Efficacy, Safety and Tolerability of ISIS 304801 in People With Partial Lipodystrophy With an Open-Label Extension

Learn more about:
Related Clinical Trial
Changes in Weight, Body Composition and Cardiac Risk After Discontinuing Abacavir Treatment in HIV-infected Individuals Changes in Weight, Body Composition and Metabolic Parameters After Discontinuing Dolutegravir or Tenofovir Disproxil Effect of Berberine on Metabolic Syndrome, Efficacy and Safety in Combination With Antiretroviral Therapy in PLWH. Hemoglobin Level, Coagulopathy Profile and Electrolyte Balance Seronegatives and Metabolic Abnormalities Protocol 2 (SAMA002): Study to Compare the Effect of Kaletra and Combivir® in HIV-Negative Healthy Subjects Myocardial Function & FFA Metabolism in HIV Metabolic Syndrome Exercise and Pioglitazone for HIV-Metabolic Syndromes Observational Study of Changes in Fat Distribution and Blood Metabolites in HIV Infected Adults Yoga for the Management of HIV-Metabolic Syndromes Pravastatin for Hyperlipidaemia in HIV. A Study of Physical and Metabolic Abnormalities in HIV Infected and Uninfected Children and Youth Exercise for Patients With HIV Infections Lactate Metabolism Study in HIV Infected Persons Quality of Life, Sleep, and Biomarkers in People With HIV/AIDS The Effect of Efavirenz and Nelfinavir on the Blood Levels of Certain Lipid-Lowering Drugs Metformin and Rosiglitazone, Alone or in Combination, in HIV-Infected Patients With Insulin and Fat Abnormalities Effects of Treatment Changes on Fat Wasting in the Arms and Legs of HIV Patients Safety Study of Antria Cell Preparation Process to Enhance Facial Fat Grafting With Adipose Derived Stem Cells Growth Hormone Dynamics and Cardiac Steatosis in HIV The Effect of Anti-HIV Treatment on Body Characteristics of HIV-Infected Children Immune Response to Pneumococcal Vaccination in Aging HIV Positive Adults Switching From Zidovudine to an NNRTI or Lopinavir/Ritonavir in Patients Treated With Zidovudine/ Lamivudine/Abacavir. Phase 1 Study to Assess the Safety and Tolerability of TAT4 Gel in Healthy Volunteers Detraining in People Living With HIV/AIDS SHARE: Simple HAART With Abacavir, Reyataz, and Epivir The Effects of Anabolic Steroids and Protease Inhibitors on People Living With HIV/AIDS Observational Study of Fat Loss in HIV Infected Adults Taking Nucleoside Reverse Transcriptase Inhibitors (NRTIs) Metabolism and Body Shape of Healthy Children and Children With Chronic Infections Changing to Nonprotease Inhibitor Treatment to Improve Side Effects Safety and Effectiveness of Fenofibrate and Pravastatin in HIV-Positive Patients With Abnormal Blood Lipids Perceived Changes in Body Build and Image in Patients Who Are Now Taking or Recently Have Stopped Taking Anti-HIV Drugs White Light Scanning to Aid Body Contouring: A Pilot Project Treatment of Abnormal Adipose Tissue Accumulation in Human Immunodeficiency Virus (HIV) Patients The Effect of Low-Dose Human Growth Hormone Therapy in HIV Infected Patients Study Comparing Reducing the Dose of Stavudine Versus Switching to Tenofovir in HIV-Infected Patients Receiving Antiretroviral Therapy The Cleveland Cardiometabolic Cohort Metabolic Abnormalities in HIV-infected Persons Clinical Evaluation of Venus Versa Octipolar Applicator for Reduction of Abdomen Circumference Factors Mediating Gut Microbiota Dysbiosis and Metabolic Disease in HIV Patients. Underlying Abnormalities in Fat and Muscle Leading to Lipodystrophy Syndrome Effects of Short-term Growth Hormone in HIV-infected Patients