Trial Outcomes & Findings for Effect of MD1003 in Progressive Multiple Sclerosis (SPI2) (NCT NCT02936037)

NCT ID: NCT02936037

Last Updated: 2020-11-23

Results Overview

Proportion of patients improved on either Expanded Disability Status Scale (EDSS) or time to walk 25 feet (TW25) : \- with decreased EDSS at M12 confirmed at M15 (where decreased EDSS is defined as a decrease of at least 1 point if initial EDSS from 3.5 to 5.5 and of at least 0.5 point if initial EDSS from 6 to 6.5) or \- with improved TW25 of at least 20% at Month 12 and Month15 compared to the lowest of the two EDSS and TW25\* scores among inclusion and randomization visits. \*The lowest TW25 value recorded among the four values obtained during the inclusion and randomization visits will be considered as the baseline TW25 value.

• Recruitment status: TERMINATED
• Study phase: PHASE3
• Target enrollment: 642 participants
• Primary outcome timeframe: 15 months
• Results posted on: 2020-11-23

Participant Flow

Participant milestones

Measure	Placebo Placebo capsule, 1 capsule tid (morning,noon and evening) for 15 months and up to 27 months. PLACEBO: an inactive substance	MD1003 MD1003 capsule, 1 capsule tid (morning,noon and evening) for 15 months and up to 27 months. MD1003 100mg capsule
Double-Blind Treatment Period STARTED	316	326
Double-Blind Treatment Period COMPLETED	267	261
Double-Blind Treatment Period NOT COMPLETED	49	65
Open Label Extension STARTED	0	528
Open Label Extension COMPLETED	0	518
Open Label Extension NOT COMPLETED	0	10

Reasons for withdrawal

Measure	Placebo Placebo capsule, 1 capsule tid (morning,noon and evening) for 15 months and up to 27 months. PLACEBO: an inactive substance	MD1003 MD1003 capsule, 1 capsule tid (morning,noon and evening) for 15 months and up to 27 months. MD1003 100mg capsule
Double-Blind Treatment Period Protocol Violation	1	4
Double-Blind Treatment Period Suicidal risk, etc.	2	8
Double-Blind Treatment Period Lack of Efficacy	4	12
Double-Blind Treatment Period Death	0	1
Double-Blind Treatment Period Adverse Event	11	11
Double-Blind Treatment Period Withdrawal by Subject	31	28
Double-Blind Treatment Period Lost to Follow-up	0	1
Open Label Extension Adverse Event	0	3
Open Label Extension Other	0	3
Open Label Extension Withdrawal by Subject	0	4

Baseline Characteristics

Effect of MD1003 in Progressive Multiple Sclerosis (SPI2)

