Trial Outcomes & Findings for Combining Lovastatin and a Parent-Implemented Language Intervention for Fragile X Syndrome (NCT NCT02642653)

Last Updated: 2019-09-11

Results Overview

The primary outcome reflects the diversity of vocabulary used. Higher scores reflect more skill. The lowest possible value is zero. No theoretical maximum can be defined because the wordless picture books can lead to a large and indeterminate set of options for the amount of talk and the vocabulary used. In a previous study of a nonpharmacological intervention, the range at baseline was 9-177, and at post-treatment, the range for the combined treated and nontreated groups was 23-214, although these values were not corrected for the number of C-units produced (McDuffie at el. 2018 Developmental Neurorehabilitation).

Recruitment status

COMPLETED

Study phase

PHASE4

Target enrollment

30 participants

Primary outcome timeframe

Baseline

Results posted on

2019-09-11

Participant Flow

Participant milestones

Participant milestones
Measure	Lovastatin and PILI Subjects will receive the Parent Implemented Language Intervention (PILI) in combination with study medication Lovastatin. Lovastatin: Once per day dosing	Placebo and PILI Subjects will receive the Parent Implemented Language Intervention (PILI) in combination with placebo. Placebo: Once per day dosing
Overall Study STARTED	14	16
Overall Study COMPLETED	12	16
Overall Study NOT COMPLETED	2	0

Reasons for withdrawal

Reasons for withdrawal
Measure	Lovastatin and PILI Subjects will receive the Parent Implemented Language Intervention (PILI) in combination with study medication Lovastatin. Lovastatin: Once per day dosing	Placebo and PILI Subjects will receive the Parent Implemented Language Intervention (PILI) in combination with placebo. Placebo: Once per day dosing
Overall Study Adverse Event	2	0

Baseline Characteristics

Combining Lovastatin and a Parent-Implemented Language Intervention for Fragile X Syndrome

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Lovastatin and PILI n=14 Participants Subjects will receive the Parent Implemented Language Intervention (PILI) in combination with study medication Lovastatin. Lovastatin: Once per day dosing	Placebo and PILI n=16 Participants Subjects will receive the Parent Implemented Language Intervention (PILI) in combination with placebo. Placebo: Once per day dosing	Total n=30 Participants Total of all reporting groups
Age, Categorical <=18 years	14 Participants n=5 Participants	16 Participants n=7 Participants	30 Participants n=5 Participants
Age, Categorical Between 18 and 65 years	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Age, Categorical >=65 years	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Age, Continuous	13.86 years STANDARD_DEVIATION 2.14 • n=5 Participants	13.17 years STANDARD_DEVIATION 2.54 • n=7 Participants	13.52 years STANDARD_DEVIATION 2.34 • n=5 Participants
Sex: Female, Male Female	2 Participants n=5 Participants	0 Participants n=7 Participants	2 Participants n=5 Participants
Sex: Female, Male Male	12 Participants n=5 Participants	16 Participants n=7 Participants	28 Participants n=5 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	0 Participants n=5 Participants	4 Participants n=7 Participants	4 Participants n=5 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	14 Participants n=5 Participants	12 Participants n=7 Participants	26 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	1 Participants n=7 Participants	1 Participants n=5 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Black or African American	0 Participants n=5 Participants	1 Participants n=7 Participants	1 Participants n=5 Participants
Race (NIH/OMB) White	14 Participants n=5 Participants	10 Participants n=7 Participants	24 Participants n=5 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants	4 Participants n=7 Participants	4 Participants n=5 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Region of Enrollment United States	14 participants n=5 Participants	16 participants n=7 Participants	30 participants n=5 Participants
Intelligence Quotient (IQ)	44.00 units on a scale STANDARD_DEVIATION 9.22 • n=5 Participants	43.13 units on a scale STANDARD_DEVIATION 6.24 • n=7 Participants	43.57 units on a scale STANDARD_DEVIATION 7.73 • n=5 Participants
Cognitive growth score	461.4 units on a scale STANDARD_DEVIATION 13.32 • n=5 Participants	462.3 units on a scale STANDARD_DEVIATION 8.57 • n=7 Participants	461.85 units on a scale STANDARD_DEVIATION 10.95 • n=5 Participants
Autism Diagnostic Observation Scale (ADOS) severity score	6.85 units on a scale STANDARD_DEVIATION 2.54 • n=5 Participants	6.75 units on a scale STANDARD_DEVIATION 2.05 • n=7 Participants	6.80 units on a scale STANDARD_DEVIATION 2.30 • n=5 Participants

