A clinical Study to Evaluate Metreleptin Treatment in Subjects with Partial Lipodystrophy over 12-Month Timeframe

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

7 Mar 2024 → ongoing

Decision date (initial)

2023-02-03

Transition trial

No

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

No

External identifiers

EU CT number

2022-501799-24-00

ClinicalTrials.gov

NCT05164341

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Therapy, Safety, Efficacy

To evaluate the efficacy of daily SC metreleptin treatment in subjects with familial partial lipodystrophy (FPLD)

Secondary objectives 1

1. To assess the effect of metreleptin on fasting blood glucose (FBG)

Conditions and MedDRA coding

partial lipodystrophy

Study design 1 period

Regulatory references

Scientific advice from competent authorities

European Medicines Agency

EMA paediatric investigation plan (PIP)

EMEA-418723-PIP03-89

Plan to share IPD

Yes

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 14

1. Age ≥12 years at Visit 1
2. 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.
3. 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)
4. 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)
5. 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.
6. 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.
7. 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.
8. 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.
9. Negative pregnancy test (urine or serum) for female subjects of childbearing potential.
10. 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.
11. 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.
12. 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.
13. 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
14. Subjects who are willing to follow the dietary restrictions recommended by the Investigator.

Exclusion criteria 17

1. Previous treatment with metreleptin.
2. Leptin levels >20.0 ng/mL
3. Acquired partial lipodystrophy (APL)
4. Radiation induced PL
5. Subjects diagnosed with Cushing’s syndrome
6. 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
7. Subjects with prior severe hypersensitivity reactions to any of the metreleptin product components
8. 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.
9. Are immunocompromised or receiving immunomodulatory drugs
10. Known history of drug or alcohol abuse within 1 year prior to Screening as assessed according to the Investigator’s judgment
11. 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.
12. For females only: currently pregnant (confirmed with a positive pregnancy test) or breastfeeding
13. 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).
14. 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
15. Subjects with ongoing or recent (within the last 3 months prior to Screening) episode of acute pancreatitis
16. 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).
17. 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).

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 2

1. Change from Baseline to Month 6 in glycated hemoglobin (HbA1c) in subjects with FPLD in Groups A and C (HbA1c ≥7%)
2. Percent change from Baseline to Month 6 in fasting triglycerides (TGs) in subjects with FPLD in Groups B and C (TG ≥500 mg/dL [5.65 mmol/L])

Secondary endpoints 2

1. Change from Baseline to Month 6 in FBG in Groups A and C (HbA1c ≥7%)
2. Change from Baseline to Month 6 in FBG in subjects with FBG above upper limit of normal (ULN)

Investigational products

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

Test 1

Placebo 1

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

Shir Fuchs Orenbach

Public contact point

Organisation

Amryt Pharmaceuticals Designated Activity Company

Contact name

Shir Fuchs Orenbach

Third parties 7

Locations

4 EU/EEA countries · 5 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 184 files

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

Application history

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