| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Improvement of Hyperphagia and related behaviors as well as Body Composition/Overweight in Prader-Willi-Syndrome |
|
| E.1.1.1 | Medical condition in easily understood language |
| improvement of addiction to eat and related behaviors as well as overweight in patients suffering of Prader-Willi-Syndrome |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Congenital, Hereditary, and Neonatal Diseases and Abnormalities [C16] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 18.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10036476 |
| E.1.2 | Term | Prader-Willi syndrome |
| E.1.2 | System Organ Class | 10010331 - Congenital, familial and genetic disorders |
|
| 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 assess changes in hyperphagia-related behaviors and total body weight for beloranib administered over 52 weeks
- To assess safety and tolerability effects of beloranib administered over 52 weeks |
|
| E.2.2 | Secondary objectives of the trial |
| - To assess changes in total body fat mass as measured by DXA for beloranib over 52 weeks (sub-study, not to be pursued at investigational sites in Germany) |
|
| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
| Dual-Energy X-ray Absorptiometry (DXA) Scan to assess body composition and BMC. |
|
| E.3 | Principal inclusion criteria |
1) Age 12-50 years, inclusive.
2) Confirmed diagnosis of PWS due to chromosome 15 micro-deletion, maternal uniparental disomy, or imprinting defect. Documentation of PWS, including variant of genetic defect in the subject’s medical record is sufficient.
3) HQ-CT score ≥11 (scale of 0-36).
4) Obese
a. Age 12-17 years: Body mass index (BMI) ≥90th percentile for age and gender (per United Kingdom [UK] Royal College of Pædiatrics and Child Health BMI charts)
b. Age 18-50 years: BMI ≥27 to ≤70 kg/m^2
5) Stable body weight for 3 months (self or guardian-reported loss/gain <10%).
6) If a subject has current diagnosis of T2DM, the following criteria must be met:
a. HbA1c <10.0%
b. Fasting glucose <240 mg/dL (<13.3 mmol/L)
c. No history of ketoacidosis or hyperosmolar coma
7) All study participants must agree to use an approved method of contraception throughout the study (unless subject is confirmed to be infertile or has a history of and/or commitment of long-term abstinence).
Females
a. Intra-uterine device (IUD) in place from Screening through study completion as deemed appropriate for patient use by the treating physician's judgement.
b. Stable hormonal contraception (with approved oral, transdermal, or depot regimen) for at least 3 months prior to Screening through study completion
Male partners of female subjects must use a barrier method (e.g. condom) in addition to the female subject having an IUD in place or using stable hormonal contraception.
Males that are sexually active
c. Barrier method (e.g., condom) from Screening through study completion
AND one of the following:
d. Female partner has IUD in place from Screening or stable hormonal contraception for at least 3 months prior to Screening through study completion
OR
e. Female partner is infertile
(Infertility for females is defined as surgically sterile or those who have had 12 months of amenorrhea and negative urine pregnancy test at Screening.)
8) Subjects must be able to provide or have a guardian who is able to provide written informed consent.
9) Subject must be current on immunizations prior to enrollment, as prescribed by their health care professional according to the investigative site’s standard of care.
10) Subjects must have at least one consistent and reliable primary caregiver who is able to accurately evaluate changes in the subject’s mood, AEs, behavior, and document MRU (e.g., planned and unplanned visits to healthcare providers, emergency room visits, hospitalization, etc.) throughout the study. The caregiver must have been caring for the subject for at least 6 months prior to study entry, is anticipated to be the subject’s primary caregiver for the duration of the trial, and spends at least 4 waking hours per day on average with the subject. The caregiver must be able to read and understand the local language or be able to communicate with Investigator/site staff. |
|
| E.4 | Principal exclusion criteria |
1) Poorly controlled severe psychiatric disorders (e.g., schizophrenia, bipolar disorder, or major depressive order), recent (within 6 months) psychotic episodes, history of suicide attempts or suicidal ideation, or any other psychiatric disorders that the Investigator believes will interfere significantly with study compliance.
2) History of any bleeding disorders, deep vein thrombosis (DVT), or thromboembolic disease.
3) Current liver, renal, pulmonary, cardiac, oncologic, or GI disease which the Investigator believes is clinically significant, including:
a. Significant cardiovascular disease including history of congestive heart failure (CHF), coronary artery disease, myocardial infarction (MI), second degree or greater heart block , prolonged time from electrocardiogram Q wave to the end of the T wave corresponding to electrical systole (QT) syndrome, or clinically significant arrhythmias.
b. Fridericia-corrected QT interval (QTcF) >460 msec for males and QTcF >480 msec for females pre-dose on Day 1.
c. Liver disease or liver function tests, aspartate aminotransferase (AST) and alanine aminotransferase (ALT) >3x upper limit of normal (ULN), alkaline phosphatase (ALP) or serum bilirubin >3x ULN, or history of hepatic cirrhosis.
d. History or presence of impaired renal function as indicated by clinically significant abnormal creatinine, blood urea nitrogen (BUN), or urinary constituents or moderate to severe renal dysfunction as defined by the Cockcroft-Gault equation (<60 mL/min).
4) Type 1 diabetes mellitus or current or recent use of insulin (more than 1 week within 3 months prior to Screening).
