Trial Outcomes & Findings for Efficacy of Nalmefene in Patients With Alcohol Dependence (NCT NCT00812461)

Last Updated: 2013-07-22

Results Overview

Number of HDDs over a month (28 days), where one HDD was defined as a day with alcohol consumption ≥60 grams (g) for men and ≥40 g for women.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

678 participants

Primary outcome timeframe

Baseline and Month 6

Results posted on

2013-07-22

Participant Flow

Participant milestones

Participant milestones
Measure	Placebo as-needed use, tablets, orally, 6 months	Nalmefene 18.06 mg as-needed use, tablets, orally, 6 months
All Randomised Patients STARTED	360	358
All Randomised Patients COMPLETED	337	341
All Randomised Patients NOT COMPLETED	23	17
All Treated Patients STARTED	337	341
All Treated Patients COMPLETED	205	194
All Treated Patients NOT COMPLETED	132	147

Reasons for withdrawal

Reasons for withdrawal
Measure	Placebo as-needed use, tablets, orally, 6 months	Nalmefene 18.06 mg as-needed use, tablets, orally, 6 months
All Treated Patients Adverse Event	8	15
All Randomised Patients Did not receive placebo/nalmefene	23	17
All Treated Patients Lack of Efficacy	13	7
All Treated Patients Non-compliance	6	9
All Treated Patients Protocol Violation	36	27
All Treated Patients Withdrawal by Subject	45	54
All Treated Patients Lost to Follow-up	11	14
All Treated Patients Other Reason	13	21

Baseline Characteristics

Efficacy of Nalmefene in Patients With Alcohol Dependence

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Placebo n=360 Participants as-needed use, tablets, orally, 6 months	Nalmefene 18.06 mg n=358 Participants as-needed use, tablets, orally, 6 months	Total n=718 Participants Total of all reporting groups
Age Continuous	44.4 years STANDARD_DEVIATION 10.7 • n=99 Participants	45.1 years STANDARD_DEVIATION 10.7 • n=107 Participants	44.8 years STANDARD_DEVIATION 10.7 • n=206 Participants
Sex: Female, Male Female	104 Participants n=99 Participants	92 Participants n=107 Participants	196 Participants n=206 Participants
Sex: Female, Male Male	256 Participants n=99 Participants	266 Participants n=107 Participants	522 Participants n=206 Participants
Previously Treated for Alcohol Dependence NO	213 participants n=99 Participants	215 participants n=107 Participants	428 participants n=206 Participants
Previously Treated for Alcohol Dependence YES	147 participants n=99 Participants	142 participants n=107 Participants	289 participants n=206 Participants
Previously Treated for Alcohol Dependence UNKNOWN	0 participants n=99 Participants	1 participants n=107 Participants	1 participants n=206 Participants
Previously Treated for Alcohol Withdrawal Symptoms] NO	292 participants n=99 Participants	300 participants n=107 Participants	592 participants n=206 Participants
Previously Treated for Alcohol Withdrawal Symptoms] YES	68 participants n=99 Participants	57 participants n=107 Participants	125 participants n=206 Participants
Previously Treated for Alcohol Withdrawal Symptoms] UNKNOWN	0 participants n=99 Participants	1 participants n=107 Participants	1 participants n=206 Participants
Total Monthly Heavy Drinking Days (HDD)	18.37 days STANDARD_DEVIATION 7.03 • n=99 Participants	19.71 days STANDARD_DEVIATION 6.96 • n=107 Participants	19.04 days STANDARD_DEVIATION 7.03 • n=206 Participants
Total Alcohol Consumption (TAC) g Alcohol/Day	88.76 g STANDARD_DEVIATION 48.15 • n=99 Participants	92.22 g STANDARD_DEVIATION 46.87 • n=107 Participants	90.49 g STANDARD_DEVIATION 47.52 • n=206 Participants
Drinking Risk Level (DRL) Low	6 participants n=99 Participants	5 participants n=107 Participants	11 participants n=206 Participants
Drinking Risk Level (DRL) Medium	82 participants n=99 Participants	68 participants n=107 Participants	150 participants n=206 Participants
Drinking Risk Level (DRL) High	134 participants n=99 Participants	129 participants n=107 Participants	263 participants n=206 Participants
Drinking Risk Level (DRL) Very High	138 participants n=99 Participants	156 participants n=107 Participants	294 participants n=206 Participants
Clinical Global Impression - Severity of Illness (CGI-S)	3.99 units on a scale STANDARD_DEVIATION 1.42 • n=99 Participants	4.05 units on a scale STANDARD_DEVIATION 1.45 • n=107 Participants	4.02 units on a scale STANDARD_DEVIATION 1.44 • n=206 Participants
Gamma-glutamyl Transferase (GGT)	97.39 international units per liter (IU/L) STANDARD_DEVIATION 165.12 • n=99 Participants	91.98 international units per liter (IU/L) STANDARD_DEVIATION 153.01 • n=107 Participants	94.69 international units per liter (IU/L) STANDARD_DEVIATION 159.09 • n=206 Participants
Alanine Aminotransferase (ALAT)	34.32 IU/L STANDARD_DEVIATION 26.06 • n=99 Participants	34.20 IU/L STANDARD_DEVIATION 22.70 • n=107 Participants	34.26 IU/L STANDARD_DEVIATION 24.42 • n=206 Participants

