| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| E.1.1.1 | Medical condition in easily understood language |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Nervous System Diseases [C10] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10049004 |
| E.1.2 | Term | Angelman's syndrome |
| E.1.2 | System Organ Class | 10010331 - Congenital, familial and genetic disorders |
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| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| The primary objective of this study is to evaluate the long-term safety and tolerability of OV101 in individuals with AS assessed by the incidence and severity of AEs and SAEs in subjects who are at least 2 years old |
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| E.2.2 | Secondary objectives of the trial |
The secondary objectives of this study are the following:
•To evaluate the long-term efficacy of OV101 treatment assessed by changes in behavior and sleep in subjects with AS who are at least 4 years old
•To evaluate the long-term safety and tolerability of OV101 treatment assessed by changes in suicidality assessments, vital sign measurements, laboratory assessments, physical examinations, and seizure frequency in subjects with AS who are at least 2 years old.
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Study enrollment criteria:
• Has completed the OV101-15-001 or OV101-16-001 study up to the end of study (EOS), or
• Has completed the OV101-19-001 (EudraCT # 2019-002907-17) study up to the end of treatment (EOT), or
• Is a sibling of a subject with AS who has completed OV101-15-001 , OV101 16 001, or OV101-19-001 (EudraCT # 2019-002907-17)
1. Has a previous diagnosis of AS with molecular confirmation.
2. Is at least 2 years old and has a body weight of at least 9 kg.
3. Has a legally acceptable representative (LAR)/caregiver capable of providing informed consent and able to attend all scheduled study visits, oversee the administration of study drug, and provide feedback regarding the subject’s symptoms and performance as described in the protocol.
4. Provides assent to the protocol (to the extent possible and in accordance with local institutional review board and regulatory requirements) and has an LAR/caregiver who will provide written informed consent. Subjects providing assent must do so at the same visit as LAR/caregiver written informed consent is provided.
5. Can swallow study drug capsules with water or ingest the contents of study drug capsules after sprinkling the capsule contents onto up to 1 teaspoon of low-fat semiliquid food.
6. If a subject is currently receiving a regimen of concomitant medications such as antiepileptic medication, gabapentin, clonidine, trazodone, melatonin, and/or a special dietary regimen, that subject’s regimen is stable for at least 4 weeks before Day 1 (first day of study drug administration) and will be maintained throughout the duration of the study (in the judgment of the investigator).
7. Has LAR/caregiver(s) who agree not to post any of the subject’s personal medical data or information related to the study on any website, message board, online support group, or social media site (eg, Facebook, Instagram, Twitter) until notified that the study is completed.
8. Female subjects who are of childbearing potential (defined as having experienced their first menarche) must agree to use either a highly effective or acceptable form of birth control during the study and for 30 days following the last dose of the study drug. Highly effective contraceptive methods are as follows:
• Combined (estrogen- and progestogen-containing) hormonal contraception associated with inhibition of ovulation: Oral, Intravaginal, Transdermal
• Progestogen-only hormonal contraception associated with inhibition of ovulation: Oral, Injectable, Implantable, Intrauterine device
• Intrauterine hormone-releasing system
• Bilateral tubal occlusion
• Vasectomized partner
• Sexual abstinence
Acceptable birth control methods that result in a failure rate of more than 1% per year include:
• Progestogen-only oral hormonal contraception, where inhibition of ovulation is not the primary mode of action
• Male or female condom with or without spermicide*
• Cap, diaphragm, or sponge with spermicide*
*A combination of male condom with either cap, diaphragm, or sponge with spermicide (double barrier methods) are also considered acceptable, but not highly effective, birth control methods.
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| E.4 | Principal exclusion criteria |
Subjects meeting any of the following criteria will be excluded from the study:
1. Discontinued from the OV101-15-001, OV101-16-001, or OV101-19-001 (EudraCT # 2019-002907-17) study due to safety reasons causally related to OV101.