Baseline characteristics by cohort

Measure	Placebo n=316 Participants Placebo capsule, 1 capsule tid (morning,noon and evening) for 15 months and up to 27 months. PLACEBO: an inactive substance	MD1003 n=326 Participants MD1003 capsule, 1 capsule tid (morning,noon and evening) for 15 months and up to 27 months. MD1003 100mg capsule	Total n=642 Participants Total of all reporting groups
Age, Continuous	52.8 years STANDARD_DEVIATION 7.60 • n=5 Participants	52.6 years STANDARD_DEVIATION 7.79 • n=7 Participants	52.7 years STANDARD_DEVIATION 7.70 • n=5 Participants
Sex: Female, Male Female	170 Participants n=5 Participants	175 Participants n=7 Participants	345 Participants n=5 Participants
Sex: Female, Male Male	146 Participants n=5 Participants	151 Participants n=7 Participants	297 Participants n=5 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	9 Participants n=5 Participants	12 Participants n=7 Participants	21 Participants n=5 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	293 Participants n=5 Participants	302 Participants n=7 Participants	595 Participants n=5 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	14 Participants n=5 Participants	12 Participants n=7 Participants	26 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	3 Participants n=5 Participants	2 Participants n=7 Participants	5 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	13 Participants n=5 Participants	8 Participants n=7 Participants	21 Participants n=5 Participants
Race (NIH/OMB) White	291 Participants n=5 Participants	306 Participants n=7 Participants	597 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	9 Participants n=5 Participants	10 Participants n=7 Participants	19 Participants n=5 Participants
Region of Enrollment Hungary	0 participants n=5 Participants	1 participants n=7 Participants	1 participants n=5 Participants
Region of Enrollment United States	109 participants n=5 Participants	109 participants n=7 Participants	218 participants n=5 Participants
Region of Enrollment Czechia	26 participants n=5 Participants	31 participants n=7 Participants	57 participants n=5 Participants
Region of Enrollment United Kingdom	31 participants n=5 Participants	30 participants n=7 Participants	61 participants n=5 Participants
Region of Enrollment Spain	30 participants n=5 Participants	31 participants n=7 Participants	61 participants n=5 Participants
Region of Enrollment Canada	35 participants n=5 Participants	37 participants n=7 Participants	72 participants n=5 Participants
Region of Enrollment Sweden	9 participants n=5 Participants	9 participants n=7 Participants	18 participants n=5 Participants
Region of Enrollment Turkey	2 participants n=5 Participants	2 participants n=7 Participants	4 participants n=5 Participants
Region of Enrollment Belgium	4 participants n=5 Participants	7 participants n=7 Participants	11 participants n=5 Participants
Region of Enrollment Poland	11 participants n=5 Participants	12 participants n=7 Participants	23 participants n=5 Participants
Region of Enrollment Italy	5 participants n=5 Participants	7 participants n=7 Participants	12 participants n=5 Participants
Region of Enrollment Australia	6 participants n=5 Participants	8 participants n=7 Participants	14 participants n=5 Participants
Region of Enrollment Germany	48 participants n=5 Participants	42 participants n=7 Participants	90 participants n=5 Participants

PRIMARY outcome

Timeframe: 15 months

Proportion of patients improved on either Expanded Disability Status Scale (EDSS) or time to walk 25 feet (TW25) :

• with decreased EDSS at M12 confirmed at M15 (where decreased EDSS is defined as a decrease of at least 1 point if initial EDSS from 3.5 to 5.5 and of at least 0.5 point if initial EDSS from 6 to 6.5)

or

• with improved TW25 of at least 20% at Month 12 and Month15

compared to the lowest of the two EDSS and TW25* scores among inclusion and randomization visits.

*The lowest TW25 value recorded among the four values obtained during the inclusion and randomization visits will be considered as the baseline TW25 value.

Outcome measures

Measure	Placebo n=316 Participants Placebo capsule, 1 capsule tid (morning,noon and evening) for 15 months and up to 27 months. PLACEBO: an inactive substance	MD1003 n=326 Participants MD1003 capsule, 1 capsule tid (morning,noon and evening) for 15 months and up to 27 months. MD1003 100mg capsule
Proportion of Patients Improved on Either Expanded Disability Status Scale (EDSS) or Time to Walk 25 Feet (TW25)	9.2 percent	12.0 percent

SECONDARY outcome

Timeframe: 3 to 27 months

12-weeks EDSS progression is defined by an increase of at least 1 point for baseline EDSS 3.5 to 5.5 and of at least 0.5 point for baseline EDSS 6 to 6.5 with respective confirmation 12 weeks later.

Date of 12-weeks confirmed EDSS progression will be the first date of an EDSS progression (as defined above) that is confirmed 12 weeks later.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: 15 months