PRIMARY outcome

Timeframe: Baseline

Outcome measures

Outcome measures
Measure	Lovastatin and PILI n=12 Participants Subjects will receive the Parent Implemented Language Intervention (PILI) in combination with study medication Lovastatin. Lovastatin: Once per day dosing	Placebo and PILI n=16 Participants Subjects will receive the Parent Implemented Language Intervention (PILI) in combination with placebo. Placebo: Once per day dosing
Expressive Language Sample Composite Score in the Home	39.63 score on a scale Standard Deviation 32.41	42.47 score on a scale Standard Deviation 18.60

PRIMARY outcome

Timeframe: 20 weeks

Outcome measures

Outcome measures
Measure	Lovastatin and PILI n=12 Participants Subjects will receive the Parent Implemented Language Intervention (PILI) in combination with study medication Lovastatin. Lovastatin: Once per day dosing	Placebo and PILI n=16 Participants Subjects will receive the Parent Implemented Language Intervention (PILI) in combination with placebo. Placebo: Once per day dosing
Expressive Language Sample Composite Score in the Home	59.32 score on a scale Standard Deviation 22.81	54.81 score on a scale Standard Deviation 16.04

SECONDARY outcome

Timeframe: Baseline

The ABC-C is a 58-item caregiver-rated behavior scale used to examine treatment effects on challenging behaviors for individuals with FXS in the following domains: (1) irritability; (2) lethargy/social withdrawal; (3) stereotypic behavior; (4) hyperactivity; and (5) inappropriate speech. Caregiver rates the subject's behavior as follows: 0 = not a problem, l = the behavior is a problem but slight in degree, 2 = the problem is moderately serious, 3 = the problem is severe in degree. Sansone et al. (2012) further subdivided social withdrawal to rate social avoidance in FXS. The subscale includes 4 items which were originally part of the Lethargy/Withdrawal subscale. This subscale captures core aspects of the FXS phenotype related to gaze avoidance, social ''escape'' behaviors, and social anxiety. Subscale score ranges from 0 to 12, higher scores reflect a more problematic behavior.

Outcome measures

Outcome measures
Measure	Lovastatin and PILI n=12 Participants Subjects will receive the Parent Implemented Language Intervention (PILI) in combination with study medication Lovastatin. Lovastatin: Once per day dosing	Placebo and PILI n=16 Participants Subjects will receive the Parent Implemented Language Intervention (PILI) in combination with placebo. Placebo: Once per day dosing
FXS- Normed Aberrant Behavior Checklist (ABC) Social Avoidance Subscale	2.5 score on a scale Standard Deviation 2.84	4.31 score on a scale Standard Deviation 3.66

SECONDARY outcome

Timeframe: 10 weeks

Outcome measures

Outcome measures
Measure	Lovastatin and PILI n=12 Participants Subjects will receive the Parent Implemented Language Intervention (PILI) in combination with study medication Lovastatin. Lovastatin: Once per day dosing	Placebo and PILI n=16 Participants Subjects will receive the Parent Implemented Language Intervention (PILI) in combination with placebo. Placebo: Once per day dosing
FXS- Normed Aberrant Behavior Checklist (ABC) Social Avoidance Subscale	2.5 score on a scale Standard Deviation 2.11	3.53 score on a scale Standard Deviation 3.68

