This study is NOT currently recruiting participants.
Number
000665-DK
Sponsoring Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Recruitment Detail
Type: Completed Study; data analyses ongoing Gender: Male & Female Min Age: 18 Years Max Age: 90 Years
Referral Letter Required
Yes
Population Exclusion(s)
Children
Keywords
Leptin receptor agonist antibody; Leptin receptor; Antibody; Familial Partial Lipodystrophy
Recruitment Keyword(s)
None
Condition(s)
Familial Partial Lipodystrophy
Investigational Drug(s)
REGN4461
Investigational Device(s)
Intervention(s)
Drug: REGN4461 - cohort 1 arm 2 Drug: REGN4461 - cohort 2 arm 2 Drug: REGN4461 - cohort 1 arm 1 Other: Placebo Drug: REGN4461 - cohort 2 arm 1
Supporting Site
National Institute of Diabetes and Digestive and Kidney Diseases
People with FPLD have low levels of the hormone leptin. This causes severe hunger or high food intake. This can lead to high sugar in the blood and high fat in the blood or liver. A drug called REGN4461 might be able to help.
Objective:
To test if REGN4461 is safe and effective in treating FPLD.
Eligibility:
People aged 18 and older with FPLD.
Design:
Participants will be screened with 3 visits over up to 10 weeks. The first visit must be at the NIH. The others can be remote. Screening will include:
Physical exam
Medical history
Fasting
Blood and urine tests
DXA imaging to estimate the amount of muscle, fat, and bone in the body.
Bioimpedance to measure body composition.
Participants will have weekly visits for about 28 weeks. They will have visits at the NIH on weeks 0, 4, 16, and 28. The others can be remote. Visits may include repeats of the screening tests and:
IV infusions of the study drug or placebo at 3 different times. They will also receive weekly injections of placebo or the study drug with
the help of a nurse. At any time, participants and the study doctor will not know whether they are receiving the drug or placebo.
MRI. They will lay on a table that glides into the scanner.
Heart tests
Participants will have a follow-up period. This will include visits to the NIH every 4 weeks for 16 weeks. Some of the study tests will be repeated.
Participants will fill out questionnaires about their appetite every day of the study.
Sponsoring Institution: National Institute of Diabetes and Digestive and Kidney Diseases
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Inclusion Criteria A patient must meet the following criteria to be eligible for inclusion in the study: 1. Male or female, >=18 years of age at the screening visit. 2. Clinical diagnosis of familial partial lipodystrophy: a) Altered body fat distribution including lipoatrophy at one or more sites, as determined by physical examination AND b) Metabolic sequelae of partial lipodystrophy, as evidenced by a medical history of at least 1 of the following: i) Fasting hypertriglyceridemia as evidence by multiple readings >150 mg/dL ii) Diabetes as evidenced by American Diabetes Association criteria iii) Hepatic steatosis as evidenced by liver ultrasound (Grade II-III) or MRI-PDFF (>5.6%) AND EITHER (c) or (d) c) History of known pathogenic mutation in an FPLD-related gene OR d) Satisfaction of PLD DXA Criteria i) In female patients with total fat percent (TF%) >=36%, trunk/leg >1.353 Note: Trunk/leg ratio (TLR) is defined as trunk fat%/leg fat% ii) In female patients with TF% <36%, TLR-(TF%*0.0311) >0.232 iii) In male patients with TF%>=27.5%, TLR>1.5 iv) In male patients with TF% <27.5%, TLR-(TF%*0.0429) >0.321 3. Fasting leptin level <=20.0 ng/mL 4. Presence of significant metabolic abnormalities satisfying 1 of the following: a) HbA1c >7.0% AND fasting TG >200 mg/dL OR b) Fasting TG >450 mg/dL 5. Stable body weight within the 3 months prior to screening (no gain or loss of >5% current weight) 6. Stable diet during the past 3 months defined as no major change in macronutrient composition (e.g., starting or stopping diets such as Adkins, Paleo, Vegetarianism, Veganism). 7. No clinically meaningful change in diabetes medication regimen in the 3 months prior to screening (addition, subtraction, or change in dosing). Changes in insulin dosing within 3 months are allowed if the change is <30% of the total daily dose. 8. No clinically meaningful change (addition, subtraction, or dose change) in medications for hyperlipidemia taken by prescription or over the counter (including fish oil or niacin) for the past 3 months prior to screening. 9. Willing and able to comply with clinic visits and study-related procedures. Note: patients incapable of completing COA assessments or unable to undergo MRI will not be excluded. 10. Provide informed consent signed by study patient or legally acceptable representative. Exclusion Criteria A patient who meets any of the following criteria will be excluded from the study: 1. Treatment with metreleptin within 3 months of the screening visit 2. Patients with a diagnosis of generalized lipodystrophy 3. Patients with a diagnosis of acquired lipodystrophy 4. Patients with a medical history of bone marrow transplant, use of an immune check-point inhibitor, or central nervous system tumor involving the hypothalamus. 