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: 15 months

Outcome measures

Outcome data not reported

OTHER_PRE_SPECIFIED outcome

Timeframe: 15 months

Outcome measures

Outcome data not reported

OTHER_PRE_SPECIFIED outcome

Timeframe: 27 months

Outcome measures

Outcome data not reported

OTHER_PRE_SPECIFIED outcome

Timeframe: 15 months

Outcome measures

Outcome data not reported

OTHER_PRE_SPECIFIED outcome

Timeframe: 15 months

Outcome measures

Outcome data not reported

OTHER_PRE_SPECIFIED outcome

Timeframe: 15 months

Outcome measures

Outcome data not reported

Adverse Events

GROUP 1

Serious events: 82 serious events

Other events: 264 other events

Deaths: 0 deaths

GROUP 2

Serious events: 87 serious events

Other events: 277 other events

Deaths: 1 deaths

Serious adverse events

Measure	GROUP 1 n=311 participants at risk Placebo capsule, 1 capsule tid (morning,noon and evening) for 15 months and up to 27 months. PLACEBO: an inactive substance	GROUP 2 n=331 participants at risk MD1003 capsule, 1 capsule tid (morning,noon and evening) for 15 months and up to 27 months. MD1003 100mg capsule
Nervous system disorders Sensory Loss	0.32% 1/311 • Number of events 1 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.	0.30% 1/331 • Number of events 1 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.
Nervous system disorders Aphasia	0.00% 0/311 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.	0.30% 1/331 • Number of events 1 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.
Nervous system disorders Cataplexy	0.32% 1/311 • Number of events 1 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.	0.00% 0/331 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.
Nervous system disorders Cerebral infarction	0.32% 1/311 • Number of events 1 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.	0.00% 0/331 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.
Nervous system disorders Cerebrovascular accident	0.32% 1/311 • Number of events 1 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.	0.00% 0/331 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.
Nervous system disorders Multiple sclerosis relapse	10.0% 31/311 • Number of events 37 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.	8.8% 29/331 • Number of events 36 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.
Nervous system disorders Multiple sclerosis	1.9% 6/311 • Number of events 7 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.	1.2% 4/331 • Number of events 4 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.
Nervous system disorders Trigeminal neuralgia	1.3% 4/311 • Number of events 4 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.	0.30% 1/331 • Number of events 1 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.
Nervous system disorders Muscle spasticity	0.32% 1/311 • Number of events 1 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.	0.91% 3/331 • Number of events 3 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.
Nervous system disorders Uhthoff's phenomenon	0.32% 1/311 • Number of events 2 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.	0.30% 1/331 • Number of events 2 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.
Nervous system disorders Hypoaesthesia	0.00% 0/311 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.	0.60% 2/331 • Number of events 2 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.
Nervous system disorders Dizziness	0.00% 0/311 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.	0.30% 1/331 • Number of events 1 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.
Nervous system disorders Encephalopathy	0.32% 1/311 • Number of events 1 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.	0.00% 0/331 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.
Nervous system disorders Facial paralysis	0.32% 1/311 • Number of events 1 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.	0.00% 0/331 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.
Nervous system disorders Facial spasm	0.00% 0/311 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.	0.30% 1/331 • Number of events 1 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.
Nervous system disorders Ischaemic stroke	0.00% 0/311 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.	0.30% 1/331 • Number of events 1 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.
Nervous system disorders Narcolepsy	0.32% 1/311 • Number of events 1 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.	0.00% 0/331 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.
Nervous system disorders Neuralgia	0.00% 0/311 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.	0.30% 1/331 • Number of events 1 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.
Nervous system disorders Normal pressure hydrocephalus	0.00% 0/311 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.	0.30% 1/331 • Number of events 1 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.
Nervous system disorders Optic neuritis	0.32% 1/311 • Number of events 1 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.	0.00% 0/331 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.
Nervous system disorders Paraparesis	0.00% 0/311 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.	0.30% 1/331 • Number of events 1 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.
Nervous system disorders Pyramidal tract syndrome	0.32% 1/311 • Number of events 1 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.	0.00% 0/331 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.
Nervous system disorders Sciatica	0.00% 0/311 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.	0.30% 1/331 • Number of events 1 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.
Nervous system disorders Transverse sinus thrombosis	0.32% 1/311 • Number of events 1 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.	0.00% 0/331 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.
Infections and infestations Urinary tract infection	1.9% 6/311 • Number of events 6 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.	0.60% 2/331 • Number of events 3 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.
Infections and infestations Pneumonia	0.64% 2/311 • Number of events 2 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.	0.91% 3/331 • Number of events 3 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.
Infections and infestations Urosepsis	0.96% 3/311 • Number of events 3 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.	0.60% 2/331 • Number of events 2 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.
Infections and infestations Bacterial infection	0.64% 2/311 • Number of events 2 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.	0.00% 0/331 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.
