A Randomized Study of BPN14770 in Male Adolescents (Aged 12 to < 18 Years) With Fragile X Syndrome

• ClinicalTrials.gov Identifier: NCT05163808
• Recruitment Status: Recruiting
• First Posted: December 20, 2021
• Last Update Posted: February 21, 2023
• Sponsor: Tetra Discovery Partners
• Information provided by (Responsible Party): Tetra Discovery Partners

Study Description

Brief Summary:

This is a 2-part study, with each part having a unique set of objectives for male adolescents aged 12 to < 18 years with fragile X syndrome (FXS). Part 1 is an open-label, single-dose, pharmacokinetics (PK) assessment of BPN14770 25 mg and 50 mg, while Part 2 is double-blind (DB) and randomized between two treatment groups (Study Drug and Placebo)

Condition or disease	Intervention/treatment	Phase
Fragile X Syndrome	Drug: zatolmilast; Drug: Placebo	Phase 2; Phase 3

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 150 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Intervention Model Description: 2 treatment Groups (Study Drug and Placebo)
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Masking Description: Double Blind
• Primary Purpose: Treatment
• Official Title: A Randomized, Double-blind, Placebo-controlled, Two-Part Study of High and Low Dose BPN14770 in Male Adolescents (Aged 12 to < 18 Years) With Fragile X Syndrome
• Actual Study Start Date: March 29, 2022
• Estimated Primary Completion Date: February 2024
• Estimated Study Completion Date: July 2024

Arms and Interventions

Arm	Intervention/treatment
Active Comparator: Study Drug; Subjects will 25mg BID dose of BPN14770	Drug: zatolmilast; Subjects will receive a low dose, high dose of zatolmilast (BPN14770) or placebo; Other Name: BPN14770
Placebo Comparator: Placebo Arm; Subjects will receive Placebo	Drug: Placebo; Placebo

Outcome Measures

Primary Outcome Measures :

1. NIH Toolbox Cognitive Battery cognition crystallized composite score [ Time Frame: 13 Weeks ]
   The change from baseline to Week 13 in the NIH Toolbox Cognitive Battery cognition crystallized composite score (NIH-TCB CCC), which is calculated from the Picture Vocabulary and Oral Reading domains.

Secondary Outcome Measures :

1. NRS patient-specific behaviors within the domains of Daily Function, Language, and Academic Skills. [ Time Frame: 13 Weeks ]
   Change from baseline to Week 13 in Numerical rating scale (NRS) scores based on patient-specific behaviors within the domains of Daily Function, Language, and Academic Skills.
2. CaGI-I for the general domains of Daily Function, Language, and Academic Skills. [ Time Frame: 13 Weeks ]
   Change from baseline to Week 13 Caregiver Global Impression of Improvement (CaGI-I) for the general domains of Daily Function, Language, and Academic Skills.
3. Investigator rated (CGI-I) for the general domains of Daily Function, Language, and Academic Skills [ Time Frame: 13 Weeks ]
   Change from baseline to Week 13 Clinical Global Impression Improvement - Investigator rated (CGI-I) for the general domains of Daily Function, Language, and Academic Skills
4. NRS scores based on patient-specific behaviors within the domain of Emotions/Behaviors [ Time Frame: 13 Weeks ]
   Change from baseline to Week 13 NRS scores based on patient-specific behaviors within the domain of Emotions/Behaviors
5. CaGI-I for the general domain of Emotions/Behaviors [ Time Frame: 13 Weeks ]
   Change from baseline to Week 13 CaGI-I for the general domain of Emotions/Behaviors
6. The NIH-TCB domains of Picture Vocabulary, Oral Reading Recognition, and Pattern Comparison Processing Speed [ Time Frame: 13 Weeks ]
   Change from baseline to Week 13 the NIH-TCB domains of Picture Vocabulary, Oral Reading Recognition, and Pattern Comparison Processing Speed
7. Vineland-3 Adaptive Behavior Scale (Vineland-3) [ Time Frame: 13 Weeks ]
   Change from baseline to Week 13 Vineland-3 Adaptive Behavior Scale (Vineland-3)
8. Verbal Knowledge test from the Stanford Binet (ed 5) (SB-5) IQ assessment [ Time Frame: 13 Weeks ]
   Change from baseline Verbal Knowledge test from the Stanford Binet (ed 5) (SB-5) IQ assessment

Eligibility Criteria

• Ages Eligible for Study: 12 Years to 18 Years (Child, Adult)
• Sexes Eligible for Study: Male
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• 1. Patient is male adolescent aged 12 to < 18 years. 2. Patient has FXS with a molecular genetic confirmation of the full fragile X mental retardation-1 (FMR1) mutation (≥ 200 CGG repetitions).

  3. Current treatment with ≤ 3 prescribed psychotropic medications. Anti-epileptic medications are permitted and are not counted as psychotropic medications if they are used for treatment of seizures. Anti-epileptics for other indications, such as the treatment of mood disorders, count towards the limit of permitted medications.

