| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Prader-Willi syndrome (PWS) |
|
| E.1.1.1 | Medical condition in easily understood language |
| Prader-Willi syndrome (PWS) |
|
| E.1.1.2 | Therapeutic area | Body processes [G] - Genetic Phenomena [G05] |
| 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 | 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 |
- Part A: to assess short-term efficacy of RGH-706 on hyperphagia in patients with PWS
- Part B: to assess the efficacy of different doses of RGH-706 on hyperphagia in patients with PWS |
|
| E.2.2 | Secondary objectives of the trial |
- To explore the effect of RGH-706 on body weight, body composition (only in Part B), and metabolic
biomarkers
- To assess pharmacokinetics (PK), safety, and tolerability of RGH-706 in patients with PWS
- To explore the effect of RGH-706 on caregiver burden and on caregiver and clinician global
impressions of severity and change |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Male or female patients aged ≥18 years at screening
2. Genetically confirmed diagnosis of PWS:
- methylation assay AND
- fluorescence in situ hybridization cytogenetic assessment or other cytogenetic testing that
confirms genetic subtype
3. HQ-CT total score ≥14 at screening
4. Body weight ≥40 kg/88 lbs and ≤200 kg/450 lbs
5. Stable body weight, self or caregiver-reported weight change ≤5% in the previous 3 months. In
addition, for Part B only: body mass index (BMI) ≥25 kg/m2
6. If a patient has a current diagnosis of type 2 diabetes mellitus, the following criteria must be met:
- Glycated hemoglobin <9.0% at screening
- No history of ketoacidosis or hyperosmolar coma
- No glucagon-like peptide-1 (GLP-1) agonist treatment in the previous 6 months
7. Negative pregnancy test for females of childbearing potential and nonlactating at screening
- All female study participants must agree to use one of the following highly effective,
nonhormonal methods of contraception from the time of signing the informed consent to at
least 4 weeks after the last dose of study treatment: intrauterine device, bilateral tubal
ligation/occlusion, or vasectomized partner, unless the patient is confirmed to be infertile or
has a history of and commitment of long-term abstinence.
Male patients with partners of childbearing potential must use highly effective contraception for
their female partner from the time of signing the informed consent to at least 4 weeks after the
last dose of study treatment. Acceptable methods of contraception include the following:
- Combined (estrogen and progestogen containing) oral, intravaginal or transdermal
contraceptive
- Progestogen-only hormonal (oral, injectable or implantable) contraceptive
- Intrauterine device or intrauterine hormone-releasing system
- Bilateral tubal occlusion
Patients who practice true abstinence are exempt from contraceptive requirements. For patients
who are exclusively in same-sex relationships, contraceptive requirements do not apply.
8. Ability and willingness to comply with protocol and study requirements
9. Patients must be able to provide or have a parent or guardian who is able to provide written
informed consent and/or assent (as applicable)
10. Patient must have been immunized (local standard mandatory vaccination) prior to enrollment, as prescribed by their health care professional according to the investigative site’s standard of care
11. Patients must have at least 1 consistent and reliable primary caregiver who is able to accurately evaluate changes in the patient’s hyperphagia symptoms, mood, AEs, and behavior throughout the study. The caregiver must have been caring for the patient for at least 3 months prior to study
entry, is anticipated to be the patient’s primary caregiver for the duration of the study, and must
spend at least 4 waking hours per day on average with the patient. The caregiver must be able to
read and understand the local language and be able to communicate with investigator/center staff.