Infections and infestations Bronchitis	0.32% 1/311 • Number of events 1 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.	0.30% 1/331 • Number of events 1 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.
Infections and infestations Appendicitis	0.32% 1/311 • Number of events 1 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.	0.00% 0/331 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.
Infections and infestations Bacteraemia	0.00% 0/311 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.	0.30% 1/331 • Number of events 1 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.
Infections and infestations Clostridium difficile colitis	0.32% 1/311 • Number of events 1 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.	0.00% 0/331 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.
Infections and infestations Clostridium difficile infection	0.00% 0/311 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.	0.30% 1/331 • Number of events 1 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.
Infections and infestations Epididymitis	0.32% 1/311 • Number of events 1 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.	0.00% 0/331 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.
Infections and infestations Escherichia urinary tract infection	0.00% 0/311 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.	0.30% 1/331 • Number of events 1 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.
Infections and infestations Gastroenteritis norovirus	0.32% 1/311 • Number of events 1 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.	0.00% 0/331 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.
Infections and infestations Haemorrhagic pneumonia	0.32% 1/311 • Number of events 1 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.	0.00% 0/331 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.
Infections and infestations Human anaplasmosis	0.32% 1/311 • Number of events 1 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.	0.00% 0/331 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.
Infections and infestations Incision site infection	0.32% 1/311 • Number of events 1 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.	0.00% 0/331 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.
Infections and infestations Lower respiratory tract infection	0.32% 1/311 • Number of events 1 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.	0.00% 0/331 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.
Infections and infestations Lung abscess	0.00% 0/311 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.	0.30% 1/331 • Number of events 1 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.
Infections and infestations Lyme disease	0.32% 1/311 • Number of events 1 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.	0.00% 0/331 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.
Infections and infestations Septic shock	0.32% 1/311 • Number of events 1 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.	0.00% 0/331 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.
Infections and infestations Viral infection	0.32% 1/311 • Number of events 1 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.	0.00% 0/331 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.
Infections and infestations Viral upper respiratory tract infection	0.32% 1/311 • Number of events 1 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.	0.00% 0/331 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.
Injury, poisoning and procedural complications Femoral neck fracture	0.64% 2/311 • Number of events 2 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.	0.30% 1/331 • Number of events 1 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.
Injury, poisoning and procedural complications Ankle fracture	0.32% 1/311 • Number of events 1 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.	0.30% 1/331 • Number of events 1 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.
Injury, poisoning and procedural complications Hip fracture	0.32% 1/311 • Number of events 1 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.	0.30% 1/331 • Number of events 1 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.
Injury, poisoning and procedural complications Tibia fracture	0.64% 2/311 • Number of events 2 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.	0.00% 0/331 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.
Injury, poisoning and procedural complications Contusion	0.00% 0/311 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.	0.30% 1/331 • Number of events 1 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.
Injury, poisoning and procedural complications Femur fracture	0.32% 1/311 • Number of events 1 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.	0.00% 0/331 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.
Injury, poisoning and procedural complications Fibula fracture	0.32% 1/311 • Number of events 1 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.	0.00% 0/331 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.
Injury, poisoning and procedural complications Heat stroke	0.00% 0/311 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.	0.30% 1/331 • Number of events 1 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.
Injury, poisoning and procedural complications Humerus fracture	0.00% 0/311 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.	0.30% 1/331 • Number of events 1 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.
Injury, poisoning and procedural complications Lumbar vertebral fracture	0.32% 1/311 • Number of events 1 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.	0.00% 0/331 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.
Injury, poisoning and procedural complications Spinal compression fracture	0.00% 0/311 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.	0.30% 1/331 • Number of events 1 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.
Injury, poisoning and procedural complications Spinal fracture	0.00% 0/311 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.	0.30% 1/331 • Number of events 1 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.
Injury, poisoning and procedural complications Sunburn	0.00% 0/311 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.	0.30% 1/331 • Number of events 1 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.
Injury, poisoning and procedural complications Upper limb fracture	0.00% 0/311 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.	0.30% 1/331 • Number of events 1 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.
