A 24-Month, Multi-Centre, Open Label Phase IV Post Authorisation Efficacy Study to Evaluate the Efficacy, Safety and Immunogenicity of Daily Subcutaneous Metreleptin Treatment in Patients with Partial Lipodystrophy
- Trial ID
- 2022-502950-14-00
- Protocol
- APL-22
- Sponsor
- Chiesi Farmaceutici S.p.A.
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to evaluate the **efficacy** of metreleptin treatment in patients with Partial Lipodystrophy (PL). This is clinically relevant as metreleptin, a recombinant human leptin analog, may address metabolic abnormalities associated with PL, potentially improving patient outcomes.
Secondary objectives include:
- Evaluating the long-term efficacy of metreleptin treatment in patients with PL.
- Assessing the efficacy of metreleptin on additional clinically relevant outcome measures.
- Assessing changes in liver volume.
- Evaluating the effect of metreleptin treatment on insulin resistance and sensitivity.
- Assessing changes in anti-diabetic or lipid-lowering medications over time.
Participants
The clinical trial involves a total of **2 participants** diagnosed with **Partial Lipodystrophy**. The study population includes both male and female subjects aged 12 years and older. Participants were selected based on a confirmed diagnosis of familial or acquired Partial Lipodystrophy, with the exclusion of other potential differential diagnoses. The trial includes individuals who have not achieved adequate metabolic control with standard treatments, as evidenced by specific HbA1c and fasting serum triglyceride levels. Participants are required to maintain a stable diet and medication regimen, including antidiabetic and lipid-lowering therapies, prior to and during the study. The trial population is characterized by a willingness to adhere to dietary restrictions and includes individuals who are either naïve to metreleptin treatment or have recently initiated treatment. The study encompasses a vulnerable population, ensuring informed consent is obtained from participants or their legal representatives. The trial does not specify any particular lifestyle considerations beyond the dietary and medication stability requirements.
Plans and Procedures
The clinical trial is designed to evaluate the efficacy, safety, and immunogenicity of daily subcutaneous **metreleptin** treatment in patients with partial lipodystrophy. This is a 24-month, multi-centre, open-label Phase IV post-authorization efficacy study. The trial will involve a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on specific criteria, such as age, informed consent, and a confirmed diagnosis of familial or acquired partial lipodystrophy. Participants must have either an HbA1c level of at least 6.5% or fasting serum triglyceride levels of at least 500 mg/dL, with standard treatments having failed to achieve adequate metabolic control.
The trial will include regular follow-up visits to monitor the primary and secondary endpoints, which include changes in glycated hemoglobin (HbA1c) and triglyceride levels at 12 and 24 months. The primary endpoints are the number of patients with a decrease of at least 0.5% in HbA1c at Month 12 compared to baseline or HbA1c less than 6.5% at Month 12, and the number of patients with a decrease of at least 30% in triglycerides at Month 12 compared to baseline. Secondary endpoints will assess similar changes at Month 24, as well as other metabolic parameters and medication adjustments.
The expected length of participant involvement is up to 24 months, with conditions for early termination including non-compliance with the protocol, adverse events, or withdrawal of consent. The study will conclude with an end-of-study visit to assess the final outcomes and gather data for analysis. The trial is categorized as a low-intervention clinical trial, with the justification provided in the submission. Participants will receive metreleptin in the form of a solution for injection, administered subcutaneously, with a maximum daily dose of 10 mg and a total dose not exceeding 7300 mg over the study period.
Treatment
The clinical trial involves the administration of **metreleptin**, an experimental medication, in the form of a powder for solution for injection. The pharmaceutical product is marketed under the name Myalepta and is available in different dosages: 3 mg, 5.8 mg, and 11.3 mg. The active substance, metreleptin, is a protein of non-human origin. The medication is administered subcutaneously, with a maximum daily dose of 10 mg and a total maximum dose of 7300 mg over the course of the study. The treatment period is set for a maximum of 24 months. The administration of metreleptin is intended to evaluate its efficacy, safety, and immunogenicity in patients with partial lipodystrophy.
In this study, no non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are utilized. The focus is solely on the administration of metreleptin. Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the prescribed regimen. The trial is designed as an open-label study, allowing for the direct observation of the effects of metreleptin without the use of blinding. The study aims to provide comprehensive data on the therapeutic potential of metreleptin in the specified patient population.
Efficacy
The efficacy of metreleptin treatment in patients with partial lipodystrophy will be assessed through a series of primary and secondary endpoints over a 24-month period. The primary endpoints include the number of patients who achieve a decrease of at least 0.5% in **glycated haemoglobin (HbA1c)** at Month 12 compared to baseline or an HbA1c level of less than 6.5% at Month 12, in patients with baseline HbA1c levels of 6.5% or higher. Additionally, the number of patients with a decrease of at least 30% in triglycerides (TG) at Month 12 compared to baseline, in patients with baseline TG levels of 500 mg/dL (5.65 mmol/L) or higher, will be evaluated.
Secondary endpoints will further assess efficacy by measuring the number of patients with a decrease of at least 0.5% in HbA1c at Month 24 compared to baseline or an HbA1c level of less than 6.5% at Month 24. The number of patients with a decrease of at least 30% in TG levels at Month 24 compared to baseline will also be recorded. Additional analyses will include changes from baseline in HbA1c and TG levels at both Month 12 and Month 24, with subgroup analysis for patients with baseline HbA1c levels of 8% or higher. Other secondary endpoints include changes in liver volume, Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) in non-insulin treated patients, and the number of patients who maintain, decrease, or increase the dose and/or dosing frequency of anti-diabetic and lipid-lowering medications. The number of patients with a 25% or greater reduction in insulin requirements at Month 12 and Month 24 will also be assessed.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Male and female patients aged ≥12 years of age at the time of signing the ICF and Child Assent Form (if applicable) prior to initiation of any study specific activities/procedures.