5. Patients with clinically significant hematologic abnormalities such as neutropenia, lymphopenia, or lymphadenopathy at screening 6. Treatment with over-the-counter or prescription medications for weight loss begun within 3 months prior to the screening visit 7. Treatment with oral glucocorticoids >7.5 mg prednisone equivalents per day or plans to begin treatment with oral glucocorticoids >7.5 mg prednisone equivalents per day during the study period 8. Treatment with oral estrogens begun within 6 months prior to the screening visit 9. Any malignancy, e.g., lymphoma, within the past 1 year, prior to screening visit except for fully treated basal cell or squamous epithelial cell carcinomas of the skin or carcinoma in situ of the cervix or anus 10. Estimated glomerular filtration rate (GFR) of <30 mL/min/1.73 m2 based on the Chronic Kidney Disease Epidemiology Collaboration (CKD-Epi) equation at screening 11. History of heart failure hospitalization, myocardial infarction, stroke, clinically-significant arrhythmia (e.g., ventricular tachycardia, or any arrhythmia requiring medication adjustment to control), transient ischemic attack, unstable angina, percutaneous or surgical revascularization procedure (coronary, carotid, or peripheral vascular), or intracardiac device placement (e.g., pacemaker) within 3 months before the screening visit 12. Advanced heart failure (New York Heart Association Class 3 to 4) or severe and uncontrolled hypertension at screening 13. Current diagnosis of Type 1 diabetes mellitus 14. History of human immunodeficiency virus (HIV) or HIV seropositivity at screening visit 15. Uncontrolled infection with hepatitis B or hepatitis C infection or known active tuberculosis at screening. Patients will be tested for hepatitis C virus (HCV) and hepatitis B virus (HBV) at screening. Patients with hepatitis B (HBV sAg+) who have controlled infection (serum HBV DNA polymerase chain reaction (PCR) that is below the limit of detection AND receiving antiviral therapy for hepatitis B) are permitted. Patients with controlled infections must undergo periodic monitoring of HBV DNA per local standards. Patients must remain on anti-viral therapy for at least 6 months beyond the last dose of investigational study drug. Patients who are hepatitis C virus antibody-positive (HCVAb+) who have controlled infection (undetectable HCV RNA by PCR either spontaneously or in response to a successful prior course of anti-HCV therapy) are permitted. 16. A patient who has a documented, positive reverse-transcriptase polymerase chain reaction (RT-PCR) or serology test for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) may be enrolled provided the patient has: (A) Recovered from COVID-19 (all COVID-19-related symptoms and major clinical findings which can potentially affect the safety of the patient should be resolved), and (B) Had 2 negative results from a health authority-authorized nucleic acid amplification (PCR) test for SARS-CoV-2 taken at least 48 hours apart, or (C) Documented vaccination. 17. Participation in any clinical research study evaluating an investigational product (IP) or therapy within 3 months and less than 5 half-lives of IP prior to the screening visit. Participation in clinical research studies that only involve procedures (eg, muscle biopsies, glycemic clamps) or testing (eg, MRI) that will not interfere with the current study is permitted. 18. Any physical examination findings and/or history of any illness that, in the opinion of the study investigator, might confound the results of the study or pose an additional risk to the patient by their participation in the study 19. Alcohol consumption >21 drinks per week for males or >14 drinks per week for females 20. Members of the clinical site study team and/or his/her immediate family, unless prior approval granted by the Sponsor. 21. Pregnant or breastfeeding women. 22. Women of child-bearing potential (WOCBP)* who are unwilling to practice highly effective contraception prior to the beginning of the placebo run-in period, during the study, and for at least 16 weeks after the last dose. Highly effective contraceptive measures include: a. Stable use of combined (estrogen and progestogen containing) hormonal contraception (oral, intravaginal, transdermal) or progestogen-only hormonal contraception (oral, injectable, implantable), associated with inhibition of ovulation initiated 2 or more menstrual cycles prior to screening Note: If patients are using oral estrogen hormonal contraception, they must have initiated it at least 6 months prior to the screening visit. b. intrauterine device (IUD); intrauterine hormone-releasing system (IUS); c. bilateral tubal ligation; d. vasectomized partner (provided that the male vasectomized partner is the sole sexual partner of the WOCBP study participant and that the vasectomized partner has obtained medical assessment of surgical success for the procedure); and/or e. sexual abstinence *WOCBP are defined as women who are fertile following menarche until becoming postmenopausal, unless permanently sterile. Permanent sterilization methods include hysterectomy, bilateral salpingectomy, and bilateral oophorectomy. A postmenopausal state is defined as age >50 years old and with no periods for 12 months. Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual intercourse during the entire period of risk associated with the study drugs. The reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the patient. Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal (coitus interruptus), spermicides only, and lactational amenorrhea method are not acceptable methods of contraception. Female condom and male condom should not be used together. 23. Sexually active adult men who are unwilling to use the following forms of medically acceptable birth control during the study drug treatment period and for 16 weeks after the last dose of study drug: vasectomy with medical assessment of surgical success OR consistent use of a condom. Sperm donation is prohibited during the study and for 16 weeks after the last dose of study drug.
