Trial Outcomes & Findings for Kappa Opioid Receptor Antagonism for the Tx of AUD and Comorbid PTSD (NCT NCT03852628)

Last Updated: 2023-09-14

Results Overview

Timeline Follow Back (TLFB) is a calendar-based method of assessing drinking patterns used to document the frequency and amount of daily alcohol consumption and to categorize the World Health Organization Risk Levels of Alcohol Use. An AUD reduction is defined as a WHO risk reduction of at least one category from baseline to week 8. The are 4 different WHO Risk Levels based on the grams of alcohol consumed per day: Very High Risk, High Risk, Medium Risk, and Low Risk (including abstinence).

Recruitment status

TERMINATED

Study phase

PHASE2

Target enrollment

69 participants

Primary outcome timeframe

Baseline and 8 weeks

Results posted on

2023-09-14

Participant Flow

Participant milestones

Participant milestones
Measure	2mg Buprenex and 380mg Vivitrol 2mg Buprenex and 380mg Vivitrol Buprenex (buprenorphine) 2mg sublingual (SL) (taken every day for 12 weeks) , with Vivitrol (naltrexone) 380mg intramuscular injection (IM) (given every 4 weeks) 2mg Buprenex and 380mg Vivitrol: Daily 2mg SL BUP (84 pills total, taken sublingual every day for 12 weeks) and Q4wks (given intramuscular, 3 injections total: at baseline, week4 and week8 ) IM NLTRX	Placebo Placebo (SL pill qd, IM injection q4weeks) Placebo pill (taken sublingual every day for 12 weeks) and IM placebo (given intramuscular injection, every 4 weeks at baseline, week4 and week8) Placebo (SL pill qd, IM injection q4weeks): Daily SL placebo (84 pills total, taken sublingual every day for 12 weeks) and Q4wks (given intramuscular, 3 injections total: at baseline, week4 and week8) IM Placebo
Overall Study STARTED	35	34
Overall Study COMPLETED	22	22
Overall Study NOT COMPLETED	13	12

Reasons for withdrawal

Reasons for withdrawal
Measure	2mg Buprenex and 380mg Vivitrol 2mg Buprenex and 380mg Vivitrol Buprenex (buprenorphine) 2mg sublingual (SL) (taken every day for 12 weeks) , with Vivitrol (naltrexone) 380mg intramuscular injection (IM) (given every 4 weeks) 2mg Buprenex and 380mg Vivitrol: Daily 2mg SL BUP (84 pills total, taken sublingual every day for 12 weeks) and Q4wks (given intramuscular, 3 injections total: at baseline, week4 and week8 ) IM NLTRX	Placebo Placebo (SL pill qd, IM injection q4weeks) Placebo pill (taken sublingual every day for 12 weeks) and IM placebo (given intramuscular injection, every 4 weeks at baseline, week4 and week8) Placebo (SL pill qd, IM injection q4weeks): Daily SL placebo (84 pills total, taken sublingual every day for 12 weeks) and Q4wks (given intramuscular, 3 injections total: at baseline, week4 and week8) IM Placebo
Overall Study Lost to Follow-up	7	6
Overall Study Lack of Efficacy	6	6