SECONDARY outcome

Timeframe: 20 weeks

Outcome measures

Outcome measures
Measure	Lovastatin and PILI n=12 Participants Subjects will receive the Parent Implemented Language Intervention (PILI) in combination with study medication Lovastatin. Lovastatin: Once per day dosing	Placebo and PILI n=16 Participants Subjects will receive the Parent Implemented Language Intervention (PILI) in combination with placebo. Placebo: Once per day dosing
FXS- Normed Aberrant Behavior Checklist (ABC) Social Avoidance Subscale	2.42 score on a scale Standard Deviation 2.84	3.38 score on a scale Standard Deviation 3.34

SECONDARY outcome

Timeframe: Baseline

A clinician rated scale utilizing history from the parents or caregiver and incorporating it into a clinical rating for severity. The CGI-S was used at the pre-treatment assessment to judge symptom severity. The 7-point scale ranges from: 1 = Normal; 2 = Borderline Ill; 3 = Mildly Ill; 4 = Moderately Ill; 5 = Markedly Ill; 6 = Severely Ill; and 7 = Extremely Ill. Therefore, the higher the score, the greater the severity of the patient's illness. Shown here are the CGI-S mean scores from the baseline visit.

Outcome measures

Outcome measures
Measure	Lovastatin and PILI n=12 Participants Subjects will receive the Parent Implemented Language Intervention (PILI) in combination with study medication Lovastatin. Lovastatin: Once per day dosing	Placebo and PILI n=16 Participants Subjects will receive the Parent Implemented Language Intervention (PILI) in combination with placebo. Placebo: Once per day dosing
Clinical Global Impression- Severity (CGI-S)	4.58 units on a scale Standard Deviation 0.67	4.50 units on a scale Standard Deviation 0.63

SECONDARY outcome

Timeframe: 10 weeks

A clinician rated scale utilizing history from the parents or caregiver and incorporating it into a clinical rating to assess for overall therapeutic response. The 7-point scale ranges from: 1 = Very much improved; 2 = Much improved; 3 = Minimally improved; 4 = No change; 5 = Minimally worse; 6 = Much worse; and 7 = Very much worse. Therefore, the lower the score, the greater the overall improvement as rated by the clinician. The CGI-I was used at the 10 week and 20 week visits. Shown here are the CGI-I mean scores from the 10-weeks end-of-study visit.

Outcome measures

Outcome measures
Measure	Lovastatin and PILI n=12 Participants Subjects will receive the Parent Implemented Language Intervention (PILI) in combination with study medication Lovastatin. Lovastatin: Once per day dosing	Placebo and PILI n=16 Participants Subjects will receive the Parent Implemented Language Intervention (PILI) in combination with placebo. Placebo: Once per day dosing
Clinical Global Impression-Improvement (CGI-I) Scale	2.92 units on a scale Standard Deviation 0.79	3.00 units on a scale Standard Deviation 0.73

SECONDARY outcome

Timeframe: 20 weeks

Outcome measures

Outcome measures
Measure	Lovastatin and PILI n=12 Participants Subjects will receive the Parent Implemented Language Intervention (PILI) in combination with study medication Lovastatin. Lovastatin: Once per day dosing	Placebo and PILI n=16 Participants Subjects will receive the Parent Implemented Language Intervention (PILI) in combination with placebo. Placebo: Once per day dosing
Clinical Global Impression-Improvement (CGI-I) Scale	2.42 units on a scale Standard Deviation 0.67	2.38 units on a scale Standard Deviation 0.72

SECONDARY outcome

Timeframe: Baseline

The measure was used to assess parental impressions of progress in two key symptoms: spoken language impairment and social impairment. The distance of the mark from one end is used as the outcome variable for analysis. Caregivers mark on a visual line measuring 10 cm with "worst behavior" at 0 cm and "best behavior" at 10 cm. For each behavior the caregiver is instructed to mark their impression of the behavior at baseline visit and again at the 10-weeks and 20-weeks visits. The calculated distance in cm between the marks drawn at the baseline and follow-up visits thereby demonstrates whether each behavior improved, worsened, or stayed the same during the study, and by how much. Shown here is the mean distance in cm from the "worst behavior" side for the Spoken Language Impairment scale, at baseline. The smaller the value, the worse the behavior. The range is minimum 0 cm to maximum 10 cm.