  4. Permitted concomitant psychotropic medications must be at a stable dose and dosing regimen for at least 4 weeks before screening and must remain stable during the period between screening and the commencement of study drug.

  5. Anti-epileptic medications must be at a stable dose and dosing regimen for 12 weeks before screening and must remain stable during the period between screening and the commencement of study drug.

  6. Patients with a history of seizure disorder who are currently receiving treatment with anti-epileptics must have been seizure-free for 3 months before screening or must be seizure-free for 2 years if not currently receiving anti-epileptics.

  7. Behavioral and other non-pharmacological treatments/interventions must be stable for 4 weeks before screening and must remain stable during the period between screening and the commencement of study drug, and throughout the study. Minor changes in hours or times of therapy that are not considered clinically significant will not be exclusionary. Changes in therapies provided through a school program, due to school vacations, are allowed.

  8. Patient 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.

  9. Patient has a parent(s), legal authorized guardian(s), or consistent caregiver(s).

  10. Patient and caregiver are able to attend the clinic regularly and reliably. 11. Patient's parent(s), legal authorized guardian(s), or consistent caregiver(s) is able to understand and sign an informed consent form to participate in the study.

  12. Patient must provide assent for participation in the study if the patient has the cognitive ability to provide assent.

Exclusion Criteria:

Diagnosis and main criteria for inclusion:

The eligibility criteria are the same for all parts of the study except for Part 1 (PK), where patients must be able to swallow capsules and must weigh at least 75 lbs (34 kg) to receive the 50 mg dose.

Patient Inclusion Criteria

1. Patient is male adolescent aged 12 to < 18 years.
2. Patient has FXS with a molecular genetic confirmation of the full fragile X mental retardation-1 (FMR1) mutation (≥ 200 CGG repetitions).
3. Current treatment with ≤ 3 prescribed psychotropic medications. Anti-epileptic medications are permitted and are not counted as psychotropic medications if they are used for treatment of seizures. Anti-epileptics for other indications, such as the treatment of mood disorders, count towards the limit of permitted medications.
4. Permitted concomitant psychotropic medications must be at a stable dose and dosing regimen for at least 4 weeks before screening and must remain stable during the period between screening and the commencement of study drug.
5. Anti-epileptic medications must be at a stable dose and dosing regimen for 12 weeks before screening and must remain stable during the period between screening and the commencement of study drug.
6. Patients with a history of seizure disorder who are currently receiving treatment with anti-epileptics must have been seizure-free for 3 months before screening or must be seizure-free for 2 years if not currently receiving anti-epileptics.
7. Behavioral and other non-pharmacological treatments/interventions must be stable for 4 weeks before screening and must remain stable during the period between screening and the commencement of study drug, and throughout the study. Minor changes in hours or times of therapy that are not considered clinically significant will not be exclusionary. Changes in therapies provided through a school program, due to school vacations, are allowed.
8. Patient 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.
9. Patient has a parent(s), legal authorized guardian(s), or consistent caregiver(s).
10. Patient and caregiver are able to attend the clinic regularly and reliably.
11. Patient's parent(s), legal authorized guardian(s), or consistent caregiver(s) is able to understand and sign an informed consent form to participate in the study.
12. Patient must provide assent for participation in the study if the patient has the cognitive ability to provide assent.
13. To participate in the Part 1 PK only: patients must be able to swallow capsules.

Patient Exclusion Criteria

1. Inability to successfully complete the NIH-TCB picture vocabulary and oral reading assessments at screening and baseline for Part 2 (DB). Patient must be able to complete these assessments at baseline to be randomized into Part 2; care should be taken that a patient enrolled into Part 1 (PK) possesses this ability if their desire is to continue to Parts 2 and 3. The ability to complete the NIH-TBC oral reading and picture vocabulary subtest at baseline is defined as the ability to complete both subtests, with (1) confirmation from the clinician administering that the test administrations are valid (noted on the administration form), and (2) generation of valid test scores for each test.

2. History of, or current cardiovascular, renal, hepatic, respiratory, gastrointestinal, psychiatric, neurologic, cerebrovascular, or other systemic disease that would place the patient at risk or potentially interfere with the interpretation of the safety, tolerability, or efficacy of the study drug.

   • Common conditions such as mild hypertension, etc. are allowed per the PI's judgment as long as they are stable and controlled by medical therapy that is constant for at least 4 weeks before randomization.

3. Renal impairment, defined as serum creatinine > 1.25 × ULN at screening.
4. Hepatic impairment, defined as alanine aminotransferase or aspartate aminotransferase elevation > 2 × ULN at screening. Note: liver function tests may be repeated after 1 week to evaluate return to acceptable limits; if liver function tests remain elevated, patient is ineligible to participate.
5. Clinically significant abnormalities, in the PI's judgment, in safety laboratory tests, vital signs, or 12-lead ECG, as measured during screening.
6. Positive COVID-19 test during screening.
7. History of substance abuse within the past year, according to PI's assessment.
8. Significant hearing or visual impairment that may affect the patient's ability to complete the test procedures.
9. Concurrent major psychiatric condition (eg, major depressive disorder, schizophrenia, or bipolar disorder) as diagnosed by the PI. Patients with additional diagnosis of autism spectrum disorder or anxiety disorder will be allowed.
10. Patient has active diseases that would interfere with participation, such as acquired immunodeficiency disorder, hepatitis C, hepatitis B, or tuberculosis.
11. Patient is an immediate family member of anyone employed by the sponsor, PI, or study staff.
12. Patient has weight < 60 lbs (27.2 kg) or a BMI greater than the 97th percentile for his age according to the Centers for Disease Control and Prevention (refer to Appendix 1). To participate in the Part 1 cohort receiving 50 mg dose, patient must weigh ≥ 75 lbs (34 kg).

