered BID by inhalation	Aclidinium/Formoterol 400/6 μg Aclidinium bromide 400 μg + formoterol fumurate 6 μg fixed dose combination (FDC) administered BID by inhalation	Aclidinium 400 μg Aclidinium bromide 400 μg administered BID by inhalation	Formoterol 12 μg Formoterol fumurate 12 μg administered BID by inhalation
Lead-in Study Lost to Follow-up	5	9	4	2	4
Lead-in Study Withdrawal by Subject	22	11	12	24	11
Lead-in Study Protocol Violation	19	10	12	13	21
Lead-in Study Lack of Efficacy	20	5	4	8	10
Lead-in Study Adverse Event	21	21	22	16	14
Lead-in Study Site termination/COPD exacerbation/other	14	10	8	9	9
Extension Study Lost to Follow-up	6	2	0	3	3
Extension Study Withdrawal by Subject	7	6	11	8	14
Extension Study Protocol Violation	0	4	3	4	3
Extension Study Lack of Efficacy	2	3	3	2	2
Extension Study Adverse Event	7	6	5	6	4
Extension Study Site termination/COPD exacerbation/other	3	8	4	6	6

Baseline Characteristics

Efficacy, Safety and Tolerability of Two Fixed Dose Combinations of Aclidinium Bromide/Formoterol Fumarate, Aclidinium Bromide, Formoterol Fumarate and Placebo for 28-Weeks Treatment in Patients With Moderate to Severe, Stable Chronic Obstructive Pulmonary Disease (COPD)

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Placebo n=146 Participants Placebo administered BID by inhalation	Aclidinium/Formoterol 400/12 μg n=182 Participants Aclidinium bromide 400 μg + formoterol fumurate 12 μg fixed dose combination (FDC) administered BID by inhalation	Aclidinium/Formoterol 400/6 μg n=204 Participants Aclidinium bromide 400 μg + formoterol fumurate 6 μg fixed dose combination (FDC) administered BID by inhalation	Aclidinium 400 μg n=194 Participants Aclidinium bromide 400 μg administered BID by inhalation	Formoterol 12 μg n=192 Participants Formoterol fumurate 12 μg administered BID by inhalation	Total n=918 Participants Total of all reporting groups
Age, Continuous	63.2 Years STANDARD_DEVIATION 8.6 • n=5 Participants	63.7 Years STANDARD_DEVIATION 9.1 • n=7 Participants	63.6 Years STANDARD_DEVIATION 9.2 • n=5 Participants	62.9 Years STANDARD_DEVIATION 8.3 • n=4 Participants	62.8 Years STANDARD_DEVIATION 8.7 • n=21 Participants	63.2 Years STANDARD_DEVIATION 8.8 • n=10 Participants
Sex: Female, Male Female	65 Participants n=5 Participants	94 Participants n=7 Participants	84 Participants n=5 Participants	90 Participants n=4 Participants	102 Participants n=21 Participants	435 Participants n=10 Participants
Sex: Female, Male Male	81 Participants n=5 Participants	88 Participants n=7 Participants	120 Participants n=5 Participants	104 Participants n=4 Participants	90 Participants n=21 Participants	483 Participants n=10 Participants

PRIMARY outcome

Timeframe: Baseline of lead-in study to follow-up call 14±3 days after last dose of investigational product (up to Week 52)

Population: The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study

Outcome measures

Outcome measures
Measure	Placebo n=146 Participants Placebo administered BID by inhalation	Aclidinium/Formmoterol 400/12 μg n=182 Participants Aclidinium bromide 400 μg + formoterol fumurate 12 μg fixed dose combination (FDC) administered BID by inhalation	Aclidinium/Formoterol 400/6 μg n=204 Participants Aclidinium bromide 400 μg + formoterol fumurate 6 μg fixed dose combination (FDC) administered BID by inhalation	Aclidinium 400 μg n=194 Participants Aclidinium bromide 400 μg administered BID by inhalation	Formoterol 12 μg n=192 Participants Formoterol fumurate 12 μg administered BID by inhalation
Percentage of Patients to Experience Any Treatment-emergent Adverse Event	56.8 Percentage of participants	65.9 Percentage of participants	61.3 Percentage of participants	67.5 Percentage of participants	64.6 Percentage of participants