Outcome measures

Outcome measures
Measure	Lovastatin and PILI n=12 Participants Subjects will receive the Parent Implemented Language Intervention (PILI) in combination with study medication Lovastatin. Lovastatin: Once per day dosing	Placebo and PILI n=16 Participants Subjects will receive the Parent Implemented Language Intervention (PILI) in combination with placebo. Placebo: Once per day dosing
Visual Analog Scale (VAS) - Spoken Language Impairment	4.06 centimeters Standard Deviation 2.43	1.94 centimeters Standard Deviation 1.41

SECONDARY outcome

Timeframe: 10 weeks

The measure was used to assess parental impressions of progress in two key symptoms: spoken language impairment and social impairment. The distance of the mark from one end is used as the outcome variable for analysis. Caregivers mark on a visual line measuring 10 cm with "worst behavior" at 0 cm and "best behavior" at 10 cm. For each behavior the caregiver is instructed to mark their impression of the behavior at baseline visit and again at the 10-weeks and 20-weeks visits. The calculated distance in cm between the marks drawn at the baseline and follow-up visits thereby demonstrates whether each behavior improved, worsened, or stayed the same during the study, and by how much. Shown here is the mean distance in cm from the "worst behavior" side for the Spoken Language Impairment scale, at 10-weeks. The smaller the value, the worse the behavior. The range is minimum 0 cm to maximum 10 cm.

Outcome measures

Outcome measures
Measure	Lovastatin and PILI n=12 Participants Subjects will receive the Parent Implemented Language Intervention (PILI) in combination with study medication Lovastatin. Lovastatin: Once per day dosing	Placebo and PILI n=16 Participants Subjects will receive the Parent Implemented Language Intervention (PILI) in combination with placebo. Placebo: Once per day dosing
Visual Analog Scale (VAS) - Spoken Language Impairment	5.28 centimeters Standard Deviation 2.69	3.09 centimeters Standard Deviation 1.14

SECONDARY outcome

Timeframe: 20 weeks

The measure was used to assess parental impressions of progress in two key symptoms: spoken language impairment and social impairment. The distance of the mark from one end is used as the outcome variable for analysis. Caregivers mark on a visual line measuring 10 cm with "worst behavior" at 0 cm and "best behavior" at 10 cm. For each behavior the caregiver is instructed to mark their impression of the behavior at baseline visit and again at the 10-weeks and 20-weeks visits. The calculated distance in cm between the marks drawn at the baseline and follow-up visits thereby demonstrates whether each behavior improved, worsened, or stayed the same during the study, and by how much. Shown here is the mean distance in cm from the "worst behavior" side for the Spoken Language Impairment scale, at 20-weeks. The smaller the value, the worse the behavior. The range is minimum 0 cm to maximum 10 cm.

Outcome measures

Outcome measures
Measure	Lovastatin and PILI n=12 Participants Subjects will receive the Parent Implemented Language Intervention (PILI) in combination with study medication Lovastatin. Lovastatin: Once per day dosing	Placebo and PILI n=16 Participants Subjects will receive the Parent Implemented Language Intervention (PILI) in combination with placebo. Placebo: Once per day dosing
Visual Analog Scale (VAS) - Spoken Language Impairment	5.66 centimeters Standard Deviation 1.99	4.18 centimeters Standard Deviation 1.53

SECONDARY outcome

Timeframe: Baseline

The measure was used to assess parental impressions of progress in two key symptoms: spoken language impairment and social impairment. The distance of the mark from one end is used as the outcome variable for analysis. Caregivers mark on a visual line measuring 10 cm with "worst behavior" at 0 cm and "best behavior" at 10 cm. For each behavior the caregiver is instructed to mark their impression of the behavior at baseline visit and again at the 10-weeks and 20-weeks visits. The calculated distance in cm between the marks drawn at the baseline and follow-up visits thereby demonstrates whether each behavior improved, worsened, or stayed the same during the study, and by how much. Shown here is the mean distance in cm from the "worst behavior" side for the Social Impairment scale, at baseline. The smaller the value, the worse the behavior. The range is minimum 0 cm to maximum 10 cm.

