Generalized Lipodystrophy
Conditions
Keywords
Immunogenicity, Antibodies, Lipodystrophy
Brief summary
MYALEPT™ (metreleptin) has been approved as an adjunct to diet as replacement therapy to treat the complications of leptin deficiency in patients with congenital or acquired generalized lipodystrophy (MYALEPT Prescribing Information). This study is a multicenter, open-label, Phase 4 trial to provide an assessment of the immunogenicity associated with metreleptin and of any major potential risks due to development of antibodies to metreleptin. The study is being conducted to comply with a postmarketing requirement.
Interventions
DRUGMetreleptin
Subjects will receive prescribed dosage of metreleptin as indicated in the USPI
Sponsors
Aegerion Pharmaceuticals, Inc.
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
1 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Provision of informed consent prior to any study specific procedures. If \<18 years of age, has a parent or guardian able to read, understand, and sign the Informed Consent Form (ICF) and a Child Assent form, communicate with the Investigator, and understand and comply with protocol requirements. Adolescent patients must also read and understand the Child Assent Form. If the child is too young or unable to read, then the Child Assent form must be explained to the child. 2. Female and/or male patients ≥1 years of age. 3. Physician-confirmed diagnosis of congenital or acquired generalized lipodystrophy and will begin treatment with MYALEPT for the first time. 4. Negative pregnancy test (urine or serum) for female patients of childbearing potential. 5. Female patients of childbearing potential must be 1 year postmenopausal, surgically sterile, or be willing to use an acceptable method of contraception (an acceptable method of contraception is defined as a barrier method in conjunction with a spermicide) for the duration of the study (from the time they sign consent). In addition, oral contraceptives, approved contraceptive implant, long-term injectable contraception, intrauterine device, or tubal ligation are allowed. Oral contraception alone is not acceptable; additional barrier methods in conjunction with spermicide must be used. 6. Male patients must be surgically sterile or be willing to use an acceptable method of contraception (defined as barrier methods in conjunction with spermicides) for the duration of the study (from the time they sign consent). 7. Patients who are blood donors should not donate blood during the study and for 3 months following their last dose of metreleptin.
Exclusion criteria
1. Involvement in the planning and/or conduct of the study (applies to both Aegerion staff and/or staff at the study site.) 2. Previous treatment with metreleptin. 3. Participation in another clinical study with an investigational product during the last 6 months. 4. Patients with prior severe hypersensitivity reactions to metreleptin or to any of the product components. 5. Known to have tested positive for human immunodeficiency virus, are immunocompromised, or are receiving immunomodulatory drugs. 6. Known history of drug or alcohol abuse within 1 year of screening. 7. Creatinine clearance \<30 mL/min using institutional standards: e.g., calculated using Cockcroft-Gault formula for patients ≥18 years of age; calculated using Schwartz equation for patients \<18 years of age. 8. For women only - currently pregnant (confirmed with positive pregnancy test) or breast-feeding. 9. 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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Evaluate the Immunogenicity Associated With Daily Subcutaneous (SC) Metreleptin Treatment in Patients With Congenital Generalized Lipodystrophy (CGL) or Acquired Generalized Lipodystrophy (AGL). | 36 months | Anti-metreleptin, anti-human leptin (HuL) binding antidrug antibody (ADA) titers over time. Category of in vitro cell-based neutralizing antibody (NAb) activity to metreleptin, and titer in the receptor blocking (RB) NAb assay in ADA positive samples over time. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Assess 2 Methods of Measuring in Vitro NAb Activity to Metreleptin. | 36 months | The percent (standard error) of patients with a positive result was compared for the RB NAb assay and the cell-based NAb assay over time. |
| Evaluate the Safety and Tolerability in Relation to the Development of or Absence of Anti-metreleptin and Anti-HuL Binding ADAs, and/or in Vitro NAb Activity to Metreleptin in Patients With CGL or AGL | 36 months | Serious adverse events (SAEs), AEs leading to discontinuation, loss of response (as assessed by glycated hemoglobin (HbA1c) and serum triglycerides), severe infections and/or sepsis, standard laboratory tests, and vital signs over time. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Evaluate the Efficacy With Daily Metreleptin in Patients With GL | 36 months | Change from Baseline in HbA1c over time. |
Countries
United States
Participant flow
Recruitment details
Patients were recruited from 4 centers in the US. Prescribing Investigators for this study were those who were certified under REMS for MYALEPT prescription and able to ensure prescription of metreleptin was as per the USPI.
