Trial Outcomes & Findings for Ibudilast and Withdrawal-Related Dysphoria (NCT NCT03489850)

Last Updated: 2021-10-07

Results Overview

Negative affect as measured by self-reported ratings of "Downhearted", "Discouraged", "Uneasy", and "Anxious". Each item was rated on a scale from 0 (not at all) to 4 (extremely). The 4 items were summed for the total negative affect score for each day, ranging from 0 - 16. Higher scores indicate more negative mood.

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

52 participants

Primary outcome timeframe

Assessed through daily prompts throughout the 2-week study period.

Results posted on

2021-10-07

Participant Flow

This study was conducted at an outpatient research clinic in a medical center. Participants were recruited through social media and mass transit advertisements. Initial screening was conducted through telephone interview, with eligible participants invited for an in-person assessment.

Participant milestones

Participant milestones
Measure	Ibudilast 20mg BID Days 1-2 50mg BID Days 3-14 Ibudilast: Ibudilast (IBUD) is a neuroimmune modulator that inhibits phosphodiesterase-4 and -10 and macrophage migration inhibitory factor.	Placebo Matched to active Placebo: Placebo is matched to ibudilast active medication.
Overall Study STARTED	24	28
Overall Study COMPLETED	23	27
Overall Study NOT COMPLETED	1	1