Safety Study of Filler Agent Composed of Autologous Mesenchymal Stem Cells and Hyaluronic Acid Raltegravir Therapy for Women With HIV and Fat Accumulation The PREFORM Study: A Study to Evaluate the Safety and Efficacy of Rotational Fractional Resection on Submental Contouring Effects of IGF-I in HIV Metabolic Disease Combination of Insulin Sensitizer and Leptin as Treatment for the HAART -Induced Metabolic Syndrome Effectiveness of Nucleoside Supplementation or Switch to Tenofovir in Reversing Fat Loss in HIV Infected Adults Lopinavir/r Monotherapy Versus Abacavir/Lamivudine and Lopinavir/r for Limb Fat Recovery in Persons With Lipoatrophy Effects of Growth Hormone Releasing Hormone in HIV A Study of Increased Lactic Acid and Abnormal Fat Distribution in HIV-Positive Patients Effects of a Uridine Supplement on HIV Infected Adults With Lipoatrophy Body Composition and Adipose Tissue in HIV Study to Evaluate Changes in Limb Fat When Switching From a Thymidine Analogue CONFORM: Rotational Fractional Resection for Submental Contouring Study of Alpha-2 Adrenergic Receptor Dysfunction in Regional Lipoatrophy TH9507 in Patients With HIV-Associated Lipodystrophy TH9507 Extension Study in Patients With HIV- Associated Lipodystrophy Study Evaluating the Impact on Fat Distribution of Nucleoside Reverse Transcriptase Inhibitor (NRTI)-Sparing Regimens in Antiretroviral Experienced Patients With Lipoatrophy Energy Expenditure of People Living With HIV/AIDS Beneficial Effect of Insulin Glulisine by Lipoatrophy and Type 1 Diabetes (LAS) Egrifta Replacement and Sleep Disordered Breathing Clinical Trial to Determine the Efficacy of Sculptra™ Dermal Filler for the Correction of Contour Deformities Caused by Lipoatrophy Clinical Trial to Assess the Effect of the Change of Efavirenz (EFV) for Lopinavir/Ritonavir (LPV/r) in Lipoatrophy in HIV-infected Patients Low Energy Diet and Familial Partial Lipodystrophy Clinical Protocol to Investigate the Efficacy of Recombinant Human Leptin (Metreleptin) in Nonalcoholic Steatohepatitis (NASH) or Nonalcoholic Fatty Liver Disease (NAFLD) Associated With Lipodystrophy A Study to Determine How and Why HIV-Infected Subjects on Anti-viral Treatment Develop Lipodystrophy Adipocyte, Insulin-resistance and Immunity : Evaluation of Interleukin-7 in Lipodystrophy, Diabetes and Obesity Compassionate Use of Metreleptin in Previously Treated People With Generalized Lipodystrophy Role of the Autonomic Nervous System in HIV-Lipodystrophy Leptin for Abnormal Lipid Kinetics in HIV Lipodystrophy Syndrome Therapeutic Approaches to HAART-Induced Lipodystrophy Different Surgical Modalities for Thigh Lipodystrophy Including Liposuction,Thigh Lift and Liposuction Assisted Thigh Lift Leptin to Treat Lipodystrophy Compassionate Use of Metreleptin in Previously Treated People With Partial Lipodystrophy Prevalence of Lipodystrophy Syndrome and Its Role as Cause of Metabolic Disturbances Efficacy, Safety and Tolerability of ISIS 304801 in People With Partial Lipodystrophy With an Open-Label Extension Shock Waves for Treatment of Gynoid Lipodystrophy and Localized Fat Corticosteroid-induced Lipodystrophy and Adipokines Short-term Effects of Leptin in People With Lipodystrophy Leptin to Treat Lipodystrophy Lipodystrophy Connect Patient Registry An Open-Label Treatment Protocol to Provide Metreleptin for the Treatment of Diabetes Mellitus and/or Hypertriglyceridemia Associated With Lipodystrophy Autologous Adipose-Derived Stem Cell Transplantation in Patients With Lipodystrophy

