Tetra PICASSO AD Trial: Study to Evaluate Effects of BPN14770 in Early Alzheimer's Subjects

Study Overview
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Brief Summary
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A Randomized, Double-blind, Placebo Controlled, 3-Arm Parallel Design Study to Evaluate the Effects of BPN14770 in Patients with Early Alzheimer's Disease

Official Title
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A Randomized , Double Blind, Placebo Controlled, 3-Arm Parallel Design Study to Evaluate the Effects of BPN14770 in Patients With Early Stage Alzheimer's Disease

Conditions
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Alzheimer's Disease

Intervention / Treatment
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* Drug: BPN14770
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Males or females between the ages of 55 and 85 years with a clinical diagnosis of early stage AD, defined according to the following criteria assessed during Screening and at Baseline : Clinical Dementia Rating (CDR) score of 0.5 or 1, with Memory Box score of 0.5 or greater MMSE score of 20 or greater RBANS DMI score ≤ 85 Note: PET imaging for amyloid is not required for diagnosis, which will be made on clinical grounds. Currently receiving a stable (at least 2 months) dose regimen of donepezil or another cholinesterase inhibitor for treatment of Alzheimer's disease. Doses of these drugs may not be changed during the trial. Note: Memantine is not permitted during the trial and must be discontinued at least 3 weeks prior to Baseline. Modified Hachinski Ischemia score < 4. Body mass index (BMI) < 38 kg/m2, inclusive, and body weight of >48 kg (105 pounds) at screening. Female subjects must be at least two years post-menopausal (subjected reported menopausal status), surgically sterile (bilateral tubal ligation, hysterectomy, or bilateral oophorectomy at least 6 months prior to first study drug administration), or willing to either (1) utilize hormonal contraception plus one barrier method or (2) use two barrier methods of contraception (e.g. diaphragm and spermicide) from initial screening until one month after taking the final dose. An intrauterine device (IUD) is considered a barrier method of contraception in this study. Male subjects must be willing to inform female partners of their participation in the study and must agree to use adequate contraceptive methods (vasectomy performed at least 6 months prior to first study drug administration, or use at least one barrier method of birth control). Able to understand and comply with the study procedures, voluntarily agree to participate in this study, and provide written informed consent prior to start of any study-specific procedures. All subjects must have a caregiver who is willing and able to ensure compliance with study medications, visits, and study procedures. Exclusion Criteria: Any medical or neurological condition (other than early stage AD) that might be a contributing cause to the subject's cognitive impairment. History of stroke or multiple (>3 discreet episodes) Transient Ischemic Attacks (TIAs), severe head trauma with cognitive sequelae, uncontrolled seizures, or unexplained prolonged loss of consciousness (> 1 minute) during the past year. Clinically significant major psychiatric illness during the past 6 months. History of unstable angina, myocardial infarction, chronic heart failure, or clinically significant conduction abnormalities during the past year. Clinically significant liver or renal disease. Clinically significant abnormality, in the Investigator's judgment, in hematology, chemistry, or urinalysis. Positive serology results for hepatitis B surface antigen (HbsAg) or hepatitis C virus (HCV). Abnormal liver function test at the Screening Visit (aspartate aminotransferase or alanine aminotransferase >2 × the upper limit of normal [ULN], or total bilirubin >1.7 × ULN, based on appropriate age and gender normal values). Subjects may be re-screened once. Marked hypotension (systolic blood pressure [BP] ˂90 mmHg or diastolic BP ˂50 mmHg) or hypertension (systolic BP ˃160 mmHg or diastolic BP ˃100 mmHg) based on sitting values. O ut-of-range results may be repeated once at Screening, and eligibility must be confirmed at Baseline. Marked bradycardia (heart rate ˂45 beats per minute [bpm]) or tachycardia (heart rate ˃115 bpm) based on supine ECG values. Out-of-range results may be repeated once at Screening, and eligibility must be confirmed at Baseline. Clinically important conduction abnormalities on ECG, or evidence or history of long QT syndrome based on supine ECG values obtained at Screening. Out-of-range results may be repeated once and eligibility confirmed at Baseline. Active gastric or duodenal ulcers or other diseases of the gastrointestinal tract that could interfere with absorption of study drug. Note: Subjects with a history of appendectomy or cholecystectomy may be enrolled. Active acute or chronic infectious diseases that would interfere with subject's participation in the study. Unable to discontinue centrally active medications (other than cholinesterase inhibitors), including memantine, psychotropic drugs other than SSRIs (which must have been stable for 2 months and remain stable throughout the study), sedative antihistamines or other centrally active medications with potential cognitive effects (e.g., CNS-penetrant beta blockers). Unable to discontinue moderate to strong inhibitors or inducers of CYP3A4, CYP2D6, or other cytochromes at least 14 days prior to the first dose of study drug. A complete listing of such inhibitors or inducers may be found in http://medicine.iupui.edu/clinpharm/ddis/main-table (Other prescription or non-prescription drugs such as antihypertensive or cholesterol lowering agents are allowed, if, in the Investigator's judgement, they would not interfere with the study medication or the cognitive testing.) A suicidal ideation intensity score of 3 or higher per screening Columbia Suicide Severity Rating Scale (CSSRS) assessment on Day 1 (Baseline) and/or any suicidal behavior within the past 28 days. History of chronic alcohol or other substance abuse, including marijuana, within the previous year prior to the Screening visit (per the current edition of the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition: DSM-5), or regular (daily) consumption of alcohol exceeding two bottles of beer, or the equivalent amount of other forms of alcohol (1 serving = 12 oz beer, 5.0 oz wine, or 1.5 oz distilled spirits). Inability or unwillingness to comply with the protocol, including performing the cognitive function tests, or likely inability to complete the study. Participation in other clinical studies involving investigational drug within the previous 30 days prior to the Screening Visit. Donation of blood within 4 weeks, or blood products within 2 weeks, prior to first study drug administration. History of clinically significant drug allergy that includes symptoms such as shortness of breath, rash, or edema. Clinically significant B12 deficiency within 12 months prior to Visit 1 (Screening). Participants on stable replacement therapy for a minimum of 3 consecutive months immediately prior to Visit 1 (Screening) may be included