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

Ibudilast and Withdrawal-Related Dysphoria

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Ibudilast n=24 Participants 20mg BID Days 1-2 50mg BID Days 3-14 Ibudilast: Ibudilast (IBUD) is a neuroimmune modulator that inhibits phosphodiesterase-4 and -10 and macrophage migration inhibitory factor.	Placebo n=28 Participants Matched to active Placebo: Placebo is matched to ibudilast active medication.	Total n=52 Participants Total of all reporting groups
Age, Continuous	34.46 years STANDARD_DEVIATION 9.24 • n=5 Participants	31.07 years STANDARD_DEVIATION 7.81 • n=7 Participants	32.63 years STANDARD_DEVIATION 8.58 • n=5 Participants
Sex: Female, Male Female	8 Participants n=5 Participants	10 Participants n=7 Participants	18 Participants n=5 Participants
Sex: Female, Male Male	16 Participants n=5 Participants	18 Participants n=7 Participants	34 Participants n=5 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	5 Participants n=5 Participants	7 Participants n=7 Participants	12 Participants n=5 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	19 Participants n=5 Participants	21 Participants n=7 Participants	40 Participants n=5 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 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	5 Participants n=7 Participants	5 Participants n=5 Participants
Drinks Per Drinking Day	5.70 drinks STANDARD_DEVIATION 2.58 • n=5 Participants	5.34 drinks STANDARD_DEVIATION 3.57 • n=7 Participants	5.51 drinks STANDARD_DEVIATION 3.13 • n=5 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	1 Participants n=7 Participants	1 Participants n=5 Participants
Race (NIH/OMB) Black or African American	5 Participants n=5 Participants	2 Participants n=7 Participants	7 Participants n=5 Participants
Race (NIH/OMB) White	17 Participants n=5 Participants	12 Participants n=7 Participants	29 Participants n=5 Participants
Race (NIH/OMB) More than one race	1 Participants n=5 Participants	5 Participants n=7 Participants	6 Participants n=5 Participants
Race (NIH/OMB) Unknown or Not Reported	1 Participants n=5 Participants	3 Participants n=7 Participants	4 Participants n=5 Participants
Region of Enrollment United States	24 participants n=5 Participants	28 participants n=7 Participants	52 participants n=5 Participants
Education	15.25 years STANDARD_DEVIATION 2.64 • n=5 Participants	15.21 years STANDARD_DEVIATION 1.75 • n=7 Participants	15.23 years STANDARD_DEVIATION 2.18 • n=5 Participants
Withdrawal Related Dysphoria	9 Participants n=5 Participants	11 Participants n=7 Participants	20 Participants n=5 Participants
Alcohol Use Disorder Symptom Count	5.29 symptoms STANDARD_DEVIATION 2.37 • n=5 Participants	4.86 symptoms STANDARD_DEVIATION 2.27 • n=7 Participants	5.06 symptoms STANDARD_DEVIATION 2.30 • n=5 Participants
Alcohol Use Disorder Identification Test Total Score	16.38 score on scale STANDARD_DEVIATION 5.90 • n=5 Participants	16.71 score on scale STANDARD_DEVIATION 6.42 • n=7 Participants	16.56 score on scale STANDARD_DEVIATION 6.12 • n=5 Participants
Alcohol Dependence Scale Total Score	13.00 score on scale STANDARD_DEVIATION 6.10 • n=5 Participants	12.07 score on scale STANDARD_DEVIATION 7.01 • n=7 Participants	12.50 score on scale STANDARD_DEVIATION 6.56 • n=5 Participants
Penn Alcohol Craving Scale Total Score	12.79 score STANDARD_DEVIATION 5.14 • n=5 Participants	12.11 score STANDARD_DEVIATION 7.04 • n=7 Participants	12.43 score STANDARD_DEVIATION 6.18 • n=5 Participants
Obsessive Compulsive Drinking Scale Total Score	14.54 score STANDARD_DEVIATION 6.05 • n=5 Participants	13.93 score STANDARD_DEVIATION 8.07 • n=7 Participants	14.21 score STANDARD_DEVIATION 7.15 • n=5 Participants
Reasons for Heavy Drinking Questionnaire - Reinforcing	23.29 score STANDARD_DEVIATION 3.51 • n=5 Participants	22.82 score STANDARD_DEVIATION 4.88 • n=7 Participants	23.04 score STANDARD_DEVIATION 4.27 • n=5 Participants
Reasons for Heavy Drinking Questionnaire - Normalizing	9.67 score STANDARD_DEVIATION 7.10 • n=5 Participants	8.29 score STANDARD_DEVIATION 7.34 • n=7 Participants	8.92 score STANDARD_DEVIATION 7.20 • n=5 Participants
Total Drinks	122.89 drinks over prior 30 days STANDARD_DEVIATION 64.58 • n=5 Participants	114.9 drinks over prior 30 days STANDARD_DEVIATION 108.72 • n=7 Participants	118.20 drinks over prior 30 days STANDARD_DEVIATION 90.32 • n=5 Participants
Drinking Days	22.21 number of days in the prior 30 days STANDARD_DEVIATION 6.87 • n=5 Participants	20.25 number of days in the prior 30 days STANDARD_DEVIATION 6.51 • n=7 Participants	21.15 number of days in the prior 30 days STANDARD_DEVIATION 6.68 • n=5 Participants
Drinks Per Day	4.10 average drinks over prior 30 days STANDARD_DEVIATION 2.15 • n=5 Participants	3.81 average drinks over prior 30 days STANDARD_DEVIATION 3.62 • n=7 Participants	3.94 average drinks over prior 30 days STANDARD_DEVIATION 3.01 • n=5 Participants
Heavy Drinking Days	10.79 number of heavy drinking days STANDARD_DEVIATION 8.29 • n=5 Participants	8.68 number of heavy drinking days STANDARD_DEVIATION 8.04 • n=7 Participants	9.65 number of heavy drinking days STANDARD_DEVIATION 8.15 • n=5 Participants
Cigarette Smokers	11 Participants n=5 Participants	14 Participants n=7 Participants	25 Participants n=5 Participants
Fagerstrom Test for Nicotine Dependence Score	2.82 score on scale STANDARD_DEVIATION 2.82 • n=5 Participants	1.07 score on scale STANDARD_DEVIATION 1.54 • n=7 Participants	1.96 score on scale STANDARD_DEVIATION 2.27 • n=5 Participants
Total Cigarettes	52.28 number of cigarettes smoked prior 30 day STANDARD_DEVIATION 79.85 • n=5 Participants	133.07 number of cigarettes smoked prior 30 day STANDARD_DEVIATION 205.78 • n=7 Participants	102.44 number of cigarettes smoked prior 30 day STANDARD_DEVIATION 197.18 • n=5 Participants
Cigarettes Per Day	7.39 cigarettes STANDARD_DEVIATION 8.70 • n=5 Participants	5.06 cigarettes STANDARD_DEVIATION 6.76 • n=7 Participants	6.14 cigarettes STANDARD_DEVIATION 7.73 • n=5 Participants
THC+ Urine	7 Participants n=5 Participants	8 Participants n=7 Participants	15 Participants n=5 Participants
Cannabis Days	11.38 number of days used in prior 30 days STANDARD_DEVIATION 9.99 • n=5 Participants	8.15 number of days used in prior 30 days STANDARD_DEVIATION 8.24 • n=7 Participants	9.64 number of days used in prior 30 days STANDARD_DEVIATION 9.14 • n=5 Participants
Beck Depression Inventory-II Total Score	12.42 score STANDARD_DEVIATION 8.47 • n=5 Participants	8.64 score STANDARD_DEVIATION 7.2 • n=7 Participants	10.38 score STANDARD_DEVIATION 8.27 • n=5 Participants

