Open-label, Phase 3b study to evaluate effectiveness, safety and pharmacokinetic parameters of metreleptin in patients under 6 years of age with generalised lipodystrophy and associated diabetes mellitus and/or hypertriglyceridaemia
- Trial ID
- 2022-501781-22-00
- Protocol
- APL-20
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this open-label, Phase 3b study is to evaluate the **effectiveness** of metreleptin in patients under 6 years of age with **generalised lipodystrophy** and associated diabetes mellitus and/or hypertriglyceridaemia. This is clinically relevant as metreleptin may offer therapeutic benefits in managing metabolic complications associated with this rare condition, potentially improving patient outcomes and quality of life.
Secondary objectives include:
- Assessing additional efficacy outcomes.
- Evaluating the possible impact of metreleptin on quality of life.
- Assessing changes in total leptin levels (metreleptin and endogenous leptin) in ADA-positive subjects and in blocking antibody-positive subjects.
- Assessing endogenous leptin levels in subjects with clinical events and in ADA-positive subjects versus ADA-negative subjects.
- Evaluating the effect of metreleptin on hyperphagia.
Participants
The clinical trial focuses on evaluating the effectiveness of metreleptin in subjects under 6 years of age diagnosed with **generalised lipodystrophy** and associated diabetes mellitus and/or hypertriglyceridaemia. The study population includes both male and female participants, all of whom are under 6 years of age. The trial involves a vulnerable population, as it includes young children with a confirmed diagnosis of generalised lipodystrophy, characterized by near-total fat loss and low leptin levels. Participants are required to be metreleptin treatment-naive and must have stable mental and physical health as assessed by the investigator. The trial population was selected based on specific inclusion criteria, including elevated HbA1c levels and/or fasting triglycerides, and a stable treatment regimen for diabetes or elevated triglycerides prior to screening. The sponsor has not provided information regarding the total number of participants in the study.
Plans and Procedures
The clinical trial is an open-label, Phase 3b study designed to evaluate the effectiveness, safety, and pharmacokinetic parameters of **metreleptin** in patients under 6 years of age with generalised lipodystrophy and associated diabetes mellitus and/or hypertriglyceridaemia. The trial is not randomized or double-blind, as it is open-label, meaning both the researchers and participants know which treatment is being administered. The study is expected to last until September 30, 2026, with recruitment starting on November 13, 2023. The maximum treatment period for participants is 12 months.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on specific criteria, such as age, treatment history, and diagnosis of generalised lipodystrophy. Following the screening, eligible participants will be enrolled and receive the investigational product, Myalepta, administered subcutaneously. Follow-up visits will occur at regular intervals to monitor the primary and secondary endpoints, including changes in fasting serum triglyceride levels and glycated haemoglobin (HbA1c) over the 12-month period. The end-of-study visit will assess the overall outcomes and any long-term effects of the treatment.
Participant involvement is expected to last for the entire 12-month treatment period unless conditions arise that necessitate early termination. Such conditions may include adverse reactions to the treatment, non-compliance with the study protocol, or withdrawal of consent by the participant's legal representative. The study aims to provide comprehensive data on the efficacy and safety of metreleptin in this specific patient population, contributing valuable insights into the management of generalised lipodystrophy in young children.
Treatment
The clinical trial involves the administration of **Myalepta**, a pharmaceutical product containing the active substance **metreleptin**. Myalepta is available in two formulations: a 3 mg and a 5.8 mg powder for solution for injection. The pharmaceutical form is a **solution for injection**, and the route of administration is **subcutaneous**. The maximum daily dose for both formulations is 10 mg, with a total maximum treatment period of 12 months. The product is provided in commercial bulk drug form, which will be labelled, packaged, and QP certified specifically for use in this clinical study. The active substance, metreleptin, is a protein of non-human origin, classified under the ATC code A16AA07. The product is not a paediatric formulation, although it is used in a paediatric population in this study.
No non-experimental treatments, such as standard-of-care therapy, placebo, or comparator treatments, are specified for this study. The trial is designed to evaluate the effectiveness, safety, and pharmacokinetic parameters of metreleptin in patients under 6 years of age with generalized lipodystrophy and associated diabetes mellitus and/or hypertriglyceridemia. Participant compliance with the dosing schedule will be monitored throughout the study period to ensure adherence to the treatment protocol.
Efficacy
The efficacy of metreleptin in the clinical trial will be assessed through a series of primary and secondary endpoints. The primary endpoints include the percent change from baseline in fasting serum triglyceride (TG) levels at Month 12 for subjects with fasting TG levels ≥2.3 mmol/L (200 mg/dL) at baseline, and the absolute change from baseline in glycated hemoglobin (HbA1c) at Month 12 for subjects with HbA1c ≥6.5% at baseline. These endpoints are designed to evaluate the effectiveness of metreleptin in managing lipid and glucose metabolism in patients with generalised lipodystrophy and associated diabetes mellitus and/or hypertriglyceridaemia.
