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

Primary Purpose

Fragile X Syndrome

Status
Enrolling by invitation
Phase
Phase 3
Locations
United States
Study Type
Interventional
Intervention
Zatolmilast/ BPN14770
Sponsored by
Tetra Discovery Partners
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Fragile X Syndrome

Eligibility Criteria

12 Years - 45 Years (Child, Adult)MaleDoes not accept healthy volunteers

Inclusion Criteria:

  1. Subject has completed the Week 13 visit, whether on treatment or discontinued from treatment, from one of two parent clinical trials with

    BPN14770:

    1. Study 204
    2. Study 301 Subjects who discontinued study treatment early due to AEs deemed related to study treatment by the investigator in one of the parent studies will NOT be eligible, regardless of whether the Week 13 visit was completed.
  2. Subjects with a history of seizure disorder who are currently receiving treatment with antiepileptics must have remained seizure-free during the parent study. Any subject experiencing a seizure during the parent study is not eligible to continue into this long-term safety study.
  3. Subject must be willing to practice barrier methods of contraception while on study, if sexually active. Abstinence is also considered a reasonable form of birth control in this study population.
  4. Subject has a parent, legal authorized guardian, or consistent caregiver.
  5. Subject and caregiver are able to attend the clinic regularly and reliably.
  6. If subject is his own legal guardian, he is able to understand and sign an informed consent form to participate in the study.
  7. For subjects who are not their own legal guardian, subject's parent/legally authorized guardian is able to understand and sign an informed consent form for their child to participate in the study.
  8. If subject is not his own legal guardian, subject must provide assent for participation in the study if he has the cognitive ability to do so.

Exclusion Criteria:

  • 1. History of, or current cardiovascular, renal, hepatic, respiratory, gastrointestinal, psychiatric, neurologic, cerebrovascular, or other systemic disease that would place the subject at risk or potentially interfere with the interpretation of the safety, tolerability, or efficacy of the study treatment. Common conditions such as mild hypertension, etc. are allowed per the principal investigator's (PI) judgement as long as they are stable and controlled by medical therapy that is constant for at least 4 weeks before randomization.

    2. Renal impairment, defined as serum creatinine >1.25×ULN per the latest available laboratory results from the parent study.

    3. Hepatic impairment, defined as ALT or AST elevation >2×ULN per the latest available laboratory results from the parent study.

    4. Clinically significant abnormalities, in the investigator's judgement, in safety laboratory tests, vital signs, or ECG, as measured at the final visit of the parent study.

    5. Substance abuse documented during the parent study.

    6. Significant hearing or visual impairment that may affect the subject's ability to complete the test procedures.

    7. Concurrent major psychiatric condition (eg, major depressive disorder, schizophrenia, or bipolar disorder) as diagnosed by the investigator. Subjects with additional diagnosis of autism spectrum disorder or anxiety disorder will be allowed.

    8. Subject has active diseases that would interfere with participation, such as acquired immunodeficiency disorder, hepatitis C, hepatitis B, or tuberculosis.

    9. Subject has participated in another clinical trial within the 30 days preceding screening OTHER THAN one of the two studies required per Inclusion Criteria 1.

Sites / Locations

  • CHOC Thompson Autism Center
  • UC Davis
  • Children's Hospital Colorado
  • Emory University School of Medicine
  • Rush University Medical Center
  • Kennedy Krieger
  • U Mass
  • Seaver Autism Center for Research & Treatment at Mount Sinai
  • Cincinatti Children's Hospital Medical Center
  • Suburban Research Associates

Arms of the Study

Arm 1

Arm Type

Other

Arm Label

Study Drug (BPN14770)

Arm Description

25mg BID Study Drug BPN14770

Outcomes

Primary Outcome Measures

Safety and tolerability of BPN14770
Long-term safety and tolerability of BPN14770 in these subjects with fragile X syndrome (FXS) who were treated in one of those parent clinical trials. Safety/tolerability endpoint: Treatment Emergent Adverse Events (TEAEs), which will be coded using the Medical Dictionary for Regulatory Activities. Subject incidence of each system organ class and unique preferred term will be tabulated, including all TEAEs, at least possibly related TEAEs, TEAEs resulting discontinuation of study treatment,TEAEs by intensity, and treatment-emergent SAEs. The safety analysis will be descriptive in nature.