PRIMARY outcome

Timeframe: Assessed through daily prompts throughout the 2-week study period.

Outcome measures

Outcome measures
Measure	Ibudilast n=24 Participants 20mg BID Days 1-2 50mg BID Days 3-14 Ibudilast: Ibudilast (IBUD) is a neuroimmune modulator that inhibits phosphodiesterase-4 and -10 and macrophage migration inhibitory factor.	Placebo n=28 Participants Matched to active Placebo: Placebo is matched to ibudilast active medication.
Negative Affect	2.91 units Standard Error 0.55	2.47 units Standard Error 0.41

SECONDARY outcome

Timeframe: 14 days

Medication effects on number of heavy drinking days. Heavy drinking is defined by the National Institute on Alcohol Abuse and Alcoholism (NIAAA) as ≥5 drinks/day for men and ≥4 drinks/day for women. Values indicate estimated probability of a heavy drinking day across time for each group.

Outcome measures

Outcome measures
Measure	Ibudilast n=24 Participants 20mg BID Days 1-2 50mg BID Days 3-14 Ibudilast: Ibudilast (IBUD) is a neuroimmune modulator that inhibits phosphodiesterase-4 and -10 and macrophage migration inhibitory factor.	Placebo n=28 Participants Matched to active Placebo: Placebo is matched to ibudilast active medication.
Heavy Drinking	24.16 predicted probability in percent Interval 17.12 to 32.94	36.80 predicted probability in percent Interval 28.43 to 46.05

SECONDARY outcome

Timeframe: 14 days

Medication effects on number of days where any drinking was reported. . Values indicate estimated probability of a drinking day across time for each group.

Outcome measures

Outcome measures
Measure	Ibudilast n=24 Participants 20mg BID Days 1-2 50mg BID Days 3-14 Ibudilast: Ibudilast (IBUD) is a neuroimmune modulator that inhibits phosphodiesterase-4 and -10 and macrophage migration inhibitory factor.	Placebo n=28 Participants Matched to active Placebo: Placebo is matched to ibudilast active medication.
Any Drinking	59.25 predicted probability in percent Interval 47.62 to 69.92	63.63 predicted probability in percent Interval 54.65 to 71.75

SECONDARY outcome

Timeframe: Day 8

Population: Participants were excluded from neuroimaging analyses for the following reasons: participant missed mid-point study visit (n=1, placebo); participant could not be scanned due to COVID-19 safety restrictions (n=1, placebo); participant began scan but ended early due to claustrophobia (n=1, ibudilast); scanner issues prevented the collection of alcohol cue reactivity data (n=1, ibudilast); and participant was found to be not safe for MRI scanning on the day-of the study visit (n=1, ibudilast).

Medication effect on alcohol cue-induced ventral striatal activation. Participants completed an fMRI alcohol cue-reactivity paradigm where they viewed pictures of alcoholic beverages, non-alcoholic beverages, blurred images, and a plus sign. The mean percent signal change between the ALC and BEV blocks was extracted from an a priori defined region of interest: bilateral ventral striatum (VS), 6 mm-radius sphere centered at ±12 6 9 in MNI space.

