A clinical trial to study the efficacy and safety of an investigational medication, beloranib, in treatment of food-related behaviour and weight in obese individuals with Prader-Willi Syndrome by comparison with placebo

• Register: EUCTR
• Last refreshed on: 2 May 2016
• Main ID: EUCTR2015-000660-33-SE
• Date of registration: 11/08/2015
• Prospective Registration: Yes
• Primary sponsor: Zafgen Inc.
• Public title: A clinical trial to study the efficacy and safety of an investigational medication, beloranib, in treatment of food-related behaviour and weight in obese individuals with Prader-Willi Syndrome by comparison with placebo
• Scientific title: Randomized, Double-Blind, Placebo Controlled, Phase 3 Trial of Beloranib in Obese Subjects with Prader-Willi Syndrome to Evaluate Food-related Behavior, Total Body Weight, and Safety Over 52 Weeks - bestPWS II
• Date of first enrolment: 30/09/2015
• Target sample size: 150
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2015-000660-33
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes Randomised: yes Open: no Single blind: no Double blind: yes Parallel group: yes Cross over: no Other: yes Other trial design description: Following week 52 all subjects may be re-randomized to an open label extension If controlled, specify comparator, Other Medicinial Product: no Placebo: yes Other: no Number of treatment arms in the trial: 2

Countries of recruitment

Belgium, Canada, Denmark, France, Germany, Italy, Spain, Sweden, United Kingdom, United States

Contacts

• Name: Clinical Science Department
• Affiliation: Zafgen Inc.

• Name: Clinical Science Department
• Affiliation: Zafgen Inc.

Key inclusion & exclusion criteria

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.
Are the trial subjects under 18? yes
Number of subjects for this age range: 60
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 90
F.1.3 Elderly (>=65 years) no
F.1.3.1 Number of subjects for this age range

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 sol

Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Improvement of Hyperphagia and related behaviors as well as Body Composition/Overweight in Prader-Willi-Syndrome
MedDRA version: 18.0 Level: PT Classification code 10036476 Term: Prader-Willi syndrome System Organ Class: 10010331 - Congenital, familial and genetic disorders

Therapeutic area: Diseases [C] - Congenital, Hereditary, and Neonatal Diseases and Abnormalities [C16]

Intervention(s)

Product Name: Subcutaneous Beloranib in Suspension
Product Code: ZGN-440
Pharmaceutical Form: Powder and solvent for suspension for injection
INN or Proposed INN: Beloranib
CAS Number: 251111-30-5
Current Sponsor code: ZGN-440
Other descriptive name: Beloranib
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 4-
Pharmaceutical form of the placebo: Powder for suspension for injection
Route of administration of the placebo: Subcutaneous use

Primary Outcome(s)

Main Objective: - 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

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.

Secondary Objective: - 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)

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

Secondary Outcome(s)

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

Secondary end point(s): The key secondary endpoints are:
1. % HQ-CT responders at the end of the double-blind 52-week randomized treatment
2. Change in total body fat mass per DXA from baseline to the end of the double-blind 52-week ramdomized treatment (sub-study)
3. Change in Low-density lipoprotein (LDL) cholesterol from baseline to the end of the double-blind 52-week randomized treatment
4. Change in high-density lipoprotein (HDL) cholesterol from baseline to the end of the double-blind 52-week randomized treatment
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)

Secondary ID(s)

ZAF-312

Source(s) of Monetary Support

Zafgen Inc.