Outcome measures

Outcome measures
Measure	Lovastatin and PILI n=12 Participants Subjects will receive the Parent Implemented Language Intervention (PILI) in combination with study medication Lovastatin. Lovastatin: Once per day dosing	Placebo and PILI n=16 Participants Subjects will receive the Parent Implemented Language Intervention (PILI) in combination with placebo. Placebo: Once per day dosing
Visual Analog Scale (VAS) - Social Impairment	3.73 centimeters Standard Deviation 1.74	2.55 centimeters Standard Deviation 1.36

SECONDARY outcome

Timeframe: 10-weeks

The measure was used to assess parental impressions of progress in two key symptoms: spoken language impairment and social impairment. The distance of the mark from one end is used as the outcome variable for analysis. Caregivers mark on a visual line measuring 10 cm with "worst behavior" at 0 cm and "best behavior" at 10 cm. For each behavior the caregiver is instructed to mark their impression of the behavior at baseline visit and again at the 10-weeks and 20-weeks visits. The calculated distance in cm between the marks drawn at the baseline and follow-up visits thereby demonstrates whether each behavior improved, worsened, or stayed the same during the study, and by how much. Shown here is the mean distance in cm from the "worst behavior" side for the Social Impairment scale, at 10-weeks. The smaller the value, the worse the behavior. The range is minimum 0 cm to maximum 10 cm.

Outcome measures

Outcome measures
Measure	Lovastatin and PILI n=12 Participants Subjects will receive the Parent Implemented Language Intervention (PILI) in combination with study medication Lovastatin. Lovastatin: Once per day dosing	Placebo and PILI n=16 Participants Subjects will receive the Parent Implemented Language Intervention (PILI) in combination with placebo. Placebo: Once per day dosing
Visual Analog Scale (VAS) - Social Impairment	4.57 centimeters Standard Deviation 2.15	3.41 centimeters Standard Deviation 1.61

SECONDARY outcome

Timeframe: 20-weeks

The measure was used to assess parental impressions of progress in two key symptoms: spoken language impairment and social impairment. The distance of the mark from one end is used as the outcome variable for analysis. Caregivers mark on a visual line measuring 10 cm with "worst behavior" at 0 cm and "best behavior" at 10 cm. For each behavior the caregiver is instructed to mark their impression of the behavior at baseline visit and again at the 10-weeks and 20-weeks visits. The calculated distance in cm between the marks drawn at the baseline and follow-up visits thereby demonstrates whether each behavior improved, worsened, or stayed the same during the study, and by how much. Shown here is the mean distance in cm from the "worst behavior" side for the Social Impairment scale, at 20-weeks. The smaller the value, the worse the behavior. The range is minimum 0 cm to maximum 10 cm.

Outcome measures

Outcome measures
Measure	Lovastatin and PILI n=12 Participants Subjects will receive the Parent Implemented Language Intervention (PILI) in combination with study medication Lovastatin. Lovastatin: Once per day dosing	Placebo and PILI n=16 Participants Subjects will receive the Parent Implemented Language Intervention (PILI) in combination with placebo. Placebo: Once per day dosing
Visual Analog Scale (VAS) - Social Impairment	5.18 centimeters Standard Deviation 1.70	3.99 centimeters Standard Deviation 2.06