Outcome measures

Outcome measures
Measure	Ibudilast n=20 Participants 20mg BID Days 1-2 50mg BID Days 3-14 Ibudilast: Ibudilast (IBUD) is a neuroimmune modulator that inhibits phosphodiesterase-4 and -10 and macrophage migration inhibitory factor.	Placebo n=25 Participants Matched to active Placebo: Placebo is matched to ibudilast active medication.
Ventral Striatum Activation	-0.08 percent signal change Standard Deviation 0.20	0.14 percent signal change Standard Deviation 0.32

Adverse Events

Ibudilast

Serious events: 0 serious events

Other events: 14 other events

Deaths: 0 deaths

Placebo

Serious events: 0 serious events

Other events: 18 other events

Deaths: 0 deaths

Serious adverse events

Adverse event data not reported

Other adverse events

Additional Information

Dr. Lara Ray

University of California Los Angeles

Phone: 310-794-5383

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Measure	Ibudilast n=24 participants at risk 20mg BID Days 1-2 50mg BID Days 3-14 Ibudilast: Ibudilast (IBUD) is a neuroimmune modulator that inhibits phosphodiesterase-4 and -10 and macrophage migration inhibitory factor.	Placebo n=28 participants at risk Matched to active Placebo: Placebo is matched to ibudilast active medication.
Gastrointestinal disorders Nausea	25.0% 6/24 • Number of events 6 • 2 weeks Side effects were elicited in open ended fashion and were reviewed by the study physicians (K.M and A.G.). Adverse events were coded using the MedDRA v22.0 coding dictionary. Treatment-emergent adverse events were defined as adverse events that started after the first dose of the study drug or worsened in intensity after the first dose of study drug.	10.7% 3/28 • Number of events 3 • 2 weeks Side effects were elicited in open ended fashion and were reviewed by the study physicians (K.M and A.G.). Adverse events were coded using the MedDRA v22.0 coding dictionary. Treatment-emergent adverse events were defined as adverse events that started after the first dose of the study drug or worsened in intensity after the first dose of study drug.
Gastrointestinal disorders Vomiting	4.2% 1/24 • Number of events 1 • 2 weeks Side effects were elicited in open ended fashion and were reviewed by the study physicians (K.M and A.G.). Adverse events were coded using the MedDRA v22.0 coding dictionary. Treatment-emergent adverse events were defined as adverse events that started after the first dose of the study drug or worsened in intensity after the first dose of study drug.	3.6% 1/28 • Number of events 1 • 2 weeks Side effects were elicited in open ended fashion and were reviewed by the study physicians (K.M and A.G.). Adverse events were coded using the MedDRA v22.0 coding dictionary. Treatment-emergent adverse events were defined as adverse events that started after the first dose of the study drug or worsened in intensity after the first dose of study drug.
Gastrointestinal disorders Diarrhea	4.2% 1/24 • Number of events 1 • 2 weeks Side effects were elicited in open ended fashion and were reviewed by the study physicians (K.M and A.G.). Adverse events were coded using the MedDRA v22.0 coding dictionary. Treatment-emergent adverse events were defined as adverse events that started after the first dose of the study drug or worsened in intensity after the first dose of study drug.	0.00% 0/28 • 2 weeks Side effects were elicited in open ended fashion and were reviewed by the study physicians (K.M and A.G.). Adverse events were coded using the MedDRA v22.0 coding dictionary. Treatment-emergent adverse events were defined as adverse events that started after the first dose of the study drug or worsened in intensity after the first dose of study drug.
Gastrointestinal disorders Dyspepsia	4.2% 1/24 • Number of events 1 • 2 weeks Side effects were elicited in open ended fashion and were reviewed by the study physicians (K.M and A.G.). Adverse events were coded using the MedDRA v22.0 coding dictionary. Treatment-emergent adverse events were defined as adverse events that started after the first dose of the study drug or worsened in intensity after the first dose of study drug.	7.1% 2/28 • Number of events 2 • 2 weeks Side effects were elicited in open ended fashion and were reviewed by the study physicians (K.M and A.G.). Adverse events were coded using the MedDRA v22.0 coding dictionary. Treatment-emergent adverse events were defined as adverse events that started after the first dose of the study drug or worsened in intensity after the first dose of study drug.