SECONDARY outcome

Timeframe: Baseline of lead-in study to end of treatment (up to Week 52)

Potentially clinically significant change: \>1.15 × upper limit of normal (ULN) for absolute cell count of basophils, eosinophils or monocytes, blood alanine aminotransferase, alkaline phosphatase, aspartate aminotransferase, total bilirubin, blood urea nitrogen, total cholesterol, creatine kinase, creatinine, gamma glutamyl transferase, lactate dehydrogenase, triglycerides or uric acid \<0.85 x lower limit of normal (LLN) or \> 1.15 ULN for hematocrit ratio, haemoglobin, lymphocytes or neutrophils absolute cell count, platelet count (thrombocytes), red or white blood cell count, calcium, fasting glucose, phosphorus, total protein, or urinary pH \<0.95 x LLN or \>1.05 x ULN for chloride, potassium, sodium Urinary glucose ≥0.015, blood or ketones or protein ≥1 or specific gravity \>1.1 × ULN The last assessment made before the first dose of investigational product in the lead-in study was used as the baseline for all safety analyses in the extension study

Outcome measures

Outcome measures
Measure	Placebo n=146 Participants Placebo administered BID by inhalation	Aclidinium/Formmoterol 400/12 μg n=182 Participants Aclidinium bromide 400 μg + formoterol fumurate 12 μg fixed dose combination (FDC) administered BID by inhalation	Aclidinium/Formoterol 400/6 μg n=204 Participants Aclidinium bromide 400 μg + formoterol fumurate 6 μg fixed dose combination (FDC) administered BID by inhalation	Aclidinium 400 μg n=194 Participants Aclidinium bromide 400 μg administered BID by inhalation	Formoterol 12 μg n=192 Participants Formoterol fumurate 12 μg administered BID by inhalation
Percentage of Patients to Experience Potentially Clinically Significant Post-baseline Clinical Laboratory Values for Hematology, Chemistry or Urinalysis	32.9 Percentage of participants	41.2 Percentage of participants	35.3 Percentage of participants	32.5 Percentage of participants	38.5 Percentage of participants

SECONDARY outcome

Timeframe: Baseline of lead-in study to end of treatment (up to Week 52)

Outcome measures

Outcome measures
Measure	Placebo n=146 Participants Placebo administered BID by inhalation	Aclidinium/Formmoterol 400/12 μg n=182 Participants Aclidinium bromide 400 μg + formoterol fumurate 12 μg fixed dose combination (FDC) administered BID by inhalation	Aclidinium/Formoterol 400/6 μg n=204 Participants Aclidinium bromide 400 μg + formoterol fumurate 6 μg fixed dose combination (FDC) administered BID by inhalation	Aclidinium 400 μg n=194 Participants Aclidinium bromide 400 μg administered BID by inhalation	Formoterol 12 μg n=192 Participants Formoterol fumurate 12 μg administered BID by inhalation
Percentage of Patients to Experience a Potentially Significant Post-baseline 12-lead ECG Value QTcF >480 msec	2.1 Percentage of participants	0.6 Percentage of participants	1.0 Percentage of participants	0.5 Percentage of participants	2.6 Percentage of participants
Percentage of Patients to Experience a Potentially Significant Post-baseline 12-lead ECG Value Heart rate ≤50 bpm & ≥15% decrease from baseline	11.0 Percentage of participants	6.0 Percentage of participants	8.3 Percentage of participants	7.2 Percentage of participants	4.7 Percentage of participants
Percentage of Patients to Experience a Potentially Significant Post-baseline 12-lead ECG Value QT interval change from baseline >30 msec	53.4 Percentage of participants	53.8 Percentage of participants	55.9 Percentage of participants	60.4 Percentage of participants	48.4 Percentage of participants
Percentage of Patients to Experience a Potentially Significant Post-baseline 12-lead ECG Value QT interval >480 msec	3.4 Percentage of participants	3.8 Percentage of participants	2.9 Percentage of participants	2.6 Percentage of participants	4.7 Percentage of participants
Percentage of Patients to Experience a Potentially Significant Post-baseline 12-lead ECG Value QTcB change from baseline >30 msec	36.3 Percentage of participants	37.0 Percentage of participants	39.7 Percentage of participants	35.6 Percentage of participants	38.4 Percentage of participants
Percentage of Patients to Experience a Potentially Significant Post-baseline 12-lead ECG Value QTcB >480 msec	7.5 Percentage of participants	8.3 Percentage of participants	9.8 Percentage of participants	5.7 Percentage of participants	8.4 Percentage of participants
Percentage of Patients to Experience a Potentially Significant Post-baseline 12-lead ECG Value QTcF change from baseline >30 msec	27.4 Percentage of participants	28.7 Percentage of participants	30.4 Percentage of participants	27.8 Percentage of participants	30.2 Percentage of participants
Percentage of Patients to Experience a Potentially Significant Post-baseline 12-lead ECG Value QRS interval ≥100 msec & ≥25% increase	6.2 Percentage of participants	6.6 Percentage of participants	3.9 Percentage of participants	2.6 Percentage of participants	4.7 Percentage of participants
Percentage of Patients to Experience a Potentially Significant Post-baseline 12-lead ECG Value PR interval ≥200 msec & ≥25% increase	2.8 Percentage of participants	2.2 Percentage of participants	1.0 Percentage of participants	3.1 Percentage of participants	1.6 Percentage of participants
Percentage of Patients to Experience a Potentially Significant Post-baseline 12-lead ECG Value Heart rate ≥110 bpm & ≥15% increase from baseline	0.7 Percentage of participants	2.7 Percentage of participants	1.0 Percentage of participants	1.0 Percentage of participants	2.1 Percentage of participants

SECONDARY outcome

Timeframe: Baseline of lead-in study to end of treatment (up to Week 52)

Potentially clinically significant change: Systolic BP ≥180 mmHg and increase ≥20 mmHg from baseline or ≤90 mmHg and decrease ≥20 mmHg from baseline Diastolic BP ≥105 mmHg and increase ≥15 mmHg from baseline or ≤50 mmHg and decrease ≥15 mmHg from baseline Pulse rate ≥110 bpm and increase ≥15% from baseline or ≤50 bpm and decrease ≥15% from baseline Weight increase or decrease ≥7% from baseline The last assessment made before the first dose of investigational product in the lead-in study was used as the baseline for all safety analyses in the extension study

Outcome measures

Outcome measures
Measure	Placebo n=146 Participants Placebo administered BID by inhalation	Aclidinium/Formmoterol 400/12 μg n=182 Participants Aclidinium bromide 400 μg + formoterol fumurate 12 μg fixed dose combination (FDC) administered BID by inhalation	Aclidinium/Formoterol 400/6 μg n=204 Participants Aclidinium bromide 400 μg + formoterol fumurate 6 μg fixed dose combination (FDC) administered BID by inhalation	Aclidinium 400 μg n=194 Participants Aclidinium bromide 400 μg administered BID by inhalation	Formoterol 12 μg n=192 Participants Formoterol fumurate 12 μg administered BID by inhalation
Percentage of Patients to Experience Potentially Clinically Significant Post-baseline Vital Signs (Pulse Rate, Systolic or Diastolic Blood Pressure or Weight)	27.4 Percentage of participants	24.2 Percentage of participants	18.6 Percentage of participants	22.2 Percentage of participants	24.5 Percentage of participants

OTHER_PRE_SPECIFIED outcome

Timeframe: Baseline of lead-in study to Week 52 of treatment

Population: The Combined intent to treat (ITT) Population defined as all patients randomized to a treatment group who took at least 1 dose of double-blind investigational product in the lead-in study (LAC-MD-31) and who had a baseline assessment and at least 1 post-baseline assessment of forced expiratory volume in 1 second (FEV1) in LAC-MD-31

Outcome measures

Outcome measures
Measure	Placebo n=331 Participants Placebo administered BID by inhalation	Aclidinium/Formmoterol 400/12 μg n=335 Participants Aclidinium bromide 400 μg + formoterol fumurate 12 μg fixed dose combination (FDC) administered BID by inhalation	Aclidinium/Formoterol 400/6 μg n=333 Participants Aclidinium bromide 400 μg + formoterol fumurate 6 μg fixed dose combination (FDC) administered BID by inhalation	Aclidinium 400 μg n=337 Participants Aclidinium bromide 400 μg administered BID by inhalation	Formoterol 12 μg n=332 Participants Formoterol fumurate 12 μg administered BID by inhalation
Change From Baseline in 1-hour Morning Post-dose Forced Expiratory Volume in One Second (FEV1)	-0.086 Liters Standard Error 0.017	0.198 Liters Standard Error 0.015	0.166 Liters Standard Error 0.015	0.112 Liters Standard Error 0.015	0.109 Liters Standard Error 0.015

OTHER_PRE_SPECIFIED outcome

Timeframe: Baseline of lead-in study to Week 52 of treatment

Outcome measures

Outcome measures
Measure	Placebo n=331 Participants Placebo administered BID by inhalation	Aclidinium/Formmoterol 400/12 μg n=335 Participants Aclidinium bromide 400 μg + formoterol fumurate 12 μg fixed dose combination (FDC) administered BID by inhalation	Aclidinium/Formoterol 400/6 μg n=333 Participants Aclidinium bromide 400 μg + formoterol fumurate 6 μg fixed dose combination (FDC) administered BID by inhalation	Aclidinium 400 μg n=337 Participants Aclidinium bromide 400 μg administered BID by inhalation	Formoterol 12 μg n=332 Participants Formoterol fumurate 12 μg administered BID by inhalation
Change From Baseline in Morning Predose (Trough) Forced Expiratory Volume in One Second (FEV1)	-0.101 Liters Standard Error 0.017	0.038 Liters Standard Error 0.015	0.005 Liters Standard Error 0.015	0.030 Liters Standard Error 0.015	0.004 Liters Standard Error 0.015

OTHER_PRE_SPECIFIED outcome

Timeframe: Baseline of lead-in study to Week 52 of treatment

The TDI measures the change from baseline in severity of breathlessness in symptomatic patients. The TDI contains a rating for 3 categories (functional impairment, magnitude of task, magnitude of effort). TDI scale ranges from -3 (major deterioration) to +3 (major improvement) including a 0 score to indicate "no change". The 3 categories are added to obtain a focal score ranging from -9 (including 0) to +9.

Outcome measures

Outcome measures
Measure	Placebo n=331 Participants Placebo administered BID by inhalation	Aclidinium/Formmoterol 400/12 μg n=335 Participants Aclidinium bromide 400 μg + formoterol fumurate 12 μg fixed dose combination (FDC) administered BID by inhalation	Aclidinium/Formoterol 400/6 μg n=333 Participants Aclidinium bromide 400 μg + formoterol fumurate 6 μg fixed dose combination (FDC) administered BID by inhalation	Aclidinium 400 μg n=337 Participants Aclidinium bromide 400 μg administered BID by inhalation	Formoterol 12 μg n=332 Participants Formoterol fumurate 12 μg administered BID by inhalation
Transition Dyspnea Index (TDI) Focal Score at End of Study	0.731 Scores on a scale Standard Error 0.277	1.812 Scores on a scale Standard Error 0.251	1.742 Scores on a scale Standard Error 0.235	1.596 Scores on a scale Standard Error 0.241	1.324 Scores on a scale Standard Error 0.246

OTHER_PRE_SPECIFIED outcome

Timeframe: Baseline of lead-in study to Week 52 of treatment

St George's Respiratory Questionnaire (SGRQ) measures COPD-specific health outcomes and consists of 3 dimension scores (symptom, activity and impact). SGRQ total score is the sum of these scores and ranges from 0 (best health status) to 100 (worst health status).

Outcome measures

Outcome measures
Measure	Placebo n=331 Participants Placebo administered BID by inhalation	Aclidinium/Formmoterol 400/12 μg n=335 Participants Aclidinium bromide 400 μg + formoterol fumurate 12 μg fixed dose combination (FDC) administered BID by inhalation	Aclidinium/Formoterol 400/6 μg n=333 Participants Aclidinium bromide 400 μg + formoterol fumurate 6 μg fixed dose combination (FDC) administered BID by inhalation	Aclidinium 400 μg n=337 Participants Aclidinium bromide 400 μg administered BID by inhalation	Formoterol 12 μg n=332 Participants Formoterol fumurate 12 μg administered BID by inhalation
Change From Baseline in St George's Respiratory Questionnaire (SGRQ) Total Score	-1.862 Scores on a scale Standard Error 0.945	-3.646 Scores on a scale Standard Error 0.861	-5.527 Scores on a scale Standard Error 0.819	-4.306 Scores on a scale Standard Error 0.847	-4.059 Scores on a scale Standard Error 0.853

Adverse Events

Placebo

Serious events: 10 serious events

Other events: 37 other events

Deaths: 0 deaths

Aclidinium/Formoterol 400/12 μg

Serious events: 14 serious events

Other events: 59 other events

Deaths: 0 deaths

Aclidinium/Formoterol 400/6 μg

Serious events: 14 serious events

Other events: 64 other events

Deaths: 0 deaths

Aclidinium 400 μg

Serious events: 15 serious events

Other events: 67 other events

Deaths: 0 deaths

Formoterol 12 μg

Serious events: 14 serious events

Other events: 62 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	Placebo n=146 participants at risk Placebo administered BID by inhalation	Aclidinium/Formoterol 400/12 μg n=182 participants at risk Aclidinium bromide 400 μg + formoterol fumurate 12 μg fixed dose combination (FDC) administered BID by inhalation	Aclidinium/Formoterol 400/6 μg n=204 participants at risk Aclidinium bromide 400 μg + formoterol fumurate 6 μg fixed dose combination (FDC) administered BID by inhalation	Aclidinium 400 μg n=194 participants at risk Aclidinium bromide 400 μg administered BID by inhalation	Formoterol 12 μg n=192 participants at risk Formoterol fumurate 12 μg administered BID by inhalation
Blood and lymphatic system disorders Anaemia	0.68% 1/146 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.00% 0/182 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.00% 0/204 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.00% 0/194 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.00% 0/192 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study
Blood and lymphatic system disorders Haemorrhagic anaemia	0.00% 0/146 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.00% 0/182 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.00% 0/204 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.00% 0/194 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.52% 1/192 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study
Blood and lymphatic system disorders Pancytopenia	0.00% 0/146 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.55% 1/182 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.00% 0/204 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.00% 0/194 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.00% 0/192 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study
Cardiac disorders Atrioventricular block second degree	0.00% 0/146 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.00% 0/182 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.00% 0/204 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.00% 0/194 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.52% 1/192 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study
Cardiac disorders Palpitations	0.00% 0/146 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.00% 0/182 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.00% 0/204 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.52% 1/194 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.00% 0/192 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study
Cardiac disorders Coronary artery disease	0.68% 1/146 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.00% 0/182 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.00% 0/204 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.00% 0/194 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.00% 0/192 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study
Cardiac disorders Acute myocardial infarction	0.00% 0/146 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.00% 0/182 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.49% 1/204 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.00% 0/194 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.00% 0/192 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study
Cardiac disorders Angina pectoris	0.00% 0/146 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.00% 0/182 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.49% 1/204 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.00% 0/194 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.00% 0/192 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study
Cardiac disorders Myocardial infarction	0.68% 1/146 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.00% 0/182 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.00% 0/204 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	1.0% 2/194 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.52% 1/192 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study
Cardiac disorders Pericardial effusion	0.00% 0/146 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.00% 0/182 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.00% 0/204 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.52% 1/194 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.00% 0/192 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study
Cardiac disorders Arrhythmia	0.68% 1/146 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.00% 0/182 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.00% 0/204 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.00% 0/194 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.00% 0/192 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study
Cardiac disorders Atrial fibrillation	0.00% 0/146 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.00% 0/182 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.49% 1/204 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.00% 0/194 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.00% 0/192 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study
Cardiac disorders Sick sinus syndrome	0.68% 1/146 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.00% 0/182 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.00% 0/204 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.00% 0/194 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.00% 0/192 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study
Cardiac disorders Cardiac arrest	0.00% 0/146 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.55% 1/182 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.00% 0/204 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.00% 0/194 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.00% 0/192 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study
Cardiac disorders Cardio-respiratory arrest	0.00% 0/146 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.00% 0/182 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.49% 1/204 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.00% 0/194 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.00% 0/192 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study
Gastrointestinal disorders Colitis ulcerative	0.00% 0/146 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.55% 1/182 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.00% 0/204 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.00% 0/194 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.00% 0/192 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study
Gastrointestinal disorders Gastritis	0.00% 0/146 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.00% 0/182 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.49% 1/204 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.00% 0/194 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.00% 0/192 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study
Gastrointestinal disorders Constipation	0.00% 0/146 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.55% 1/182 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.00% 0/204 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.00% 0/194 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.00% 0/192 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study
Gastrointestinal disorders Enterocolitis	0.00% 0/146 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.55% 1/182 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.00% 0/204 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.00% 0/194 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.00% 0/192 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study
Gastrointestinal disorders Lower gastrointestinal haemorrhage	0.00% 0/146 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.55% 1/182 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.00% 0/204 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.00% 0/194 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.00% 0/192 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study
Gastrointestinal disorders Gastrointestinal haemorrhage	0.00% 0/146 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.00% 0/182 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.49% 1/204 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.00% 0/194 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.00% 0/192 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study
General disorders Asthenia	0.00% 0/146 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.00% 0/182 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.49% 1/204 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.00% 0/194 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.00% 0/192 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study
General disorders Death	0.68% 1/146 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.55% 1/182 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.00% 0/204 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.00% 0/194 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.00% 0/192 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study
General disorders Drug withdrawal syndrome	0.00% 0/146 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.55% 1/182 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.00% 0/204 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.00% 0/194 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.00% 0/192 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study
Infections and infestations Diverticulitis	0.68% 1/146 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.00% 0/182 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.00% 0/204 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.00% 0/194 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	1.0% 2/192 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study
Infections and infestations Cellulitis	0.00% 0/146 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.00% 0/182 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.49% 1/204 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.00% 0/194 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	1.0% 2/192 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study
Infections and infestations Postoperative wound infection	0.00% 0/146 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.55% 1/182 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.00% 0/204 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.00% 0/194 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.00% 0/192 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study
Infections and infestations Device related infection	0.00% 0/146 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.00% 0/182 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.00% 0/204 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.52% 1/194 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.00% 0/192 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study
Infections and infestations Influenza	0.00% 0/146 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.00% 0/182 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.00% 0/204 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.52% 1/194 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.00% 0/192 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study
Infections and infestations Lobar pneumonia	0.00% 0/146 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.00% 0/182 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.49% 1/204 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.52% 1/194 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.00% 0/192 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study
Infections and infestations Pneumonia	0.00% 0/146 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.00% 0/182 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	1.5% 3/204 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	1.0% 2/194 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.00% 0/192 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study
Infections and infestations Sepsis	0.00% 0/146 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.00% 0/182 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.49% 1/204 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.52% 1/194 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.00% 0/192 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study
Infections and infestations Urinary tract infection	0.00% 0/146 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.55% 1/182 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.00% 0/204 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.00% 0/194 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.00% 0/192 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study
Infections and infestations Pneumonia viral	0.00% 0/146 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.55% 1/182 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.00% 0/204 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.00% 0/194 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.00% 0/192 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study
Infections and infestations Bronchitis viral	0.00% 0/146 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.00% 0/182 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.00% 0/204 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.00% 0/194 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.52% 1/192 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study
Injury, poisoning and procedural complications Fibula fracture	0.00% 0/146 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.00% 0/182 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.00% 0/204 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.00% 0/194 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.52% 1/192 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study
Injury, poisoning and procedural complications Hip fracture	0.00% 0/146 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.00% 0/182 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.00% 0/204 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.52% 1/194 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.00% 0/192 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study
Injury, poisoning and procedural complications Tibia fracture	0.00% 0/146 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.00% 0/182 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.00% 0/204 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.00% 0/194 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.52% 1/192 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study
Injury, poisoning and procedural complications Post laminectomy syndrome	0.00% 0/146 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.00% 0/182 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.00% 0/204 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.00% 0/194 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.52% 1/192 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study
Injury, poisoning and procedural complications Fall	0.00% 0/146 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.55% 1/182 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.49% 1/204 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.00% 0/194 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.00% 0/192 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study
Injury, poisoning and procedural complications Accidental overdose	0.00% 0/146 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.55% 1/182 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.00% 0/204 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.00% 0/194 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.00% 0/192 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study
Injury, poisoning and procedural complications Pelvic fracture	0.00% 0/146 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.00% 0/182 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.49% 1/204 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.00% 0/194 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.00% 0/192 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study
Injury, poisoning and procedural complications Ulna fracture	0.00% 0/146 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.00% 0/182 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.00% 0/204 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.52% 1/194 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.00% 0/192 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study
Investigations International normalised ratio increased	0.00% 0/146 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.00% 0/182 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.49% 1/204 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.00% 0/194 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.00% 0/192 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study
Investigations Electrocardiogram abnormal	0.68% 1/146 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.55% 1/182 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.00% 0/204 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.00% 0/194 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.00% 0/192 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study
Metabolism and nutrition disorders Diabetes mellitus	0.00% 0/146 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.00% 0/182 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.00% 0/204 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.00% 0/194 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.52% 1/192 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study
Metabolism and nutrition disorders Hypoglycaemia	0.68% 1/146 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.00% 0/182 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.00% 0/204 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.00% 0/194 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.00% 0/192 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study
Metabolism and nutrition disorders Hyponatraemia	0.00% 0/146 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.55% 1/182 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.00% 0/204 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.00% 0/194 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.00% 0/192 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study
Metabolism and nutrition disorders Hypovolaemia	0.00% 0/146 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.55% 1/182 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.00% 0/204 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.00% 0/194 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.00% 0/192 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study
Metabolism and nutrition disorders Dehydration	0.00% 0/146 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.00% 0/182 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.00% 0/204 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.52% 1/194 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.00% 0/192 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study
Musculoskeletal and connective tissue disorders Back pain	0.00% 0/146 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.55% 1/182 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.00% 0/204 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.00% 0/194 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.52% 1/192 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study
Musculoskeletal and connective tissue disorders Musculoskeletal pain	0.00% 0/146 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.00% 0/182 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.00% 0/204 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.52% 1/194 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.00% 0/192 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study
Musculoskeletal and connective tissue disorders Osteoarthritis	0.00% 0/146 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.00% 0/182 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.00% 0/204 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.00% 0/194 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.52% 1/192 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study
Musculoskeletal and connective tissue disorders Lumbar spinal stenosis	0.00% 0/146 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.00% 0/182 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.00% 0/204 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.00% 0/194 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.52% 1/192 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Bladder transitional cell carcinoma	0.00% 0/146 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.00% 0/182 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.00% 0/204 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.00% 0/194 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.52% 1/192 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Lung adenocarcinoma	0.00% 0/146 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.00% 0/182 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.00% 0/204 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.52% 1/194 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.00% 0/192 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Metastatic renal cell carcinoma	0.00% 0/146 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.00% 0/182 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.00% 0/204 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.00% 0/194 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.52% 1/192 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Transitional cell carcinoma	0.00% 0/146 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.55% 1/182 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.00% 0/204 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.00% 0/194 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.00% 0/192 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study
Nervous system disorders Cerebrovascular accident	0.00% 0/146 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.00% 0/182 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.00% 0/204 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	1.0% 2/194 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.00% 0/192 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study
Nervous system disorders Carotid artery stenosis	0.00% 0/146 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.00% 0/182 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.49% 1/204 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.00% 0/194 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.00% 0/192 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study
Nervous system disorders Cervical myelopathy	0.00% 0/146 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.00% 0/182 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.49% 1/204 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.00% 0/194 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.00% 0/192 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study
Nervous system disorders Ataxia	0.00% 0/146 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.55% 1/182 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.00% 0/204 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.00% 0/194 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.00% 0/192 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study
Nervous system disorders Syncope	0.68% 1/146 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.00% 0/182 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.98% 2/204 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.00% 0/194 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.52% 1/192 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study
Nervous system disorders Convulsion	0.00% 0/146 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.00% 0/182 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.00% 0/204 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.52% 1/194 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.00% 0/192 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study
Psychiatric disorders Anxiety	0.00% 0/146 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.00% 0/182 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.00% 0/204 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.00% 0/194 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.52% 1/192 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study
Psychiatric disorders Affective disorder	0.00% 0/146 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.00% 0/182 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.00% 0/204 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.00% 0/194 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.52% 1/192 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study
Renal and urinary disorders Renal failure acute	0.00% 0/146 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.00% 0/182 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.00% 0/204 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.52% 1/194 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.00% 0/192 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study
Renal and urinary disorders Nephrolithiasis	0.00% 0/146 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.00% 0/182 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.49% 1/204 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.00% 0/194 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.00% 0/192 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study
Respiratory, thoracic and mediastinal disorders Acute respiratory failure	0.00% 0/146 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.00% 0/182 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.98% 2/204 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.52% 1/194 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.52% 1/192 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study
Respiratory, thoracic and mediastinal disorders Pulmonary mass	0.00% 0/146 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	1.1% 2/182 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.00% 0/204 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.00% 0/194 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.00% 0/192 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study
Vascular disorders Deep vein thrombosis	0.68% 1/146 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.00% 0/182 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.00% 0/204 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.00% 0/194 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.00% 0/192 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study
Vascular disorders Peripheral vascular disorder	0.00% 0/146 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.55% 1/182 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.00% 0/204 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.00% 0/194 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.00% 0/192 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study
Vascular disorders Hypertension	0.68% 1/146 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.00% 0/182 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.00% 0/204 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.00% 0/194 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.52% 1/192 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study
Vascular disorders Hypotension	0.00% 0/146 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.00% 0/182 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.98% 2/204 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.00% 0/194 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	0.52% 1/192 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study

Other adverse events

Other adverse events
Measure	Placebo n=146 participants at risk Placebo administered BID by inhalation	Aclidinium/Formoterol 400/12 μg n=182 participants at risk Aclidinium bromide 400 μg + formoterol fumurate 12 μg fixed dose combination (FDC) administered BID by inhalation	Aclidinium/Formoterol 400/6 μg n=204 participants at risk Aclidinium bromide 400 μg + formoterol fumurate 6 μg fixed dose combination (FDC) administered BID by inhalation	Aclidinium 400 μg n=194 participants at risk Aclidinium bromide 400 μg administered BID by inhalation	Formoterol 12 μg n=192 participants at risk Formoterol fumurate 12 μg administered BID by inhalation
Respiratory, thoracic and mediastinal disorders Cough	2.1% 3/146 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	2.7% 5/182 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	2.9% 6/204 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	6.2% 12/194 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	2.6% 5/192 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study
Infections and infestations Nasopharyngitis	4.8% 7/146 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	7.7% 14/182 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	6.9% 14/204 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	9.3% 18/194 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	6.8% 13/192 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study
Infections and infestations Urinary tract infection	5.5% 8/146 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	8.2% 15/182 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	6.4% 13/204 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	4.1% 8/194 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	5.7% 11/192 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study
Infections and infestations Upper respiratory tract infection	5.5% 8/146 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	2.7% 5/182 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	3.9% 8/204 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	4.6% 9/194 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	4.2% 8/192 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study
Respiratory, thoracic and mediastinal disorders Chronic obstructive pulmonary disease	15.8% 23/146 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	20.3% 37/182 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	22.1% 45/204 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	22.7% 44/194 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study	24.0% 46/192 • Follow-up call 14±3 days after end of treatment (Week 28±5 days) The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study

Additional Information

Study Director

AstraZeneca

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee Publication of the results by the Principal Investigator (PI) will be subject to mutual agreement between the PI and the sponsor
Publication restrictions are in place

Restriction type: OTHER