A 2-Period Crossover Study of BPN14770 in Adults Males With Fragile X Syndrome

A Randomized, Double-blind, Placebo-controlled, 2-period Crossover Study of BPN14770 in Adult Males With Fragile X Syndrome

This is a single-center, randomized, double-blind, 2-period crossover study to explore the effects of BPN14770 on cognitive function and behavior in subjects with Fragile X Syndrome. Subjects will receive both active treatment with BPN14770 capsules and matching placebo capsules in the course of the study. One treatment will be administered during each of the 12-week study periods.

A total of 30 subjects will be enrolled. The study consists of a screening period of up to 28 days prior to initial treatment, followed by two double-blind treatment periods, each 12 weeks long. A final follow-up visit or phone contact for safety is planned one week after the conclusion of Period 2.

Eligible subjects will be randomized in a blinded, balanced (1:1) fashion to receive either 25 mg BPN14770 capsules or matching placebo capsules during Period 1, followed by the opposite treatment during Period 2. One capsule will be taken twice daily during both double-blind periods.

Subjects will return to the clinic at the end of Weeks 2, 6, and 12 of each study period. Cognitive and behavioral evaluations will be repeated at Weeks 6 and 12 of each Period. Additionally, patients will be monitored for adverse events via a telephone call at the end of Week 1 of each Period, and one week following completion of Period 2 or following early discontinuation.

During clinic visits, adverse effects will be assessed, and laboratory measures, vital signs, and ECGs will be performed. Suicidality risk will also be evaluated at each clinic visit; if a concern is detected, the subject will be referred for further evaluation and treatment. Cognitive and behavioral assessments will be performed during each clinic visit. Pharmacodynamic measures of CNS function will be obtained to evaluated effects of the drug in the brain. Pharmacokinetic samples will be collected to confirm that study drug is present and to estimate plasma exposure at Week 12 of each Period.

Inclusion Criteria:

1. Subject is male aged 18 to 45 years, inclusive.
2. Subject has Fragile X Syndrome with a molecular genetic confirmation of the full Fragile X Mental Retardation (FMR1) mutation (≥200 CGG repetitions).
3. Current treatment with no more than 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 2 weeks prior to Screening and must remain stable during the period between Screening and the commencement of study medication.
5. Anti-epileptic medications must be at a stable dose and dosing regimen for 12 weeks prior to Screening and must remain stable during the period between Screening and the commencement of study medication.
6. Subjects with a history of seizure disorder who are currently receiving treatment with anti-epileptics must have been seizure-free for 3 months preceding Screening, or must be seizure-free for 3 years if not currently receiving anti-epileptics.
7. Behavioral and therapy treatments/interventions must be stable for 4 weeks prior to Screening and must remain stable during the period between Screening and the commencement of study medication, 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. 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.
9. Subject has a parent, legal authorized guardian or consistent caregiver.
10. Subject and caregiver are able to attend the clinic regularly and reliably.
11. Subject is able to swallow tablets and capsules.
12. For subjects who are not their own legal guardian, subject's parent/legal authorized guardian is able to understand and sign an informed consent form to participate in the study.
13. If subject is his/her own legal guardian, he/she can understand and sign informed consent to participate in the study.
14. If subject is not their own legal guardian, the subject provides assent for participation in the study, if the subject has the cognitive ability to provide assent.

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 medication. Common diseases such as mild hypertension, well-controlled type 2 diabetes mellitus (hemoglobin A1C [Hgb A1C] <6.5%), etc. are allowed per the investigator's judgment 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 x ULN at screening

3. Hepatic impairment, defined as ALT or AST elevation > 2 x ULN at screening. Note:

   LFTs may be repeated after 1 week to evaluate return to acceptable limits; if LFTs remain elevated, subject is ineligible to participate.

4. Clinically significant abnormalities, in the investigator's judgment, in safety laboratory tests, vital signs, or ECG, as measured during Screening.

5. History of substance abuse within the past year, according to investigator assessment.

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

7. Concurrent major psychiatric condition (e.g., 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 is planning to commence psychotherapy or cognitive behavior therapy (CBT) during the period of the study or had begun psychotherapy or CBT within 4 weeks prior to Screening.

10. Subject is related to anyone employed by the sponsor, investigator, or study staff.

11. Subject has BMI less than 18 or greater than 36.

12. Subject has participated in another clinical trial within the 30 days preceding Screening.