A 12-Month Randomized, Multicenter, Double-Blind, Placebo-Controlled Phase 3 Study to Evaluate the Safety and Efficacy of Daily Subcutaneous Metreleptin Treatment in Subjects with Partial Lipodystrophy
- Trial ID
- 2022-501799-24-00
- Protocol
- APG-20
- Sponsor
- Chiesi Farmaceutici S.p.A.
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to evaluate the **efficacy** of daily subcutaneous metreleptin treatment in subjects with familial partial **lipodystrophy** (FPLD). This is clinically relevant as FPLD is a rare disorder characterized by abnormal fat distribution, which can lead to metabolic complications. Assessing the efficacy of metreleptin, a recombinant-methionyl human leptin, could provide insights into potential therapeutic benefits for managing this condition.
Secondary objectives include assessing the effect of metreleptin on fasting blood glucose (FBG). This is important as FPLD is often associated with insulin resistance and hyperglycemia, and understanding the impact of metreleptin on FBG could further elucidate its role in metabolic regulation in affected individuals.
Participants
The clinical trial involves a total of **49 participants** diagnosed with familial partial **lipodystrophy** (FPLD). The study population includes both male and female subjects, with an age range starting from 12 years and above. Participants are required to be in generally stable health, with specific attention to metabolic control, as indicated by HbA1c levels and fasting triglycerides. The selection process for the trial population was based on a clinical diagnosis of FPLD, confirmed through physical examination and genetic or familial evidence. Participants are expected to adhere to dietary restrictions as recommended by the Investigator and maintain stable antidiabetic and lipid-lowering therapies if applicable. The trial does not include a vulnerable population, and both genders are represented. Key lifestyle considerations include the requirement for stable dietary habits and the use of effective contraception methods for participants of reproductive potential. The trial's inclusion criteria ensure that participants have a confirmed diagnosis of FPLD and meet specific metabolic and health stability requirements.
Plans and Procedures
The clinical trial is a **randomized**, **double-blind**, **placebo-controlled** Phase 3 study designed to evaluate the safety and efficacy of daily subcutaneous **metreleptin** treatment in subjects with **partial lipodystrophy**. The trial is set to span a duration of 12 months, with an estimated recruitment start date of February 1, 2024, and an estimated end date of December 30, 2025. Participants will be randomly assigned to receive either the active treatment, Myalepta 11.3 mg powder for solution for injection, or a placebo, both administered via subcutaneous injection. The primary endpoints include the change from baseline to Month 6 in glycated hemoglobin (HbA1c) and fasting triglycerides (TGs) in subjects with familial partial lipodystrophy (FPLD).
The sequence of study visits begins with an inclusion (screening) visit, where eligibility criteria are assessed, including age, diagnosis of FPLD, and metabolic control parameters. Following successful screening, participants will undergo randomization and commence treatment. Follow-up visits will occur at regular intervals to monitor safety, efficacy, and adherence to the treatment regimen. These visits will include assessments of HbA1c, fasting TGs, and other metabolic parameters. The end-of-study visit will conclude the trial, with final evaluations of the primary and secondary endpoints.
Participant involvement is expected to last for the entire 12-month duration of the trial. However, conditions that may lead to early termination from the study include non-compliance with the study protocol, adverse events that compromise participant safety, or withdrawal of consent. The trial is conducted under strict adherence to ethical guidelines, ensuring that all participants provide informed consent prior to any study-specific procedures. The study aims to provide valuable insights into the therapeutic potential of metreleptin in managing partial lipodystrophy, with the ultimate goal of improving patient outcomes.
Treatment
The clinical trial involves the administration of **Myalepta**, a pharmaceutical product containing the active substance **metreleptin**. Myalepta is provided as a **powder for solution for injection** and is intended for subcutaneous administration. The dosage form is specifically designed for injection, with a maximum daily dose of 10 mg. The treatment is administered daily over a period of 12 months. Metreleptin is a recombinant-methionyl human leptin, classified under the ATC code A16AA07. The product is manufactured by Amryt Pharmaceuticals DAC and is authorized for use in the European Union. The administration of Myalepta is monitored to ensure participant compliance with the dosing schedule.
The study also includes a **placebo** comparator, referred to as "Metreleptin for injection (placebo)." This placebo is used to maintain the double-blind nature of the trial, ensuring that neither the participants nor the investigators are aware of the treatment assignments. The placebo is designed to mimic the appearance and administration route of the active treatment, although it contains no active substance. The placebo is administered with the same frequency and duration as the active treatment, ensuring consistency in the study protocol.
