An Initial Study of AZD7325 in Adults With Fragile X Syndrome

Study Overview
=================
Brief Summary
-----------------
This study will investigate the safety, tolerability and blood pharmacodynamics of treatment with oral administration of AZD7325 at 5 mg BID, 15 mg BID, and placebo BID, in adults with Fragile X Syndrome. The study also will also investigate measures of efficacy and biomarkers during treatment.

Official Title
-----------------
An Initial Double-Blind, Placebo-Controlled Two-Dose Crossover Study of AZD7325 in Adults With Fragile X Syndrome

Conditions
-----------------
Fragile X Syndrome

Intervention / Treatment
-----------------
* Drug: AZD7325 (High-Dose)
* Drug: AZD7325 (Low-Dose)
* Drug: Placebo oral capsule


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Diagnostic confirmation of full mutation FXS 50 ≥ Age ≥18 years. Males and Females included in study. General good health as determined by physical exam, medical history and laboratory work up. FXS genetic reports at screening IQ less than or equal to 80. Note: IQ cutoff is used as a means to exclude cases of females with FXS who have the full mutation, but may have neurotypical development (ie: do not have the full FXS phenotype despite positive FXS genetic testing) due to variability in X chromosome inactivation patterns. Male study participants who are sexually active with a female partner of childbearing potential must be surgically sterilized, practicing abstinence, or agree to use highly effective methods of birth control (defined in the list below), and not rely on barrier methods and spermicide alone, from the time of screening until 1 week after final dose of study drug. Male study participants must also not donate sperm from the time of screening until 1 week after final dose of study drug. Given that AZD7325 is not mutagenic, there is no mandatory requirement for condom use, either for avoidance of procreation or in the case of treated males with a pregnant partner. Women of childbearing potential may be included in the study provided they are established on, and continue to use, highly effective contraceptive methods from the time of screening until 1 week after the final dose of study drug. Highly effective methods of contraception associated with inhibition of ovulation (either oral, intravaginal or transdermal), progestin-only hormonal contraception associated with inhibition of ovulation (either oral [specifically Micronor, Nor-QD or their generic equivalents], injectable or implantable). Aberrant Behavior Checklist total score of 20 or higher at screening Exclusion Criteria: Concomitant use of modulators of GABA A neurotransmission. (examples) Use of more than three psychotropic drugs that do not directly impact GABA transmission, and/or unstable dosing of any psychotropic medication in the 4 weeks prior to baseline visit. Subjects are prohibited from use of strong and moderate modulators of CYP3A and CYP2C19 during the screening (at least 2 weeks before initiation of the study) and treatment periods of the study. Such prohibited drugs are outlined in http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm292362.pdf CNS-suppressing agents such as central analgesics, muscle relaxants, benzodiazepines, other sedatives, and should also limit alcohol intake to ≤1 alcoholic beverage per day. Unstable seizure disorder as defined by any seizure in the 6 months prior to baseline visit and/or a change in any anti-convulsant drug dosing in the 60 days prior to study entry. All patients with abnormal baseline safety lab assessments including, but not limited to ALT or AST greater than 1.5 the upper limit of normal, total bilirubin or creatinine greater than 1 time the upper limit of normal or other clinically relevant lab abnormality or abnormality in ECG, HR or BP at screening as judged by the investigator. Clinical relevant history or presence of any medical disorder judged by the investigator at potentially interfering with this trial. History of or current abuse of drugs or alcohol including prescription medication. For female subjects of child bearing potential (women 50 & under is amenorrhoeic for 12 months or more (following cessation of exogenous hormonal treatments - if these have been previously taken) and with luteinizing hormone (LH) and follicle stimulating hormone (FSH) levels in the post-menopausal range) a positive pregnancy test.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 50 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Placebo - Low-Dose - High-Dose<br>Placebo AZD7325 5mg BID in gelatin capsules AZD7325 15mg BID in gelatin capsules | Drug: AZD7325 (High-Dose)<br>* 15mg PO BID<br>Drug: AZD7325 (Low-Dose)<br>* 5mg PO BID<br>Drug: Placebo oral capsule<br>* Placebo will be dosed similar to AZD7325, in terms of dosage form, frequency and duration.<br>|
| Experimental: Placebo - High-Dose - Low-Dose<br>Placebo AZD7325 15mg BID in gelatin capsules AZD7325 5mg BID in gelatin capsules | Drug: AZD7325 (High-Dose)<br>* 15mg PO BID<br>Drug: AZD7325 (Low-Dose)<br>* 5mg PO BID<br>Drug: Placebo oral capsule<br>* Placebo will be dosed similar to AZD7325, in terms of dosage form, frequency and duration.<br>|
| Experimental: Low-Dose - Placebo - High-Dose<br>AZD7325 5mg BID in gelatin capsules Placebo AZD7325 15mg BID in gelatin capsules | Drug: AZD7325 (High-Dose)<br>* 15mg PO BID<br>Drug: AZD7325 (Low-Dose)<br>* 5mg PO BID<br>Drug: Placebo oral capsule<br>* Placebo will be dosed similar to AZD7325, in terms of dosage form, frequency and duration.<br>|
| Experimental: Low-Dose - High-Dose - Placebo<br>AZD7325 5mg BID in gelatin capsules AZD7325 15mg BID in gelatin capsules Placebo | Drug: AZD7325 (High-Dose)<br>* 15mg PO BID<br>Drug: AZD7325 (Low-Dose)<br>* 5mg PO BID<br>Drug: Placebo oral capsule<br>* Placebo will be dosed similar to AZD7325, in terms of dosage form, frequency and duration.<br>|
| Experimental: High-Dose - Low-Dose - Placebo<br>AZD7325 15mg BID in gelatin capsules AZD7325 5mg BID in gelatin capsules Placebo | Drug: AZD7325 (High-Dose)<br>* 15mg PO BID<br>Drug: AZD7325 (Low-Dose)<br>* 5mg PO BID<br>Drug: Placebo oral capsule<br>* Placebo will be dosed similar to AZD7325, in terms of dosage form, frequency and duration.<br>|
| Experimental: High-Dose - Placebo - Low-Dose<br>AZD7325 15mg BID in gelatin capsules Placebo AZD7325 5mg BID in gelatin capsules | Drug: AZD7325 (High-Dose)<br>* 15mg PO BID<br>Drug: AZD7325 (Low-Dose)<br>* 5mg PO BID<br>Drug: Placebo oral capsule<br>* Placebo will be dosed similar to AZD7325, in terms of dosage form, frequency and duration.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Amyloid Precursor Protein (APP) | Short-term treatment of peripheral APP dysregulation by correcting elevated levels | Through end of study, approximately 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in the Social Withdrawal subscale score of the Aberrant Behavior Checklist (ABC) | The ABC is the gold standard parent/caregiver reported behavioral outcome measure for use in developmental disability clinical trials. | Through end of study, approximately 12 weeks | 
| Change in the Pediatric Anxiety Rating Scale (PARS) | The PARS is the gold standard parent/caregiver reported anxiety outcome measure for use in Fragile X Syndrome clinical trials. | Through end of study, approximately 12 weeks |