Brief Title

Efficacy, Safety and Tolerability of ISIS 304801 in People With Partial Lipodystrophy With an Open-Label Extension

Official Title

A Randomized, Double Blind, Placebo-Controlled Study to Assess Efficacy, Safety and Tolerability of ISIS 304801 in Patients With Partial Lipodystrophy With an Open-Label Extension

Brief Summary

      Background:

      Partial lipodystrophy is a deficiency of body fat in parts of the body (usually the arms and
      legs). People with partial lipodystrophy often get high blood triglyceride (fat) level,
      insulin resistance, diabetes and other problems. Researchers think the new drug ISIS 304801
      can help treat health problems caused by partial lipodystrophy.

      Objective:

      To see if ISIS 304801 will improve blood fat (triglyceride levels), diabetes, and liver
      disease, and reduce some risks for heart disease caused by partial lipodystrophy.

      Eligibility:

      Adults at least 18 years old with partial lipodystrophy.

      Design:

      Participants will be screened during a 1-week stay at NIH. They will have:

      Blood and urine tests

      Physical exam.

      Assignment to get either the study drug or placebo.

      Instructions for how to inject the drug.

      Body measurements.

      Heart tests.

      Participants will give themselves injections of the drug or placebo once a week at home. Some
      may test blood sugar by finger pricks. They will have monthly phone calls and nurse visits to
      take blood tests.

      After 4 months, participants may continue the study for 1 year. All participants will get the
      study drug.

      Participants will have study visits at NIH every 4 months. These may include:

      Insulin sensitivity measurement: Insulin and sugar will be infused through 2 intravenous (IV)
      lines in the arms. Blood will be drawn.

      Sugar and fat metabolism measured by IV infusions and blood tests.

      Special x-ray scan to measure body fat.

      Liquid meal then blood collected by IV catheter in the arm.

      Magnetic resonance imaging scans.

      Neck ultrasound.

      Questionnaires.

      Liver biopsy (optional)

      Injection of heparin (a blood thinner) before a blood test.

      After finishing the drug, participants will have 1 nurse visit and 1 visit to NIH.

      ...
    

Detailed Description

      Background:

      Lipodystrophy is a rare disease of deficient adipose mass, characterized by severe
      hypertriglyceridemia as well as insulin resistance, diabetes mellitus, fatty liver disease,
      acute pancreatitis, and early cardiovascular events. Apolipoprotein C-III (apoC-III)
      regulates triglyceride metabolism, and apoC-III levels strongly correlate with serum
      triglycerides in a variety of patient populations. Patients with genetically low levels of
      apoC-III have lower triglycerides and reduced cardiovascular disease, while individuals with
      genetically elevated levels of apoC-III have higher triglycerides and increased non-alcoholic
      fatty liver disease and insulin resistance. Pharmacologic reduction of apoC-III using
      anti-sense oligonucleotides (ASOs) reduce triglycerides by ~60-70% in a tested patient
      populations.

      Aim:

      The purpose of this study is to determine if apoC-III reduction using an ASO to apoC-III
      (ISIS 304801) will reduce triglycerides and improve insulin resistance, diabetes, and hepatic
      steatosis in patients with lipodystrophy.

      The primary hypothesis to be tested is:

        1. ISIS 304801will reduce log10 fasting serum triglycerides.

           Secondary and tertiary hypotheses to be tested are:

        2. ISIS 304801will improve glucose metabolism by improving insulin resistance.

        3. ISIS 304801 will reduce hepatic steatosis.

        4. ISIS 304801 will improve cardiovascular risk markers.

      We will also explore the mechanism of action of apoC-III ASO by studying lipoprotein lipase
      activity and lipoprotein particle distribution.

      Methods:

      This study will enroll up to 20 patients with partial lipodystrophy with a goal of 10 study
      completers. The study will be conducted in two phases. The first is a 16-week, randomized,
      double-blind, placebo-controlled design. Subjects will be treated with ISIS 304801 at a
      target dose of 300 mg per week or placebo. Following this phase, all subjects will enter a 12
      month open-label extension in which they will receive active drug. Patients who experience
      benefit (triglyceride lowering greater than or equal to 50%) may receive an additional 12
      months of open-label drug (up to 24 months, total). Measurement of the primary outcome (serum
      triglycerides) and key secondary outcomes will be performed at baseline prior to the
      intervention, after 13 weeks (primary outcome only) or 16 weeks (primary and secondary
      outcomes) of blinded drug or placebo, and after an additional 4 months of active drug in
      subjects initially randomized to placebo.
    

Study Phase

Phase 2

Study Type

Interventional


Primary Outcome

Change in Log 10 Fasting Triglycerides.

Secondary Outcome

 Change in Lipolysis Rate (Glycerol)

Condition

Lipodystrophy

Intervention

ISIS 304801

Study Arms / Comparison Groups

 Placebo
Description:  Placebo administered subcutaneously (SC)

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Drug

Estimated Enrollment

5

Start Date

December 23, 2015

Completion Date

September 26, 2019

Primary Completion Date

September 26, 2019

Eligibility Criteria

        -  INCLUSION CRITERIA:

          -  Age greater than or equal to 18 years at enrollment (the time of informed consent,
             week -1)

          -  Fasting triglyceride (TG) levels greater than or equal to 500 mg/dL (greater than or
             equal to 5.7 mmol/L) at enrollment. If the fasting TG value is <500 mg/dL (<5.7
             mmol/L) but greater than or equal to 350 mg/dL (greater than or equal to 4.0 mmol/L)
             up to two additional tests may be performed in order to qualify, and a single level
             greater than or equal to 500 mg/dL will permit enrollment.