Efficacy
The efficacy of daily subcutaneous **metreleptin** treatment in subjects with familial partial lipodystrophy (FPLD) will be assessed through a series of primary and secondary endpoints. The primary endpoints include the change from baseline to Month 6 in glycated hemoglobin (HbA1c) for subjects with FPLD in Groups A and C, where HbA1c is greater than or equal to 7%, and the percent change from baseline to Month 6 in fasting triglycerides (TGs) for subjects in Groups B and C, where TGs are greater than or equal to 500 mg/dL (5.65 mmol/L).
Secondary endpoints will evaluate the change from baseline to Month 6 in fasting blood glucose (FBG) for Groups A and C, where HbA1c is greater than or equal to 7%, as well as the change in FBG for subjects with FBG above the upper limit of normal. These efficacy parameters will be measured and collected at specified timepoints, with baseline measurements taken prior to the initiation of treatment and follow-up assessments conducted at Month 6. The analysis of these endpoints will provide insights into the therapeutic impact of metreleptin on metabolic control in FPLD patients.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Age ≥12 years at Visit 1
- Diagnosis of FPLD, defined as: • Clinical diagnosis of FPLD based on deficiency of subcutaneous body fat in a partial fashion assessed by physical examination and low skinfold thickness in anterior thigh by caliper measurement (males ≤10 mm and females ≤22 mm), plus 1 of the following: o Documented genetic diagnosis of FPLD (mutations in genes known to be associated with lipodystrophy, e.g., LMNA, PPARG, AKT2, or PLIN1). OR o Documented evidence of positive family history (first-degree biological relative) of FPLD (based on genetic or clinical diagnosis) PLUS 1 minor criterion (below). OR o 2 minor criteria (below) in the absence of a genetic diagnosis or family history, plus all the additional criteria (below, following the minor criteria). MINOR Criteria: Diabetes mellitus with requirement for high doses of insulin, e.g., requiring ≥200 U/day, ≥2 U/kg/day, or currently taking U-500 insulin. Presence of acanthosis nigricans on physical examination. History of polycystic ovary syndrome (PCOS) or PCOS-like symptoms (hirsutism, oligomenorrhea, and/or polycystic ovaries). History of pancreatitis associated with hypertriglyceridemia. Evidence of non-alcoholic fatty liver disease (NAFLD): hepatomegaly and/or elevated transaminases in the absence of a known cause of liver disease or radiographic evidence of hepatic steatosis (e.g., on former ultrasound, magnetic resonance imaging [MRI] or computed tomography [CT]). Additional Criteria (required in the absence of a genetic diagnosis or documented evidence of family history): Age ≥18 years at Visit 1 Leptin levels <8.0 ng/mL in males and <12.0 ng/mL in females. BMI <35 kg/m2. Subcutaneous body fat distribution pattern indicative of FPLD assessed by DXA at Screening, including percent fat mass of the trunk to percent fat mass of the legs (Fat Mass Ratio FMR) >1.5.
- Confirmation by the Investigator that the potential differential diagnosis of FPLD has been excluded (e.g., Cushing’s syndrome, anorexia nervosa, cachexia, diencephalic syndrome, Rabson-Mendenhall syndrome, leprechaunism, SHORT syndrome, mandibuloacral dysplasia, progeroid syndromes)
- Subjects with poor metabolic control defined as: • HbA1c ≥7% (at Visit 1 and Visit 3) and/or • Fasting TGs ≥500 mg/dL (5.65 mmol/L, at Visit 1 and Visit 3)
- Subjects with HbA1c ≥7% should be receiving optimized stable antidiabetic therapy for at least 3 months prior to Screening and their diet (as reported by the subjects) should be stable and in line with medical recommendations.
- Subjects with diabetes and HbA1c <7% should be receiving stable treatment regimen (diet and/or antidiabetic treatment) for at least 6 weeks prior to Screening and their diet (as reported by the subjects) should be stable and in line with medical recommendations.
- Subjects with fasting TGs ≥500 mg/dL (5.65 mmol/L) should be receiving a stable lipid-lowering therapy for at least 6 weeks prior to Screening (unless these medications were not tolerated or are contra-indicated) and their diet (as reported by the subjects) should be stable and in line with medical recommendations.
- Subjects receiving antidiabetic and/or lipid-lowering therapy prior to the beginning of the study must be kept stable on optimized and stable dose for at least 6 weeks prior to Randomization (Visit 4). For subjects on insulin, a stable dose is defined as no more than 20% fluctuation. For all other therapies, a stable dose is defined as no dose change.
