AMO-01 to Treat Adolescents and Adults With Phelan-McDermid Syndrome (PMS) and Co-morbid Epilepsy

Study Overview
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Brief Summary
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The purpose of this study is to investigate the safety, tolerability and efficacy of a single 6-hour intravenous infusion of AMO-01 to treat adolescents and adults with PMS and co-morbid epilepsy. Phelan-McDermid Syndrome (PMS) is a neurodevelopmental disorder characterized by a chromosomal deletion or mutation at 22q13.3 that contains the SHANK3/ProSAP2 gene. A key co-morbidity in PMS is the presence of epilepsy. Currently there are no approved treatments for PMS. Furthermore, there has been relatively little clinical study of pharmacological interventions for PMS. AMO-01 may provide benefit to PMS patients exhibiting behavioral abnormalities and seizures.

Official Title
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An Open-label Study to Investigate the Safety, Tolerability and Efficacy of a Single 6-hour Intravenous Infusion of AMO-01 to Treat Adolescents and Adults With Phelan-McDermid Syndrome (PMS) and Co-morbid Epilepsy

Conditions
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Phelan-McDermid Syndrome, Epilepsy

Intervention / Treatment
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* Drug: AMO-01


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects under study must have a diagnosis of Phelan McDermid syndrome (PMS) with genetic confirmation of pathogenic SHANK3 deletion or mutation. Subjects must be post pubertal males or females aged ≥12 years and ≤45 years at Screening. Subject must have a diagnosis of epilepsy. Subjects must have a syndrome-specific Clinical Global Impression- Severity Score of 4 or greater at Screening Subject's parent or legally authorized representative (LAR) must provide written informed consent before any study related procedures are conducted. Where a parent or LAR provides consent, there must also be assent from the subject (as required by local regulations). Subject's caregiver must be willing and able to support the subject's participation for the duration of the study. Subject's caregiver is able and willing to maintain an accurate and complete daily written seizure diary for the entire duration of the study. Exclusion Criteria: Receiving medications/therapies not stable (i.e. changed) within 4 weeks prior to Screening. For each enrollee, every effort should be made to maintain stable regimens of allowed concomitant medications and allowed non -medicine based therapies throughout the course of the study, from Screening until the last study assessment. Known hypersensitivity to farnesylated dibenzodiazepinone or any of the formulation components. Subjects with a history of uncontrolled hypotension or hypertension (Polysorbate 80 is a major constituent of AMO-01 and can cause hypotension). Subjects that have received Coumadin or heparin in the 2 weeks preceding Screening. Medical illness or other concern which would cause the investigator to conclude that the subject will not be able to perform the study procedures or assessments or would confound interpretation of data obtained during assessments. Females who are pregnant, lactating or not willing to use a protocol-defined acceptable contraception method if sexually active and not surgically sterile. Males, engaged in sexual relations with a female of child bearing potential, not using an acceptable contraception method if sexually active and not surgically sterile. Clinically significant abnormalities in safety laboratory tests, vital signs or ECG, as measured at Screening (may repeat to confirm). Current clinically significant (as determined by the investigator) neurological, cardiovascular, renal, hepatic, endocrine or respiratory disease that may impact the interpretability of the study results. Current clinically significant (as determined by the investigator) lymphedema that may compromise venous access and/or may have an adverse impact on study drug distribution and clearance. Judged clinically to be at risk of suicide by the investigator. Average QTcF value of >450 msec at Screening (may repeat to confirm). Subjects in whom an indwelling intravenous line could not be established or maintained.

Ages Eligible for Study
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Minimum Age: 12 Years
Maximum Age: 45 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
Intervention Model: Single Group Assignment
Interventional Model Description: Single Group, open label
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: AMO-01<br>Intravenous Infusion | Drug: AMO-01<br>* Subjects will receive a single 6-hour intravenous infusion for a total dose administration or 120 mg/m2 of AMO-01.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Adverse Events | An adverse event is defined as any untoward medical occurrence in a study subject, temporally associated with the use of the experimental medication, whether or not considered related to the medication. An adverse event can therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of the experimental medication. Adverse events will be monitored throughout all 8 weeks of study participation. | 8 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in CGI - Improvement Scale | Clinical Global Impressions (CGI) Rating Scales are commonly used to measure symptom severity and global improvement in treatment studies of patients with developmental disorders. There Severity Scale (CGI-S) is a 7-point scale that requires the clinician to rate the severity of illness at the time of assessment. The Improvement Scale (CGI-I) is a 7-point scale (1, very much improved; 2, much improved; 3, minimally improved; 4, no change; 5, minimally worse; 6, much worse; or 7, very much worse.) that requires the clinician to assess how much the illness has improved or worsened relative to baseline. | baseline and 8 weeks | 
| Clinician-completed PMS Domain Specific Causes for Concerns Visual Analogue Scale (VAS) | 9 item visual analogue scale completed by the clinician that scores the severity of concerns in domains that are clinically relevant in PMS. For each subject, the clinician is instructed to identify the top 4 or 5 that are of particular concern and that the clinician would most like to see change during the course of treatment with the study medication. The severity of the clinician's concern in each domain is scored by using a 10 cm visual analogue scale, with anchors of 0 not at all severe at the left and 100 very severe at the right end. | 8 weeks | 
| Top 3 Caregiver Concerns VAS | The Top 3 concerns visual analogue scale allows caregivers to identify their main three causes of concern, related to the subject's PMS. Caregivers will be asked to rate each of the three causes for concern by drawing a vertical mark on a 10 cm long visual analogue scale, with anchors of 0 not at all severe at the left end and 100 very severe at the right end. | 4 weeks | 
| Aberrant Behavior Checklist (ABC) | rating scaled used to monitor an array of behavioral features among patients with intellectual disabilities. It takes 15-30 minutes to complete. 16 items, Each item is scored as 0 (never a problem), 1 (slight problem), 2 (moderately serious problem), or 3 (severe problem). with total from 0 to 48. | 4 weeks | 
| Repetitive Behavior Scale-Revised (RBS-R) | 42-item rating scale that is completed by a parent or caregiver. It reports on the severity of repetitive behaviors. each item scored on 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. with total score from 0 (mild) to 126 (severe). | 4 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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AMO-01, Shank3, Clinical Trial