Trial Outcomes & Findings for Effect of Nintedanib on Biomarkers of Extracellular Matrix Turnover in Patients With Idiopathic Pulmonary Fibrosis and Limited Forced Vital Capacity Impairment (NCT NCT02788474)

Last Updated: 2023-12-21

Results Overview

The rate of change (slope) in blood C-reactive protein degraded by matrix metalloproteinase-1/8 (CRPM) from baseline to week 12 is presented. The mean presented is the adjusted rate based on a random coefficient regression (CRPM log 10 transformed) with fixed effects for gender, age, height and random effect of patient specific intercept and time.

Recruitment status

COMPLETED

Study phase

PHASE4

Target enrollment

347 participants

Primary outcome timeframe

baseline and 12 weeks

Results posted on

2023-12-21

Participant Flow

The trial comprised of 2 treatment periods (52 weeks). The first treatment period was a 12-week, randomised, double-blind, placebo-controlled, parallel-group period whereas the second treatment period was a 40-week, single-arm, open-label, active treatment (nintedanib 150 milligram (mg) twice daily (bid)) period.

Participants with idiopathic pulmonary fibrosis (IPF) were eligible for the trial if they fulfilled all of the inclusion criteria and none of the exclusion criteria.

Participant milestones

Participant milestones
Measure	Placebo/ Nintedanib Participants received soft gelatin capsules of matching placebo for 12 weeks in double blind period and Nintedanib 150 milligram (mg) twice daily (bid) for 40 weeks in open label period. 1 capsule of Nintedanib 150 mg bid had possibility to be reduced to 100 mg bid to manage adverse events (AEs)	Nintedanib/ Nintedanib Participants received soft gelatin capsules of Nintedanib 150 mg bid for 12 weeks in double blind period and for 40 weeks in open label period. 1 capsule of 150 mg bid had possibility to be reduced to 100 mg bid to manage adverse events (AEs)
Double Blind Treatment Period STARTED	231	116
Double Blind Treatment Period Treated	230	116
Double Blind Treatment Period COMPLETED	221	112
Double Blind Treatment Period NOT COMPLETED	10	4
Open Label Treatment Period STARTED	221	112
Open Label Treatment Period COMPLETED	189	100
Open Label Treatment Period NOT COMPLETED	32	12

Reasons for withdrawal

Reasons for withdrawal
Measure	Placebo/ Nintedanib Participants received soft gelatin capsules of matching placebo for 12 weeks in double blind period and Nintedanib 150 milligram (mg) twice daily (bid) for 40 weeks in open label period. 1 capsule of Nintedanib 150 mg bid had possibility to be reduced to 100 mg bid to manage adverse events (AEs)	Nintedanib/ Nintedanib Participants received soft gelatin capsules of Nintedanib 150 mg bid for 12 weeks in double blind period and for 40 weeks in open label period. 1 capsule of 150 mg bid had possibility to be reduced to 100 mg bid to manage adverse events (AEs)
Double Blind Treatment Period Not treated	1	0
Double Blind Treatment Period Patient's refusal	3	0
Double Blind Treatment Period Adverse Event	6	4
Open Label Treatment Period Adverse Event	29	9
Open Label Treatment Period Other than reason specified	1	0
Open Label Treatment Period Patient's refusal	1	3
Open Label Treatment Period Non-compliance	1	0

Baseline Characteristics

Effect of Nintedanib on Biomarkers of Extracellular Matrix Turnover in Patients With Idiopathic Pulmonary Fibrosis and Limited Forced Vital Capacity Impairment

