Open-label study to evaluate metreleptin in children under 6 years of age with generalised lipodystrophy

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Amryt Pharmaceuticals Designated Activity Company

Participant type

Pediatric, Patients

Age range

0-17 years

Gender

Male and Female

Therapeutic area

Phenomena and Processes [G] - Metabolism [G03]

Trial duration

9 Feb 2024 → 11 May 2026

Decision date (initial)

2024-03-15

Transition trial

No

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Funding sources

Amryt Pharmaceuticals Designated Activity Company

External identifiers

EU CT number

2022-501781-22-00

ClinicalTrials.gov

NCT06502990

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Therapy, Safety, Pharmacokinetic, Efficacy

To evaluate the effectiveness of metreleptin in subjects under 6 years of age with generalised lipodystrophy and associated diabetes mellitus and/or hypertriglyceridaemia

Secondary objectives 5

1. Additional efficacy outcomes
2. Assess possible impact of metreleptin on quality of life
3. Assess change in total leptin (metreleptin and endogenous leptin) levels in ADA-positive subjects and in blocking antibody-positive subjects
4. Assess endogenous leptin levels in subjects with clinical events and in ADA-positive subjects versus ADA negative subjects
5. Assess effect of metreleptin on hyperphagia

Conditions and MedDRA coding

Generalised lipodystrophy

Study design 3 periods

Regulatory references

Scientific advice from competent authorities

European Medicines Agency

EMA paediatric investigation plan (PIP)

EMEA-001701-PIP01-14

Plan to share IPD

Yes

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 9

1. 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).
2. Metreleptin treatment naive
3. 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.
4. 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).
5. Elevated HbA1c ≥6.5% and/or fasting triglycerides ≥2.3 mmol/L (200 mg/dL).
6. 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.
7. 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.
8. 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.
9. Subject with stable mental and physical health per Investigator’s opinion.

Exclusion criteria 13

1. Weight <9 kg at Screening (Visit 1)
2. 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.
3. Symptomatic biliary obstruction or hyperbilirubinemia (i.e., total bilirubin >2x ULN, except with a documented diagnosis of Gilbert’s disease).
4. Chronic renal insufficiency with glomerular filtration rate (GFR) <60 mL/min calculated using the Schwartz Formula
5. 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.
6. In the judgement of the Investigator, precocious puberty or endocrine disorder that would affect growth (e.g., uncontrolled hypothyroidism, premature adrenarche).
7. History of malignancy (except for treated basal cell or squamous cell skin cancer) occurring within the past 3 years.
8. Subjects with ongoing or recent (within last 3 months) episode of acute pancreatitis.
9. 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).
10. Any clinically significant uncontrolled medical condition, that in the Investigator’s opinion would jeopardise subject participation or the interpretation of study results.
11. Undergone major surgery/surgical therapy for any cause within 1 month prior to Screening (Visit 1) or planned procedure during the study.
12. 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).
13. Known allergy or hypersensitivity to any of the investigational product or materials.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 2

1. Percent change from baseline in fasting serum TG levels at Month 12 for subjects with fasting TG levels ≥2.3 mmol/L (200 mg/dL) at baseline
2. Absolute change from baseline in glycated haemoglobin (HbA1c) at Month 12 for subjects with HbA1c ≥6.5% at baseline

Secondary endpoints 20

1. Proportion of subjects of those with Baseline HbA1c ≥6.5% achieving target actual decreases of at least 0.5%, 1%, 1.5%, 2% absolute decrease in HbA1c or HbA1c <6.5% or HbA1c <5.7% at Month 12
2. Proportion of subjects of those with Baseline HbA1c ≥5.7% achieving target actual decreases of at least 0.5%, 1%, 1.5%, 2% absolute decrease in HbA1c or HbA1c <5.7% at Month 12
3. Proportion of subjects of those with fasting serum TG ≥ 1.7 mmol/L (150 mg/dL) achieving target actual decreases from baseline of at least 15%, 20%, 25%, 30%, 35%, 40% at Month 12
4. Proportion of subjects of those with fasting serum TG ≥ 2.3 mmol/L (200 mg/dL) achieving target actual decreases from baseline of at least 15%, 20%, 25%, 30%, 35%, 40% at Month 12
5. Percent change from baseline in fasting serum TG levels at Month 12 for subjects with fasting TG levels ≥1.7 mmol/L (150 mg/dL) at baseline
6. Absolute change from baseline in HbA1c at Month 12 for subjects with HbA1c ≥5.7% at baseline
7. Actual change from baseline to Month 12 in fasting plasma glucose (FPG) levels overall and in subjects with baseline FPG above normal
8. Change from baseline to Month 6, 9 and 12 in fasting insulin in subjects with fasting insulin above upper limit of normal at baseline
9. Change from baseline in liver volume and liver span as assessed by ultrasound at each post-baseline visit through Month 12
10. Proportion of subjects with decreased severity of hepatic steatosis based on ultrasound in subjects with hepatic steatosis
11. Change from baseline in liver fibrosis scores as assessed by liver elastography
12. Change in liver transaminase levels (AST, ALT) in subjects with elevated transaminase levels at baseline
13. Proportion of subjects with normal transaminase levels (AST, ALT) in subjects with elevated transaminase levels at baseline
14. Change in use of medications (e.g., insulin) from screening through Month 12
15. Change in Pediatric Quality of Life Inventory (PedsQL)/ PedsQL Infant Scales from baseline to Month 6 and to Month 12
16. Change over time in total leptin as determined by Enzyme-linked Immunosorbent Assay (ELISA) in all ADA-positive subjects
17. Change over time in total leptin as determined by ELISA in blocking antibody-positive subjects
18. Correlation of endogenous leptin levels with clinical events (i.e., loss of efficacy or serious/severe infections)
19. Change over time in endogenous leptin levels as determined by Mass Spectrometry in all ADA positive subjects versus ADA negative subjects
20. Change in Hyperphagia Questionnaire for Clinical Trials (HQ-CT) from baseline to each post-baseline visit through Month 12

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 2

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Amryt Pharmaceuticals Designated Activity Company

Sponsor organisation

Amryt Pharmaceuticals Designated Activity Company

Address

45 Mespil Road, Ballsbridge Ballsbridge

City

Dublin 4

Postcode

D04 W2F1

Country

Ireland

Scientific contact point

Organisation

Amryt Pharmaceuticals Designated Activity Company

Contact name

Shir Fuchs Orenbach

Public contact point

Organisation

Amryt Pharmaceuticals Designated Activity Company

Contact name

Clinical Development, Global Rare Diseases

Third parties 3

Locations

4 EU/EEA countries · 12 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 70 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

15 submissions — initial application plus substantial / non-substantial modifications