PRIMARY outcome

Timeframe: Baseline and Month 6

Population: Full-analysis set (FAS) - all patients in the all-patients-treated set (APTS) who had at least one valid post-baseline assessment in the main treatment period of both co-primary efficacy variables (HDD and TAC) and had an average alcohol consumption at medium Drinking Risk Level (DRL) or above according to WHO criteria at Baseline.

Number of HDDs over a month (28 days), where one HDD was defined as a day with alcohol consumption ≥60 grams (g) for men and ≥40 g for women.

Outcome measures

Outcome measures
Measure	Placebo n=229 Participants as-needed use, tablets, orally, 6 months	Nalmefene 18.06 mg n=212 Participants as-needed use, tablets, orally, 6 months
Change From Baseline in the Monthly Number of Heavy Drinking Days (HDDs)	-10.58 days Standard Error 0.52	-12.30 days Standard Error 0.54

PRIMARY outcome

Timeframe: Baseline and Month 6

Population: FAS

TAC was defined as mean daily alcohol consumption in g/day over a month (28 days).

Outcome measures

Outcome measures
Measure	Placebo n=229 Participants as-needed use, tablets, orally, 6 months	Nalmefene 18.06 mg n=212 Participants as-needed use, tablets, orally, 6 months
Change From Baseline in the Monthly Total Alcohol Consumption (TAC)	-54.06 g Standard Error 2.23	-59.01 g Standard Error 2.29

SECONDARY outcome

Timeframe: Month 6

Population: FAS

RSDRL response was defined as a downward shift from baseline in Drinking Risk Level (DRL); for patients at very high risk at Baseline: a shift to medium risk or below, and for patients at high or medium risk at Baseline: a shift to low risk or below.

Outcome measures

Outcome measures
Measure	Placebo n=326 Participants as-needed use, tablets, orally, 6 months	Nalmefene 18.06 mg n=329 Participants as-needed use, tablets, orally, 6 months
Drinking Risk Level (RSDRL) Response	47.9 percentage of participants	45.6 percentage of participants

SECONDARY outcome

Timeframe: Baseline and Week 24

Population: FAS

The Clinical Global Impression - Severity of Illness (CGI-S) provides the clinician's impression of the patient's current state of mental illness. The clinician uses his or her clinical experience of this patient population to rate the severity of the patient's current mental illness on a 7-point scale ranging from 1 (Normal - not at all ill) to 7 (among the most extremely ill patients).

Outcome measures

Outcome measures
Measure	Placebo n=225 Participants as-needed use, tablets, orally, 6 months	Nalmefene 18.06 mg n=203 Participants as-needed use, tablets, orally, 6 months
Change From Baseline in Clinical Status Using CGI-S	-1.04 units on a scale Standard Error 0.08	-1.27 units on a scale Standard Error 0.08

SECONDARY outcome

Timeframe: Week 24

Population: FAS

The Clinical Global Impression - Global Improvement (CGI-I) provides the clinician's impression of the patient's improvement (or worsening). The clinician assesses the patient's condition relative to a baseline on a 7-point scale ranging from 1 (very much improved) to 7 (very much worse).