Secondary endpoints will further explore the efficacy of metreleptin by assessing various parameters at Month 12. These include the proportion of subjects achieving specific decreases in HbA1c and fasting serum TG levels, changes in fasting plasma glucose (FPG) levels, fasting insulin, liver volume, liver span, and liver fibrosis scores. Additionally, changes in liver transaminase levels, medication use, Pediatric Quality of Life Inventory (PedsQL) scores, and leptin levels will be evaluated. The Hyperphagia Questionnaire for Clinical Trials (HQ-CT) will also be used to assess changes in hyperphagia symptoms. These assessments will be conducted using validated laboratory tests and patient-reported outcomes, ensuring a comprehensive evaluation of metreleptin's efficacy over the 12-month treatment period.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Male and female subjects aged < 6 years of age at the time of LAR signing the informed consent form (ICF) prior to initiation of any study specific activities/procedures and < 6 years of age at Enrolment/ Baseline (Visit 2).
- Metreleptin treatment naive
- Confirmed diagnosis of generalised LD as demonstrated by one of the following criteria (a or b or c): a. Documented genetic diagnosis of generalised LD (mutations in genes known to be associated with congenital generalised LD) OR b. Imaging (e.g., dual-energy x-ray absorptiometry, whole body magnetic resonance imaging) documenting near total fat loss OR c. Clinical diagnosis of generalised LD supported by low leptin levels for age/gender and evidence of insulin resistance (e.g., fasting insulin > 30 mcU/ml, acanthosis nigricans, metabolic abnormalities due to insulin resistance). Clinical diagnoses need to be reviewed by the medical monitor.
- Confirmation by the Investigator that the potential differential diagnosis of generalised LD has been excluded (e.g., auto-inflammatory syndromes, progeroid syndromes, SHORT syndrome, malnutrition/starvation, anorexia nervosa, cachexia, HIV-associated wasting, diencephalic syndrome, thyrotoxicosis, adrenocortical insufficiency, severe chronic inflammation, poorly controlled type 1 diabetes mellitus).
- Elevated HbA1c ≥6.5% and/or fasting triglycerides ≥2.3 mmol/L (200 mg/dL).
- Subjects with diabetes should be receiving stable treatment regimen (diet and/or antidiabetic treatment) for at least 90 days prior to Screening (Visit 1) and during the screening period. If a subject is on insulin, a stable dose is defined as no more than a 20% fluctuation in insulin dose. Diet (as reported by the subject/LAR/caregiver) should be stable and in line with medical recommendations.
- Subjects with elevated fasting TG levels should be receiving stable treatment regimen (diet and/or lipid lowering therapy) for at least 6 weeks prior to Screening (Visit 1) and during the screening period. Diet (as reported by the subject/LAR/caregiver) should be stable and in line with medical recommendations.
- LAR capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the ICF and in this protocol. Subject assent to be obtained per local requirements.
- Subject with stable mental and physical health per Investigator’s opinion.
Exclusion Criteria
- Weight <9 kg at Screening (Visit 1)
- ALT or AST >8 x ULN. If a subject has AST or ALT between 3-8 x ULN, the Investigator should discuss the case with the Sponsor to determine whether it is in the interest of the subject to be enrolled.
- Symptomatic biliary obstruction or hyperbilirubinemia (i.e., total bilirubin >2x ULN, except with a documented diagnosis of Gilbert’s disease).
- Chronic renal insufficiency with glomerular filtration rate (GFR) <60 mL/min calculated using the Schwartz Formula
- Known active Hepatitis B, Hepatitis C or autoimmune hepatitis. Note: No testing for Hepatitis B and Hepatitis C is required unless mandated by local health authority.
- In the judgement of the Investigator, precocious puberty or endocrine disorder that would affect growth (e.g., uncontrolled hypothyroidism, premature adrenarche).
- History of malignancy (except for treated basal cell or squamous cell skin cancer) occurring within the past 3 years.
- Subjects with ongoing or recent (within last 3 months) 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).
- Any clinically significant uncontrolled medical condition, that in the Investigator’s opinion would jeopardise subject participation or the interpretation of study results.
- Undergone major surgery/surgical therapy for any cause within 1 month prior to Screening (Visit 1) or planned procedure during the study.
- Treatment with any investigational Medicinal Product (IMP) within 6 months or 5 times the terminal half-life of the corresponding IMP, whichever is longer, prior to Screening (Visit 1).
- Known allergy or hypersensitivity to any of the investigational product or materials.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Belgium | Not Recruiting | 13 Nov 2023 | 2 |
 France | Not Recruiting | 13 Nov 2023 | 2 |
 Germany | Not Recruiting | 13 Nov 2023 | 6 |
 Italy | Not Recruiting | 13 Nov 2023 | 15 |
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 | 12 | PRD8130527 |
Myalepta 5.8 mg powder for solution for injection | Test | POWDER FOR SOLUTION FOR INJECTION | SUBCUTANEOUS | 10 | 12 | PRD8130606 |