Injury, poisoning and procedural complications Wrist fracture	0.00% 0/311 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.	0.30% 1/331 • Number of events 1 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.
Gastrointestinal disorders Vomiting	0.00% 0/311 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.	0.30% 1/331 • Number of events 3 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.
Gastrointestinal disorders Constipation	0.00% 0/311 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.	0.30% 1/331 • Number of events 2 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.
Gastrointestinal disorders Crohn's disease	0.32% 1/311 • Number of events 2 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.	0.00% 0/331 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.
Gastrointestinal disorders Diaphragmatic hernia, obstructive	0.00% 0/311 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.	0.30% 1/331 • Number of events 1 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.
Gastrointestinal disorders Gastrointestinal perforation	0.32% 1/311 • Number of events 1 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.	0.00% 0/331 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.
Gastrointestinal disorders Haematochezia	0.00% 0/311 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.	0.30% 1/331 • Number of events 1 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.
Gastrointestinal disorders Oesophagitis	0.00% 0/311 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.	0.30% 1/331 • Number of events 1 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.
Gastrointestinal disorders Rectal prolapse	0.00% 0/311 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.	0.30% 1/331 • Number of events 1 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.
Psychiatric disorders Depression	0.32% 1/311 • Number of events 1 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.	0.30% 1/331 • Number of events 2 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.
Psychiatric disorders Confusional state	0.00% 0/311 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.	0.30% 1/331 • Number of events 2 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.
Psychiatric disorders Suicide attempt	0.00% 0/311 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.	0.60% 2/331 • Number of events 2 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.
Psychiatric disorders Bipolar I disorder	0.00% 0/311 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.	0.30% 1/331 • Number of events 1 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.
Psychiatric disorders Bipolar disorder	0.32% 1/311 • Number of events 1 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.	0.00% 0/331 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.
Psychiatric disorders Breathing-related sleeping disorder	0.32% 1/311 • Number of events 1 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.	0.00% 0/331 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.
Psychiatric disorders Disorientation	0.00% 0/311 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.	0.30% 1/331 • Number of events 1 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.
Psychiatric disorders Substance-induced psychotic disorder	0.00% 0/311 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.	0.30% 1/331 • Number of events 1 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.
Musculoskeletal and connective tissue disorders Muscular weakness	0.32% 1/311 • Number of events 1 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.	1.2% 4/331 • Number of events 4 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.
Musculoskeletal and connective tissue disorders Pain in extremity	0.32% 1/311 • Number of events 1 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.	0.30% 1/331 • Number of events 1 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.
Musculoskeletal and connective tissue disorders Intervertebral disc protrusion	0.32% 1/311 • Number of events 1 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.	0.00% 0/331 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.
Musculoskeletal and connective tissue disorders Joint stiffness	0.00% 0/311 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.	0.30% 1/331 • Number of events 1 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.
Musculoskeletal and connective tissue disorders Muscle spasms	0.32% 1/311 • Number of events 1 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.	0.00% 0/331 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.
Respiratory, thoracic and mediastinal disorders Pulmonary embolism	0.64% 2/311 • Number of events 2 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.	0.60% 2/331 • Number of events 2 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.
Respiratory, thoracic and mediastinal disorders Chronic obstructive pulmonary disease	0.00% 0/311 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.	0.60% 2/331 • Number of events 3 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.
Respiratory, thoracic and mediastinal disorders Asthma	0.00% 0/311 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.	0.30% 1/331 • Number of events 1 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.
Respiratory, thoracic and mediastinal disorders Pleural effusion	0.00% 0/311 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.	0.30% 1/331 • Number of events 1 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.
Respiratory, thoracic and mediastinal disorders Pulmonary mass	0.32% 1/311 • Number of events 1 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.	0.00% 0/331 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.
Cardiac disorders Atrial fibrillation	0.00% 0/311 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.	0.91% 3/331 • Number of events 3 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.
Cardiac disorders Acute myocardial infarction	0.32% 1/311 • Number of events 1 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.	0.30% 1/331 • Number of events 1 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.
Cardiac disorders Cardiac failure	0.00% 0/311 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.	0.30% 1/331 • Number of events 1 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.
Cardiac disorders Myocardial infarction	0.00% 0/311 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.	0.30% 1/331 • Number of events 1 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.