Outcome measures

Outcome measures
Measure	Placebo n=225 Participants as-needed use, tablets, orally, 6 months	Nalmefene 18.06 mg n=203 Participants as-needed use, tablets, orally, 6 months
Change in Clinical Status Using the CGI-I	2.68 units on a scale Standard Error 0.08	2.51 units on a scale Standard Error 0.08

SECONDARY outcome

Timeframe: Week 24

Population: FAS

GGT values

Outcome measures

Outcome measures
Measure	Placebo n=224 Participants as-needed use, tablets, orally, 6 months	Nalmefene 18.06 mg n=207 Participants as-needed use, tablets, orally, 6 months
Liver Function Test Gamma-glutamyl Transferase (GGT)	44.9 IU/L Geometric Coefficient of Variation 75.7	43.3 IU/L Geometric Coefficient of Variation 75.2

SECONDARY outcome

Timeframe: Week 24

Population: FAS

ALAT values

Outcome measures

Outcome measures
Measure	Placebo n=222 Participants as-needed use, tablets, orally, 6 months	Nalmefene 18.06 mg n=205 Participants as-needed use, tablets, orally, 6 months
Liver Function Test Alanine Aminotransferase (ALAT)	27.2 IU/L Geometric Coefficient of Variation 56.3	25.0 IU/L Geometric Coefficient of Variation 55.7

Adverse Events

Placebo

Serious events: 14 serious events

Other events: 102 other events

Deaths: 0 deaths

Nalmefene 18.06 mg

Serious events: 7 serious events

Other events: 157 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Other adverse events
Measure	Placebo n=337 participants at risk as-needed use, tablets, orally, 6 months	Nalmefene 18.06 mg n=341 participants at risk as-needed use, tablets, orally, 6 months
Gastrointestinal disorders Diarrhoea	5.3% 18/337 • Serious Adverse Events: 24 weeks, a 4-week run-out period, and a safety follow-up (visit/telephone call) scheduled for 4 weeks after completion of the study or after withdrawal from the study. Other Adverse Events: 24 weeks and a 4-week run-out period.	2.3% 8/341 • Serious Adverse Events: 24 weeks, a 4-week run-out period, and a safety follow-up (visit/telephone call) scheduled for 4 weeks after completion of the study or after withdrawal from the study. Other Adverse Events: 24 weeks and a 4-week run-out period.
Gastrointestinal disorders Nausea	5.9% 20/337 • Serious Adverse Events: 24 weeks, a 4-week run-out period, and a safety follow-up (visit/telephone call) scheduled for 4 weeks after completion of the study or after withdrawal from the study. Other Adverse Events: 24 weeks and a 4-week run-out period.	17.3% 59/341 • Serious Adverse Events: 24 weeks, a 4-week run-out period, and a safety follow-up (visit/telephone call) scheduled for 4 weeks after completion of the study or after withdrawal from the study. Other Adverse Events: 24 weeks and a 4-week run-out period.
Gastrointestinal disorders Vomiting	2.4% 8/337 • Serious Adverse Events: 24 weeks, a 4-week run-out period, and a safety follow-up (visit/telephone call) scheduled for 4 weeks after completion of the study or after withdrawal from the study. Other Adverse Events: 24 weeks and a 4-week run-out period.	5.6% 19/341 • Serious Adverse Events: 24 weeks, a 4-week run-out period, and a safety follow-up (visit/telephone call) scheduled for 4 weeks after completion of the study or after withdrawal from the study. Other Adverse Events: 24 weeks and a 4-week run-out period.
Infections and infestations Nasopharyngitis	5.9% 20/337 • Serious Adverse Events: 24 weeks, a 4-week run-out period, and a safety follow-up (visit/telephone call) scheduled for 4 weeks after completion of the study or after withdrawal from the study. Other Adverse Events: 24 weeks and a 4-week run-out period.	6.5% 22/341 • Serious Adverse Events: 24 weeks, a 4-week run-out period, and a safety follow-up (visit/telephone call) scheduled for 4 weeks after completion of the study or after withdrawal from the study. Other Adverse Events: 24 weeks and a 4-week run-out period.
Nervous system disorders Dizziness	4.2% 14/337 • Serious Adverse Events: 24 weeks, a 4-week run-out period, and a safety follow-up (visit/telephone call) scheduled for 4 weeks after completion of the study or after withdrawal from the study. Other Adverse Events: 24 weeks and a 4-week run-out period.	15.2% 52/341 • Serious Adverse Events: 24 weeks, a 4-week run-out period, and a safety follow-up (visit/telephone call) scheduled for 4 weeks after completion of the study or after withdrawal from the study. Other Adverse Events: 24 weeks and a 4-week run-out period.
Nervous system disorders Headache	7.7% 26/337 • Serious Adverse Events: 24 weeks, a 4-week run-out period, and a safety follow-up (visit/telephone call) scheduled for 4 weeks after completion of the study or after withdrawal from the study. Other Adverse Events: 24 weeks and a 4-week run-out period.	12.6% 43/341 • Serious Adverse Events: 24 weeks, a 4-week run-out period, and a safety follow-up (visit/telephone call) scheduled for 4 weeks after completion of the study or after withdrawal from the study. Other Adverse Events: 24 weeks and a 4-week run-out period.
Psychiatric disorders Anxiety	5.0% 17/337 • Serious Adverse Events: 24 weeks, a 4-week run-out period, and a safety follow-up (visit/telephone call) scheduled for 4 weeks after completion of the study or after withdrawal from the study. Other Adverse Events: 24 weeks and a 4-week run-out period.	3.2% 11/341 • Serious Adverse Events: 24 weeks, a 4-week run-out period, and a safety follow-up (visit/telephone call) scheduled for 4 weeks after completion of the study or after withdrawal from the study. Other Adverse Events: 24 weeks and a 4-week run-out period.
Psychiatric disorders Insomnia	6.8% 23/337 • Serious Adverse Events: 24 weeks, a 4-week run-out period, and a safety follow-up (visit/telephone call) scheduled for 4 weeks after completion of the study or after withdrawal from the study. Other Adverse Events: 24 weeks and a 4-week run-out period.	14.4% 49/341 • Serious Adverse Events: 24 weeks, a 4-week run-out period, and a safety follow-up (visit/telephone call) scheduled for 4 weeks after completion of the study or after withdrawal from the study. Other Adverse Events: 24 weeks and a 4-week run-out period.

Additional Information

H. Lundbeck A/S

Phone: +45 3630 1311

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee The main publication has to be published before any sub publication. The investigators shall obtain Lundbeck's written approval before publishing any publication relating to nalmefene, the Study, the Protocol and/or the results recorded during the Study.
Publication restrictions are in place

Restriction type: OTHER

Measure	Placebo n=337 participants at risk as-needed use, tablets, orally, 6 months	Nalmefene 18.06 mg n=341 participants at risk as-needed use, tablets, orally, 6 months
Cardiac disorders Myocardial infarction	0.00% 0/337 • Serious Adverse Events: 24 weeks, a 4-week run-out period, and a safety follow-up (visit/telephone call) scheduled for 4 weeks after completion of the study or after withdrawal from the study. Other Adverse Events: 24 weeks and a 4-week run-out period.	0.29% 1/341 • Serious Adverse Events: 24 weeks, a 4-week run-out period, and a safety follow-up (visit/telephone call) scheduled for 4 weeks after completion of the study or after withdrawal from the study. Other Adverse Events: 24 weeks and a 4-week run-out period.
Gastrointestinal disorders Pancreatitis acute	0.30% 1/337 • Serious Adverse Events: 24 weeks, a 4-week run-out period, and a safety follow-up (visit/telephone call) scheduled for 4 weeks after completion of the study or after withdrawal from the study. Other Adverse Events: 24 weeks and a 4-week run-out period.	0.00% 0/341 • Serious Adverse Events: 24 weeks, a 4-week run-out period, and a safety follow-up (visit/telephone call) scheduled for 4 weeks after completion of the study or after withdrawal from the study. Other Adverse Events: 24 weeks and a 4-week run-out period.
Gastrointestinal disorders Rectal haemorrhage	0.30% 1/337 • Serious Adverse Events: 24 weeks, a 4-week run-out period, and a safety follow-up (visit/telephone call) scheduled for 4 weeks after completion of the study or after withdrawal from the study. Other Adverse Events: 24 weeks and a 4-week run-out period.	0.00% 0/341 • Serious Adverse Events: 24 weeks, a 4-week run-out period, and a safety follow-up (visit/telephone call) scheduled for 4 weeks after completion of the study or after withdrawal from the study. Other Adverse Events: 24 weeks and a 4-week run-out period.
General disorders Sudden death	0.00% 0/337 • Serious Adverse Events: 24 weeks, a 4-week run-out period, and a safety follow-up (visit/telephone call) scheduled for 4 weeks after completion of the study or after withdrawal from the study. Other Adverse Events: 24 weeks and a 4-week run-out period.	0.29% 1/341 • Serious Adverse Events: 24 weeks, a 4-week run-out period, and a safety follow-up (visit/telephone call) scheduled for 4 weeks after completion of the study or after withdrawal from the study. Other Adverse Events: 24 weeks and a 4-week run-out period.
Infections and infestations Pneumonia	0.30% 1/337 • Serious Adverse Events: 24 weeks, a 4-week run-out period, and a safety follow-up (visit/telephone call) scheduled for 4 weeks after completion of the study or after withdrawal from the study. Other Adverse Events: 24 weeks and a 4-week run-out period.	0.00% 0/341 • Serious Adverse Events: 24 weeks, a 4-week run-out period, and a safety follow-up (visit/telephone call) scheduled for 4 weeks after completion of the study or after withdrawal from the study. Other Adverse Events: 24 weeks and a 4-week run-out period.
Infections and infestations Pyothorax	0.30% 1/337 • Serious Adverse Events: 24 weeks, a 4-week run-out period, and a safety follow-up (visit/telephone call) scheduled for 4 weeks after completion of the study or after withdrawal from the study. Other Adverse Events: 24 weeks and a 4-week run-out period.	0.00% 0/341 • Serious Adverse Events: 24 weeks, a 4-week run-out period, and a safety follow-up (visit/telephone call) scheduled for 4 weeks after completion of the study or after withdrawal from the study. Other Adverse Events: 24 weeks and a 4-week run-out period.
Infections and infestations Subcutaneous abscess	0.30% 1/337 • Serious Adverse Events: 24 weeks, a 4-week run-out period, and a safety follow-up (visit/telephone call) scheduled for 4 weeks after completion of the study or after withdrawal from the study. Other Adverse Events: 24 weeks and a 4-week run-out period.	0.00% 0/341 • Serious Adverse Events: 24 weeks, a 4-week run-out period, and a safety follow-up (visit/telephone call) scheduled for 4 weeks after completion of the study or after withdrawal from the study. Other Adverse Events: 24 weeks and a 4-week run-out period.