2. Has a circumstance, condition, concomitant disease (eg, gastrointestinal, renal, hepatic, endocrine, respiratory, or cardiovascular system disease), or any clinically significant finding that could interfere with the conduct of the study or that would pose an unacceptable risk to the subject in this study.
3. Has poorly controlled seizures defined as any of the following:
• Weekly seizures of any frequency with a duration of more than 3 minutes each
• Weekly seizures occurring more than 3 times per week, each with a duration of less than 3 minutes
• Investigator assessment
4. Has any of the following laboratory abnormalities: total bilirubin >1.5 × upper limit of normal (ULN), unless known Gilbert’s syndrome; alanine aminotransferase or aspartate aminotransferase >2.5 × ULN; serum creatinine >1.2 × ULN; absolute neutrophil count <1.5 × 109/L; platelets <80 × 109/L; hemoglobin <80 g/L; or thyroid stimulating hormone >1.25 × ULN or <0.8 × lower limit of normal. Retesting of clinical laboratory parameters may be allowed after consultation with the medical monitor or designee.
5. Use of benzodiazepines, zolpidem, zaleplon, zopiclone, eszopiclone, barbiturates, or ramelteon for sleep, or minocycline or levodopa within the 4 weeks prior to Day 1 or during the study. Benzodiazepines administered as needed or regularly scheduled for indications other than insomnia and benzodiazepines for seizure control are permitted.
6. Is at risk of harming self and/or others (based on investigator assessment).
7. With the exception of an Ovid study of OV101, has enrolled in any clinical or used any investigational agent or device, or has participated in any investigational procedure, within the 30 days before screening or does so concurrently with this study.
8. Is allergic to OV101 or any excipients of study drug.
9. The subject or LAR/caregiver is unable to comply with study requirements (based on investigator assessment).
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Safety Endpoints
The following safety endpoints will be evaluated for subjects who are at least 2 years old:
• Incidence of SAEs, TEAEs, treatment-related TEAEs, and TEAEs leading to study discontinuation
• Vital sign measurements
• Clinical safety laboratory values
• Physical examination
• Assessment of suicidality
• The 28-day seizure frequency
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Clinic visits at Weeks 12, 36, 64, 96, 128, and 160 (EOT). |
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| E.5.2 | Secondary end point(s) |
LAR/Caregiver-Completed Endpoints (for Subjects at Least 4 Years Old)
• Change from baseline in the CSHQ total and subscale scores
• Change from baseline in sleep diary parameters:
o Latency of sleep onset (LSO), defined as time from beginning of rest period to start of sleep onset
o Sleep efficiency, defined as the percentage of total sleep time out of duration of the rest period
o Total daytime sleep, defined as duration of sleep time in the active interval
Clinician-Completed Endpoints (for Subjects at Least 4 Years Old)
• CGI-I-AS scores
• Change from baseline in CGI-S-AS scores:
o The CGI-S-AS symptoms overall score
o The CGI-S-AS domain scores
• Change from baseline in the VABS-3 overall composite and subscale scores:
o Communication domain and its subdomains
o Socialization domain and its subdomains
o Daily Living Skills domain and its subdomains
o Maladaptive Behavior domain and its subdomains
Exploratory Endpoints
LAR/Caregiver-Completed Endpoints (for Subjects at Least 4 Years Old)
• Change from baseline in PedQoLI total and subscale scores
Clinician-Completed Endpoints (for Subjects at Least 4 Years Old)
• Change from baseline in the VABS-3 Motor Skills domain and its subdomains
Endpoints for Relationship Exploration
• Endpoints of interest may be identified to explore the relationships among them.
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Clinic visits at Weeks 12, 36, 64, 96, 128, and 160 (EOT). |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
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| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 3 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Australia |
| Germany |
| Israel |
| Netherlands |
| United States |
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| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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| The end of the study is defined as the date on which the last subject completes the last visit (includes the phone EOS visit). |
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 4 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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