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Effects of ACC Inhibitor on Lipid and Lipoprotein Metabolism

Primary Purpose

NASH (Nonalcoholic Steatohepatitis), NAFLD (Nonalcoholic Fatty Liver Disease)

Status
Withdrawn
Phase
Phase 1
Locations
Study Type
Interventional
Intervention
PF-05221304
Placebo
Sponsored by
Columbia University
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional basic science trial for NASH (Nonalcoholic Steatohepatitis) focused on measuring NASH, NAFLD, non-alcoholic steatohepatitis, liver disease

Eligibility Criteria

18 Years - 70 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Body mass index (BMI) of ≥ 25 kg/m2 but < 40 kg/m2 and at least 2 of 5 traits of metabolic syndrome (fasting blood glucose >100 mg/dl or diagnosis of diabetes mellitus; BP >130/85; fasting TG >150 mg/dl; HDL cholesterol <40 mg/dl for men and <50 mg/dl for women; waist circumference >101 cm for men and >89 cm for women).
  • NASH will be defined as a FibroScan® of CAP >280 db/m and >7 kPa, OR demonstrated by liver biopsy, plus:
  • ALT > ULN but < 5 X ULN.
  • FIB4 score <3.5 (see below)
  • BP of ≤ 160/100 mmHg.
  • Alkaline phosphatase ≤ ULN.
  • Total bilirubin ≤ ULN (unless the subject has Gilbert's syndrome, a benign genetic problem where bilirubin is not conjugated normally and indirect bilirubin (unconjugated bilirubin increases) in which case direct bilirubin must be ≤ ULN with total bilirubin > ULN).
  • Platelet count ≥ LLN (155,000/mm3).
  • Albumin ≥ LLN (3.0 g/L).
  • INR ≤ 1.3.
  • Fasting serum triglycerides ≤ 350 mg/dL either non-pharmacologically managed or pharmacologically managed with stable doses of up to 3 oral agents for at least 6 months. They may be receiving statins if the dose has been stable for at least 3 months.
  • Subjects may have diabetes but must have an HbA1C ≤ 8.0% with glycemic control either non-pharmacologically managed or pharmacologically managed with stable doses of up to 3 oral agents for at least 6 months. Subjects taking a stable dose of long-acting insulin or an injectable GLP-1 inhibitor may be enrolled at the discretion of the investigators.
  • No changes in drugs affecting blood lipid or glucose or insulin levels will be permitted during the study without approval by the investigators.

Exclusion Criteria:

  • Individuals with a history of plasma TG >1000 mg/dl and/or pancreatitis.
  • Females of childbearing potential.
  • Chronic kidney disease defined by estimated glomerular filtration rate < 30 ml/min/1.73 m² by the modification of diet in renal disease equation.
  • Documented chronic hepatitis B or C. Subjects with hepatitis C are eligible provided there is proof of sustained virology response (SVR) for ≥ 3 years.
  • History of active malignancy within 5 years (subjects with non-melanoma skin cancer may be included).
  • Any other disease, condition, or laboratory value that, in the opinion of the principal investigator or clinical study team would place the subject at an unacceptable risk or interfere with the evaluation of the investigative product.
  • History of organ transplantation (other than corneal).
  • History of hepatobiliary malignancy even if subject "cured".
  • Pancreas divisum or a congenital abnormality of the pancreas
  • History of pancreatic surgery.
  • Subjects taking anti -coagulants or anti-platelet agents other than 81 mg ASA daily.
  • Treatment with immunomodulators.
  • Drugs associated with acute pancreatitis as asparaginase, azathioprine, didanosine, mecaptourinol, mesalamine, opiates, pentamidine, pentavalent anti-monials, valproic acid, and rifampin.
  • OATP inhibitors such as gemfibrozil and cyclosporinea. Drugs substrates for CYP3A4/5 with a narrow therapeutic index - these include: alfentanil, astemizole, cisapride, cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, tacrolimus, and terfenadine will be reason for exclusion.

a = the major clearance mechanism of PF-05221304 is active uptake into liver (mainly via hepatic transporters OATP1B1/1B3) followed by hepatic carbonyl reductase 1, 11b-hydroxysteroid dehydrogenase, and CYP 3A4/5-mediated metabolism. It is anticipated that potent OATP inhibitors may increase plasma concentrations of PF-05221304. As such, subjects treated with clinically relevant OATP inhibitors will be excluded from this study.