- Negative pregnancy test (urine or serum) for female subjects of childbearing potential.
- Female subjects must be postmenopausal (defined as cessation of menses for at least 1 year), surgically sterile (hysterectomy, bilateral oophorectomy, or tubal ligation), or willing to use a highly effective method of contraception (such methods include combined [estrogen and progestogen containing] hormonal contraception associated with inhibition of ovulation: oral/intravaginal; transdermal/progestogen-only hormonal contraception associated with inhibition of ovulation: oral/injectable; implantable/intrauterine device [IUD]/intrauterine hormone-releasing system [IUS]/bilateral tubal occlusion/vasectomized partner/ sexual abstinence) for the duration of the study (from the time they sign an informed consent/assent form [ICF], until 4 weeks after the last dose of study treatment). Hormonal contraception alone (including oral, injectable, transdermal, and implantable) is not acceptable; an additional barrier method must be used. Intravaginal hormonal contraception or IUS alone are allowed per Investigator’s discretion. Subjects will not be permitted to commence oral contraceptives while taking study treatment during the study.
- Male subjects must be surgically sterile or willing to use an acceptable method of contraception for the duration of the study (from the time they sign an ICF), until 4 weeks after the last dose of study treatment. An acceptable method of contraception would be a barrier method, such as condoms, restraining from having sex, or a partner using the approved methods of contraception for female subjects as per Inclusion Criteria #10.
- Subjects who are blood/egg/sperm donors should be willing to halt donations during the study and for 4 weeks following their last dose of study treatment.
- Subjects who are willing to provide informed consent/assent prior to any study-specific procedures. If a minor, the subject has a parent or legal guardian able to read, understand, and sign the ICF and/or a Child Assent Form (if applicable), communicate with the Investigator, and understand and comply with the protocol requirements. Adolescent subjects must also read and understand the Child Assent Form
- Subjects who are willing to follow the dietary restrictions recommended by the Investigator.
Exclusion Criteria
- Previous treatment with metreleptin.
- Leptin levels >20.0 ng/mL
- Acquired partial lipodystrophy (APL)
- Radiation induced PL
- Subjects diagnosed with Cushing’s syndrome
- Treatment with any Investigational Medicinal Product (IMP) within 6 months or 5 times the terminal half-life of the corresponding IMP, whichever is longer, before the Screening visit
- Subjects with prior severe hypersensitivity reactions to any of the metreleptin product components
- Known to have tested positive for human immunodeficiency virus (HIV) or known to be diagnosed with HIV-related LD. Positive HIV test in countries requiring HIV testing.
- Are immunocompromised or receiving immunomodulatory drugs
- Known history of drug or alcohol abuse within 1 year prior to Screening as assessed according to the Investigator’s judgment
- Estimated glomerular filtration rate (eGFR) <30 mL/min/1.73m2 calculated by CKD-EPI for subjects ≥18 years of age and by Bedside Schwartz for subjects <18 years of age.
- For females only: currently pregnant (confirmed with a positive pregnancy test) or breastfeeding
- Any condition where, in the opinion of the Investigator, participation in this study may pose a significant risk to the subject or could render the subject unable to successfully complete the study (e.g., life expectancy <12 months).
- Subjects whose antidiabetic/lipid-lowering therapies and/or other concomitant medications that may affect the primary endpoint results (such as appetite suppressing medications) are not stable at Screening and are likely to require a change in dose during the treatment period
- Subjects with ongoing or recent (within the last 3 months prior to Screening) episode of acute pancreatitis
- Diagnosis of clinically significant hematological abnormalities (including but not limited to clinically significant leukopenia, neutropenia, bone marrow abnormalities, leukemia or lymphoma, or clinically significant pathological lymphadenopathy).
- Malignancy that is ongoing/not in remission or that currently requires or has required active treatment within the past 3 years (with the exception of basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or carcinoma in situ [e.g., breast carcinoma, cervical cancer in situ] that have undergone potentially curative therapy).
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Belgium | Not Recruiting | 01 Feb 2024 | 4 |
 The Netherlands | Not Recruiting | 01 Feb 2024 | — |
 Poland | Not Recruiting | 01 Feb 2024 | 5 |
 Spain | Not Recruiting | 01 Feb 2024 | 2 |
| Netherlands | — | — | 5 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
Metreleptin for injectionplacebo | Placebo | N/A | — | — | — | N/A |
Myalepta 11.3 mg powder for solution for injection | Test | POWDER FOR SOLUTION FOR INJECTION | SUBCUTANEOUS INJECTION | 10 | 12 | PRD8130316 |