Baseline Characteristics

Kappa Opioid Receptor Antagonism for the Tx of AUD and Comorbid PTSD

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	2mg Buprenex and 380mg Vivitrol n=35 Participants 2mg Buprenex and 380mg Vivitrol Buprenex (buprenorphine) 2mg sublingual (SL) (taken every day for 12 weeks) , with Vivitrol (naltrexone) 380mg intramuscular injection (IM) (given every 4 weeks) 2mg Buprenex and 380mg Vivitrol: Daily 2mg SL BUP (84 pills total, taken sublingual every day for 12 weeks) and Q4wks (given intramuscular, 3 injections total: at baseline, week4 and week8 ) IM NLTRX	Placebo n=34 Participants Placebo (SL pill qd, IM injection q4weeks) Placebo pill (taken sublingual every day for 12 weeks) and IM placebo (given intramuscular injection, every 4 weeks at baseline, week4 and week8) Placebo (SL pill qd, IM injection q4weeks): Daily SL placebo (84 pills total, taken sublingual every day for 12 weeks) and Q4wks (given intramuscular, 3 injections total: at baseline, week4 and week8) IM Placebo	Total n=69 Participants Total of all reporting groups
Age, Continuous	50.9 Years STANDARD_DEVIATION 10.6 • n=5 Participants	49.2 Years STANDARD_DEVIATION 13.1 • n=7 Participants	50.1 Years STANDARD_DEVIATION 11.8 • n=5 Participants
Sex: Female, Male Female	6 Participants n=5 Participants	6 Participants n=7 Participants	12 Participants n=5 Participants
Sex: Female, Male Male	29 Participants n=5 Participants	28 Participants n=7 Participants	57 Participants n=5 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	2 Participants n=5 Participants	1 Participants n=7 Participants	3 Participants n=5 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	32 Participants n=5 Participants	32 Participants n=7 Participants	64 Participants n=5 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	1 Participants n=5 Participants	1 Participants n=7 Participants	2 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	0 Participants n=5 Participants	0 Participants n=7 Participants	0 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	18 Participants n=5 Participants	20 Participants n=7 Participants	38 Participants n=5 Participants
Race (NIH/OMB) White	13 Participants n=5 Participants	13 Participants n=7 Participants	26 Participants n=5 Participants
Race (NIH/OMB) More than one race	2 Participants n=5 Participants	0 Participants n=7 Participants	2 Participants n=5 Participants
Race (NIH/OMB) Unknown or Not Reported	2 Participants n=5 Participants	1 Participants n=7 Participants	3 Participants n=5 Participants
Served in U.S. Military?	31 Participants n=5 Participants	28 Participants n=7 Participants	59 Participants n=5 Participants
Anti-Depressant Use?	19 Participants n=5 Participants	17 Participants n=7 Participants	36 Participants n=5 Participants
Enrolling Study Site Tuscaloosa	24 Participants n=5 Participants	23 Participants n=7 Participants	47 Participants n=5 Participants
Enrolling Study Site West Haven	11 Participants n=5 Participants	10 Participants n=7 Participants	21 Participants n=5 Participants
Enrolling Study Site Wayne State University	0 Participants n=5 Participants	1 Participants n=7 Participants	1 Participants n=5 Participants

PRIMARY outcome

Timeframe: Baseline and 8 weeks

Population: Includes all randomized participants that completed the baseline and Week 8 visit, and reported enough consecutive days of alcohol consumption at the week 8 visit (defined as being within one standard deviation of the population mean for the 28-day look back period).

Outcome measures

Outcome measures
Measure	2mg Buprenex and 380mg Vivitrol n=30 Participants 2mg Buprenex and 380mg Vivitrol Buprenex (buprenorphine) 2mg sublingual (SL) (taken every day for 12 weeks) , with Vivitrol (naltrexone) 380mg intramuscular injection (IM) (given every 4 weeks) 2mg Buprenex and 380mg Vivitrol: Daily 2mg SL BUP (84 pills total, taken sublingual every day for 12 weeks) and Q4wks (given intramuscular, 3 injections total: at baseline, week4 and week8 ) IM NLTRX	Placebo n=28 Participants Placebo (SL pill qd, IM injection q4weeks) Placebo pill (taken sublingual every day for 12 weeks) and IM placebo (given intramuscular injection, every 4 weeks at baseline, week4 and week8) Placebo (SL pill qd, IM injection q4weeks): Daily SL placebo (84 pills total, taken sublingual every day for 12 weeks) and Q4wks (given intramuscular, 3 injections total: at baseline, week4 and week8) IM Placebo
Number of Participants With a Reduction in Alcohol Use Disorder (AUD), With TLFB Tool	17 Participants	23 Participants

PRIMARY outcome

Timeframe: Baseline and 8 weeks

Population: All randomized participants that completed the baseline and week 8 visit.

The Clinician-Administered PTSD Scale for DSM-5 (CAPS-5) is a 30-item structured interview to assess PTSD diagnosis and symptom severity. The CAPS-5 produces a PTSD Total Symptom Severity Score (TSSS) that ranges from 0 to 80, with a higher score indication worse PTSD symptoms. For this study, a reduction in PTSD symptoms is defined as a 10 or more point decrease in the CAPS-5 Total Symptom Severity Score (TSSS) from baseline to week 8.