Sites / Locations

    Arms of the Study

    Arm 1

    Arm 2

    Arm Type

    Active Comparator

    Placebo Comparator

    Arm Label

    PF-0522130

    Placebo

    Arm Description

    PF-05221304 10 mg daily (two 5mg tablets daily in the morning).

    Placebo (two tablets daily in the morning).

    Outcomes

    Primary Outcome Measures

    Rate of Secretion (also called production-PR) of VLDL TG (mg/kg/day)
    This is also called the production rate of very low density lipoprotein (VLDL) triglycerides (TG).
    Fractional Clearance Rate (FCR) of VLDL TG (pool/day)
    This is obtained from the modeling of enrichment data obtained by mass spectrometry.

    Secondary Outcome Measures

    Full Information

    First Posted
    May 15, 2020
    Last Updated
    August 19, 2021
    Sponsor
    Columbia University
    Collaborators
    Pfizer
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    1. Study Identification

    Unique Protocol Identification Number
    NCT04395950
    Brief Title
    Effects of ACC Inhibitor on Lipid and Lipoprotein Metabolism
    Official Title
    A Phase 1B, Single-Blinded, Linear Two Period, Placebo-controlled Study to Evaluate the Effects of 10 mg/Day of PF-05221304, Liver Targeted Acetyl-CoA Carboxylase Inhibitor (ACCi) on Very Low Density Lipoprotein ApoB100 and TG Secretion
    Study Type
    Interventional

    2. Study Status

    Record Verification Date
    August 2021
    Overall Recruitment Status
    Withdrawn
    Why Stopped
    Poor enrollment
    Study Start Date
    December 2020 (Anticipated)
    Primary Completion Date
    August 19, 2021 (Actual)
    Study Completion Date
    August 19, 2021 (Actual)

    3. Sponsor/Collaborators

    Responsible Party, by Official Title
    Sponsor
    Name of the Sponsor
    Columbia University
    Collaborators
    Pfizer

    4. Oversight

    Studies a U.S. FDA-regulated Drug Product
    Yes
    Studies a U.S. FDA-regulated Device Product
    No
    Data Monitoring Committee
    Yes

    5. Study Description

    Brief Summary
    The purpose of this study is to assess the effects of an investigational drug, PF-05221304 (PF'1304) on the way the liver handles fat. The planned study will identify why the fat in the blood increases at the same time this drug reduces fat in the liver. The study will have two treatment periods of 6 weeks each, separated by a 3 week rest period with no treatment. The subjects will receive the active drug in one of the 6 week treatment periods and a placebo in the other 6 week period. The investigators will know when the subjects are receiving active treatment or placebo, but the subject will not know.
    Detailed Description
    Nonalcoholic Fatty Liver Disease (NAFLD) is a condition in which fat builds up in the liver. As its name suggests, it is not associated to heavy alcohol use. Non-Alcoholic Steatohepatitis (NASH) is a condition of liver inflammation and damage that is caused by the buildup of fat in the liver. It is usually associated with prediabetes, diabetes (high blood sugar in the blood), a high concentration of fat (triglycerides) in the blood, and obesity (increase in fat all over the body). The signs and symptoms of NASH are often not seen until the liver is damaged beyond repair, making NASH very difficult to diagnose (be picked up by your doctor) in its early stages where treatments might be able to reverse the damage. There are no treatments currently approved for people with NASH but several new medications are under study in people with NAFLD or NASH. This study uses a treatment being developed for treating NASH. The investigators will conduct a study to assess the effects of PF-05221304 (PF'1304) on the way the liver handles fat. In early studies, this new drug has shown promise for lowering the level of fat in the liver. However, it also, unexpectedly, increases the level of fat in the blood, which could increase the risk of heart disease and inflammation of the pancreas. The planned study will identify why the fat in the blood increases. Subjects will undergo a screening period where we will obtain medical history and physical exam. Additionally, we will obtain the results of liver imaging or liver biopsy previously performed by the subject's doctor that confirm the presence of an abnormal amount of liver fat and liver stiffness. The enrolled subjects will receive placebo (an inactive pill) during the first 6 weeks, followed by a 3 week washout period and then 6 weeks of active treatment. Blood samples will be collected during outpatient visits to check for study safety and measurements of fat in the blood and particles that carry that fat. There will also be 2 long outpatient studies that last approximately 15 hours each, where we will test why there is increase in fat blood levels during treatment with PF'1304. All visits will occur at the CUIMC Irving Institute for Clinical and Translational Research. Subject risk will be minimized through strict eligibility criteria to avoid enrollment of unstable or high-risk subjects and by close monitoring of adverse events (AE's), laboratory parameters, and vital signs during the study. In addition, blood fat levels will be measured on an ongoing basis.

