| 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 |
To evaluate the efficacy of OV101 versus placebo as assessed by the Clinical Global Impressions-Improvement-Angelman syndrome (CGI-I-AS) score at Week 12
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| E.2.2 | Secondary objectives of the trial |
Key objectives
-To evaluate the efficacy of OV101 vs placebo as assessed by the proportion of subjects who experience any meaningful improvement on study treatment (defined as CGI-I-AS score of 1, 2, or 3 at week 12)
-To evaluate the efficacy of OV101 vs placebo as assessed by the proportion of subjects who experience a response of much improved or very much improved (defined as CGI-I-AS score of 1 or 2 at week 12)
Other objectives
-To evaluate the efficacy of OV101 vs placebo on latency of sleep onset, sleep efficiency, and daytime sleep assessed by actigraphy
-To evaluate the efficacy of OV101 vs placebo on Communications, Socialization, Daily Living Skills, Motor Skills, and Maladaptive Behavior domains assessed by VABS-3.
-To evaluate the efficacy of OV101 vs placebo based on the (CGI-S-AS) Symptoms Overall score.
- To evaluate the relationships of CGI-S-AS Symptoms Overall and CGI-S-AS domains at baseline with CGI-I-AS at Week 12. |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1.Is male or female and 2 to 12 years old (inclusive) at the time of informed
consent.
2. Has a diagnosis of AS with molecular confirmation
3. Has a CGI-S-AS score of 3 or more.
4. Meets the following age-appropriate body weight criterion:
a) Subjects 2 to 3 years old must have a minimum body weight of 9 kg.
b) Subjects 4 years and older must be between 17 kg and 64 kg (inclusive).
5. Has a legally acceptable representative (LAR)/caregiver capable of providing written 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.
6. Provides assent to the protocol (to the extent possible and in accordance with local institutional review board [IRB] and regulatory requirements). Subjects providing assent must do so at the same visit as LAR/caregiver written informed consent is provided.
7. Can swallow study drug capsules with water or ingest the contents of study drug capsules after sprinkling the contents of each capsule onto up to 1 teaspoon of low-fat semiliquid food.
8. If a subject is currently receiving a regimen of concomitant medications such as antiepileptic medication, gabapentin, clonidine, trazodone, melatonin, or a special diet 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).
9. If a subject is a sibling in a family with multiple children diagnosed with AS, then only one of the siblings may enroll in study. The eldest eligible subject should be enrolled (investigator discretion may be used to enroll a younger sibling instead).
10. Has LAR(s)/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(s), online support group(s), or social media site (eg, Facebook, Instagram, Twitter, etc.) until notified that the study is completed.
11. Female subjects who are of child-bearing 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. Highly effective contraceptive methods are as follows:
a. Combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation:
• Oral
• Intravaginal
• Transdermal
b. Progestogen-only hormonal contraception associated with inhibition of ovulation:
• Oral
• Injectable
• Implantable
c. Intrauterine device
d. Intrauterine hormone-releasing system
e. Bilateral tubal occlusion
f. Vasectomized partner
g. Sexual abstinence
Acceptable birth control methods that result in a failure rate of more than 1% per year include:
a. Progestogen-only oral hormonal contraception, where inhibition of ovulation is not the primary mode of action.
b. Male or female condom with or without spermicide.
c. Cap, diaphragm, or sponge with spermicide.
d. 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 |
1. Has a circumstance or concomitant disease (eg, gastrointestinal, renal, hepatic, endocrine, respiratory, or cardiovascular system disease), condition, or any clinically significant finding at screening that could interfere with the conduct of the study or that would pose an unacceptable risk to the subject in the opinion of the investigator.
2. Has poorly controlled seizures defined as any of the following:
a. Weekly seizures of any frequency with a duration more than 3 minutes.
b. Weekly seizures occurring more than 3 times per week, each with a duration
of less than 3 minutes.
c. Investigator assessment.
3. 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 English:
1. Has a circumstance or concomitant disease (eg, gastrointestinal, renal, hepatic, endocrine, respiratory, or cardiovascular system disease), condition, or any clinically significant finding at screening that could interfere with the conduct of the study or that would pose an unacceptable risk to the subject in the opinion of the investigator.
2. Has poorly controlled seizures defined as any of the following:
a. Weekly seizures of any frequency with a duration more than 3 minutes.
b. Weekly seizures occurring more than 3 times per week, each with a duration
of less than 3 minutes.
c. Investigator assessment.
3. 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.
4. 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 for situational anxiety related to occasional procedures or events are permitted, and benzodiazepines are also permitted for seizure control.
5. Cannot tolerate wearing the actigraph for at least 7 consecutive days (including 2 consecutive weekend days) during the 28-day screening period of the study, after 3 attempts.
6. Is at risk of harming self and/or others (based on investigator assessment).
7. Has enrolled in any other interventional clinical study 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).
10. Is a family member of the investigator and/or study site staff.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| The CGI-I-AS score at Week 12 |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
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| E.5.2 | Secondary end point(s) |
Key Secondary Endpoints
• CGI-I-AS response (at least minimally improved) defined as CGI-I-AS score of 1, 2, or 3 at week 12
• CGI-I-AS response (at least much improved) defined as CGI-I-AS score of 1 or 2 at week 12
Other Secondary Endpoints
Actigraphy assessment scores, change from baseline to Week 12
• Latency of sleep onset (LSO), defined as time from beginning of rest period to start of sleep onset
• Sleep efficiency, defined as the percentage of total sleep time out of duration of the rest period
• Total daytime sleep, defined as duration of sleep time in the active interval
• VABS-3 assessment scores; change from baseline to Week 12
-Communication domain and its subdomains
-Socialization domain and its subdomains
-Daily Living Skills domain and its subdomains
-Motor Skills domain and its subdomains
-Maladaptive Behavior domain and its subdomains
• The CGI-S-AS scores, change from baseline to Week 12.
-The CGI-S-AS symptoms overall score
-The CGI-S-AS domain scores
• The relationship between CGI-S-AS at baseline and CGI-I-AS at Week 12
• The relationship between each of CGI-S-AS domains at baseline and CGI-I-AS at Week 12
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
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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 | Yes |
| 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 | No |
| 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 | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| 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 | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| 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 | 4 |
| 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 |
| Italy |
| 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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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | |
| E.8.9.1 | In the Member State concerned months | 4 |
| E.8.9.1 | In the Member State concerned days | 15 |
| 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 | 15 |
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