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Placebo/ Nintedanib n=230 Participants Participants received soft gelatin capsules of matching placebo for 12 weeks in double blind period and Nintedanib 150 milligram (mg) twice daily (bid) for 40 weeks in open label period. 1 capsule of Nintedanib 150 mg bid had possibility to be reduced to 100 mg bid to manage adverse events (AEs)	Nintedanib/ Nintedanib n=116 Participants Participants received soft gelatin capsules of Nintedanib 150 mg bid for 12 weeks in double blind period and for 40 weeks in open label period. 1 capsule of 150 mg bid had possibility to be reduced to 100 mg bid to manage adverse events (AEs)	Total n=346 Participants Total of all reporting groups
Age, Continuous	70.2 years STANDARD_DEVIATION 7.2 • n=5 Participants	70.5 years STANDARD_DEVIATION 7.7 • n=7 Participants	70.3 years STANDARD_DEVIATION 7.4 • n=5 Participants
Sex: Female, Male Female	61 Participants n=5 Participants	23 Participants n=7 Participants	84 Participants n=5 Participants
Sex: Female, Male Male	169 Participants n=5 Participants	93 Participants n=7 Participants	262 Participants n=5 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	19 Participants n=5 Participants	9 Participants n=7 Participants	28 Participants n=5 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	193 Participants n=5 Participants	96 Participants n=7 Participants	289 Participants n=5 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	18 Participants n=5 Participants	11 Participants n=7 Participants	29 Participants n=5 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Asian	68 Participants n=5 Participants	35 Participants n=7 Participants	103 Participants n=5 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Black or African American	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) White	144 Participants n=5 Participants	70 Participants n=7 Participants	214 Participants n=5 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Unknown or Not Reported	18 Participants n=5 Participants	11 Participants n=7 Participants	29 Participants n=5 Participants

PRIMARY outcome

Timeframe: baseline and 12 weeks

Population: Treated set (TS) including participants with available data for this endpoint.

Outcome measures

Outcome measures
Measure	Placebo/ Nintedanib n=229 Participants Participants received soft gelatin capsules of matching placebo for 12 weeks in double blind period and Nintedanib 150 milligram (mg) twice daily (bid) for 40 weeks in open label period. 1 capsule of Nintedanib 150 mg bid had possibility to be reduced to 100 mg bid to manage adverse events (AEs)	Nintedanib/ Nintedanib n=116 Participants Participants received soft gelatin capsules of Nintedanib 150 mg bid for 12 weeks in double blind period and for 40 weeks in open label period. 1 capsule of 150 mg bid had possibility to be reduced to 100 mg bid to manage adverse events (AEs)
The Rate of Change (Slope) in Blood C-reactive Protein Degraded by Matrix Metalloproteinase-1/8 (CRPM) From Baseline to Week 12.	-0.00190 nanogram/ millitre/ month (ng/ mL/ mth) Standard Error 0.00165	-0.00257 nanogram/ millitre/ month (ng/ mL/ mth) Standard Error 0.00232

SECONDARY outcome

Timeframe: 52 weeks

Population: Treated set

For this endpoint, disease progression was defined by absolute FVC (percentage of predicted) decline ≥10% or death up to Week 52 based on in-clinic supervised spirometry. This is a key secondary endpoint of the trial. This outcome measure is "percentage of patients with disease progression" and CRPM is included in the various models as a factor/covariate, and that this outcome measure, the percentage of progressors are displayed under "Measured values"

Outcome measures

Outcome measures
Measure	Placebo/ Nintedanib n=230 Participants Participants received soft gelatin capsules of matching placebo for 12 weeks in double blind period and Nintedanib 150 milligram (mg) twice daily (bid) for 40 weeks in open label period. 1 capsule of Nintedanib 150 mg bid had possibility to be reduced to 100 mg bid to manage adverse events (AEs)	Nintedanib/ Nintedanib n=116 Participants Participants received soft gelatin capsules of Nintedanib 150 mg bid for 12 weeks in double blind period and for 40 weeks in open label period. 1 capsule of 150 mg bid had possibility to be reduced to 100 mg bid to manage adverse events (AEs)
Percentage of Patients With Disease Progression as Defined by Absolute Forced Vital Capacity (FVC) Decline >=10% or Death Until Week 52	30.43 Percentage of participants Interval 24.85 to 36.66	25.00 Percentage of participants Interval 18.01 to 33.6

SECONDARY outcome

Timeframe: baseline and 12 weeks

Population: Treated set (TS) including participants with available data for this endpoint.

The rate of change in blood Collagen 1 degraded by matrix metalloproteinase-2/9/13 (C1M) from baseline to week 12 is presented. The mean presented is the adjusted rate based on a random coefficient regression (C1M (negative reciprocal root transformation)) with fixed effects for gender, age, height and random effect of patient specific intercept and time.