Secondary Outcome Measures

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

Full Information

First Posted
April 29, 2022
Last Updated
February 15, 2023
Sponsor
Tetra Discovery Partners
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1. Study Identification

Unique Protocol Identification Number
NCT05367960
Brief Title
An Open-Label Extension Study of BPN14770 in Subjects With Fragile X Syndrome
Official Title
An Open-Label Extension Study of BPN14770 in Subjects With Fragile X Syndrome
Study Type
Interventional

2. Study Status

Record Verification Date
May 2022
Overall Recruitment Status
Enrolling by invitation
Study Start Date
November 1, 2022 (Actual)
Primary Completion Date
February 2024 (Anticipated)
Study Completion Date
December 2024 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Tetra Discovery Partners

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
This is an open-label extension (OLE) study for subjects completing one of two double-blind clinical trials with BPN14770, Study BPN14770-CNS-301(in adult males) and Study BPN14770-CNS-204 (in adolescent males).
Detailed Description
This is an open-label extension (OLE) study for subjects completing one of two double-blind clinical trials with BPN14770, Study BPN14770-CNS-301(in adult males) and Study BPN14770-CNS-204 (in adolescent males). The primary objective of this OLE is to assess the long-term safety and tolerability of BPN14770 in these subjects with fragile X syndrome (FXS) who were treated in one of those parent clinical trials.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Fragile X Syndrome

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
300 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Study Drug (BPN14770)
Arm Type
Other
Arm Description
25mg BID Study Drug BPN14770
Intervention Type
Drug
Intervention Name(s)
Zatolmilast/ BPN14770
Intervention Description
25mg zatolmilast/BPN14770
Primary Outcome Measure Information:
Title
Safety and tolerability of BPN14770
Description
Long-term safety and tolerability of BPN14770 in these subjects with fragile X syndrome (FXS) who were treated in one of those parent clinical trials. Safety/tolerability endpoint: Treatment Emergent Adverse Events (TEAEs), which will be coded using the Medical Dictionary for Regulatory Activities. Subject incidence of each system organ class and unique preferred term will be tabulated, including all TEAEs, at least possibly related TEAEs, TEAEs resulting discontinuation of study treatment,TEAEs by intensity, and treatment-emergent SAEs. The safety analysis will be descriptive in nature.
Time Frame
12 months
Secondary Outcome Measure Information:
Title
National Institute of Health (NIH)- Toolbox Cognitive Battery (TCB)
Description
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.
Time Frame
12 Months
Title
Numerical rating scale scores (NRS) scores
Description
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.
Time Frame
12 Months
Title
Caregiver Global Impression of Improvement (CaGI-I) assessments:
Description
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.
Time Frame
12 Months
Title
Clinical Global Impression Severity (CGI-S) assessments:
Description
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.
Time Frame
12 Months
Title
Vineland-3 Adaptive Behavior Scale (Vineland-3)
Description
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).
Time Frame
12 Months
Title
Verbal Knowledge Test from the Stanford-Binet (ed 5) IQ assessment
Description
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.
Time Frame
12 Months
Title
Aberrant Behavior Checklist (ABC) scores
Description
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.
Time Frame
12 Months
Title
Anxiety, Depression, and Mood Scale (ADAMS) scores
Description
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.
Time Frame
12 Months

10. Eligibility

Sex
Male
Gender Based
Yes
Gender Eligibility Description
Male
Minimum Age & Unit of Time
12 Years
Maximum Age & Unit of Time
45 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Subject has completed the Week 13 visit, whether on treatment or discontinued from treatment, from one of two parent clinical trials with BPN14770: Study 204 Study 301 Subjects who discontinued study treatment early due to AEs deemed related to study treatment by the investigator in one of the parent studies will NOT be eligible, regardless of whether the Week 13 visit was completed. Subjects with a history of seizure disorder who are currently receiving treatment with antiepileptics must have remained seizure-free during the parent study. Any subject experiencing a seizure during the parent study is not eligible to continue into this long-term safety study. Subject must be willing to practice barrier methods of contraception while on study, if sexually active. Abstinence is also considered a reasonable form of birth control in this study population. Subject has a parent, legal authorized guardian, or consistent caregiver. Subject and caregiver are able to attend the clinic regularly and reliably. If subject is his own legal guardian, he is able to understand and sign an informed consent form to participate in the study. For subjects who are not their own legal guardian, subject's parent/legally authorized guardian is able to understand and sign an informed consent form for their child to participate in the study. If subject is not his own legal guardian, subject must provide assent for participation in the study if he has the cognitive ability to do so. Exclusion Criteria: 1. History of, or current cardiovascular, renal, hepatic, respiratory, gastrointestinal, psychiatric, neurologic, cerebrovascular, or other systemic disease that would place the subject at risk or potentially interfere with the interpretation of the safety, tolerability, or efficacy of the study treatment. Common conditions such as mild hypertension, etc. are allowed per the principal investigator's (PI) judgement as long as they are stable and controlled by medical therapy that is constant for at least 4 weeks before randomization. 2. Renal impairment, defined as serum creatinine >1.25×ULN per the latest available laboratory results from the parent study. 3. Hepatic impairment, defined as ALT or AST elevation >2×ULN per the latest available laboratory results from the parent study. 4. Clinically significant abnormalities, in the investigator's judgement, in safety laboratory tests, vital signs, or ECG, as measured at the final visit of the parent study. 5. Substance abuse documented during the parent study. 6. Significant hearing or visual impairment that may affect the subject's ability to complete the test procedures. 7. Concurrent major psychiatric condition (eg, major depressive disorder, schizophrenia, or bipolar disorder) as diagnosed by the investigator. Subjects with additional diagnosis of autism spectrum disorder or anxiety disorder will be allowed. 8. Subject has active diseases that would interfere with participation, such as acquired immunodeficiency disorder, hepatitis C, hepatitis B, or tuberculosis. 9. Subject has participated in another clinical trial within the 30 days preceding screening OTHER THAN one of the two studies required per Inclusion Criteria 1.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Elizabeth Berry-Kravis, MD
Organizational Affiliation
Rush University Medical Center
Official's Role
Principal Investigator
Facility Information:
Facility Name
CHOC Thompson Autism Center
City
Orange
State/Province
California
ZIP/Postal Code
92868
Country
United States
Facility Name
UC Davis
City
Sacramento
State/Province
California
ZIP/Postal Code
95817
Country
United States
Facility Name
Children's Hospital Colorado
City
Denver
State/Province
Colorado
ZIP/Postal Code
80045
Country
United States
Facility Name
Emory University School of Medicine
City
Atlanta
State/Province
Georgia
ZIP/Postal Code
30307
Country
United States
Facility Name
Rush University Medical Center
City
Chicago
State/Province
Illinois
ZIP/Postal Code
60612
Country
United States
Facility Name
Kennedy Krieger
City
Baltimore
State/Province
Maryland
ZIP/Postal Code
21205
Country
United States
Facility Name
U Mass
City
Worcester
State/Province
Massachusetts
ZIP/Postal Code
01655
Country
United States
Facility Name
Seaver Autism Center for Research & Treatment at Mount Sinai
City
New York
State/Province
New York
ZIP/Postal Code
10029
Country
United States
Facility Name
Cincinatti Children's Hospital Medical Center
City
Cincinnati
State/Province
Ohio
ZIP/Postal Code
45229
Country
United States
Facility Name
Suburban Research Associates
City
Media
State/Province
Pennsylvania
ZIP/Postal Code
19063
Country
United States

12. IPD Sharing Statement

Plan to Share IPD
No

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

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