Cardiac disorders Silent myocardial infarction	0.32% 1/311 • Number of events 1 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.	0.00% 0/331 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Cervix carcinoma	0.32% 1/311 • Number of events 1 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.	0.00% 0/331 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Cystadenocarcinoma ovary	0.00% 0/311 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.	0.30% 1/331 • Number of events 1 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Intraductal proliferative breast lesion	0.32% 1/311 • Number of events 1 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.	0.00% 0/331 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Ovarian cancer	0.32% 1/311 • Number of events 1 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.	0.00% 0/331 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Ovarian cancer metastatic	0.32% 1/311 • Number of events 1 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.	0.00% 0/331 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Pituitary tumour benign	0.32% 1/311 • Number of events 1 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.	0.00% 0/331 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Rectal adenoma	0.00% 0/311 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.	0.30% 1/331 • Number of events 1 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Testis cancer	0.32% 1/311 • Number of events 1 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.	0.00% 0/331 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.
General disorders Fatigue	0.32% 1/311 • Number of events 1 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.	0.60% 2/331 • Number of events 2 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.
General disorders General physical health deterioration	0.32% 1/311 • Number of events 1 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.	0.30% 1/331 • Number of events 1 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.
General disorders Gait disturbance	0.00% 0/311 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.	0.30% 1/331 • Number of events 1 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.
General disorders Pain	0.00% 0/311 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.	0.30% 1/331 • Number of events 1 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.
Surgical and medical procedures Elective procedure	0.32% 1/311 • Number of events 1 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.	0.30% 1/331 • Number of events 1 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.
Surgical and medical procedures Neurological rehabilitation	0.32% 1/311 • Number of events 1 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.	0.30% 1/331 • Number of events 1 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.
Surgical and medical procedures Gastric banding reversal	0.00% 0/311 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.	0.30% 1/331 • Number of events 1 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.
Surgical and medical procedures Rehabilitation therapy	0.00% 0/311 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.	0.30% 1/331 • Number of events 1 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.
Eye disorders Eye pain	0.32% 1/311 • Number of events 1 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.	0.00% 0/331 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.
Eye disorders Eyelid ptosis	0.32% 1/311 • Number of events 1 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.	0.00% 0/331 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.
Eye disorders Vision blurred	0.32% 1/311 • Number of events 1 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.	0.00% 0/331 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.
Eye disorders Vitreous haemorrhage	0.00% 0/311 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.	0.30% 1/331 • Number of events 1 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.
Renal and urinary disorders Nephrolithiasis	0.32% 1/311 • Number of events 1 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.	0.00% 0/331 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.
Renal and urinary disorders Pelvi-ureteric obstruction	0.00% 0/311 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.	0.30% 1/331 • Number of events 1 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.
Renal and urinary disorders Ureteric stenosis	0.00% 0/311 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.	0.30% 1/331 • Number of events 1 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.
Renal and urinary disorders Ureterolithiasis	0.32% 1/311 • Number of events 1 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.	0.00% 0/331 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.
Vascular disorders Deep vein thrombosis	0.00% 0/311 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.	0.60% 2/331 • Number of events 2 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.
Vascular disorders Peripheral arterial occlusive disease	0.00% 0/311 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.	0.30% 1/331 • Number of events 2 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.
Hepatobiliary disorders Cholecystitis	0.00% 0/311 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.	0.30% 1/331 • Number of events 1 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.
Hepatobiliary disorders Cholelithiasis	0.00% 0/311 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.	0.30% 1/331 • Number of events 1 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.
Metabolism and nutrition disorders Dehydration	0.00% 0/311 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.	0.30% 1/331 • Number of events 2 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.
Reproductive system and breast disorders Cervical dysplasia	0.32% 1/311 • Number of events 1 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.	0.00% 0/331 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.
Reproductive system and breast disorders Ovarian cyst	0.00% 0/311 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.	0.30% 1/331 • Number of events 1 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.
Blood and lymphatic system disorders Leukopenia	0.32% 1/311 • Number of events 1 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.	0.00% 0/331 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.
Congenital, familial and genetic disorders Factor V Leiden mutation	0.00% 0/311 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.	0.30% 1/331 • Number of events 1 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.
Ear and labyrinth disorders Vertigo	0.00% 0/311 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.	0.30% 1/331 • Number of events 1 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.
Product Issues Device failure	0.32% 1/311 • Number of events 1 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.	0.00% 0/331 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.