Adverse Events

Lovastatin and PILI

Serious events: 0 serious events

Other events: 11 other events

Deaths: 0 deaths

Placebo and PILI

Serious events: 0 serious events

Other events: 13 other events

Deaths: 0 deaths

Serious adverse events

Adverse event data not reported

Other adverse events

Additional Information

Dr. Randi Hagerman

University of California Davis

Phone: 9167030247

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Measure	Lovastatin and PILI n=12 participants at risk Subjects will receive the Parent Implemented Language Intervention (PILI) in combination with study medication Lovastatin. Lovastatin: Once per day dosing	Placebo and PILI n=16 participants at risk Subjects will receive the Parent Implemented Language Intervention (PILI) in combination with placebo. Placebo: Once per day dosing
Psychiatric disorders Abnormal vocalizations	8.3% 1/12 • Number of events 1 • From baseline to follow-up (20-weeks)	6.2% 1/16 • Number of events 1 • From baseline to follow-up (20-weeks)
Psychiatric disorders Agitation	0.00% 0/12 • From baseline to follow-up (20-weeks)	6.2% 1/16 • Number of events 1 • From baseline to follow-up (20-weeks)
Psychiatric disorders Anxiety	8.3% 1/12 • Number of events 1 • From baseline to follow-up (20-weeks)	6.2% 1/16 • Number of events 1 • From baseline to follow-up (20-weeks)
Gastrointestinal disorders Decreased Appetite	0.00% 0/12 • From baseline to follow-up (20-weeks)	18.8% 3/16 • Number of events 3 • From baseline to follow-up (20-weeks)
Gastrointestinal disorders Diarrhea	8.3% 1/12 • Number of events 1 • From baseline to follow-up (20-weeks)	12.5% 2/16 • Number of events 3 • From baseline to follow-up (20-weeks)
Psychiatric disorders Disruptive behavior	8.3% 1/12 • Number of events 1 • From baseline to follow-up (20-weeks)	0.00% 0/16 • From baseline to follow-up (20-weeks)
Nervous system disorders Dizziness	0.00% 0/12 • From baseline to follow-up (20-weeks)	6.2% 1/16 • Number of events 1 • From baseline to follow-up (20-weeks)
Nervous system disorders Dry Mouth	0.00% 0/12 • From baseline to follow-up (20-weeks)	6.2% 1/16 • Number of events 1 • From baseline to follow-up (20-weeks)
Infections and infestations Ear infection	0.00% 0/12 • From baseline to follow-up (20-weeks)	6.2% 1/16 • Number of events 1 • From baseline to follow-up (20-weeks)
Hepatobiliary disorders Elevated Bilirubin	0.00% 0/12 • From baseline to follow-up (20-weeks)	6.2% 1/16 • Number of events 1 • From baseline to follow-up (20-weeks)
Psychiatric disorders Emotional Lability	0.00% 0/12 • From baseline to follow-up (20-weeks)	12.5% 2/16 • Number of events 2 • From baseline to follow-up (20-weeks)
Blood and lymphatic system disorders Epistaxis	8.3% 1/12 • Number of events 1 • From baseline to follow-up (20-weeks)	6.2% 1/16 • Number of events 1 • From baseline to follow-up (20-weeks)
Eye disorders Eye Infection	0.00% 0/12 • From baseline to follow-up (20-weeks)	6.2% 1/16 • Number of events 2 • From baseline to follow-up (20-weeks)
General disorders Fatigue	0.00% 0/12 • From baseline to follow-up (20-weeks)	6.2% 1/16 • Number of events 1 • From baseline to follow-up (20-weeks)
General disorders Fever	8.3% 1/12 • Number of events 2 • From baseline to follow-up (20-weeks)	0.00% 0/16 • From baseline to follow-up (20-weeks)
Gastrointestinal disorders Gastrointestinal issues	16.7% 2/12 • Number of events 2 • From baseline to follow-up (20-weeks)	25.0% 4/16 • Number of events 5 • From baseline to follow-up (20-weeks)
