Safety of L1-79 in Autism

Study Overview
=================
Brief Summary
-----------------
This is a five-arm designed to assess the safety of L1-79 that incorporates 15 prospectively randomized, placebo controlled patients and 5 open label patients at either 100 tid (three times daily) or 200 tid dosing for 28 days. The open label patients will be assessed for the purpose of understanding PK/PD and to determine if there are any EKG changes associated with the administration of L1-79. Additional safety information will be provided by the 30 patients randomized 2:1 active:placebo.

Detailed Description
-----------------
Protocol Number: HT 02-121 Protocol Title: Phase 2 Safety Study of L1-79 for the Treatment of Autism Study Phase: 2 The first cohort of 20 patients to be enrolled will all receive L1-79 100 mg t.i.d., and will be comprised of 3 groups of patients. The first group of patients to receive 100 mg will differ from the others in that they will get blood samples drawn for PK analysis and EKGs will be taken. The safety and PK data from this group will be submitted for FDA review and acceptance before the 200 mg t.i.d. cohort will be enrolled. The remaining 15 patients in this cohort will be randomized to receive either L1-79 100 mg t.i.d. or placebo on a 2:1 basis (2 L1-79 patients for each placebo patient). While the FDA is reviewing the data from the first 5 patients all 100 mg t.i.d. patients will continue to be treated. The second cohort is identical to the first. The initial 5 patients to be enrolled will differ from the others in that they will get blood samples drawn for PK analysis and EKGs will be taken. The remaining 15 patients in this cohort will be randomized to receive either L1-79 200 mg t.i.d. or placebo on a 2:1 active:placebo. Sample Size: N=40 Group 1 (n=5) open100mg L1-79 (1x100mg capsule+1 placebo capsule) Group 2 (n=10) blind100mg L1-79 (1x100mg capsule+1 placebo capsule) Group 3 (n=5) open200 mg L1-79 (2x100 mg capsules) Group 4 (n=10) blind200 mg L1-79 (2x100 mg capsules) Group 5 (n=10) Placebo (2 placebo capsules) All Groups will receive the assigned study drug three-times daily Study Population: Male subjects with autism between the ages of 13 and 21 years of age who meet the entry criteria and who are able to complete standardized measures allowing them to participate in this study. Evaluation Schedule: Subjects will be evaluated within one week prior to study accession, and weekly throughout the dosing period, and again 4 weeks after the cessation of treatment. The Assigned Dosage Groups (Groups 1 and 3) will have PK blood draws and EKG the randomized group will not have. Safety Measures: All Groups will have regularly scheduled complete history and physical examination that includes orthostatic blood pressure measurements, vital signs, CBC, differential, platelet counts, urine analysis, and serum analytes including: total protein, albumin, glucose, BUN, creatinine, direct and total bilirubin, alkaline phosphatase, phosphorous, calcium, AST, ALT, sodium, potassium, chloride, bicarbonate, T4, TSH, and adverse events assessments. The Assigned Groups (1 and 3) will also have electrocardiograms taken at the study screening visit and weekly throughout the treatment interval.

Official Title
-----------------
A Phase 2 Safety Study of L1-79 for the Treatment of Autism

Conditions
-----------------
Autism

Intervention / Treatment
-----------------
* Drug: L1-79
* Drug: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Males who are not sexually active 13 and 21 years of age Signed informed consent Normal clinical laboratory values DSM-5 compliant diagnosis of autism spectrum disorder, confirmed by the Autistic Diagnosis Interview Review (ADIR), and by the Autism Diagnosis Observation Schedule (ADOS) score consistent with a diagnosis of autism No more than one concomitant medication for the treatment of autism, on a stable for at least 2 weeks prior to enrollment and no planned changes in psychosocial interventions during the trial No medications for any other pathology Exclusion Criteria: Any co-morbidities, including Fragile-X syndrome, epilepsy, Retts syndrome, ADHD, or other disease or syndrome aside from autism that requires treatment Any other psychiatric disorder, or out of range lab values DSM-5 diagnosis of schizophrenia, schizoaffective disorder, alcohol use disorder Active medical problems: unstable seizures (>2 in past month) Concomitant physical illness

Ages Eligible for Study
-----------------
Minimum Age: 13 Years
Maximum Age: 21 Years

Sexes Eligible for Study
-----------------
Male

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

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

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 100 mg open<br>open-label lead-in 100 mg L1-79 t.i.d. | Drug: L1-79<br> <br> |
| Experimental: 100 mg blinded<br>blinded and randomized 100 mg L1-79 t.i.d. | Drug: L1-79<br> <br> |
| Experimental: 200 mg open<br>open-label lead-in 200 mg L1-79 t.i.d. | Drug: L1-79<br> <br> |
| Experimental: 200 mg blinded<br>blinded and randomized 200 mg L1-79 t.i.d. | Drug: L1-79<br> <br> |
| Placebo Comparator: Placebo<br>placebo t.i.d. | Drug: Placebo<br> <br> |

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adverse event frequency | Adverse events will be solicited over 56 days from the start of treatment | 56 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline in CGI | The attending physicians assessment as quantified by the Clinical Global Impressions Scale completed at baseline and weekly through 56 days of treatment and follow-up. | Week 0 and weekly for first 28 days, and at day 56. | 
| Change from Baseline in Vineland Adaptive Behavior Scales - 2nd Edition | Changes from baseline in Communication and Socialization domain of Vineland Adaptive Behavior Scale 2nd edition (VABS II) | Day 0 and at days 28 and 56. | 
| Change from Baseline in the Autism Diagnostic Observation Schedule (ADOS) | Changes from baseline in the Autism Diagnostic Observation Schedule (ADOS) total and domain scores. | Day 0 and at days 28 and 56. | 
| Change from baseline in Aberrant Behavior Checklist - Community | Weekly Changes from baseline in the Aberrant Behavior Checklist-Community (ABC-C) domains of irritability, social withdrawal and lethargy, hyperactivity, inappropriate speech and stereotypical behavior. | Week 0 and weekly for first 28 days, and at day 56. | 
| Change from baseline in the Social Responsiveness Scale - 2nd edition (SRS-2) | Weekly changes from baseline in overall and subdomains of the Social Responsiveness Scale (SRS). | Week 0 and weekly for first 28 days, and at day 56. | 
| Changes from baseline in the Repetitive Behavior Scale - Revised (RBS-R). | Weekly changes from baseline in the overall and subdomains of the Repetitive Behavior Scale - Revised (RBS-R). | Week 0 and weekly for first 28 days, and at day 56. | 
| Plasma concentrations of L1-79 | Blood will be collected from assigned patients in each dose group at baseline visit one hour after dose and again at each clinic visit at random times after dose for determination of L1-79 concentrations | Week 0 and weekly for 28 days; random sampling times will be employed |