- Confirmed diagnosis of familial or acquired PL.
- Confirmation by the Investigator that the potential differential diagnosis of LD has been excluded (e.g., Cushing’s syndrome, anorexia nervosa, cachexia, diencephalic syndrome, Rabson-Mendenhall syndrome, leprechaunism, SHORT syndrome, mandibuloacral dysplasia, progeroid syndromes, localised scleroderma, lichen sclerosus et atrophicus, annular lipodystrophy, semi-circular lipoatrophy, local panniculitis due to connective tissue diseases and autoimmune disorders, intradermal or subcutaneous related lipoatrophy [e.g., insulin, acupuncture, recombinant growth hormone], progressive hemifacial atrophy [Parry- Romberg syndrome])
- Patients must have: a) HbA1c level ≥6.5% and/or b) Fasting serum TG levels ≥500 mg/dL (5.65 mmol/L)
- Standard treatments have failed to achieve adequate metabolic control: a) Patients with HbA1c level ≥6.5% must be on stable dose of anti-diabetic therapy for at least 90 days prior to screening (diet and/or antidiabetic medications) and their diet (as reported by the patients) should be stable and in line with medical recommendations. b) Patients with fasting serum TG levels ≥500 mg/dL (5.65 mmol/L) must be on stable dose of lipid-lowering agents 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 patients) should be stable and in line with medical recommendations.
- Patients receiving antidiabetic and/or lipid-lowering therapy prior to the beginning of the study must be kept stable on optimised treatment based on the Investigator’s judgement and stable during the screening period. For patients on insulin, a stable dose is defined as no more than 20% change in total daily insulin dose. For all other therapies, a stable dose is defined as no dose change.
- Patients are willing to follow the dietary restrictions recommended by the Investigator.
- Metreleptin naïve and planned to receive commercial supply of metreleptin or currently treated with commercially supplied metreleptin. Patients currently treated with metreleptin can only be enrolled subject to medical monitor approval and should meet all the following criteria: a) Initiated treatment within 6 months prior to Screening b) Have retained serum samples taken prior to initiation of metreleptin, that can be used to evaluate leptin levels and immunogenicity c) Have documented HbA1c and TG levels prior to initiation of metreleptin (unless these can be assessed based on the retained serum samples).
- Females of childbearing potential 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 an effective method of contraception (such methods include combined [estrogen and progestogen containing] hormonal contraception: oral / intravaginal; transdermal / progestogen-only hormonal contraception: oral / injectable; implantable / intrauterine device [IUD] / intrauterine hormone-releasing system [IUS] / bilateral tubal occlusion / vasectomised partner/ sexual abstinence / condoms) for the duration of the study (from the time they sign an ICF and Child Assent Form (if applicable), until 4 weeks after the last dose of study drug). Hormonal contraception alone, including oral, injectable, transdermal, and implantable forms, is not acceptable; an additional barrier method must be used. Intravaginal hormonal contraception or IUS alone are allowed per the Investigator’s discretion. Patients on oral contraceptives will not be required to discontinue medication. Female patients will not be permitted to commence oral contraceptives while taking study treatment during the study.
- Patient and/or his/her legal representative has/have been informed, has/have read and understood the patient ICF and Child Assent Form (if applicable), has/have given written informed consent and is/are willing to comply with the protocol requirements. If the child is too young or unable to read, then the Child Assent Form must be explained to the child.
Exclusion Criteria
- Known to have tested positive for human immunodeficiency virus (HIV) or known to be diagnosed with HIV-related LD
- Any condition where, in the opinion of the Investigator, participation in this study may pose a significant risk to the patient or could render the patient unable to successfully complete the study (e.g., life expectancy <12 months).
- Known history of severe hypersensitivity reactions to any of the metreleptin product components.
- 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 Bedside Schwartz for patients <18 years and CKD-EPI for patients ≥18 years.
- Patients whose anti-diabetic/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.
- 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.
- For females only - currently pregnant (confirmed with positive pregnancy test) or breastfeeding.
- Positive pregnancy test (urine or serum) for females of childbearing potential.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 France | Recruiting | 04 Dec 2023 | 5 |
 Germany | Recruiting | 04 Dec 2023 | 2 |
 Italy | Recruiting | 04 Dec 2023 | 2 |
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 |
|---|---|---|---|---|---|---|
Myalepta 3 mg powder for solution for injection | Test | POWDER FOR SOLUTION FOR INJECTION | SUBCUTANEOUS | 10 | 24 | PRD8130526 |
Myalepta 5.8 mg powder for solution for injection | Test | POWDER FOR SOLUTION FOR INJECTION | SUBCUTANEOUS | 10 | 24 | PRD8130605 |
Myalepta 3 mg powder for solution for injection | Test | POWDER FOR SOLUTION FOR INJECTION | SUBCUTANEOUS | 10 | 24 | PRD8130527 |
Myalepta 11.3 mg powder for solution for injection | Test | POWDER FOR SOLUTION FOR INJECTION | SUBCUTANEOUS | 10 | 24 | PRD8130315 |
Myalepta 11.3 mg powder for solution for injection | Test | POWDER FOR SOLUTION FOR INJECTION | SUBCUTANEOUS | 10 | 24 | PRD8130316 |
Myalepta 5.8 mg powder for solution for injection | Test | POWDER FOR SOLUTION FOR INJECTION | SUBCUTANEOUS | 10 | 24 | PRD8130606 |