The primary caregiver must be willing and able to complete all required study assessments. |
|
| E.4 | Principal exclusion criteria |
1. Hypersensitivity to RGH-706 or any of the excipients (gelatin, starch, or magnesium stearate)
2. Severe psychiatric disorders (eg, schizophrenia, bipolar disorder, or major depressive disorder),
recent (within 6 months) psychotic or depressive episodes or any other psychiatric disorder that
may interfere with study participation or assessments as judged by the investigator
3. Risk of suicide according to the investigator’s judgment, based upon all available source
information including Columbia–Suicide Severity Rating Scale (C-SSRS) at screening, any
current suicidal ideation (ie, within 1 year), or a history of active suicidal ideation or suicide
attempts
4. Uncontrollable diabetes mellitus or diabetes mellitus requiring insulin administration
5. Poorly controlled hypothyroidism or hyperthyroidism at screening (thyroid stimulating hormone ≥10 µIU/mL or free thyroxine or free tri-iodothyronine >upper limit of normal)
6. Chronic or acute liver disease (eg, hepatic fibrosis or cirrhosis, cholecystitis or biliary obstruction, alcoholic liver disease, infectious hepatitis, primary biliary cirrhosis, primary sclerotizing cholangitis, autoimmune hepatitis, Wilson’s disease, iron overload, alpha-1-antitrypsin deficiency, drug-induced liver injury, known or suspected hepatocellular carcinoma). History of liver transplant, or current placement on a liver transplant list.
7. History of bariatric surgery procedure (eg, gastric band, gastric bypass, sleeve gastrectomy,
gastric balloon implantation), current gastric band
8. Severe obstructive sleep apnea
9. Presence or history of any medical condition that limits participation in the study (eg, clinically
relevant cardiovascular disease including but not limited to heart failure, angina pectoris,
myocardial infarction, stroke, claudication, limb ischemia, renal, hepatic or respiratory
insufficiency, symptoms suggesting acute infections including severe skin infection or gastrointestinal disease)
10. History of malignancy (other than surgically cured nonmelanoma skin cancer or cervical cancer)
within 5 years of screening
11. Systolic blood pressure (BP) ≥160 mmHg and/or diastolic BP ≥100 mmHg, pulse rate ≥100/min
at screening, one repeat allowed
12. Use of weight lowering pharmacotherapy including but not limited to GLP-1 agonist within
6 months prior to screening. Participation in nonpharmaceutical interventions which could impact weight (ie, diets, behavioral interventions) and have been introduced or changed within 90 days of screening or are planned to change during study participation. Diet attempts using herbal
supplements, dietary supplements, or over-the-counter medications at screening or within 90 days
before screening
13. Patients on the following systemic concomitant medications who have not been on stable dose,
defined as no more than ±25% variation in dose, for at least 3 months prior to study entry:
- Growth hormone, glucocorticoids, vasopressin, testosterone, other hormone or hormone replacement therapies, antidiabetes medications (must have been stable for ≥6 months),
modafinil, atypical antipsychotics, antidepressants, psychostimulant medication for
attention deficit hyperactivity disorder
14. Use of strong cytochrome P450 3A4 inhibitors (eg, clarithromycin, itraconazole, and
ketoconazole) or inducers (eg, rifampicin) within 30 days prior to dosing
15. Clinically relevant arrhythmias or arrhythmias requiring treatment at screening
16. Known QT prolongation (congenital prolonged QT syndrome, acquired prolonged QT syndrome,
including drug induced prolonged QT syndrome) at screening (electrocardiograms [ECG]
≥450 ms for men and ≥470 ms for women confirmed by repeat measurement)
17. Clinically relevant laboratory abnormalities including but not limited to the following:
- Transaminase (aspartate transaminase, alanine transaminase) or alkaline phosphatase or total bilirubin >upper limit of normal, one repeat allowed
- Serum triglyceride level ≥350 mg/dL at screening
- Creatinine clearance (estimated glomerular filtration rate <80 mL/min)
18. Known or suspected abuse of alcohol or abuse of drugs or testing positive for amphetamine,
methamphetamine, cannabinoids, cocaine, opioids, or phencyclidine at screening
19. Female who is pregnant, breastfeeding, or intends to become pregnant during the study and
4 weeks after the last dose of study treatment
20. Participation in any other clinical study involving any study drug or participation in any other
type of medical research judged not to be scientifically or medically compatible with this study
within the previous 3 months
21. Known human immunodeficiency virus, hepatitis B virus, or hepatitis C virus infection or testing
positive at screening
22. Known chronic infection or chronic inflammatory disease requiring systemic treatment
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
- Part A: Change from baseline in the 9-item HQ-CT total score at Visit 5
- Part B: Change from baseline in the 9-item HQ-CT total score at Visit 7 |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
- Part A: from baseline at Visit 5
- Part B: from baseline at Visit 7 |
|
| E.5.2 | Secondary end point(s) |
Part A:
- Change from baseline in the 9-item HQ-CT total score at Visits 4, 6, 7, and 8
- Change from baseline in HQ-CT domain scores (drive and severity, self-directed behavior) at
Visits 4, 5, 6, 7, and 8
- Absolute change from baseline in body weight at each visit
- Percentage change from baseline in body weight at each visit
- Change from baseline in waist circumference at each visit
- Change from baseline in BMI at each visit
- Change from baseline in metabolic biomarkers measured from serum at Visit 5 (fasting
plasma/serum glucose , insulin, homeostatic model assessment [HOMA], uric acid, and
high-sensitivity C-reactive protein [hs-CRP])
- Change from baseline in Clinical Global Impression–Severity (CGI-S) score at Visits 4, 5, and 6
- Clinical Global Impression-Improvement (CGI-I) score at Visits 4 and 5
- Change from baseline in CaGI-S score at Visits 4 and 5
- CaGI-C score at Visits 4, 5, 6, 7, and 8
- Change from baseline in ZBI-22 total score at Visit 5
- Safety: Treatment-emergent AEs (TEAEs), clinical laboratory evaluations (hematology, clinical
chemistry, coagulation and lipids, thyroid function test, and urinalysis), vital signs measurements
(body temperature, pulse rate, respiration rate, BP), 12-lead ECGs, C-SSRS, and physical
examinations
Part B
- Change from baseline in the 9-item HQ-CT total score at Visits 5, 6, and 8
- Change from baseline in the HQ-CT domain scores (drive and severity, self-directed behavior) at
Visits 5, 6, 7, and 8
- Absolute change from baseline in body weight at each visit
- Percentage change from baseline in body weight at each visit
- Change from baseline in waist circumference at each visit
- Change from baseline in BMI at each visit
- Change from baseline in total body mass; lean body mass; and total, visceral, and subcutaneous fat
mass measured by Lunar iDXA at Visit 7
- Change from baseline in metabolic biomarkers measured from serum at Visits 5, 6 and 7 (fasting
plasma/serum glucose, insulin, HOMA, uric acid, and hs-CRP)
- Change from baseline in CGI-S score at Visits 5, 6, 7, and 8
- CGI-I score at Visits 5, 6, and 7
- Change from baseline in CaGI-S score at Visits 5, 6, and 7
- CaGI-C score at Visits 5, 6, 7, and 8
- Change from baseline in ZBI-22 total score at Visit 7
- Safety: TEAEs, clinical laboratory evaluations (hematology, clinical chemistry, coagulation and
lipids, thyroid function test, and urinalysis), vital signs measurements (body temperature, pulse rate,
respiration rate, BP), 12-lead ECGs, C-SSRS, and physical examinations |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Part A:
- from baseline at Visits 4, 6, 7, and 8
- from baseline at each visit
- from baseline at Visit 5
- from baseline at Visits 4, 5, and 6
- at Visits 4 and 5
- from baseline at Visits 4 and 5
- at Visits 4, 5, 6, 7, and 8
- from baseline at Visit 5
Part B
- from baseline at Visits 5, 6, and 8
- from baseline at Visits 5, 6, 7, and 8
- from baseline at each visit
- from baseline at Visit 7
- from baseline at Visits 5, 6 and 7
- from baseline at Visits 5, 6, 7, and 8
- at Visits 5, 6, and 7
- baseline at Visits 5, 6, and 7
- at Visits 5, 6, 7, and 8
- from baseline at Visit 7 |
|
| 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 | No |
| 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 |
|
| 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) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| 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 | 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 | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 4 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 25 |
| 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 |
| United States |
| Czechia |
| France |
| Italy |
| Spain |
|
| E.8.7 | Trial has a data monitoring committee | No |
| 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 | 2 |
| E.8.9.1 | In the Member State concerned months | 4 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| 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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