5) Uncontrolled endocrine disorders (e.g., Cushing syndrome, Addison’s, hypothyroidism, hypogonadism), except T2DM with HbA1c<10%.
6) Clinically significant and abnormal Screening hematology lab results or recurring infections, or if any of the following are observed (regardless of the Investigator’s assessment of clinical significance):
a. Hemoglobin <10 g/dL (<100 g/L)
b. Absolute neutrophil count (ANC) <2000/mm^3
c. Platelets <135 x 10^9/L
7) Results of Screening clinical laboratory tests (complete blood count [CBC] with differential and platelets, chemistry, and urinalysis profile) and ECG outside normal range and considered to be clinically significant by the Investigator.
8) Subjects on the following systemic concomitant medications who have not been on stable dose (or stable weight based dose), defined as no more than ±25% variation in dose, for at least 3 months prior to study entry:
a. Growth hormone
b. Glucocorticoids
c. Vasopressin
d. Thyroid hormone
e. Testosterone
f. Other hormone or hormone replacement therapies
g. Anti-obesity agents (must have been stable for ≥6 months)
h. Anti-diabetes medications (except for glucagon-like peptide-1 [GLP-1] analogues or sodium-glucose linked transporter 2 (SGLT2) inhibitors must have been stable for ≥6 months)
i. Modafinil
j. Atypical anti-psychotics
k. Anti-depressive
l. Attention deficit hyperactivity disorder (ADHD) medications
9) Vital signs unstable, or with the following values:
a. Systolic blood pressure >160 mm Hg
b. Diastolic blood pressure >100 mm Hg
c. Pulse rate >100 beats per minute (bpm)
10) Recent (within the last year) and/or recurrent history of autonomic dysfunction (e.g., unexplained syncope or palpitations).
11) Current or anticipated chronic use (more than 2 days) of narcotics or opiates.
12) Significant history of abuse of drugs or solvents in the year before Screening, or history of alcohol abuse in the past year before Screening or currently drinks in excess of 21 units or servings per week.
13) Participation in any clinical study with an investigational drug/device within 3 months, or prior clinical studies involving beloranib (ZGN-433 or ZGN-440).
14) Positive result for tuberculosis (TB), human immunodeficiency virus (HIV), Hepatitis B virus (HBV), or Hepatitis C virus (HCV) prior to randomization and initiation of dosing with blinded study drug.
15) Allergies to intralipid, soybean, eggs, peanuts, glycerol/ glycerin, or serious adverse reaction or hypersensitivity to any drug which the Investigator believes is clinically significant and relevant to study participation.
16) Significant blood loss or blood donation >500 mL within 3 months.
17) Females who are pregnant, nursing, or intend to become pregnant during the study.
18) Subjects who are not able or willing to have DXA scans or are above the acceptable weight limit of the DXA scanner (not applicable for subjects enrolled at sites which are not participating in the sub-study).
19) Subjects who are planning or likely to undergo surgery during the course of the study.
20) Volunteer is, in the opinion of the Investigator, not suitable to participate in the study (e.g., clinically significant illness in the 8 weeks before Screening).
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
The co-primary efficacy endpoints are:
- Change from baseline to the end of the double-blind 52-week randomized treatment for hyperphagia-related behavior (HQ-CT total score)
- Percent change from baseline to the end of the double-blind 52-week randomized treatment in total body weight
For each of these two endpoints, baseline is defined as the measurement obtained at the most recent assessment on or prior to the date of first randomized dose. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
- Hyperphagia-related behavior checklist should be completed by the caregiver for at least 7 days prior to arriving at the site at the following visits: Day 1, Week 4, 12, 26, 42 ,52 and Early Termination.
- Weight to be assessed at: Day 1, Week 4, 8, 12, 18, 26, 34, 42, 52 and Early Termination |
|
| E.5.2 | Secondary end point(s) |
The key secondary endpoints, each of which is defined as the change from baseline to the end of the double-blind 52-week randomized treatment, are:
1. % HQ-CT responders
2. Total body fat mass per DXA (sub-study)
3. Low-density lipoprotein (LDL) cholesterol
4. High-density lipoprotein (HDL) cholesterol
Additional secondary endpoints, each of which is defined as the change from baseline to the end of the double-blind 52-week randomized treatment, are:
1. Total body mass per DXA (sub-study)
2. Number of active skin lesions
3. High-sensitivity C-reactive protein (hs-CRP)
4. Triglyceride
5. Total cholesterol
6. Total lean body mass per DXA (sub-study) |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
- (sub-study) Total body fat mass, total body mass, total lean body mass, all per DXA :
Week 26, 52, Early Termination
-% HQ-CT responders:
Week 4, 12, 26, 42, 52, Early Termination
- Total cholesterol, Triglyceride, Low-density lipoprotein (LDL) cholesterol, High-density lipoprotein (HDL), High-sensitivity C-reactive protein (hs-CRP)cholesterol, Number of active skin lesions:
Day 1, Week 4, 12, 26, 42, 52, Early Termination |
|
| 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 | 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 | Yes |
| E.8.1.7.1 | Other trial design description |
| Following week 52 all subjects may be re-randomized to an open label extension |
|
| 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
| Information not present in EudraCT |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Information not present in EudraCT |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 28 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | 11 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 11 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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