    6. Conditions and Keywords

    Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
    NASH (Nonalcoholic Steatohepatitis), NAFLD (Nonalcoholic Fatty Liver Disease)
    Keywords
    NASH, NAFLD, non-alcoholic steatohepatitis, liver disease

    7. Study Design

    Primary Purpose
    Basic Science
    Study Phase
    Phase 1
    Interventional Study Model
    Sequential Assignment
    Masking
    Participant
    Allocation
    Non-Randomized
    Enrollment
    0 (Actual)

    8. Arms, Groups, and Interventions

    Arm Title
    PF-0522130
    Arm Type
    Active Comparator
    Arm Description
    PF-05221304 10 mg daily (two 5mg tablets daily in the morning).
    Arm Title
    Placebo
    Arm Type
    Placebo Comparator
    Arm Description
    Placebo (two tablets daily in the morning).
    Intervention Type
    Drug
    Intervention Name(s)
    PF-05221304
    Other Intervention Name(s)
    PF1304
    Intervention Description
    PF-05221304 10 mg daily (two 5mg tablets daily in the morning for 6 weeks)
    Intervention Type
    Drug
    Intervention Name(s)
    Placebo
    Other Intervention Name(s)
    Placebo tablets
    Intervention Description
    Placebo two tablets daily in the morning for 6 weeks
    Primary Outcome Measure Information:
    Title
    Rate of Secretion (also called production-PR) of VLDL TG (mg/kg/day)
    Description
    This is also called the production rate of very low density lipoprotein (VLDL) triglycerides (TG).
    Time Frame
    Up to 20 weeks
    Title
    Fractional Clearance Rate (FCR) of VLDL TG (pool/day)
    Description
    This is obtained from the modeling of enrichment data obtained by mass spectrometry.
    Time Frame
    Up to 20 weeks