13. Patient has participated in another clinical trial within the 30 days before screening.

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Contacts and Locations

Contacts

Contact: CEO; 616-224-0084; info@tetratherapeutics.com

Locations

United States, Arizona

Phoenix Childrens Hospital Barrow Neurological Institute; Not yet recruiting

Phoenix, Arizona, United States, 85016

Contact: Danni Brown 602-933-6297 dbrown4@phoenixchildrens.com

Principal Investigator: Raz, MD

United States, California

CHOC Thompson Autism Center; Not yet recruiting

Orange, California, United States, 92868

Contact: Oliver Vasquez 714-509-4273 Oliver.Vasquez@choc.org

Principal Investigator: Jonathan Megerian, MD

UC Davis; Not yet recruiting

Sacramento, California, United States, 95817

Contact: Ellery Santos 916-703-0200 esantos@ucdavis.edu

Principal Investigator: Randi Hagerman, MD

United States, Colorado

Children's Hospital Colorado; Not yet recruiting

Denver, Colorado, United States, 80045

Contact: Sailor Brukardt 920-810-9347 Sailor.brukardt@childrenscolorado.org

Principal Investigator: Nicole Tartaglia, MD

United States, Georgia

Emory University School of Medicine; Not yet recruiting

Atlanta, Georgia, United States, 30307

Contact: Jean Luan McColl 404-778-8619 jean.luan@emory.edu

Principal Investigator: Amy Talboy, MD

United States, Illinois

Rush University Medical Center; Recruiting

Chicago, Illinois, United States, 60612

Contact: Loren R Escot 312-942-2164 Loren_Escot@rush.edu

Principal Investigator: Elizabeth Berry-Kravis, MD,PhD

United States, Maryland

Kennedy Krieger; Not yet recruiting

Baltimore, Maryland, United States, 21205

Contact: Kim Zapata 443-923-3868 Zapata@kennedykrieger.org

Principal Investigator: Dejan Budimirovic

United States, Massachusetts

U Mass; Recruiting

Worcester, Massachusetts, United States, 01655

Contact: Arline Mata 774-455-4100 ChildResearch@umassmed.edu

Principal Investigator: Jean Frazier, MD

United States, New York

Seaver Autism Center for Research & Treatment at Mount Sinai; Not yet recruiting

New York, New York, United States, 10029

Contact: Venus Fan 929-989-7016 venus.fan@mssm.edu

Principal Investigator: Reymundo Lozano, MD

United States, Ohio

Cincinatti Children's Hospital Medical Center; Recruiting

Cincinnati, Ohio, United States, 45229

Contact: Dakota Gallimore 513-516-2113 Dakota.Gallimore@cchmc.org

Principal Investigator: Ernest Pedapati, MD

United States, Pennsylvania

Suburban Research Associates; Recruiting

Media, Pennsylvania, United States, 19063

Contact: Meghan Varano 610-891-9024 ext 1111 mvarano@suburbanresearch.com

Principal Investigator: Hatti, MD

United States, South Carolina

Greenwood Genetic Center; Recruiting

Greenwood, South Carolina, United States, 29646

Contact: Caleb Hinzman 864-672-6912 chinzman@ggc.org

Principal Investigator: Caroline Buchanan

United States, Utah

University of Utah and Primary Childrens Hospital; Not yet recruiting

Salt Lake City, Utah, United States, 84113

Contact: Carly Straley 801-598-7509 Carly.Straley@hsc.utah.edu

Principal Investigator: Victoria Wilkins, MD

Sponsors and Collaborators

Tetra Discovery Partners

More Information

• Responsible Party: Tetra Discovery Partners
• ClinicalTrials.gov Identifier: NCT05163808
• Other Study ID Numbers: BPN14770-CNS-204
• First Posted: December 20, 2021
• Last Update Posted: February 21, 2023
• Last Verified: February 2023

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:

Fragile X Syndrome; Syndrome; Disease; Pathologic Processes; Mental Retardation, X-Linked; Intellectual Disability; Neurobehavioral Manifestations; Neurologic Manifestations; Nervous System Diseases; Sex Chromosome Disorders; Chromosome Disorders; Congenital Abnormalities; Genetic Diseases, Inborn; Genetic Diseases, X-Linked; Heredodegenerative Disorders, Nervous System; BPN14770; Phosphodiesterase 4 Inhibitors; Phosphodiesterase Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action