Nervous system disorders Headache	8.3% 1/12 • Number of events 1 • From baseline to follow-up (20-weeks)	12.5% 2/16 • Number of events 2 • From baseline to follow-up (20-weeks)
Psychiatric disorders Hyperactivity	16.7% 2/12 • Number of events 2 • From baseline to follow-up (20-weeks)	0.00% 0/16 • From baseline to follow-up (20-weeks)
Renal and urinary disorders Incontinence	8.3% 1/12 • Number of events 1 • From baseline to follow-up (20-weeks)	0.00% 0/16 • From baseline to follow-up (20-weeks)
Psychiatric disorders Insomnia	0.00% 0/12 • From baseline to follow-up (20-weeks)	6.2% 1/16 • Number of events 1 • From baseline to follow-up (20-weeks)
Psychiatric disorders Irritability	0.00% 0/12 • From baseline to follow-up (20-weeks)	6.2% 1/16 • Number of events 1 • From baseline to follow-up (20-weeks)
Skin and subcutaneous tissue disorders Itchiness	0.00% 0/12 • From baseline to follow-up (20-weeks)	12.5% 2/16 • Number of events 3 • From baseline to follow-up (20-weeks)
Reproductive system and breast disorders Menstrual Cramps	8.3% 1/12 • Number of events 1 • From baseline to follow-up (20-weeks)	0.00% 0/16 • From baseline to follow-up (20-weeks)
Injury, poisoning and procedural complications Musculoskeletal injury	0.00% 0/12 • From baseline to follow-up (20-weeks)	6.2% 1/16 • Number of events 1 • From baseline to follow-up (20-weeks)
Psychiatric disorders Obsessive compulsive behavior	0.00% 0/12 • From baseline to follow-up (20-weeks)	6.2% 1/16 • Number of events 1 • From baseline to follow-up (20-weeks)
Skin and subcutaneous tissue disorders Rash	25.0% 3/12 • Number of events 3 • From baseline to follow-up (20-weeks)	6.2% 1/16 • Number of events 1 • From baseline to follow-up (20-weeks)
Respiratory, thoracic and mediastinal disorders Rhinorrhea	0.00% 0/12 • From baseline to follow-up (20-weeks)	6.2% 1/16 • Number of events 1 • From baseline to follow-up (20-weeks)
Nervous system disorders Sedation	0.00% 0/12 • From baseline to follow-up (20-weeks)	6.2% 1/16 • Number of events 1 • From baseline to follow-up (20-weeks)
Psychiatric disorders Self-injurious behavior	0.00% 0/12 • From baseline to follow-up (20-weeks)	6.2% 1/16 • Number of events 1 • From baseline to follow-up (20-weeks)
Infections and infestations Sinus Infection	0.00% 0/12 • From baseline to follow-up (20-weeks)	6.2% 1/16 • Number of events 1 • From baseline to follow-up (20-weeks)
Infections and infestations Skin_Infection	8.3% 1/12 • Number of events 2 • From baseline to follow-up (20-weeks)	12.5% 2/16 • Number of events 2 • From baseline to follow-up (20-weeks)
Psychiatric disorders Sleep Disturbance	8.3% 1/12 • Number of events 1 • From baseline to follow-up (20-weeks)	6.2% 1/16 • Number of events 1 • From baseline to follow-up (20-weeks)
Injury, poisoning and procedural complications Sprain	0.00% 0/12 • From baseline to follow-up (20-weeks)	6.2% 1/16 • Number of events 1 • From baseline to follow-up (20-weeks)
Infections and infestations Upper Respiratory Infection	58.3% 7/12 • Number of events 10 • From baseline to follow-up (20-weeks)	50.0% 8/16 • Number of events 12 • From baseline to follow-up (20-weeks)
Gastrointestinal disorders Vomiting	8.3% 1/12 • Number of events 1 • From baseline to follow-up (20-weeks)	0.00% 0/16 • From baseline to follow-up (20-weeks)
Metabolism and nutrition disorders Weight Loss	0.00% 0/12 • From baseline to follow-up (20-weeks)	6.2% 1/16 • Number of events 1 • From baseline to follow-up (20-weeks)
Injury, poisoning and procedural complications Skin abrasion	8.3% 1/12 • Number of events 1 • From baseline to follow-up (20-weeks)	0.00% 0/16 • From baseline to follow-up (20-weeks)