Outcome measures

Outcome measures
Measure	Placebo/ Nintedanib n=229 Participants Participants received soft gelatin capsules of matching placebo for 12 weeks in double blind period and Nintedanib 150 milligram (mg) twice daily (bid) for 40 weeks in open label period. 1 capsule of Nintedanib 150 mg bid had possibility to be reduced to 100 mg bid to manage adverse events (AEs)	Nintedanib/ Nintedanib n=116 Participants Participants received soft gelatin capsules of Nintedanib 150 mg bid for 12 weeks in double blind period and for 40 weeks in open label period. 1 capsule of 150 mg bid had possibility to be reduced to 100 mg bid to manage adverse events (AEs)
The Rate of Change in Blood Collagen 1 Degraded by Matrix Metalloproteinase-2/9/13 (C1M) From Baseline to Week 12	0.00041 ng/ml/mth Standard Error 0.00127	0.00162 ng/ml/mth Standard Error 0.00172

SECONDARY outcome

Timeframe: baseline and 12 weeks

Population: Treated set (TS) including participants with available data for this endpoint.

The rate of change in blood Collagen 3 degraded by matrix metalloproteinase-9 (C3M) from baseline to week 12 is presented. The mean presented is the adjusted rate based on a random coefficient regression (C3M- log 10 transformation) with fixed effects for gender, age, height and random effect of patient specific intercept and time.

Outcome measures

Outcome measures
Measure	Placebo/ Nintedanib n=229 Participants Participants received soft gelatin capsules of matching placebo for 12 weeks in double blind period and Nintedanib 150 milligram (mg) twice daily (bid) for 40 weeks in open label period. 1 capsule of Nintedanib 150 mg bid had possibility to be reduced to 100 mg bid to manage adverse events (AEs)	Nintedanib/ Nintedanib n=116 Participants Participants received soft gelatin capsules of Nintedanib 150 mg bid for 12 weeks in double blind period and for 40 weeks in open label period. 1 capsule of 150 mg bid had possibility to be reduced to 100 mg bid to manage adverse events (AEs)
The Rate of Change in Blood Collagen 3 Degraded by Matrix Metalloproteinase-9 (C3M) From Baseline to Week 12	-0.00091 ng/ml/mth Standard Error 0.00158	-0.00398 ng/ml/mth Standard Error 0.00219

Adverse Events

Placebo (Double Blind Period)

Serious events: 18 serious events

Other events: 103 other events

Deaths: 0 deaths

Nintedanib (Double Blind Period)

Serious events: 8 serious events

Other events: 80 other events

Deaths: 0 deaths

Nintedanib (Open Label Period)

Serious events: 65 serious events

Other events: 277 other events

Deaths: 9 deaths

Serious adverse events

Other adverse events

Additional Information

Boehringer Ingelheim, Call Center

Boehringer Ingelheim

Phone: 1-800-243-0127

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee Boehringer Ingelheim (BI) acknowledges that investigators have the right to publish the study results. Investigators shall provide BI with a copy of any publication or presentation for review prior to any submission. Such review will be done with regard to proprietary information, information related to patentable inventions, medical, scientific, and statistical accuracy within 60 days. BI may request a delay of the publication in order to protect BI's intellectual property rights.
Publication restrictions are in place