Other adverse events

Measure	GROUP 1 n=311 participants at risk Placebo capsule, 1 capsule tid (morning,noon and evening) for 15 months and up to 27 months. PLACEBO: an inactive substance	GROUP 2 n=331 participants at risk MD1003 capsule, 1 capsule tid (morning,noon and evening) for 15 months and up to 27 months. MD1003 100mg capsule
Infections and infestations Urinary tract infection	16.1% 50/311 • Number of events 94 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.	14.5% 48/331 • Number of events 74 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.
Infections and infestations Nasopharyngitis	18.6% 58/311 • Number of events 76 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.	11.8% 39/331 • Number of events 53 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.
Infections and infestations Upper respiratory tract infection	8.7% 27/311 • Number of events 34 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.	7.6% 25/331 • Number of events 33 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.
Nervous system disorders Multiple sclerosis relapse	10.0% 31/311 • Number of events 37 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.	8.8% 29/331 • Number of events 36 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.
Musculoskeletal and connective tissue disorders Arthralgia	8.4% 26/311 • Number of events 31 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.	7.6% 25/331 • Number of events 29 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.
Musculoskeletal and connective tissue disorders Muscular weakness	7.7% 24/311 • Number of events 33 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.	6.0% 20/331 • Number of events 27 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.
Musculoskeletal and connective tissue disorders Back pain	6.8% 21/311 • Number of events 21 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.	5.7% 19/331 • Number of events 25 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.
Injury, poisoning and procedural complications Fall	11.9% 37/311 • Number of events 60 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.	13.3% 44/331 • Number of events 84 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.
Injury, poisoning and procedural complications Contusion	7.4% 23/311 • Number of events 26 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.	3.9% 13/331 • Number of events 20 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.
Gastrointestinal disorders Constipation	5.1% 16/311 • Number of events 16 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.	5.4% 18/331 • Number of events 19 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.
General disorders Fatigue	8.4% 26/311 • Number of events 28 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.	7.3% 24/331 • Number of events 26 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.
General disorders Gait disturbance	5.5% 17/311 • Number of events 21 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.	6.6% 22/331 • Number of events 28 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.
Investigations Laboratory test interference	0.32% 1/311 • Number of events 1 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.	7.6% 25/331 • Number of events 28 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.
Psychiatric disorders Depression	3.9% 12/311 • Number of events 12 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.	5.1% 17/331 • Number of events 23 • Adverse events were collected over 27 months for the double-blind period, and was to be collected for 39 months in open-label extension before premature termination of the study.

Additional Information

Dr Frédéric SEDEL, Chief Scientific Officer and Co-founder

MedDay Pharmaceuticals

Phone: +33180401440

Email: frederic.sedel@medday-pharma.com

Results disclosure agreements

• Principal investigator is a sponsor employee
• Publication restrictions are in place