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.
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.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
QUADRUPLE
Enrollment
42
Eric Bartky MD, Bartky Health Care Center
Livingston, New Jersey, United States
F. Peter Halas MD, Sea Girt Pediatrics
Sea Girt, New Jersey, United States
Adverse Events
Number of Participants with On-treatment Adverse Events. To be conservative, it was pre-specified that all placebo data be combined (open-label, first cohort, and second cohort) for the safety population. For the efficacy population open-label data was excluded due to potential bias and placebo arms from the first and second cohort were presented separately due to differences in efficacy questionnaires completion in the first and second cohorts. Theses differences were not relevant to the adverse event data.
Time frame: 4 weeks
Change From Baseline in Clinical Global Impression Scale (CGI)
The Clinical Global Impression (CGI) has two components: the CGI-Severity (CGI-S), which rates illness severity, and the CGI-Improvement (CGI-I), which rates the change in illness severity from baseline. The CGI-S is rated on the following seven-point scale with 1 being normal and 7 being among the most extremely ill subjects. The CGI-I score is rated on a seven-point scale with 1 being very much improved and 7 being very much worse. Higher values of the CGI-S score indicate a "worse" state. CGI-I scores of 5 or greater indicate decline, CGI I scores of 3 or lower indicate improvement, and a CGI-I score of 4 indicates no change.
Time frame: Week 0 and Week 4
Change From Baseline in Vineland Adaptive Behavior Scale - 2nd Edition Socialization Standard Score
The Vineland Adaptive Behavior Scales, Second Edition (VABS-II) indicates adaptive functioning and consists of four major domains. Only the communication and socialization domains were done in this study. The VABS-II data is comprised of Socialization. Socialization Standard Scores may range from 20 to 160, with a population mean of 100 and a standard deviation of 15. Lower Vineland Adaptive Behavior Socialization Standard Scores indicate a "worse" state. A positive value of change from baseline indicates improvement.
Time frame: Day 0 and Week 4
Change From Baseline in Vineland Adaptive Behavior Scale - 2nd Edition Communication Standard Score
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The Vineland Adaptive Behavior Scales, Second Edition (VABS-II) indicates adaptive functioning and consists of four major domains. Only the communication and socialization domains were done in this study. The VABS-II is comprised of Communication. Communication Standard Scores may range from 20 to 160, with a population mean of 100 and a standard deviation of 15. Lower Vineland Adaptive Behavior Communication Standard Scores indicate a "worse" state. A positive value of change from baseline indicates improvement.
Time frame: Week 0 and Week 4
Change From Baseline in the Autism Diagnostic Observation Schedule 2nd Edition (ADOS-2) Overall Total Score
The Autism Diagnostic Observation Schedule 2nd Edition (ADOS-2) is the "Gold Standard" for assessing severity of ASD and position on the autism spectrum. The ADOS-2 is a semi-structured, standardized assessment of: Communication, Social interaction, Play, and Restricted and repetitive behaviors. The total scores range from 15 to 60, and the cut-off score to determine autism is 30. More specifically, a score of \<30 is classified as non-autism, a score of 30-36 is classified as mild to moderate autism, and a score of ≥37 is classified as severe autism. A higher ADOS-2 value indicates a "worse" state. A negative value of change from baseline indicates an improvement.
Time frame: Day 0 and Week 4
Change From Baseline in the Social Responsiveness Scale - 2nd Edition (SRS-2) Total T-score
Social Responsiveness Scale - 2nd edition (SRS-2) identifies social impairment associated with ASD and quantifies its severity. Raw and T-scores will be collected for SRS-2 Total, Social Awareness, Social Cognition, Social Communication, Social Motivation, Restricted Interest and Repetitive Behavior, DSM-5 Social Communication, and DSM-5 Restrictive Interest and Repetitive Behavior. Each domain has a varied but similar ranges of possible scores from 32 points-114 points. All T-scores have a mean of 50 points with a standard deviation of 10 points. A higher SRS-2 total T-score indicates greater impairment. A negative change from baseline indicates improvement.
Time frame: Week 0 and Week 4
Change From Baseline in Aberrant Behavior Checklist - Community (ABC-C)
The Aberrant Behavior Checklist - Community (ABC-C) is a 58-symptom checklist for assessing problem behaviors of children and adults with developmental disabilities (intellectual disability, ASD, cerebral palsy, epilepsy) that resolve onto five subscales. The subscales and the respective number of items are as follows: (a) irritability (15 items, scores range from 0-45), (b) lethargy/social withdrawal (16 items, scores range from 0-48), (c) stereotypic behavior (7 items, scores range from 0-21), (d) hyperactivity/noncompliance (16 items, scores range from 0-48), and (e) inappropriate speech (4 items, scores range from 0-12). Higher ABC-C subscale scores indicates a "worse" outcome. A negative value of change from baseline indicates improvement.
Time frame: Week 0 to Week 4
Change From Baseline in the Repetitive Behavior Scale - Revised (RBS-R) Total Score
The RBS-R is a 43-item self-report questionnaire that is used to measure the breadth of repetitive behavior in children, adolescents, and adults with Autism Spectrum disorders. Behaviors are rated on a 4-point scale: 0-Behavior does not occur, 1-Behavior occurs and is a mild problem, 2-Behavior occurs and is a moderate problem, 3-Behavior occurs and is a severe problem. The total score is the sum of all 6 subscale scores and ranges from 0-127, stereotypic behavior ranges from 0-18, self-injurious behavior ranges from 0-24, compulsive behavior ranges from 0-24, ritualistic behavior ranges from 0-18, sameness behavior ranges from 0-33 and restricted behaviors ranges from 0-12. A higher RBS-R score indicates a "worse" state. A negative value of change from baseline indicates an improvement.
Time frame: Week 0 and Week 4