Pre-assignment details
At Screening, consenting patients were assessed to ensure that they met eligibility criteria. The informed consent and health insurance portability and accountability act Authorization forms were signed prior to performing any Protocol-required procedures. The assessments conducted at the Screening Visit. When all Screening results were available, individuals were notified of their eligibility status.
Participants by arm
| Arm | Count |
|---|---|
| Metreleptin Subjects will receive prescribed dosage of metreleptin as indicated in the USPI Patients (males and females) ≤ 40 kg: 0.06mg/kg Male patients \> 40 kg: 2.5mg Female patients \> 40 kg: 5mg | 11 |
| Total | 11 |
Baseline characteristics
| Characteristic | Metreleptin |
|---|---|
| Age, Categorical <=18 years | 3 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 8 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 9 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Lipodystrophy diagnosis Acquired Generalised Lipodystrophy | 5 Participants |
| Lipodystrophy diagnosis Congenital Generalised Lipodystrophy | 6 Participants |
| Medical History Diabetes | 7 Participants |
| Medical History Hepatic cirrhosis | 1 Participants |
| Medical History Hepatic steatosis | 3 Participants |
| Medical History Hypertension | 4 Participants |
| Medical History Hypertriglyceridemia | 8 Participants |
| Medical History Pancreatitis | 5 Participants |
| Medical History Polycystic ovary syndrome | 2 Participants |
| Medical History Proteinuric | 2 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants |
| Race (NIH/OMB) White | 9 Participants |
| Sex: Female, Male Female | 9 Participants |
| Sex: Female, Male Male | 2 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 1 / 11 |
| other Total, other adverse events | 11 / 11 |
| serious Total, serious adverse events | 7 / 11 |
Outcome results
Primary
Evaluate the Immunogenicity Associated With Daily Subcutaneous (SC) Metreleptin Treatment in Patients With Congenital Generalized Lipodystrophy (CGL) or Acquired Generalized Lipodystrophy (AGL).
Anti-metreleptin, anti-human leptin (HuL) binding antidrug antibody (ADA) titers over time. Category of in vitro cell-based neutralizing antibody (NAb) activity to metreleptin, and titer in the receptor blocking (RB) NAb assay in ADA positive samples over time.
Time frame: 36 months
Population: Only ADA positive participants were analysed for neutralizing activity.
| Arm | Measure | Group | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|---|
| Metreleptin | Evaluate the Immunogenicity Associated With Daily Subcutaneous (SC) Metreleptin Treatment in Patients With Congenital Generalized Lipodystrophy (CGL) or Acquired Generalized Lipodystrophy (AGL). | NAb cell based + | ADA+ | 1 Participants |
| Metreleptin | Evaluate the Immunogenicity Associated With Daily Subcutaneous (SC) Metreleptin Treatment in Patients With Congenital Generalized Lipodystrophy (CGL) or Acquired Generalized Lipodystrophy (AGL). | NAb receptor blocking+ | ADA+ | 10 Participants |
| Metreleptin | Evaluate the Immunogenicity Associated With Daily Subcutaneous (SC) Metreleptin Treatment in Patients With Congenital Generalized Lipodystrophy (CGL) or Acquired Generalized Lipodystrophy (AGL). | ADA positive | ADA+ | 10 Participants |
Secondary
Assess 2 Methods of Measuring in Vitro NAb Activity to Metreleptin.
The percent (standard error) of patients with a positive result was compared for the RB NAb assay and the cell-based NAb assay over time.