    10. Eligibility

    Sex
    All
    Minimum Age & Unit of Time
    18 Years
    Maximum Age & Unit of Time
    70 Years
    Accepts Healthy Volunteers
    No
    Eligibility Criteria
    Inclusion Criteria: Body mass index (BMI) of ≥ 25 kg/m2 but < 40 kg/m2 and at least 2 of 5 traits of metabolic syndrome (fasting blood glucose >100 mg/dl or diagnosis of diabetes mellitus; BP >130/85; fasting TG >150 mg/dl; HDL cholesterol <40 mg/dl for men and <50 mg/dl for women; waist circumference >101 cm for men and >89 cm for women). NASH will be defined as a FibroScan® of CAP >280 db/m and >7 kPa, OR demonstrated by liver biopsy, plus: ALT > ULN but < 5 X ULN. FIB4 score <3.5 (see below) BP of ≤ 160/100 mmHg. Alkaline phosphatase ≤ ULN. Total bilirubin ≤ ULN (unless the subject has Gilbert's syndrome, a benign genetic problem where bilirubin is not conjugated normally and indirect bilirubin (unconjugated bilirubin increases) in which case direct bilirubin must be ≤ ULN with total bilirubin > ULN). Platelet count ≥ LLN (155,000/mm3). Albumin ≥ LLN (3.0 g/L). INR ≤ 1.3. Fasting serum triglycerides ≤ 350 mg/dL either non-pharmacologically managed or pharmacologically managed with stable doses of up to 3 oral agents for at least 6 months. They may be receiving statins if the dose has been stable for at least 3 months. Subjects may have diabetes but must have an HbA1C ≤ 8.0% with glycemic control either non-pharmacologically managed or pharmacologically managed with stable doses of up to 3 oral agents for at least 6 months. Subjects taking a stable dose of long-acting insulin or an injectable GLP-1 inhibitor may be enrolled at the discretion of the investigators. No changes in drugs affecting blood lipid or glucose or insulin levels will be permitted during the study without approval by the investigators. Exclusion Criteria: Individuals with a history of plasma TG >1000 mg/dl and/or pancreatitis. Females of childbearing potential. Chronic kidney disease defined by estimated glomerular filtration rate < 30 ml/min/1.73 m² by the modification of diet in renal disease equation. Documented chronic hepatitis B or C. Subjects with hepatitis C are eligible provided there is proof of sustained virology response (SVR) for ≥ 3 years. History of active malignancy within 5 years (subjects with non-melanoma skin cancer may be included). Any other disease, condition, or laboratory value that, in the opinion of the principal investigator or clinical study team would place the subject at an unacceptable risk or interfere with the evaluation of the investigative product. History of organ transplantation (other than corneal). History of hepatobiliary malignancy even if subject "cured". Pancreas divisum or a congenital abnormality of the pancreas History of pancreatic surgery. Subjects taking anti -coagulants or anti-platelet agents other than 81 mg ASA daily. Treatment with immunomodulators. Drugs associated with acute pancreatitis as asparaginase, azathioprine, didanosine, mecaptourinol, mesalamine, opiates, pentamidine, pentavalent anti-monials, valproic acid, and rifampin. OATP inhibitors such as gemfibrozil and cyclosporinea. Drugs substrates for CYP3A4/5 with a narrow therapeutic index - these include: alfentanil, astemizole, cisapride, cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, tacrolimus, and terfenadine will be reason for exclusion. a = the major clearance mechanism of PF-05221304 is active uptake into liver (mainly via hepatic transporters OATP1B1/1B3) followed by hepatic carbonyl reductase 1, 11b-hydroxysteroid dehydrogenase, and CYP 3A4/5-mediated metabolism. It is anticipated that potent OATP inhibitors may increase plasma concentrations of PF-05221304. As such, subjects treated with clinically relevant OATP inhibitors will be excluded from this study.
    Overall Study Officials:
    First Name & Middle Initial & Last Name & Degree
    Henry Ginsberg, MD
    Organizational Affiliation
    Columbia University
    Official's Role
    Principal Investigator

    12. IPD Sharing Statement

    Plan to Share IPD
    No
    Citations:
    PubMed Identifier
    21616678
    Citation
    Choi SH, Ginsberg HN. Increased very low density lipoprotein (VLDL) secretion, hepatic steatosis, and insulin resistance. Trends Endocrinol Metab. 2011 Sep;22(9):353-63. doi: 10.1016/j.tem.2011.04.007. Epub 2011 May 26.
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    Donnelly KL, Smith CI, Schwarzenberg SJ, Jessurun J, Boldt MD, Parks EJ. Sources of fatty acids stored in liver and secreted via lipoproteins in patients with nonalcoholic fatty liver disease. J Clin Invest. 2005 May;115(5):1343-51. doi: 10.1172/JCI23621.
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    Effects of ACC Inhibitor on Lipid and Lipoprotein Metabolism

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