Gastrointestinal disorders Frequent Bowel Movements	4.2% 1/24 • Number of events 1 • 2 weeks Side effects were elicited in open ended fashion and were reviewed by the study physicians (K.M and A.G.). Adverse events were coded using the MedDRA v22.0 coding dictionary. Treatment-emergent adverse events were defined as adverse events that started after the first dose of the study drug or worsened in intensity after the first dose of study drug.	0.00% 0/28 • 2 weeks Side effects were elicited in open ended fashion and were reviewed by the study physicians (K.M and A.G.). Adverse events were coded using the MedDRA v22.0 coding dictionary. Treatment-emergent adverse events were defined as adverse events that started after the first dose of the study drug or worsened in intensity after the first dose of study drug.
General disorders Gut pain	0.00% 0/24 • 2 weeks Side effects were elicited in open ended fashion and were reviewed by the study physicians (K.M and A.G.). Adverse events were coded using the MedDRA v22.0 coding dictionary. Treatment-emergent adverse events were defined as adverse events that started after the first dose of the study drug or worsened in intensity after the first dose of study drug.	3.6% 1/28 • Number of events 1 • 2 weeks Side effects were elicited in open ended fashion and were reviewed by the study physicians (K.M and A.G.). Adverse events were coded using the MedDRA v22.0 coding dictionary. Treatment-emergent adverse events were defined as adverse events that started after the first dose of the study drug or worsened in intensity after the first dose of study drug.
Nervous system disorders Dizziness	0.00% 0/24 • 2 weeks Side effects were elicited in open ended fashion and were reviewed by the study physicians (K.M and A.G.). Adverse events were coded using the MedDRA v22.0 coding dictionary. Treatment-emergent adverse events were defined as adverse events that started after the first dose of the study drug or worsened in intensity after the first dose of study drug.	3.6% 1/28 • Number of events 1 • 2 weeks Side effects were elicited in open ended fashion and were reviewed by the study physicians (K.M and A.G.). Adverse events were coded using the MedDRA v22.0 coding dictionary. Treatment-emergent adverse events were defined as adverse events that started after the first dose of the study drug or worsened in intensity after the first dose of study drug.
Nervous system disorders Headache	4.2% 1/24 • Number of events 1 • 2 weeks Side effects were elicited in open ended fashion and were reviewed by the study physicians (K.M and A.G.). Adverse events were coded using the MedDRA v22.0 coding dictionary. Treatment-emergent adverse events were defined as adverse events that started after the first dose of the study drug or worsened in intensity after the first dose of study drug.	3.6% 1/28 • Number of events 1 • 2 weeks Side effects were elicited in open ended fashion and were reviewed by the study physicians (K.M and A.G.). Adverse events were coded using the MedDRA v22.0 coding dictionary. Treatment-emergent adverse events were defined as adverse events that started after the first dose of the study drug or worsened in intensity after the first dose of study drug.
Nervous system disorders Disorientation	4.2% 1/24 • Number of events 1 • 2 weeks Side effects were elicited in open ended fashion and were reviewed by the study physicians (K.M and A.G.). Adverse events were coded using the MedDRA v22.0 coding dictionary. Treatment-emergent adverse events were defined as adverse events that started after the first dose of the study drug or worsened in intensity after the first dose of study drug.	0.00% 0/28 • 2 weeks Side effects were elicited in open ended fashion and were reviewed by the study physicians (K.M and A.G.). Adverse events were coded using the MedDRA v22.0 coding dictionary. Treatment-emergent adverse events were defined as adverse events that started after the first dose of the study drug or worsened in intensity after the first dose of study drug.
Nervous system disorders Blurred Vision	4.2% 1/24 • Number of events 1 • 2 weeks Side effects were elicited in open ended fashion and were reviewed by the study physicians (K.M and A.G.). Adverse events were coded using the MedDRA v22.0 coding dictionary. Treatment-emergent adverse events were defined as adverse events that started after the first dose of the study drug or worsened in intensity after the first dose of study drug.	0.00% 0/28 • 2 weeks Side effects were elicited in open ended fashion and were reviewed by the study physicians (K.M and A.G.). Adverse events were coded using the MedDRA v22.0 coding dictionary. Treatment-emergent adverse events were defined as adverse events that started after the first dose of the study drug or worsened in intensity after the first dose of study drug.