Outcome measures

Outcome measures
Measure	2mg Buprenex and 380mg Vivitrol n=28 Participants 2mg Buprenex and 380mg Vivitrol Buprenex (buprenorphine) 2mg sublingual (SL) (taken every day for 12 weeks) , with Vivitrol (naltrexone) 380mg intramuscular injection (IM) (given every 4 weeks) 2mg Buprenex and 380mg Vivitrol: Daily 2mg SL BUP (84 pills total, taken sublingual every day for 12 weeks) and Q4wks (given intramuscular, 3 injections total: at baseline, week4 and week8 ) IM NLTRX	Placebo n=27 Participants Placebo (SL pill qd, IM injection q4weeks) Placebo pill (taken sublingual every day for 12 weeks) and IM placebo (given intramuscular injection, every 4 weeks at baseline, week4 and week8) Placebo (SL pill qd, IM injection q4weeks): Daily SL placebo (84 pills total, taken sublingual every day for 12 weeks) and Q4wks (given intramuscular, 3 injections total: at baseline, week4 and week8) IM Placebo
Number of Participants With a Reduction in CAPS-5 Total Symptom Severity Score (TSSS) of 10 or More Points	14 Participants	15 Participants

PRIMARY outcome

Timeframe: Baseline and 8 Weeks

AUD is measured by the Timeline Follow Back (TLFB). This instrument documents the amount of daily alcohol consumption (in grams) and categorizes the World Health Organization Risk Levels of Alcohol Use. The are 4 different WHO Risk Levels: Very High Risk, High Risk, Medium Risk, and Low Risk (including abstinence). An AUD reduction is defined as a WHO risk reduction of at least one category from baseline to week 8. PTSD symptom is measured by the Clinician-Administered PTSD Scale for DSM-5 (CAPS-5). This 30-item interview assesses PTSD diagnosis and symptom severity. The CAPS-5 Total Symptom Severity Score (TSSS) ranges from 0 to 80, with higher scores indicating worse symptoms. A reduction in PTSD symptom is defined as a 10+ point decrease in the TSSS from baseline to week 8. A positive response for the composite primary outcome measure is defined as at least a 1-category risk reduction on the WHO s and at least a 10-point decrease in TSSS from baseline to Week 8.

Outcome measures

Outcome measures
Measure	2mg Buprenex and 380mg Vivitrol n=28 Participants 2mg Buprenex and 380mg Vivitrol Buprenex (buprenorphine) 2mg sublingual (SL) (taken every day for 12 weeks) , with Vivitrol (naltrexone) 380mg intramuscular injection (IM) (given every 4 weeks) 2mg Buprenex and 380mg Vivitrol: Daily 2mg SL BUP (84 pills total, taken sublingual every day for 12 weeks) and Q4wks (given intramuscular, 3 injections total: at baseline, week4 and week8 ) IM NLTRX	Placebo n=27 Participants Placebo (SL pill qd, IM injection q4weeks) Placebo pill (taken sublingual every day for 12 weeks) and IM placebo (given intramuscular injection, every 4 weeks at baseline, week4 and week8) Placebo (SL pill qd, IM injection q4weeks): Daily SL placebo (84 pills total, taken sublingual every day for 12 weeks) and Q4wks (given intramuscular, 3 injections total: at baseline, week4 and week8) IM Placebo
Composite Outcome Measure for a Reduction in Both Alcohol Use Disorder (AUD) and Post-Traumatic Stress Disorder (PTSD) Symptoms	10 Participants	12 Participants

Adverse Events

2mg Buprenex and 380mg Vivitrol

Serious events: 3 serious events

Other events: 22 other events

Deaths: 0 deaths

Placebo

Serious events: 0 serious events

Other events: 16 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	2mg Buprenex and 380mg Vivitrol n=35 participants at risk 2mg Buprenex and 380mg Vivitrol Buprenex (buprenorphine) 2mg sublingual (SL) (taken every day for 12 weeks) , with Vivitrol (naltrexone) 380mg intramuscular injection (IM) (given every 4 weeks) 2mg Buprenex and 380mg Vivitrol: Daily 2mg SL BUP (84 pills total, taken sublingual every day for 12 weeks) and Q4wks (given intramuscular, 3 injections total: at baseline, week4 and week8 ) IM NLTRX	Placebo n=34 participants at risk Placebo (SL pill qd, IM injection q4weeks) Placebo pill (taken sublingual every day for 12 weeks) and IM placebo (given intramuscular injection, every 4 weeks at baseline, week4 and week8) Placebo (SL pill qd, IM injection q4weeks): Daily SL placebo (84 pills total, taken sublingual every day for 12 weeks) and Q4wks (given intramuscular, 3 injections total: at baseline, week4 and week8) IM Placebo
Cardiac disorders Congestive Heart Failure, Exacerbation	2.9% 1/35 • Number of events 1 • From baseline visit (after first treatment allocation) through the Week 14 study visit.	0.00% 0/34 • From baseline visit (after first treatment allocation) through the Week 14 study visit.
Injury, poisoning and procedural complications Fractured Vertebrae	2.9% 1/35 • Number of events 1 • From baseline visit (after first treatment allocation) through the Week 14 study visit.	0.00% 0/34 • From baseline visit (after first treatment allocation) through the Week 14 study visit.
Psychiatric disorders Alcohol Withdrawal Syndrome	2.9% 1/35 • Number of events 2 • From baseline visit (after first treatment allocation) through the Week 14 study visit.	0.00% 0/34 • From baseline visit (after first treatment allocation) through the Week 14 study visit.

Other adverse events

Additional Information

PASA Core Leadership

RTI International

Phone: 919-541-6002

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Restriction type: LTE60

Measure	2mg Buprenex and 380mg Vivitrol n=35 participants at risk 2mg Buprenex and 380mg Vivitrol Buprenex (buprenorphine) 2mg sublingual (SL) (taken every day for 12 weeks) , with Vivitrol (naltrexone) 380mg intramuscular injection (IM) (given every 4 weeks) 2mg Buprenex and 380mg Vivitrol: Daily 2mg SL BUP (84 pills total, taken sublingual every day for 12 weeks) and Q4wks (given intramuscular, 3 injections total: at baseline, week4 and week8 ) IM NLTRX	Placebo n=34 participants at risk Placebo (SL pill qd, IM injection q4weeks) Placebo pill (taken sublingual every day for 12 weeks) and IM placebo (given intramuscular injection, every 4 weeks at baseline, week4 and week8) Placebo (SL pill qd, IM injection q4weeks): Daily SL placebo (84 pills total, taken sublingual every day for 12 weeks) and Q4wks (given intramuscular, 3 injections total: at baseline, week4 and week8) IM Placebo
Gastrointestinal disorders Abdominal cramps	0.00% 0/35 • From baseline visit (after first treatment allocation) through the Week 14 study visit.	2.9% 1/34 • Number of events 1 • From baseline visit (after first treatment allocation) through the Week 14 study visit.
Gastrointestinal disorders Acid reflux (esophageal)	0.00% 0/35 • From baseline visit (after first treatment allocation) through the Week 14 study visit.	2.9% 1/34 • Number of events 1 • From baseline visit (after first treatment allocation) through the Week 14 study visit.
General disorders Adverse drug reaction	2.9% 1/35 • Number of events 1 • From baseline visit (after first treatment allocation) through the Week 14 study visit.	0.00% 0/34 • From baseline visit (after first treatment allocation) through the Week 14 study visit.
Psychiatric disorders Alcohol withdrawal syndrome	5.7% 2/35 • Number of events 3 • From baseline visit (after first treatment allocation) through the Week 14 study visit.	0.00% 0/34 • From baseline visit (after first treatment allocation) through the Week 14 study visit.
Nervous system disorders Alcoholic seizure	2.9% 1/35 • Number of events 1 • From baseline visit (after first treatment allocation) through the Week 14 study visit.	0.00% 0/34 • From baseline visit (after first treatment allocation) through the Week 14 study visit.
Psychiatric disorders Anxiety aggravated	2.9% 1/35 • Number of events 2 • From baseline visit (after first treatment allocation) through the Week 14 study visit.	0.00% 0/34 • From baseline visit (after first treatment allocation) through the Week 14 study visit.
Cardiac disorders Bradycardia	2.9% 1/35 • Number of events 1 • From baseline visit (after first treatment allocation) through the Week 14 study visit.	0.00% 0/34 • From baseline visit (after first treatment allocation) through the Week 14 study visit.
Infections and infestations Cellulitis	2.9% 1/35 • Number of events 1 • From baseline visit (after first treatment allocation) through the Week 14 study visit.	0.00% 0/34 • From baseline visit (after first treatment allocation) through the Week 14 study visit.
General disorders Chest pain	0.00% 0/35 • From baseline visit (after first treatment allocation) through the Week 14 study visit.	2.9% 1/34 • Number of events 3 • From baseline visit (after first treatment allocation) through the Week 14 study visit.
Gastrointestinal disorders Chills	0.00% 0/35 • From baseline visit (after first treatment allocation) through the Week 14 study visit.	5.9% 2/34 • Number of events 3 • From baseline visit (after first treatment allocation) through the Week 14 study visit.
Cardiac disorders Congestive cardiac failure aggravated	2.9% 1/35 • Number of events 1 • From baseline visit (after first treatment allocation) through the Week 14 study visit.	0.00% 0/34 • From baseline visit (after first treatment allocation) through the Week 14 study visit.
Gastrointestinal disorders Constipation	2.9% 1/35 • Number of events 1 • From baseline visit (after first treatment allocation) through the Week 14 study visit.	0.00% 0/34 • From baseline visit (after first treatment allocation) through the Week 14 study visit.
Nervous system disorders Crawling Sensation	2.9% 1/35 • Number of events 1 • From baseline visit (after first treatment allocation) through the Week 14 study visit.	0.00% 0/34 • From baseline visit (after first treatment allocation) through the Week 14 study visit.
Metabolism and nutrition disorders Decreased appetite	2.9% 1/35 • Number of events 1 • From baseline visit (after first treatment allocation) through the Week 14 study visit.	2.9% 1/34 • Number of events 1 • From baseline visit (after first treatment allocation) through the Week 14 study visit.
Psychiatric disorders Depressed mood	2.9% 1/35 • Number of events 2 • From baseline visit (after first treatment allocation) through the Week 14 study visit.	0.00% 0/34 • From baseline visit (after first treatment allocation) through the Week 14 study visit.
Psychiatric disorders Depression	0.00% 0/35 • From baseline visit (after first treatment allocation) through the Week 14 study visit.	5.9% 2/34 • Number of events 2 • From baseline visit (after first treatment allocation) through the Week 14 study visit.