Ages Eligible for Study
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Minimum Age: 55 Years
Maximum Age: 85 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: BPN14770 10mg bid<br>10 mg bid dose of the Drug BPN14770 | Drug: BPN14770<br>* Drug BPN14770<br>|
| Experimental: BPN 14770 25mg bid<br>25mg bid dose of the Drug BPN14770 | Drug: BPN14770<br>* Drug BPN14770<br>|
| Placebo Comparator: Placebo<br> | Drug: Placebo<br>* Placebo<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Repeatable Battery for the Assessment of Neurological Status- Delayed Memory Index (RBANS- DMI) | Change from baseline of RBANS-DMI score. Power based on true difference of 7.15 units on normalized mean of score of 100 between 25mg dose Arm vs Placebo | Week 13 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Repeatable Battery for the Assessment of Neurological Status (RBANS) total score | Comparison of RBANs Total scores to baseline at each timepoint | Weeks 1,2,4,8,13 | 
| Alzheimer's Disease Cooperative Study Activities of Daily Living Inventory (ADCS-ADL) | ADCS-ADL total score compared to baseline at each time point | Week 8, 13 | 
| Mini-Mental State Exam (MMSE) Score | MMSE total score versus baseline at each timepoint | Weeks 1,2,4,8,13 | 
| Clinical Dementia Rating Sum of Boxes Score (CDR-SB) | CDR-SB versus Baseline at each timepoint | Week 13 | 
| Clinical Global Impression - Improvement (CGI-I) Score | CGI-I Score versus Baseline at each timepoint | Week 1,2,4,8,13 | 
| Pharmacokinetics: Maximum Drug Plasma Levels | Maximum Drug plasma concentration levels by study arm | Weeks 1,4,8,13 |