        OR

          -  Fasting TG levels greater than or equal to 200 mg/DL (2.6 mmol/L) with a hemoglobin
             A1C over 7%.

          -  Willing to maintain their customary physical activity level and to follow a diet
             moderate in carbohydrates and fats with a focus on complex carbohydrates and replacing
             saturated for unsaturated fats

          -  Clinical diagnosis of lipodystrophy 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: men (less than or equal to 10mm) and women
             (less than or equal to 22mm), plus one of the following:

               -  Genetic diagnosis of familial PL (e.g., mutations in LMNA, PPARG, AKT2, or PLIN1
                  genes) OR

                    -  Family history of familial PL or abnormal and similar fat distribution plus
                       1 minor criterion (below), OR

                    -  2 minor criteria (below) in the absence of genetic diagnosis of family
                       history

                    -  MINOR Criteria

                    -  Diabetes mellitus with requirement for high doses of insulin, eg, requiring
                       greater than or equal to 200 U/day,greater than or equal to 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: Hepatomegaly and/or elevated
                       transaminases in the absence of a known cause of liver disease or
                       Radiographic evidence of hepatic steatosis (e.g., on ultrasound or CT)

          -  Satisfy one of the following:

               -  Females: Non-pregnant and non-lactating; surgically sterile (e.g., tubal
                  occlusion, hysterectomy, bilateral salpingectomy, bilateral oophorectomy),
                  post-menopausal (defined as 12 months of spontaneous amenorrhea in females >55
                  years of age or, in females less than or equal to 55 years, 12 months of
                  spontaneous amenorrhea without an alternative medical cause and
                  follicle-stimulating hormone (FSH) levels in the postmenopausal range for the
                  laboratory involved), abstinent, or if engaged in sexual relations of
                  child-bearing potential, patient is using an acceptable contraceptive method from
                  time of signing the informed consent form until at least 13 weeks after the last
                  dose of Study Drug administration.

               -  Males: Surgically sterile, abstinent, or if engaged in sexual relations with a
                  female of child bearing potential, patient is utilizing an acceptable
                  contraceptive method from the time of signing the informed consent form until at
                  least 13 weeks after the last dose of study drug administration.

        Note: Abstinence is only an effective method of birth control when this is the preferred
        and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation,
        symptothermal, post-ovulation methods), declaration of abstinence for the duration of a
        trial and withdrawal are not acceptable methods of contraception.

        EXCLUSION CRITERIA:

          -  A diagnosis of generalized lipodystrophy

          -  Current or history of autoimmune diseases (even with a diagnosis of PL) unless
             approved by the Investigator and Sponsor Medical Monitor

          -  Acute pancreatitis within 4 weeks of enrollment

          -  History within 6 months of enrollment of acute or unstable cardiac ischemia
             (myocardial infarction, acute coronary syndrome, new onset angina), stroke, transient
             ischemic attack, or unstable congestive heart failure requiring a change in medication

          -  Major surgery within 3 months of enrollment

          -  History of heart failure with New York Heart Association functional classification
             (NYHA) greater than Class II

          -  Uncontrolled hypertension (blood pressure [BP] >160/100 mm Hg)

          -  Any of the following laboratory values at enrollment:

               -  Cardiac troponin T > upper limit of normal (ULN)

               -  Measured or estimated (in case of triglycerides > 400 mg/dL) LDL-C >130 mg/dL on
                  maximal tolerated statin therapy

               -  Hemoglobin HbA1c greater than or equal to 9.5%

               -  Hepatic:

                    -  Total bilirubin >ULN

                    -  Alanine transaminase (ALT) >3.0 x ULN. Higher levels will be permitted after
                       a safety review by a hepatologist, that includes no evidence of cirrhosis.

                    -  Aspartate aminotransferase ( (AST) >3.0 x ULN. Higher levels will be
                       permitted after a safety review by a hepatologist, that includes no evidence
                       of cirrhosis.

               -  Renal:

                    -  Persistently positive (2 out of 3 tests greater than or equal to trace
                       positive) for blood on urine dipstick. In the event of a positive test
                       eligibility may be confirmed with urine microscopy showing less than or
                       equal to 5 red blood cells per high power field (urine will be screened at
                       admission and repeated if abnormal). If red blood cell counts (RBC) are high
                       every effort will be made to determine if the source is renal or benign,
                       such as from menstrual bleeding. If the presence of RBC is determined to be
                       from a non-renal source, the PI will make the decision to proceed with
                       protocol testing and/or randomization.

                    -  Two out of three consecutive tests greater than or equal to 1+ for protein
                       on urine dipstick. In the event of a positive test eligibility may be
                       confirmed by either a spot urine albumin to creatinine ratio <1000mg/g or a
                       quantitative total urine albumin measurement of < 1g/24 hrs (urine will be
                       screened at admission and repeated if abnormal)

                    -  Estimated creatinine clearance calculated according to the formula of
                       Cockcroft and Gault <60 mL/min

               -  Platelet count below 140,000 K/uL

               -  Clinically significant (as determined by the Investigator or Sponsor)
                  abnormalities on laboratory examination that will increase risk to the patient or
                  interfere with data integrity

          -  Uncontrolled hypothyroidism (abnormal thyroid function tests should be approved by the
             Investigator)

          -  History within 6 months of enrollment of screening of drug or alcohol abuse

          -  History of bleeding diathesis or coagulopathy or clinically significant abnormality in
             coagulation parameters at enrollment

          -  Active infection requiring systemic antiviral or antimicrobial therapy that will not
             be completed prior to enrollment

          -  Known history of or positive test for human immunodeficiency virus (HIV), hepatitis C
             or chronic hepatitis B

          -  Malignancy within 5 years, except for basal or squamous cell carcinoma of the skin or
             carcinoma in situ of the cervix that has been successfully treated

          -  Treatment with another investigational drug, biological agent, or device within one
             month of enrollment, or 5 half-lives of investigational agent, whichever is longer

          -  Unwilling to comply with contraceptive and lifestyle (diet/exercise) requirements

          -  Use of any of the following:

               -  Use of metreleptin within the last 3 months prior to enrollment

               -  Antidiabetic, lipid lowering, or atypical antipsychotic medication, unless on a
                  stable dose for at least 3 months prior to enrollment

               -  Insulin unless on a stable daily insulin dose regimen (+/- 20 %) for at least 4
                  weeks prior to enrollment

               -  Use of nicotinic acid or derivatives within the last 4 weeks prior to enrollment

               -  Systemic corticosteroids or anabolic steroids within 6 weeks prior to enrollment
                  unless approved by the Investigator

               -  Antihypertensive medication unless on a stable dose for at least 4 weeks prior to
                  enrollment

               -  Tamoxifen, estrogens or progestins unless on a stable dose for at least 4 months
                  prior to enrollment and dose and regimen expected to remain constant throughout
                  the study

               -  Oral anticoagulants unless on a stable dose for at least 4 weeks prior to
                  enrollment and regular clinical monitoring is performed

               -  Prior exposure to ISIS 304801

               -  Anti-obesity drugs [e.g., the combination of phentermine and extended-release
                  topiramate (Osymia, orlistat (Xenical), liraglutide [rDNA origin] injection
                  (Saxenda) and lorcaserin (Belvig), phentermine, amphetamines, herbal
                  preparations] within 12 weeks prior to screening

               -  Any other medication unless stable at least 4 weeks prior to enrollment
                  (occasional or intermittent use of over-the-counter medications will be allowed
                  at Investigator s discretion)

          -  Blood donation of 50 to 499 mL within 30 days or of >499 mL within 60 days

          -  Have any other conditions, which, in the opinion of the Investigator or the Sponsor
             would make the patient unsuitable for inclusion, or could interfere with the patient
             participating in or completing the study
      

Gender

All

Ages

18 Years - N/A

Accepts Healthy Volunteers

No

Contacts

Rebecca J Brown, M.D., , 

Location Countries

United States

Location Countries

United States

Administrative Informations


NCT ID

NCT02639286

Organization ID

160038

Secondary IDs

16-DK-0038

Responsible Party

Sponsor

Study Sponsor

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)


Study Sponsor

Rebecca J Brown, M.D., Principal Investigator, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)


Verification Date

January 3, 2020