A patient must meet the following criteria to be eligible for inclusion in the study:
1. Male or female, >=18 years of age at the screening visit.
2. Clinical diagnosis of familial partial lipodystrophy:
a) Altered body fat distribution including lipoatrophy at one or more sites, as determined by physical examination
AND
b) Metabolic sequelae of partial lipodystrophy, as evidenced by a medical history of at least 1 of the following:
i) Fasting hypertriglyceridemia as evidence by multiple readings >150 mg/dL
ii) Diabetes as evidenced by American Diabetes Association criteria
iii) Hepatic steatosis as evidenced by liver ultrasound (Grade II-III) or MRI-PDFF (>5.6%)
AND EITHER (c) or (d)
c) History of known pathogenic mutation in an FPLD-related gene
OR
d) Satisfaction of PLD DXA Criteria
i) In female patients with total fat percent (TF%) >=36%, trunk/leg >1.353
Note: Trunk/leg ratio (TLR) is defined as trunk fat%/leg fat%
ii) In female patients with TF% <36%, TLR-(TF%*0.0311) >0.232
iii) In male patients with TF%>=27.5%, TLR>1.5
iv) In male patients with TF% <27.5%, TLR-(TF%*0.0429) >0.321
3. Fasting leptin level <=20.0 ng/mL
4. Presence of significant metabolic abnormalities satisfying 1 of the following:
a) HbA1c >7.0% AND fasting TG >200 mg/dL
b) Fasting TG >450 mg/dL
5. Stable body weight within the 3 months prior to screening (no gain or loss of >5% current weight)
6. Stable diet during the past 3 months defined as no major change in macronutrient
composition (e.g., starting or stopping diets such as Adkins, Paleo, Vegetarianism,
Veganism).
7. No clinically meaningful change in diabetes medication regimen in the 3 months prior to screening (addition, subtraction, or change in dosing). Changes in insulin dosing within 3 months are allowed if the change is <30% of the total daily dose.
8. No clinically meaningful change (addition, subtraction, or dose change) in medications for hyperlipidemia taken by prescription or over the counter (including fish oil or niacin) for the past 3 months prior to screening.
9. Willing and able to comply with clinic visits and study-related procedures.
Note: patients incapable of completing COA assessments or unable to undergo MRI will not be excluded.
10. Provide informed consent signed by study patient or legally acceptable representative.
Exclusion Criteria
A patient who meets any of the following criteria will be excluded from the study:
1. Treatment with metreleptin within 3 months of the screening visit
2. Patients with a diagnosis of generalized lipodystrophy
3. Patients with a diagnosis of acquired lipodystrophy
4. Patients with a medical history of bone marrow transplant, use of an immune check-point inhibitor, or central nervous system tumor involving the hypothalamus.