Restriction type: OTHER

Measure	Placebo (Double Blind Period) n=230 participants at risk Participants received soft gelatin capsules of matching placebo for 12 weeks in double blind period.	Nintedanib (Double Blind Period) n=116 participants at risk Participants received soft gelatin capsules of Nintedanib 150 mg bid for 12 weeks in double blind period.	Nintedanib (Open Label Period) n=333 participants at risk Participants received soft gelatin capsules of Nintedanib 150 mg bid for 40 weeks in open label period. 1 capsule of 150 mg bid had possibility to be reduced to 100 mg bid to manage adverse events. Participants initially on placebo in the double blind period also received Nintedanib 150 mg bid in the open label period.
Gastrointestinal disorders Abdominal pain	3.5% 8/230 • Serious Adverse Event (SAE) & Non SAE: All adverse events (AEs) that occurred between first drug intake and 28 days after last drug intake (end of the Residual effect period (REP)); up to 53 weeks All cause mortality: All AEs during the course of the clinical trial; up to 56 weeks Treated set is used for reporting adverse events	5.2% 6/116 • Serious Adverse Event (SAE) & Non SAE: All adverse events (AEs) that occurred between first drug intake and 28 days after last drug intake (end of the Residual effect period (REP)); up to 53 weeks All cause mortality: All AEs during the course of the clinical trial; up to 56 weeks Treated set is used for reporting adverse events	4.8% 16/333 • Serious Adverse Event (SAE) & Non SAE: All adverse events (AEs) that occurred between first drug intake and 28 days after last drug intake (end of the Residual effect period (REP)); up to 53 weeks All cause mortality: All AEs during the course of the clinical trial; up to 56 weeks Treated set is used for reporting adverse events
Gastrointestinal disorders Constipation	1.3% 3/230 • Serious Adverse Event (SAE) & Non SAE: All adverse events (AEs) that occurred between first drug intake and 28 days after last drug intake (end of the Residual effect period (REP)); up to 53 weeks All cause mortality: All AEs during the course of the clinical trial; up to 56 weeks Treated set is used for reporting adverse events	5.2% 6/116 • Serious Adverse Event (SAE) & Non SAE: All adverse events (AEs) that occurred between first drug intake and 28 days after last drug intake (end of the Residual effect period (REP)); up to 53 weeks All cause mortality: All AEs during the course of the clinical trial; up to 56 weeks Treated set is used for reporting adverse events	4.2% 14/333 • Serious Adverse Event (SAE) & Non SAE: All adverse events (AEs) that occurred between first drug intake and 28 days after last drug intake (end of the Residual effect period (REP)); up to 53 weeks All cause mortality: All AEs during the course of the clinical trial; up to 56 weeks Treated set is used for reporting adverse events
Gastrointestinal disorders Diarrhoea	18.3% 42/230 • Serious Adverse Event (SAE) & Non SAE: All adverse events (AEs) that occurred between first drug intake and 28 days after last drug intake (end of the Residual effect period (REP)); up to 53 weeks All cause mortality: All AEs during the course of the clinical trial; up to 56 weeks Treated set is used for reporting adverse events	46.6% 54/116 • Serious Adverse Event (SAE) & Non SAE: All adverse events (AEs) that occurred between first drug intake and 28 days after last drug intake (end of the Residual effect period (REP)); up to 53 weeks All cause mortality: All AEs during the course of the clinical trial; up to 56 weeks Treated set is used for reporting adverse events	64.6% 215/333 • Serious Adverse Event (SAE) & Non SAE: All adverse events (AEs) that occurred between first drug intake and 28 days after last drug intake (end of the Residual effect period (REP)); up to 53 weeks All cause mortality: All AEs during the course of the clinical trial; up to 56 weeks Treated set is used for reporting adverse events
Gastrointestinal disorders Nausea	6.5% 15/230 • Serious Adverse Event (SAE) & Non SAE: All adverse events (AEs) that occurred between first drug intake and 28 days after last drug intake (end of the Residual effect period (REP)); up to 53 weeks All cause mortality: All AEs during the course of the clinical trial; up to 56 weeks Treated set is used for reporting adverse events	14.7% 17/116 • Serious Adverse Event (SAE) & Non SAE: All adverse events (AEs) that occurred between first drug intake and 28 days after last drug intake (end of the Residual effect period (REP)); up to 53 weeks All cause mortality: All AEs during the course of the clinical trial; up to 56 weeks Treated set is used for reporting adverse events	17.1% 57/333 • Serious Adverse Event (SAE) & Non SAE: All adverse events (AEs) that occurred between first drug intake and 28 days after last drug intake (end of the Residual effect period (REP)); up to 53 weeks All cause mortality: All AEs during the course of the clinical trial; up to 56 weeks Treated set is used for reporting adverse events
Gastrointestinal disorders Vomiting	3.0% 7/230 • Serious Adverse Event (SAE) & Non SAE: All adverse events (AEs) that occurred between first drug intake and 28 days after last drug intake (end of the Residual effect period (REP)); up to 53 weeks All cause mortality: All AEs during the course of the clinical trial; up to 56 weeks Treated set is used for reporting adverse events	7.8% 9/116 • Serious Adverse Event (SAE) & Non SAE: All adverse events (AEs) that occurred between first drug intake and 28 days after last drug intake (end of the Residual effect period (REP)); up to 53 weeks All cause mortality: All AEs during the course of the clinical trial; up to 56 weeks Treated set is used for reporting adverse events	12.6% 42/333 • Serious Adverse Event (SAE) & Non SAE: All adverse events (AEs) that occurred between first drug intake and 28 days after last drug intake (end of the Residual effect period (REP)); up to 53 weeks All cause mortality: All AEs during the course of the clinical trial; up to 56 weeks Treated set is used for reporting adverse events
Infections and infestations Bronchitis	2.2% 5/230 • Serious Adverse Event (SAE) & Non SAE: All adverse events (AEs) that occurred between first drug intake and 28 days after last drug intake (end of the Residual effect period (REP)); up to 53 weeks All cause mortality: All AEs during the course of the clinical trial; up to 56 weeks Treated set is used for reporting adverse events	2.6% 3/116 • Serious Adverse Event (SAE) & Non SAE: All adverse events (AEs) that occurred between first drug intake and 28 days after last drug intake (end of the Residual effect period (REP)); up to 53 weeks All cause mortality: All AEs during the course of the clinical trial; up to 56 weeks Treated set is used for reporting adverse events	6.9% 23/333 • Serious Adverse Event (SAE) & Non SAE: All adverse events (AEs) that occurred between first drug intake and 28 days after last drug intake (end of the Residual effect period (REP)); up to 53 weeks All cause mortality: All AEs during the course of the clinical trial; up to 56 weeks Treated set is used for reporting adverse events
Infections and infestations Lower respiratory tract infection	3.0% 7/230 • Serious Adverse Event (SAE) & Non SAE: All adverse events (AEs) that occurred between first drug intake and 28 days after last drug intake (end of the Residual effect period (REP)); up to 53 weeks All cause mortality: All AEs during the course of the clinical trial; up to 56 weeks Treated set is used for reporting adverse events	3.4% 4/116 • Serious Adverse Event (SAE) & Non SAE: All adverse events (AEs) that occurred between first drug intake and 28 days after last drug intake (end of the Residual effect period (REP)); up to 53 weeks All cause mortality: All AEs during the course of the clinical trial; up to 56 weeks Treated set is used for reporting adverse events	5.4% 18/333 • Serious Adverse Event (SAE) & Non SAE: All adverse events (AEs) that occurred between first drug intake and 28 days after last drug intake (end of the Residual effect period (REP)); up to 53 weeks All cause mortality: All AEs during the course of the clinical trial; up to 56 weeks Treated set is used for reporting adverse events
Infections and infestations Nasopharyngitis	8.3% 19/230 • Serious Adverse Event (SAE) & Non SAE: All adverse events (AEs) that occurred between first drug intake and 28 days after last drug intake (end of the Residual effect period (REP)); up to 53 weeks All cause mortality: All AEs during the course of the clinical trial; up to 56 weeks Treated set is used for reporting adverse events	8.6% 10/116 • Serious Adverse Event (SAE) & Non SAE: All adverse events (AEs) that occurred between first drug intake and 28 days after last drug intake (end of the Residual effect period (REP)); up to 53 weeks All cause mortality: All AEs during the course of the clinical trial; up to 56 weeks Treated set is used for reporting adverse events	14.7% 49/333 • Serious Adverse Event (SAE) & Non SAE: All adverse events (AEs) that occurred between first drug intake and 28 days after last drug intake (end of the Residual effect period (REP)); up to 53 weeks All cause mortality: All AEs during the course of the clinical trial; up to 56 weeks Treated set is used for reporting adverse events
Infections and infestations Upper respiratory tract infection	3.9% 9/230 • Serious Adverse Event (SAE) & Non SAE: All adverse events (AEs) that occurred between first drug intake and 28 days after last drug intake (end of the Residual effect period (REP)); up to 53 weeks All cause mortality: All AEs during the course of the clinical trial; up to 56 weeks Treated set is used for reporting adverse events	2.6% 3/116 • Serious Adverse Event (SAE) & Non SAE: All adverse events (AEs) that occurred between first drug intake and 28 days after last drug intake (end of the Residual effect period (REP)); up to 53 weeks All cause mortality: All AEs during the course of the clinical trial; up to 56 weeks Treated set is used for reporting adverse events	6.0% 20/333 • Serious Adverse Event (SAE) & Non SAE: All adverse events (AEs) that occurred between first drug intake and 28 days after last drug intake (end of the Residual effect period (REP)); up to 53 weeks All cause mortality: All AEs during the course of the clinical trial; up to 56 weeks Treated set is used for reporting adverse events
Investigations Alanine aminotransferase increased	0.87% 2/230 • Serious Adverse Event (SAE) & Non SAE: All adverse events (AEs) that occurred between first drug intake and 28 days after last drug intake (end of the Residual effect period (REP)); up to 53 weeks All cause mortality: All AEs during the course of the clinical trial; up to 56 weeks Treated set is used for reporting adverse events	6.0% 7/116 • Serious Adverse Event (SAE) & Non SAE: All adverse events (AEs) that occurred between first drug intake and 28 days after last drug intake (end of the Residual effect period (REP)); up to 53 weeks All cause mortality: All AEs during the course of the clinical trial; up to 56 weeks Treated set is used for reporting adverse events	5.1% 17/333 • Serious Adverse Event (SAE) & Non SAE: All adverse events (AEs) that occurred between first drug intake and 28 days after last drug intake (end of the Residual effect period (REP)); up to 53 weeks All cause mortality: All AEs during the course of the clinical trial; up to 56 weeks Treated set is used for reporting adverse events
Investigations Aspartate aminotransferase increased	1.7% 4/230 • Serious Adverse Event (SAE) & Non SAE: All adverse events (AEs) that occurred between first drug intake and 28 days after last drug intake (end of the Residual effect period (REP)); up to 53 weeks All cause mortality: All AEs during the course of the clinical trial; up to 56 weeks Treated set is used for reporting adverse events	5.2% 6/116 • Serious Adverse Event (SAE) & Non SAE: All adverse events (AEs) that occurred between first drug intake and 28 days after last drug intake (end of the Residual effect period (REP)); up to 53 weeks All cause mortality: All AEs during the course of the clinical trial; up to 56 weeks Treated set is used for reporting adverse events	4.8% 16/333 • Serious Adverse Event (SAE) & Non SAE: All adverse events (AEs) that occurred between first drug intake and 28 days after last drug intake (end of the Residual effect period (REP)); up to 53 weeks All cause mortality: All AEs during the course of the clinical trial; up to 56 weeks Treated set is used for reporting adverse events
Investigations Gamma-glutamyltransferase increased	0.87% 2/230 • Serious Adverse Event (SAE) & Non SAE: All adverse events (AEs) that occurred between first drug intake and 28 days after last drug intake (end of the Residual effect period (REP)); up to 53 weeks All cause mortality: All AEs during the course of the clinical trial; up to 56 weeks Treated set is used for reporting adverse events	4.3% 5/116 • Serious Adverse Event (SAE) & Non SAE: All adverse events (AEs) that occurred between first drug intake and 28 days after last drug intake (end of the Residual effect period (REP)); up to 53 weeks All cause mortality: All AEs during the course of the clinical trial; up to 56 weeks Treated set is used for reporting adverse events	5.1% 17/333 • Serious Adverse Event (SAE) & Non SAE: All adverse events (AEs) that occurred between first drug intake and 28 days after last drug intake (end of the Residual effect period (REP)); up to 53 weeks All cause mortality: All AEs during the course of the clinical trial; up to 56 weeks Treated set is used for reporting adverse events
Investigations Weight decreased	0.87% 2/230 • Serious Adverse Event (SAE) & Non SAE: All adverse events (AEs) that occurred between first drug intake and 28 days after last drug intake (end of the Residual effect period (REP)); up to 53 weeks All cause mortality: All AEs during the course of the clinical trial; up to 56 weeks Treated set is used for reporting adverse events	5.2% 6/116 • Serious Adverse Event (SAE) & Non SAE: All adverse events (AEs) that occurred between first drug intake and 28 days after last drug intake (end of the Residual effect period (REP)); up to 53 weeks All cause mortality: All AEs during the course of the clinical trial; up to 56 weeks Treated set is used for reporting adverse events	7.8% 26/333 • Serious Adverse Event (SAE) & Non SAE: All adverse events (AEs) that occurred between first drug intake and 28 days after last drug intake (end of the Residual effect period (REP)); up to 53 weeks All cause mortality: All AEs during the course of the clinical trial; up to 56 weeks Treated set is used for reporting adverse events
Metabolism and nutrition disorders Decreased appetite	4.3% 10/230 • Serious Adverse Event (SAE) & Non SAE: All adverse events (AEs) that occurred between first drug intake and 28 days after last drug intake (end of the Residual effect period (REP)); up to 53 weeks All cause mortality: All AEs during the course of the clinical trial; up to 56 weeks Treated set is used for reporting adverse events	10.3% 12/116 • Serious Adverse Event (SAE) & Non SAE: All adverse events (AEs) that occurred between first drug intake and 28 days after last drug intake (end of the Residual effect period (REP)); up to 53 weeks All cause mortality: All AEs during the course of the clinical trial; up to 56 weeks Treated set is used for reporting adverse events	11.7% 39/333 • Serious Adverse Event (SAE) & Non SAE: All adverse events (AEs) that occurred between first drug intake and 28 days after last drug intake (end of the Residual effect period (REP)); up to 53 weeks All cause mortality: All AEs during the course of the clinical trial; up to 56 weeks Treated set is used for reporting adverse events
Musculoskeletal and connective tissue disorders Back pain	2.2% 5/230 • Serious Adverse Event (SAE) & Non SAE: All adverse events (AEs) that occurred between first drug intake and 28 days after last drug intake (end of the Residual effect period (REP)); up to 53 weeks All cause mortality: All AEs during the course of the clinical trial; up to 56 weeks Treated set is used for reporting adverse events	2.6% 3/116 • Serious Adverse Event (SAE) & Non SAE: All adverse events (AEs) that occurred between first drug intake and 28 days after last drug intake (end of the Residual effect period (REP)); up to 53 weeks All cause mortality: All AEs during the course of the clinical trial; up to 56 weeks Treated set is used for reporting adverse events	7.2% 24/333 • Serious Adverse Event (SAE) & Non SAE: All adverse events (AEs) that occurred between first drug intake and 28 days after last drug intake (end of the Residual effect period (REP)); up to 53 weeks All cause mortality: All AEs during the course of the clinical trial; up to 56 weeks Treated set is used for reporting adverse events
Nervous system disorders Headache	3.0% 7/230 • Serious Adverse Event (SAE) & Non SAE: All adverse events (AEs) that occurred between first drug intake and 28 days after last drug intake (end of the Residual effect period (REP)); up to 53 weeks All cause mortality: All AEs during the course of the clinical trial; up to 56 weeks Treated set is used for reporting adverse events	6.0% 7/116 • Serious Adverse Event (SAE) & Non SAE: All adverse events (AEs) that occurred between first drug intake and 28 days after last drug intake (end of the Residual effect period (REP)); up to 53 weeks All cause mortality: All AEs during the course of the clinical trial; up to 56 weeks Treated set is used for reporting adverse events	5.1% 17/333 • Serious Adverse Event (SAE) & Non SAE: All adverse events (AEs) that occurred between first drug intake and 28 days after last drug intake (end of the Residual effect period (REP)); up to 53 weeks All cause mortality: All AEs during the course of the clinical trial; up to 56 weeks Treated set is used for reporting adverse events
Respiratory, thoracic and mediastinal disorders Cough	7.0% 16/230 • Serious Adverse Event (SAE) & Non SAE: All adverse events (AEs) that occurred between first drug intake and 28 days after last drug intake (end of the Residual effect period (REP)); up to 53 weeks All cause mortality: All AEs during the course of the clinical trial; up to 56 weeks Treated set is used for reporting adverse events	4.3% 5/116 • Serious Adverse Event (SAE) & Non SAE: All adverse events (AEs) that occurred between first drug intake and 28 days after last drug intake (end of the Residual effect period (REP)); up to 53 weeks All cause mortality: All AEs during the course of the clinical trial; up to 56 weeks Treated set is used for reporting adverse events	11.4% 38/333 • Serious Adverse Event (SAE) & Non SAE: All adverse events (AEs) that occurred between first drug intake and 28 days after last drug intake (end of the Residual effect period (REP)); up to 53 weeks All cause mortality: All AEs during the course of the clinical trial; up to 56 weeks Treated set is used for reporting adverse events