Nervous system disorders Somnolence	0.00% 0/24 • 2 weeks Side effects were elicited in open ended fashion and were reviewed by the study physicians (K.M and A.G.). Adverse events were coded using the MedDRA v22.0 coding dictionary. Treatment-emergent adverse events were defined as adverse events that started after the first dose of the study drug or worsened in intensity after the first dose of study drug.	3.6% 1/28 • Number of events 1 • 2 weeks Side effects were elicited in open ended fashion and were reviewed by the study physicians (K.M and A.G.). Adverse events were coded using the MedDRA v22.0 coding dictionary. Treatment-emergent adverse events were defined as adverse events that started after the first dose of the study drug or worsened in intensity after the first dose of study drug.
Nervous system disorders Insomnia	8.3% 2/24 • Number of events 2 • 2 weeks Side effects were elicited in open ended fashion and were reviewed by the study physicians (K.M and A.G.). Adverse events were coded using the MedDRA v22.0 coding dictionary. Treatment-emergent adverse events were defined as adverse events that started after the first dose of the study drug or worsened in intensity after the first dose of study drug.	3.6% 1/28 • Number of events 1 • 2 weeks Side effects were elicited in open ended fashion and were reviewed by the study physicians (K.M and A.G.). Adverse events were coded using the MedDRA v22.0 coding dictionary. Treatment-emergent adverse events were defined as adverse events that started after the first dose of the study drug or worsened in intensity after the first dose of study drug.
Psychiatric disorders Libido Increased	0.00% 0/24 • 2 weeks Side effects were elicited in open ended fashion and were reviewed by the study physicians (K.M and A.G.). Adverse events were coded using the MedDRA v22.0 coding dictionary. Treatment-emergent adverse events were defined as adverse events that started after the first dose of the study drug or worsened in intensity after the first dose of study drug.	3.6% 1/28 • Number of events 1 • 2 weeks Side effects were elicited in open ended fashion and were reviewed by the study physicians (K.M and A.G.). Adverse events were coded using the MedDRA v22.0 coding dictionary. Treatment-emergent adverse events were defined as adverse events that started after the first dose of the study drug or worsened in intensity after the first dose of study drug.
Psychiatric disorders Depression	0.00% 0/24 • 2 weeks Side effects were elicited in open ended fashion and were reviewed by the study physicians (K.M and A.G.). Adverse events were coded using the MedDRA v22.0 coding dictionary. Treatment-emergent adverse events were defined as adverse events that started after the first dose of the study drug or worsened in intensity after the first dose of study drug.	10.7% 3/28 • Number of events 3 • 2 weeks Side effects were elicited in open ended fashion and were reviewed by the study physicians (K.M and A.G.). Adverse events were coded using the MedDRA v22.0 coding dictionary. Treatment-emergent adverse events were defined as adverse events that started after the first dose of the study drug or worsened in intensity after the first dose of study drug.
Psychiatric disorders Anxiety	8.3% 2/24 • Number of events 2 • 2 weeks Side effects were elicited in open ended fashion and were reviewed by the study physicians (K.M and A.G.). Adverse events were coded using the MedDRA v22.0 coding dictionary. Treatment-emergent adverse events were defined as adverse events that started after the first dose of the study drug or worsened in intensity after the first dose of study drug.	3.6% 1/28 • Number of events 1 • 2 weeks Side effects were elicited in open ended fashion and were reviewed by the study physicians (K.M and A.G.). Adverse events were coded using the MedDRA v22.0 coding dictionary. Treatment-emergent adverse events were defined as adverse events that started after the first dose of the study drug or worsened in intensity after the first dose of study drug.
