An Open-Label Extension Study of BPN14770 in Subjects With Fragile X Syndrome

National Institute of Health (NIH)- Toolbox Cognitive Battery (TCB):

cognitive battery assessing cognition from baseline to week 6, 12, 24, 26, 52 in the NIH-TCB CCC, which is calculated from the Picture Vocabulary and Oral Reading domains.

Numerical rating scale scores (NRS) scores: parent(s), legal authorized guardian(s), or consistent caregiver(s)-rated assessment of subject-specific behavioral anchors for domains of Daily Function, Language, Academic Skills (subjects from Study 204 only), and Emotions/Behaviors versus Baseline The 3 subject-specific behaviors per domain, as selected by the caregiver in the parent study, will be used for rating throughout the clinical trial. For each of the 3 behaviors chosen within each domain, the parent(s), legal authorized guardian(s), or consistent caregiver(s) will rate the individual from 0 "worst problem" to 10 "no problem at all" so that improvements or worsening in the specific behavior over the treatment period can be evaluated. The caregiver completing the assessment should remain the same at all applicable visits throughout the trial.

Caregiver Global Impression of Improvement (CaGI-I) assessments: for the general domains of Daily Function, Language, Academic Skills (subjects from Study 204 only), and Emotions/Behaviors versus baseline. The CaGI-I is a global measure to provide a caregiver's perspective of a subject's overall condition. The assessment of improvement is a 7-point scale that requires the caregiver to assess how much the subject's illness has improved or worsened relative to a baseline state (Week 13 of the parent study) at the beginning of the intervention, and rated as: 1, very much better; 2, much better; 3, a little better; 4, no change; 5, a little worse; 6, much worse; or 7, very much worse.

Clinical Global Impression Severity (CGI-S) assessments: for general domains of Daily Function, Language, Academic Skills (subjects from Study 204 only), and Emotions/Behaviors versus baseline. In this study, the general domains of Daily Function, Language, Academic Skills (Study 204 subjects only), and Emotions/Behaviors will be assessed using the CGI-S and CGI-I assessment tools. The assessment of severity will be made with a 7-point scale: 1, none; 2, very mild; 3, mild; 4, moderate; 5, marked; 6, severe; 7, extremely severe. The comparison will be made with respect to the overall experience of the clinician with individuals of the same age and sex. In this study, the general domains of Daily Function, Language, Academic Skills (Study 204 subjects only), and Emotions/Behaviors will be assessed. The CGI-S must be administered by the same rater for a given subject at all applicable visits throughout the trial.

Vineland-3 Adaptive Behavior Scale (Vineland-3): clinician-administered comprehensive interview yielding adaptive behavior composite score and domain standard scores in domains of communication (receptive, expressive, and written adaptive language functions), daily living skills (personal, domestic, and community skills), and socialization (interpersonal relationships, play and leisure time, and coping abilities) versus baseline. The Vineland-3 is a clinician-administered comprehensive interview yielding adaptive behavior composite score and domain standard scores in domains of: Communication (receptive, expressive, and written adaptive language functions); Daily Living Skills (personal, domestic, and community skills); and Socialization (interpersonal relationships, play and leisure time, and coping abilities) (Pepperdine 2017).

Verbal Knowledge Test from the Stanford-Binet (ed 5) IQ assessment versus baseline.

The Verbal Knowledge test is a specific subtest within the SB-5 instrument. This test asks an individual to define everyday words. A full SB-5 assessment of IQ obtained anytime in the 6 months before Day 1 may have been used, provided that individual items scores or z-deviation scores for each item were available. If the required assessment was not available in this time frame, the full SB-5 assessment was completed within the screening window and prior to conducting the NIH-TCB assessments at screening. The same screening SB-5 used in the parent study should be used for the screening assessment in this OLE study. The SB-5 subtest for Verbal Knowledge test does not need be performed at screening, since the results from the parent study is available; the Verbal Knowledge test must be performed at Week 52/early termination.

Aberrant Behavior Checklist (ABC) scores: parent(s), legal authorized guardian(s), or consistent caregiver(s)-rated scale with six subscales to assess irritability, lethargy, hyperactivity, inappropriate speech, and social avoidance, using the FXS-specific factoring system (ABC-FX) versus baseline. The ABC is a 58-item parent(s), legal authorized guardian(s), or consistent caregiver(s) rating scale used to assess behaviors in FXS across 6 dimensions or subscales: inappropriate speech, irritability, hyperactivity, lethargy/withdrawal, stereotypy, and social avoidance (Sansone 2012).

Items are evaluated on a 4-point Likert scale ranging from 0 (not at all a problem) to 3 (the problem is severe in degree). This scale has been used extensively in FXS in clinical trials and other projects. The ABC will be scored using the FXS-specific factoring system (ABC-FX). The caregiver completing the assessment should remain the same at all applicable visits throughout the trial.

Anxiety, Depression, and Mood Scale (ADAMS) scores: parent(s), legal authorized guardian(s), or consistent caregiver(s)-rated scale with a total score and six subscores to assess inappropriate speech, irritability, hyperactivity, lethargy/withdrawal, stereotypy, and social avoidance versus baseline. The ADAMS is a 28-item behavior-based informant instrument rated by the parent(s), legal authorized guardian(s), or consistent caregiver(s). The scale is composed of 5 factors, which address Manic/Hyperactive Behavior, Depressed Mood, Social Avoidance, General Anxiety, and Obsessive/Compulsive Behavior. A caregiver identified upon enrollment of subject should have intimate knowledge of the subject's situation and level of impairment to be able to provide accurate information as required to complete the ADAMS. The caregiver completing the assessment should remain the same at all applicable visits throughout the trial.