Injury, poisoning and procedural complications Accidental overdose	0.30% 1/337 • Serious Adverse Events: 24 weeks, a 4-week run-out period, and a safety follow-up (visit/telephone call) scheduled for 4 weeks after completion of the study or after withdrawal from the study. Other Adverse Events: 24 weeks and a 4-week run-out period.	0.00% 0/341 • Serious Adverse Events: 24 weeks, a 4-week run-out period, and a safety follow-up (visit/telephone call) scheduled for 4 weeks after completion of the study or after withdrawal from the study. Other Adverse Events: 24 weeks and a 4-week run-out period.
Injury, poisoning and procedural complications Alcohol poisoning	0.30% 1/337 • Serious Adverse Events: 24 weeks, a 4-week run-out period, and a safety follow-up (visit/telephone call) scheduled for 4 weeks after completion of the study or after withdrawal from the study. Other Adverse Events: 24 weeks and a 4-week run-out period.	0.00% 0/341 • Serious Adverse Events: 24 weeks, a 4-week run-out period, and a safety follow-up (visit/telephone call) scheduled for 4 weeks after completion of the study or after withdrawal from the study. Other Adverse Events: 24 weeks and a 4-week run-out period.
Injury, poisoning and procedural complications Drug toxicity	0.30% 1/337 • Serious Adverse Events: 24 weeks, a 4-week run-out period, and a safety follow-up (visit/telephone call) scheduled for 4 weeks after completion of the study or after withdrawal from the study. Other Adverse Events: 24 weeks and a 4-week run-out period.	0.00% 0/341 • Serious Adverse Events: 24 weeks, a 4-week run-out period, and a safety follow-up (visit/telephone call) scheduled for 4 weeks after completion of the study or after withdrawal from the study. Other Adverse Events: 24 weeks and a 4-week run-out period.
Injury, poisoning and procedural complications Fall	0.00% 0/337 • Serious Adverse Events: 24 weeks, a 4-week run-out period, and a safety follow-up (visit/telephone call) scheduled for 4 weeks after completion of the study or after withdrawal from the study. Other Adverse Events: 24 weeks and a 4-week run-out period.	0.29% 1/341 • Serious Adverse Events: 24 weeks, a 4-week run-out period, and a safety follow-up (visit/telephone call) scheduled for 4 weeks after completion of the study or after withdrawal from the study. Other Adverse Events: 24 weeks and a 4-week run-out period.
Injury, poisoning and procedural complications Fibula fracture	0.30% 1/337 • Serious Adverse Events: 24 weeks, a 4-week run-out period, and a safety follow-up (visit/telephone call) scheduled for 4 weeks after completion of the study or after withdrawal from the study. Other Adverse Events: 24 weeks and a 4-week run-out period.	0.00% 0/341 • Serious Adverse Events: 24 weeks, a 4-week run-out period, and a safety follow-up (visit/telephone call) scheduled for 4 weeks after completion of the study or after withdrawal from the study. Other Adverse Events: 24 weeks and a 4-week run-out period.
Injury, poisoning and procedural complications Head injury	0.00% 0/337 • Serious Adverse Events: 24 weeks, a 4-week run-out period, and a safety follow-up (visit/telephone call) scheduled for 4 weeks after completion of the study or after withdrawal from the study. Other Adverse Events: 24 weeks and a 4-week run-out period.	0.29% 1/341 • Serious Adverse Events: 24 weeks, a 4-week run-out period, and a safety follow-up (visit/telephone call) scheduled for 4 weeks after completion of the study or after withdrawal from the study. Other Adverse Events: 24 weeks and a 4-week run-out period.
Injury, poisoning and procedural complications Intentional overdose	0.89% 3/337 • Serious Adverse Events: 24 weeks, a 4-week run-out period, and a safety follow-up (visit/telephone call) scheduled for 4 weeks after completion of the study or after withdrawal from the study. Other Adverse Events: 24 weeks and a 4-week run-out period.	0.00% 0/341 • Serious Adverse Events: 24 weeks, a 4-week run-out period, and a safety follow-up (visit/telephone call) scheduled for 4 weeks after completion of the study or after withdrawal from the study. Other Adverse Events: 24 weeks and a 4-week run-out period.
Injury, poisoning and procedural complications Tendon rupture	0.00% 0/337 • Serious Adverse Events: 24 weeks, a 4-week run-out period, and a safety follow-up (visit/telephone call) scheduled for 4 weeks after completion of the study or after withdrawal from the study. Other Adverse Events: 24 weeks and a 4-week run-out period.	0.29% 1/341 • Serious Adverse Events: 24 weeks, a 4-week run-out period, and a safety follow-up (visit/telephone call) scheduled for 4 weeks after completion of the study or after withdrawal from the study. Other Adverse Events: 24 weeks and a 4-week run-out period.
Injury, poisoning and procedural complications Tibia fracture	0.30% 1/337 • Serious Adverse Events: 24 weeks, a 4-week run-out period, and a safety follow-up (visit/telephone call) scheduled for 4 weeks after completion of the study or after withdrawal from the study. Other Adverse Events: 24 weeks and a 4-week run-out period.	0.00% 0/341 • Serious Adverse Events: 24 weeks, a 4-week run-out period, and a safety follow-up (visit/telephone call) scheduled for 4 weeks after completion of the study or after withdrawal from the study. Other Adverse Events: 24 weeks and a 4-week run-out period.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Bile duct cancer	0.30% 1/337 • Serious Adverse Events: 24 weeks, a 4-week run-out period, and a safety follow-up (visit/telephone call) scheduled for 4 weeks after completion of the study or after withdrawal from the study. Other Adverse Events: 24 weeks and a 4-week run-out period.	0.00% 0/341 • Serious Adverse Events: 24 weeks, a 4-week run-out period, and a safety follow-up (visit/telephone call) scheduled for 4 weeks after completion of the study or after withdrawal from the study. Other Adverse Events: 24 weeks and a 4-week run-out period.
Nervous system disorders Dizziness	0.30% 1/337 • Serious Adverse Events: 24 weeks, a 4-week run-out period, and a safety follow-up (visit/telephone call) scheduled for 4 weeks after completion of the study or after withdrawal from the study. Other Adverse Events: 24 weeks and a 4-week run-out period.	0.00% 0/341 • Serious Adverse Events: 24 weeks, a 4-week run-out period, and a safety follow-up (visit/telephone call) scheduled for 4 weeks after completion of the study or after withdrawal from the study. Other Adverse Events: 24 weeks and a 4-week run-out period.
Nervous system disorders Epilepsy	0.30% 1/337 • Serious Adverse Events: 24 weeks, a 4-week run-out period, and a safety follow-up (visit/telephone call) scheduled for 4 weeks after completion of the study or after withdrawal from the study. Other Adverse Events: 24 weeks and a 4-week run-out period.	0.00% 0/341 • Serious Adverse Events: 24 weeks, a 4-week run-out period, and a safety follow-up (visit/telephone call) scheduled for 4 weeks after completion of the study or after withdrawal from the study. Other Adverse Events: 24 weeks and a 4-week run-out period.
Nervous system disorders Subarachnoid haemorrhage	0.00% 0/337 • Serious Adverse Events: 24 weeks, a 4-week run-out period, and a safety follow-up (visit/telephone call) scheduled for 4 weeks after completion of the study or after withdrawal from the study. Other Adverse Events: 24 weeks and a 4-week run-out period.	0.29% 1/341 • Serious Adverse Events: 24 weeks, a 4-week run-out period, and a safety follow-up (visit/telephone call) scheduled for 4 weeks after completion of the study or after withdrawal from the study. Other Adverse Events: 24 weeks and a 4-week run-out period.
Psychiatric disorders Alcoholism	0.00% 0/337 • Serious Adverse Events: 24 weeks, a 4-week run-out period, and a safety follow-up (visit/telephone call) scheduled for 4 weeks after completion of the study or after withdrawal from the study. Other Adverse Events: 24 weeks and a 4-week run-out period.	0.59% 2/341 • Serious Adverse Events: 24 weeks, a 4-week run-out period, and a safety follow-up (visit/telephone call) scheduled for 4 weeks after completion of the study or after withdrawal from the study. Other Adverse Events: 24 weeks and a 4-week run-out period.
Psychiatric disorders Suicidal behaviour	0.30% 1/337 • Serious Adverse Events: 24 weeks, a 4-week run-out period, and a safety follow-up (visit/telephone call) scheduled for 4 weeks after completion of the study or after withdrawal from the study. Other Adverse Events: 24 weeks and a 4-week run-out period.	0.00% 0/341 • Serious Adverse Events: 24 weeks, a 4-week run-out period, and a safety follow-up (visit/telephone call) scheduled for 4 weeks after completion of the study or after withdrawal from the study. Other Adverse Events: 24 weeks and a 4-week run-out period.
Vascular disorders Arteritis	0.30% 1/337 • Serious Adverse Events: 24 weeks, a 4-week run-out period, and a safety follow-up (visit/telephone call) scheduled for 4 weeks after completion of the study or after withdrawal from the study. Other Adverse Events: 24 weeks and a 4-week run-out period.	0.00% 0/341 • Serious Adverse Events: 24 weeks, a 4-week run-out period, and a safety follow-up (visit/telephone call) scheduled for 4 weeks after completion of the study or after withdrawal from the study. Other Adverse Events: 24 weeks and a 4-week run-out period.
Vascular disorders Hypotension	0.30% 1/337 • Serious Adverse Events: 24 weeks, a 4-week run-out period, and a safety follow-up (visit/telephone call) scheduled for 4 weeks after completion of the study or after withdrawal from the study. Other Adverse Events: 24 weeks and a 4-week run-out period.	0.00% 0/341 • Serious Adverse Events: 24 weeks, a 4-week run-out period, and a safety follow-up (visit/telephone call) scheduled for 4 weeks after completion of the study or after withdrawal from the study. Other Adverse Events: 24 weeks and a 4-week run-out period.