Psychiatric disorders Grief Reaction	0.00% 0/24 • 2 weeks Side effects were elicited in open ended fashion and were reviewed by the study physicians (K.M and A.G.). Adverse events were coded using the MedDRA v22.0 coding dictionary. Treatment-emergent adverse events were defined as adverse events that started after the first dose of the study drug or worsened in intensity after the first dose of study drug.	3.6% 1/28 • Number of events 1 • 2 weeks Side effects were elicited in open ended fashion and were reviewed by the study physicians (K.M and A.G.). Adverse events were coded using the MedDRA v22.0 coding dictionary. Treatment-emergent adverse events were defined as adverse events that started after the first dose of the study drug or worsened in intensity after the first dose of study drug.
Psychiatric disorders Irritability	4.2% 1/24 • Number of events 1 • 2 weeks Side effects were elicited in open ended fashion and were reviewed by the study physicians (K.M and A.G.). Adverse events were coded using the MedDRA v22.0 coding dictionary. Treatment-emergent adverse events were defined as adverse events that started after the first dose of the study drug or worsened in intensity after the first dose of study drug.	3.6% 1/28 • Number of events 1 • 2 weeks Side effects were elicited in open ended fashion and were reviewed by the study physicians (K.M and A.G.). Adverse events were coded using the MedDRA v22.0 coding dictionary. Treatment-emergent adverse events were defined as adverse events that started after the first dose of the study drug or worsened in intensity after the first dose of study drug.
Respiratory, thoracic and mediastinal disorders Cold (Influenza)	8.3% 2/24 • Number of events 2 • 2 weeks Side effects were elicited in open ended fashion and were reviewed by the study physicians (K.M and A.G.). Adverse events were coded using the MedDRA v22.0 coding dictionary. Treatment-emergent adverse events were defined as adverse events that started after the first dose of the study drug or worsened in intensity after the first dose of study drug.	7.1% 2/28 • Number of events 2 • 2 weeks Side effects were elicited in open ended fashion and were reviewed by the study physicians (K.M and A.G.). Adverse events were coded using the MedDRA v22.0 coding dictionary. Treatment-emergent adverse events were defined as adverse events that started after the first dose of the study drug or worsened in intensity after the first dose of study drug.
Respiratory, thoracic and mediastinal disorders Asthmatic Crisis	4.2% 1/24 • Number of events 1 • 2 weeks Side effects were elicited in open ended fashion and were reviewed by the study physicians (K.M and A.G.). Adverse events were coded using the MedDRA v22.0 coding dictionary. Treatment-emergent adverse events were defined as adverse events that started after the first dose of the study drug or worsened in intensity after the first dose of study drug.	0.00% 0/28 • 2 weeks Side effects were elicited in open ended fashion and were reviewed by the study physicians (K.M and A.G.). Adverse events were coded using the MedDRA v22.0 coding dictionary. Treatment-emergent adverse events were defined as adverse events that started after the first dose of the study drug or worsened in intensity after the first dose of study drug.
General disorders Cold Sweat	4.2% 1/24 • Number of events 1 • 2 weeks Side effects were elicited in open ended fashion and were reviewed by the study physicians (K.M and A.G.). Adverse events were coded using the MedDRA v22.0 coding dictionary. Treatment-emergent adverse events were defined as adverse events that started after the first dose of the study drug or worsened in intensity after the first dose of study drug.	0.00% 0/28 • 2 weeks Side effects were elicited in open ended fashion and were reviewed by the study physicians (K.M and A.G.). Adverse events were coded using the MedDRA v22.0 coding dictionary. Treatment-emergent adverse events were defined as adverse events that started after the first dose of the study drug or worsened in intensity after the first dose of study drug.
General disorders Lethargy	4.2% 1/24 • Number of events 1 • 2 weeks Side effects were elicited in open ended fashion and were reviewed by the study physicians (K.M and A.G.). Adverse events were coded using the MedDRA v22.0 coding dictionary. Treatment-emergent adverse events were defined as adverse events that started after the first dose of the study drug or worsened in intensity after the first dose of study drug.	3.6% 1/28 • Number of events 1 • 2 weeks Side effects were elicited in open ended fashion and were reviewed by the study physicians (K.M and A.G.). Adverse events were coded using the MedDRA v22.0 coding dictionary. Treatment-emergent adverse events were defined as adverse events that started after the first dose of the study drug or worsened in intensity after the first dose of study drug.