Gastrointestinal disorders Diarrhea	0.00% 0/35 • From baseline visit (after first treatment allocation) through the Week 14 study visit.	2.9% 1/34 • Number of events 1 • From baseline visit (after first treatment allocation) through the Week 14 study visit.
Investigations Diastolic BP increased	2.9% 1/35 • Number of events 2 • From baseline visit (after first treatment allocation) through the Week 14 study visit.	0.00% 0/34 • From baseline visit (after first treatment allocation) through the Week 14 study visit.
Nervous system disorders Dizziness	5.7% 2/35 • Number of events 2 • From baseline visit (after first treatment allocation) through the Week 14 study visit.	0.00% 0/34 • From baseline visit (after first treatment allocation) through the Week 14 study visit.
Reproductive system and breast disorders Erectile dysfunction	5.7% 2/35 • Number of events 2 • From baseline visit (after first treatment allocation) through the Week 14 study visit.	0.00% 0/34 • From baseline visit (after first treatment allocation) through the Week 14 study visit.
Injury, poisoning and procedural complications Fall	2.9% 1/35 • Number of events 1 • From baseline visit (after first treatment allocation) through the Week 14 study visit.	0.00% 0/34 • From baseline visit (after first treatment allocation) through the Week 14 study visit.
General disorders Fatigue	11.4% 4/35 • Number of events 4 • From baseline visit (after first treatment allocation) through the Week 14 study visit.	5.9% 2/34 • Number of events 5 • From baseline visit (after first treatment allocation) through the Week 14 study visit.
Musculoskeletal and connective tissue disorders Fibromyalgia worsened	2.9% 1/35 • Number of events 1 • From baseline visit (after first treatment allocation) through the Week 14 study visit.	0.00% 0/34 • From baseline visit (after first treatment allocation) through the Week 14 study visit.
Injury, poisoning and procedural complications Fractured vertebra	2.9% 1/35 • Number of events 1 • From baseline visit (after first treatment allocation) through the Week 14 study visit.	0.00% 0/34 • From baseline visit (after first treatment allocation) through the Week 14 study visit.
Nervous system disorders Headache	2.9% 1/35 • Number of events 1 • From baseline visit (after first treatment allocation) through the Week 14 study visit.	2.9% 1/34 • Number of events 1 • From baseline visit (after first treatment allocation) through the Week 14 study visit.
Cardiac disorders Heart racing	0.00% 0/35 • From baseline visit (after first treatment allocation) through the Week 14 study visit.	2.9% 1/34 • Number of events 1 • From baseline visit (after first treatment allocation) through the Week 14 study visit.
Investigations Heart rate increased	2.9% 1/35 • Number of events 1 • From baseline visit (after first treatment allocation) through the Week 14 study visit.	0.00% 0/34 • From baseline visit (after first treatment allocation) through the Week 14 study visit.
Skin and subcutaneous tissue disorders Hyperhidrosis	0.00% 0/35 • From baseline visit (after first treatment allocation) through the Week 14 study visit.	2.9% 1/34 • Number of events 1 • From baseline visit (after first treatment allocation) through the Week 14 study visit.
Metabolism and nutrition disorders Hypokalemia	2.9% 1/35 • Number of events 1 • From baseline visit (after first treatment allocation) through the Week 14 study visit.	0.00% 0/34 • From baseline visit (after first treatment allocation) through the Week 14 study visit.
General disorders Injection site pain	17.1% 6/35 • Number of events 7 • From baseline visit (after first treatment allocation) through the Week 14 study visit.	14.7% 5/34 • Number of events 5 • From baseline visit (after first treatment allocation) through the Week 14 study visit.
Injury, poisoning and procedural complications Knee Fracture	0.00% 0/35 • From baseline visit (after first treatment allocation) through the Week 14 study visit.	2.9% 1/34 • Number of events 1 • From baseline visit (after first treatment allocation) through the Week 14 study visit.
Musculoskeletal and connective tissue disorders Knee Pain	0.00% 0/35 • From baseline visit (after first treatment allocation) through the Week 14 study visit.	2.9% 1/34 • Number of events 1 • From baseline visit (after first treatment allocation) through the Week 14 study visit.
Nervous system disorders Lethargy	2.9% 1/35 • Number of events 1 • From baseline visit (after first treatment allocation) through the Week 14 study visit.	0.00% 0/34 • From baseline visit (after first treatment allocation) through the Week 14 study visit.
Psychiatric disorders Libido decreased	0.00% 0/35 • From baseline visit (after first treatment allocation) through the Week 14 study visit.	2.9% 1/34 • Number of events 1 • From baseline visit (after first treatment allocation) through the Week 14 study visit.
Nervous system disorders Lightheadedness	2.9% 1/35 • Number of events 1 • From baseline visit (after first treatment allocation) through the Week 14 study visit.	0.00% 0/34 • From baseline visit (after first treatment allocation) through the Week 14 study visit.
Nervous system disorders Migraine aggravated	0.00% 0/35 • From baseline visit (after first treatment allocation) through the Week 14 study visit.	2.9% 1/34 • Number of events 1 • From baseline visit (after first treatment allocation) through the Week 14 study visit.
Nervous system disorders Myalgia of lower extremities	2.9% 1/35 • Number of events 1 • From baseline visit (after first treatment allocation) through the Week 14 study visit.	0.00% 0/34 • From baseline visit (after first treatment allocation) through the Week 14 study visit.
Gastrointestinal disorders Nausea	14.3% 5/35 • Number of events 5 • From baseline visit (after first treatment allocation) through the Week 14 study visit.	2.9% 1/34 • Number of events 1 • From baseline visit (after first treatment allocation) through the Week 14 study visit.
Psychiatric disorders Nightmares	0.00% 0/35 • From baseline visit (after first treatment allocation) through the Week 14 study visit.	2.9% 1/34 • Number of events 1 • From baseline visit (after first treatment allocation) through the Week 14 study visit.
Gastrointestinal disorders Numbness of tongue	0.00% 0/35 • From baseline visit (after first treatment allocation) through the Week 14 study visit.	2.9% 1/34 • Number of events 1 • From baseline visit (after first treatment allocation) through the Week 14 study visit.
Gastrointestinal disorders Pain stomach	0.00% 0/35 • From baseline visit (after first treatment allocation) through the Week 14 study visit.	2.9% 1/34 • Number of events 1 • From baseline visit (after first treatment allocation) through the Week 14 study visit.
Surgical and medical procedures Product used for unknown indication	0.00% 0/35 • From baseline visit (after first treatment allocation) through the Week 14 study visit.	2.9% 1/34 • Number of events 1 • From baseline visit (after first treatment allocation) through the Week 14 study visit.
Investigations Pulse increased	2.9% 1/35 • Number of events 1 • From baseline visit (after first treatment allocation) through the Week 14 study visit.	0.00% 0/34 • From baseline visit (after first treatment allocation) through the Week 14 study visit.
Injury, poisoning and procedural complications Rib fracture	2.9% 1/35 • Number of events 1 • From baseline visit (after first treatment allocation) through the Week 14 study visit.	0.00% 0/34 • From baseline visit (after first treatment allocation) through the Week 14 study visit.
Nervous system disorders Short-term memory loss	5.7% 2/35 • Number of events 2 • From baseline visit (after first treatment allocation) through the Week 14 study visit.	0.00% 0/34 • From baseline visit (after first treatment allocation) through the Week 14 study visit.
Nervous system disorders Somnolence	0.00% 0/35 • From baseline visit (after first treatment allocation) through the Week 14 study visit.	2.9% 1/34 • Number of events 1 • From baseline visit (after first treatment allocation) through the Week 14 study visit.
Psychiatric disorders Suicidal ideation	0.00% 0/35 • From baseline visit (after first treatment allocation) through the Week 14 study visit.	2.9% 1/34 • Number of events 2 • From baseline visit (after first treatment allocation) through the Week 14 study visit.
Nervous system disorders Syncope	0.00% 0/35 • From baseline visit (after first treatment allocation) through the Week 14 study visit.	5.9% 2/34 • Number of events 2 • From baseline visit (after first treatment allocation) through the Week 14 study visit.
Cardiac disorders Tachycardia	2.9% 1/35 • Number of events 1 • From baseline visit (after first treatment allocation) through the Week 14 study visit.	2.9% 1/34 • Number of events 1 • From baseline visit (after first treatment allocation) through the Week 14 study visit.
Blood and lymphatic system disorders Thrombocytopenia	2.9% 1/35 • Number of events 1 • From baseline visit (after first treatment allocation) through the Week 14 study visit.	0.00% 0/34 • From baseline visit (after first treatment allocation) through the Week 14 study visit.
Infections and infestations Viral infection	0.00% 0/35 • From baseline visit (after first treatment allocation) through the Week 14 study visit.	2.9% 1/34 • Number of events 1 • From baseline visit (after first treatment allocation) through the Week 14 study visit.
Eye disorders Visual disturbances	2.9% 1/35 • Number of events 1 • From baseline visit (after first treatment allocation) through the Week 14 study visit.	0.00% 0/34 • From baseline visit (after first treatment allocation) through the Week 14 study visit.
Psychiatric disorders Vivid dreams	0.00% 0/35 • From baseline visit (after first treatment allocation) through the Week 14 study visit.	2.9% 1/34 • Number of events 1 • From baseline visit (after first treatment allocation) through the Week 14 study visit.
Gastrointestinal disorders Vomiting	2.9% 1/35 • Number of events 1 • From baseline visit (after first treatment allocation) through the Week 14 study visit.	0.00% 0/34 • From baseline visit (after first treatment allocation) through the Week 14 study visit.
General disorders Weakness	2.9% 1/35 • Number of events 1 • From baseline visit (after first treatment allocation) through the Week 14 study visit.	0.00% 0/34 • From baseline visit (after first treatment allocation) through the Week 14 study visit.