Time frame: 36 months
Population: Only ADA+ participants were analysed for neutralizing activity.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Metreleptin | Assess 2 Methods of Measuring in Vitro NAb Activity to Metreleptin. | NAb receptor blocking+ | 10 Participants |
| Metreleptin | Assess 2 Methods of Measuring in Vitro NAb Activity to Metreleptin. | NAb cell based+ | 1 Participants |
Secondary
Evaluate the Safety and Tolerability in Relation to the Development of or Absence of Anti-metreleptin and Anti-HuL Binding ADAs, and/or in Vitro NAb Activity to Metreleptin in Patients With CGL or AGL
Serious adverse events (SAEs), AEs leading to discontinuation, loss of response (as assessed by glycated hemoglobin (HbA1c) and serum triglycerides), severe infections and/or sepsis, standard laboratory tests, and vital signs over time.
Time frame: 36 months
| Arm | Measure | Group | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|---|
| Metreleptin | Evaluate the Safety and Tolerability in Relation to the Development of or Absence of Anti-metreleptin and Anti-HuL Binding ADAs, and/or in Vitro NAb Activity to Metreleptin in Patients With CGL or AGL | All AE | AEs leading to discomntinuation | 11 Participants |
| Metreleptin | Evaluate the Safety and Tolerability in Relation to the Development of or Absence of Anti-metreleptin and Anti-HuL Binding ADAs, and/or in Vitro NAb Activity to Metreleptin in Patients With CGL or AGL | SAE | AEs leading to discomntinuation | 7 Participants |
| Metreleptin | Evaluate the Safety and Tolerability in Relation to the Development of or Absence of Anti-metreleptin and Anti-HuL Binding ADAs, and/or in Vitro NAb Activity to Metreleptin in Patients With CGL or AGL | AEs leading to discontinuation | AEs leading to discomntinuation | 1 Participants |
| Metreleptin | Evaluate the Safety and Tolerability in Relation to the Development of or Absence of Anti-metreleptin and Anti-HuL Binding ADAs, and/or in Vitro NAb Activity to Metreleptin in Patients With CGL or AGL | Severe infections and/or sepsis | AEs leading to discomntinuation | 2 Participants |
| Metreleptin | Evaluate the Safety and Tolerability in Relation to the Development of or Absence of Anti-metreleptin and Anti-HuL Binding ADAs, and/or in Vitro NAb Activity to Metreleptin in Patients With CGL or AGL | Blood Triglycerides increased | AEs leading to discomntinuation | 3 Participants |
| Metreleptin | Evaluate the Safety and Tolerability in Relation to the Development of or Absence of Anti-metreleptin and Anti-HuL Binding ADAs, and/or in Vitro NAb Activity to Metreleptin in Patients With CGL or AGL | Glycosylated haemoglobin increased | AEs leading to discomntinuation | 1 Participants |
Other Pre-specified
Evaluate the Efficacy With Daily Metreleptin in Patients With GL
Change from Baseline in HbA1c over time.
Time frame: 36 months
Population: Only subjects who reached the visits (Month 12, 24 ,36) were included in the analysis
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Metreleptin | Evaluate the Efficacy With Daily Metreleptin in Patients With GL | Absolute change in HbA1c from baseline to Month 24 | -0.5 Percentage |
| Metreleptin | Evaluate the Efficacy With Daily Metreleptin in Patients With GL | Absolute change in HbA1c from baseline to Month 12 | -0.3 Percentage |
| Metreleptin | Evaluate the Efficacy With Daily Metreleptin in Patients With GL | Absolute change in HbA1c from baseline to Month 36 | -0.7 Percentage |
Other Pre-specified
Evaluate the Efficacy With Daily Metreleptin in Patients With GL
Percent change from Baseline in fasting triglycerides over time.
Time frame: 36 months
Population: Only subjects who reached the visits (Month 12, 24 ,36) were included in the analysis
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Metreleptin | Evaluate the Efficacy With Daily Metreleptin in Patients With GL | Precent change in triglycerides from baseline to Month 12 | -49.68 Percent Change |
| Metreleptin | Evaluate the Efficacy With Daily Metreleptin in Patients With GL | Precent change in triglycerides from baseline to Month 24 | -46.72 Percent Change |
| Metreleptin | Evaluate the Efficacy With Daily Metreleptin in Patients With GL | Precent change in triglycerides from baseline to Month 36 | -58.12 Percent Change |