5. Patients with clinically significant hematologic abnormalities such as neutropenia, lymphopenia, or lymphadenopathy at screening
6. Treatment with over-the-counter or prescription medications for weight loss begun within 3 months prior to the screening visit
7. Treatment with oral glucocorticoids >7.5 mg prednisone equivalents per day or plans to begin treatment with oral glucocorticoids >7.5 mg prednisone equivalents per day during the study period
8. Treatment with oral estrogens begun within 6 months prior to the screening visit
9. Any malignancy, e.g., lymphoma, within the past 1 year, prior to screening visit except for fully treated basal cell or squamous epithelial cell carcinomas of the skin or carcinoma in situ of the cervix or anus
10. Estimated glomerular filtration rate (GFR) of <30 mL/min/1.73 m2 based on the Chronic Kidney Disease Epidemiology Collaboration (CKD-Epi) equation at screening
11. History of heart failure hospitalization, myocardial infarction, stroke, clinically-significant arrhythmia (e.g., ventricular tachycardia, or any arrhythmia requiring medication adjustment to control), transient ischemic attack, unstable angina, percutaneous or surgical revascularization procedure (coronary, carotid, or peripheral vascular), or intracardiac device placement (e.g., pacemaker) within 3 months before the screening visit
12. Advanced heart failure (New York Heart Association Class 3 to 4) or severe and uncontrolled hypertension at screening
13. Current diagnosis of Type 1 diabetes mellitus
14. History of human immunodeficiency virus (HIV) or HIV seropositivity at screening visit
15. Uncontrolled infection with hepatitis B or hepatitis C infection or known active tuberculosis at screening.
Patients will be tested for hepatitis C virus (HCV) and hepatitis B virus (HBV) at screening.
Patients with hepatitis B (HBV sAg+) who have controlled infection (serum HBV DNA polymerase chain reaction (PCR) that is below the limit of detection AND receiving antiviral therapy for hepatitis B) are permitted. Patients with controlled infections must undergo periodic monitoring of HBV DNA per local standards. Patients must remain on anti-viral therapy for at least 6 months beyond the last dose of investigational study drug.
Patients who are hepatitis C virus antibody-positive (HCVAb+) who have controlled infection (undetectable HCV RNA by PCR either spontaneously or in response to a successful prior course of anti-HCV therapy) are permitted.
16. A patient who has a documented, positive reverse-transcriptase polymerase chain reaction (RT-PCR) or serology test for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) may be enrolled provided the patient has: (A) Recovered from COVID-19 (all COVID-19-related symptoms and major clinical findings which can potentially affect the safety of the patient should be resolved), and (B) Had 2 negative results from a health authority-authorized nucleic acid amplification (PCR) test for SARS-CoV-2 taken at least 48 hours apart, or (C) Documented vaccination.
17. Participation in any clinical research study evaluating an investigational product (IP) or therapy within 3 months and less than 5 half-lives of IP prior to the screening visit. Participation in clinical research studies that only involve procedures (eg, muscle biopsies, glycemic clamps) or testing (eg, MRI) that will not interfere with the current study is permitted.
18. Any physical examination findings and/or history of any illness that, in the opinion of the study investigator, might confound the results of the study or pose an additional risk to the patient by their participation in the study
19. Alcohol consumption >21 drinks per week for males or >14 drinks per week for females
20. Members of the clinical site study team and/or his/her immediate family, unless prior approval granted by the Sponsor.
21. Pregnant or breastfeeding women.
22. Women of child-bearing potential (WOCBP)* who are unwilling to practice highly effective contraception prior to the beginning of the placebo run-in period, during the study, and for at least 16 weeks after the last dose. Highly effective contraceptive measures include:
a. Stable use of combined (estrogen and progestogen containing) hormonal contraception (oral, intravaginal, transdermal) or progestogen-only hormonal contraception (oral, injectable, implantable), associated with inhibition of ovulation initiated 2 or more
menstrual cycles prior to screening
Note: If patients are using oral estrogen hormonal contraception, they must have initiated it at least 6 months prior to the screening visit.
b. intrauterine device (IUD); intrauterine hormone-releasing system (IUS);
c. bilateral tubal ligation;
d. vasectomized partner (provided that the male vasectomized partner is the sole sexual partner of the WOCBP study participant and that the vasectomized partner has obtained medical assessment of surgical success for the procedure); and/or
e. sexual abstinence *WOCBP are defined as women who are fertile following menarche until becoming postmenopausal, unless permanently sterile. Permanent sterilization methods include hysterectomy, bilateral salpingectomy, and bilateral oophorectomy. A postmenopausal state is defined as age >50 years old and with no periods for 12 months. Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual intercourse during the entire period of risk associated with the study drugs. The reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the patient. Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal (coitus interruptus), spermicides only, and lactational amenorrhea method are not acceptable methods of contraception. Female condom and male condom should not be used together.
23. Sexually active adult men who are unwilling to use the following forms of medically acceptable birth control during the study drug treatment period and for 16 weeks after the last dose of study drug: vasectomy with medical assessment of surgical success OR consistent use of a condom. Sperm donation is prohibited during the study and for 16 weeks after the last dose of study drug.
Principal Investigator
Referral Contact
For more information: