| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
Treatment of obesity associated with genetic defects upstream of the MC4 receptor in the leptin-melanocortin pathway. Diseases that are the result of genetic defects affecting the MC4R pathway, concerned by the trial:
- Bardet-Diedl syndrome
- Biallelic PPL
- Heterozygotous PPL
(PPL : POMC pro-opiomelanocortin, PCSK1 proprotein convertase subtilisin/kexin type1 , LEPR leptin receptor) |
|
| E.1.1.1 | Medical condition in easily understood language |
| Obesity caused by rare genetic defects in patients causing extreme hunger |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Nutritional and Metabolic Diseases [C18] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 23.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10084105 |
| E.1.2 | Term | Leptin receptor deficiency |
| E.1.2 | System Organ Class | 10010331 - Congenital, familial and genetic disorders |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 23.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10083937 |
| E.1.2 | Term | Pro-opiomelanocortin deficiency |
| E.1.2 | System Organ Class | 10010331 - Congenital, familial and genetic disorders |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10048680 |
| E.1.2 | Term | Bardet-Biedl 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 compare the pharmacokinetics (PK) of the once daily (QD) and once weekly (QW) formulations of setmelanotide |
|
| E.2.2 | Secondary objectives of the trial |
Secondary:
To assess the safety of the QW formulation of setmelanotide with up to 6 months (26 weeks) of drug
administration
Exploratory:
To evaluate the efficacy of the QD and QW formulations on weight-related parameters produced by
setmelanotide over 3 months (13 weeks) of administration
To assess the weight-related efficacy of the QW formulation of setmelanotide on weight-related
parameters over up to 6 months (26 weeks) of drug administration
To assess the efficacy of the QD and QW formulations of setmelanotide on metabolic parameters
To evaluate the impact of QW vs QD setmelanotide treatment on patient- and/or caregiver-reported
outcomes relating to hunger
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. All patients must have met the criteria for diagnosis of a gene defect in the MC4R pathway (BBS, biallelic PPL, heterozygous PPL), for which they are being treated with QD setmelanotide.
2. Patients must be ≥6 years old at screening.
3. Patients must have been taking the setmelanotide QD formulation for at least 6 months in the LTE trial with acceptable safety and tolerability, and the dose level must have been stable at 2, 2.5 or 3 mg of setmelanotide for at least the last 3 months prior to starting the Run-in Period.
4. Patient and/or parent or guardian is able to communicate well with the Investigator, to understand and comply with the requirements of the trial and is able to understand and sign the written informed consent/assent.
5. Patient must meet one of the following requirements:
Female participants of childbearing potential, defined as fertile, following menarche and until becoming post-menopausal unless permanently sterile (hysterectomy, bilateral salpingectomy, or bilateral oophorectomy), must be confirmed non-pregnant and agree to use a highly effective form of contraception throughout the trial and for 90 days following the trial. Highly effective forms of contraception are detailed below and in Section 8.8.7:
- Combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation (oral, intravaginal, or transdermal)
- Progestin-only hormonal contraception associated with inhibition of ovulation (oral, implantable, or injectable)
- Intrauterine device (IUD)
- Intrauterine hormone-releasing system
- Bilateral tubal occlusion
- Vasectomy/vasectomized partner (provided that the vasectomized partner is the sole sexual partner of the female participant, and the vasectomized partner has received medical assessment of surgical success)
- Sexual abstinence, only if it is the preferred and usual lifestyle of the patient
Female participants of non-childbearing potential, defined as: permanently sterile (status post hysterectomy, bilateral oophorectomy, or bilateral salpingectomy), or post-menopausal for at least 12 months (and confirmed with a screening follicle-stimulating hormone (FSH) level in the post-menopausal lab range) do not require contraception during the trial .
Younger female patients who have not achieved sexual maturity at trial entry will be assessed for Tanner staging and required to comply with contraception requirements at first menarche.
Male participants with female partners of childbearing potential must agree to use a highly effective method of contraception if they become sexually active during the trial or within 90 days following their participation in the trial. Male patients must also not donate sperm during and for 90 days following their participation in the trial. |
|
| E.4 | Principal exclusion criteria |
1. HbA1C >9.0% at screening.
2. Has taken a medication that is approved to treat obesity (e.g., orlistat, lorcaserin, phentermine-topiramate, naltrexone-bupropion) within 3 months prior to starting the Run-in Period. Glucagon-like peptide-1 (GLP) -1) receptor agonists being prescribed for the treatment of obesity are not allowed.
3. History of significant liver disease or liver injury, or a current liver assessment due to abnormal liver tests for an etiology other than nonalcoholic fatty liver disease (NAFLD). Thus, any underlying etiology besides NAFLD, including diagnosed nonalcoholic steatohepatitis (NASH), other causes of hepatitis, or history of hepatic cirrhosis is exclusionary, but the presence of NAFLD is not exclusionary.
4. Moderate to severe renal dysfunction as defined by a glomerular filtration rate <30 mL/min. (based upon the Chronic Kidney Disease Epidemiology Collaboration [CKD-EPI] creatinine equation 2021 from the National Kidney Foundation). In patients <18 years of age the Bedside Schwartz Equation should be used to calculate estimated glomerular filtration rate (eGFR).
5. Significant dermatologic findings relating to melanoma or pre-melanoma skin lesions (excluding non-invasive basal or squamous cell lesion), determined as part of comprehensive skin evaluation performed by the Investigator during screening. Any concerning lesions identified during the Screening Period will be biopsied and results must be known to be benign prior to enrollment. If the pretreatment biopsy results are of concern, the patient should be excluded from the trial.
6. Diagnosis of schizophrenia, bipolar disorder, personality disorder, or other psychiatric disorders that the Investigator believes will interfere significantly with trial compliance. Neurocognitive disorders affecting ability to consent will not be disqualifying as long as an appropriate guardian able to give consent has been appointed.
7. Clinically significant depression or suicidality as defined by: any suicidal ideation of type 4 or 5 on the C SSRS, any lifetime history of a suicide attempt, or any suicidal behavior in the last month or a Patient Health Questionnaire-9 (PHQ-9) score of ≥15 during Screening in patients with no significant neurocognitive deficits.
8. Patient is not suitable, in the opinion of the Investigator, to participate in the trial.
9. Hypersensitivity to the active substance or to any of the excipients of the investigational products (active or placebo).
10. Inability to comply with the QW and QD injection regimens.
11. Participation in any clinical trial with an investigational drug/device within 3 months prior to the first day of dosing, with the exception of a setmelanotide clinical trial.
12. Legally protected persons per local regulations (e.g., those that fall under the L1121-6 article of the Public Health code in France) or other applicable local laws.
13. The patient or a relative of the patient is the investigator or a sub-investigator, research assistant, pharmacist, trial coordinator, or other staff directly involved with the conduct of the trial. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Comparison of steady-state PK parameters (maximum plasma concentration [Cmax,], time to
maximum plasma concentration [Tmax], trough plasma concentration [Ctrough], area under the
plasma concentration-time curve over the dosing interval [AUC0-tau]) for QW compared with QD
setmelanotide |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
Secondary endpoints :
Safety outcomes, including AEs/SAEs, ISRs and changes in laboratory parameters, vital signs, ECG recordings, and physical examination findings, etc.
Exploratory endpoints:
Proportion of patients who achieve the following change in body mass index (BMI) from baseline to Week 14 for QW vs QD setmelanotide groups:
1. > ‒2.5% and < 2.5% change
2. ≥ 2.5% increase
3. ≥ 2.5% decrease
Change and percent change in BMI from baseline to Week 14 for QW vs QD setmelanotide groups, and for up to 6 months (26 weeks) for all patients
Change and percent change in body weight in adult patients ≥18 years of age, and change in BMI Z-score and change in percentage of 95th percentile of age- and sex-predicted BMI for patients <18 years of age, from baseline to Week 14 for QW vs QD setmelanotide groups, and for up to 6 months (26 weeks) for all patients
Change from baseline to Week 14 for in the QW vs QD setmelanotide groups, and for up to 6 months (26 weeks) for all patients in:
- waist circumference,
- lipid levels, and
- HbA1c
Change in average daily most/worst hunger and global hunger scores from baseline to Week 14 for QW vs QD groups and for up to 6 months (26 weeks) for all patients
Change in total score from baseline to Week 14 in Symptoms of Hyperphagia (patient/caregiver versions) for QW vs QD groups and for up to 6 months (26 weeks) for all patients |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| End points are assessed from baseline to end of treatment. |
|
| 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 | 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 | No |
| E.8.1.6 | Cross over | Yes |
| 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 | 1 |
| 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 |
| Canada |
| Puerto Rico |
| United States |
| France |
| Germany |
| Netherlands |
| United Kingdom |
|
| 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 | 1 |
| 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 | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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