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

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Chiesi Farmaceutici S.p.A.

Participant type

Pediatric, Patients

Age range

0-17 years, 18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Phenomena and Processes [G] - Metabolism [G03]

Trial duration

8 Dec 2023 → ongoing

Decision date (initial)

2023-10-10

Transition trial

No

Low-intervention

Yes

Rare-disease indication

Yes

Vulnerable population

Yes

Funding sources

Amryt Pharma DAC, 45 Mespil Road, Dublin 4, Ireland

External identifiers

EU CT number

2022-502950-14-00

ClinicalTrials.gov

NCT06484868

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Others, Efficacy

To evaluate the efficacy of metreleptin treatment in patients with PL.

Secondary objectives 5

1. To evaluate the long-term efficacy of metreleptin treatment in patients with PL.
2. To assess the efficacy of metreleptin on additional clinically relevant outcome measures.
3. To assess changes in liver volume.
4. To assess the effect of metreleptin treatment on insulin resistance and sensitivity.
5. To assess change in anti-diabetic or lipid-lowering medications over time.

Conditions and MedDRA coding

Partial Lipodystrophy

Study design 3 periods

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 10

1. 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.
2. Confirmed diagnosis of familial or acquired PL.
3. 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])
4. Patients must have: a) HbA1c level ≥6.5% and/or b) Fasting serum TG levels ≥500 mg/dL (5.65 mmol/L)
5. 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.
6. 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.
7. Patients are willing to follow the dietary restrictions recommended by the Investigator.
8. 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).
9. 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.
10. 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 9

1. Known to have tested positive for human immunodeficiency virus (HIV) or known to be diagnosed with HIV-related LD
2. 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).
3. Known history of severe hypersensitivity reactions to any of the metreleptin product components.
4. Known history of drug or alcohol abuse within 1 year prior to Screening as assessed according to the Investigator’s judgment.
5. 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.
6. 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.
7. 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.
8. For females only - currently pregnant (confirmed with positive pregnancy test) or breastfeeding.
9. Positive pregnancy test (urine or serum) for females of childbearing potential.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 2

1. Number of patients with decrease of at least 0.5% in glycated haemoglobin (HbA1c) at Month 12 compared to Baseline or HbA1c <6.5 % at Month 12, in patients with baseline HbA1c ≥6.5%.
2. Number of patients with decrease of at least 30% in triglycerides (TG) at Month 12 compared to Baseline, in patients with baseline TG levels ≥500 mg/dL (5.65 mmol/L).

Secondary endpoints 10

1. Number of patients with decrease of at least 0.5% in HbA1c at Month 24 compared to Baseline or HbA1c <6.5 % at Month 24, in patients with baseline HbA1c ≥6.5%.
2. Number of patients with decrease of at least 30% in TG levels at Month 24 compared to Baseline, in patients with baseline TG levels ≥500 mg/dL (5.65 mmol/L).
3. Change from baseline in HbA1c at Month 12 and Month 24 in patients with baseline HbA1c ≥6.5% (Subgroup analysis for patients with HbA1c ≥8% will be conducted)
4. Percent change from baseline in TG levels at Month 12 and Month 24 in patients with baseline TG ≥500 mg/dL (5.65 mmol/L).
5. Number of patients achieving at least 1 of the below criteria: o 0.5% decrease in HbA1c at Month 12 compared to Baseline or HbA1c <6.5 % at Month 12 o 30% decrease in fasting serum TG at Month 12
6. Change from baseline in liver volume at Month 12 and Month 24.
7. Change from baseline in Homeostatic Model Assessment of Insulin Resistance (HOMAIR) (fasting glucose and insulin) in noninsulin treated patients at Month 12 and Month 24.
8. Number of patients who maintained, decreased, or increased dose and/or dosing frequency of anti-diabetic medications.
9. Number of patients who maintained, decreased, or increased dose and/or dosing frequency of lipid-lowering medications.
10. Number of patients with ≥25% reduction in insulin requirements at Month 12 and Month 24.

Investigational products

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

Test 6

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Chiesi Farmaceutici S.p.A.

Sponsor organisation

Chiesi Farmaceutici S.p.A.

Address

Via Palermo 26/a

City

Parma

Postcode

43122

Country

Italy

Scientific contact point

Organisation

Amryt Pharmaceuticals Designated Activity Company

Contact name

Chiara Garofalo

Public contact point

Organisation

Amryt Pharmaceuticals Designated Activity Company

Contact name

Clinical Development, Global Rare Diseases

Third parties 5

Locations

3 EU/EEA countries · 13 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 19 files

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

Application history

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