Effects of ACC Inhibitor on Lipid and Lipoprotein Metabolism

NCT04395950

Last updated date
Study Location
Columbia University Irving Medical Center
New York, New York, 10032, United States
Contact
212-305-9562

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Eligibility Criteria
condition
The disease, disorder, syndrome, illness, or injury that is being studied.
NASH (Nonalcoholic Steatohepatitis), NAFLD (Nonalcoholic Fatty Liver Disease)
Sex
Females and Males
Age
Pediatric Trials: 0-17 Years
Adult Trials: 18+ Years
18-70 years
Inclusion Criteria
The factors, or reasons, that allow a person to participate in a clinical study.
Show details

- 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).

- NAFLD will be defined as liver fat ≥8% by MRI-proton density fat fraction (PDFF) and a FibroScanTM of Controlled Attenuation Parameter (CAP) >280 db/m and >7 kilopascals (kPa); both performed after a 4 hr fast and will be otherwise stable, including:

- Alanine aminotransferase (ALT) > ULN but < 5x ULN.

- 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 ≥ lower level normal (LLN) (155,000/mm3).

- Albumin ≥ LLN (3.0 g/L).

- International Normalized Ration (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 (glucagon like peptide-1 (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
The factors, or reasons, that prevent a person from participating in a clinical study.
Show details


- 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 aspirin
(ASA) daily.


- Treatment with immunomodulators.


- Drugs associated with acute pancreatitis as asparaginase, azathioprine, didanosine,
mercaptourinol, mesalamine, opiates, pentamidine, pentavalent antimonials, valproic
acid, and rifampin.


- Organic-anion-transporting polypeptides (OATP) inhibitors such as gemfibrozil and
cyclosporine (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).


- Drugs substrates for cytochromes P450 (CYP)3A4/5 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.

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NASH (Nonalcoholic Steatohepatitis), NAFLD (Nonalcoholic Fatty Liver Disease)Effects of ACC Inhibitor on Lipid and Lipoprotein Metabolism
NCT04395950
  1. New York, New York
ALL GENDERS
18 Years+
years
MULTIPLE SITES
Advanced Information
Descriptive Information
Brief Title  ICMJE Effects of ACC Inhibitor on Lipid and Lipoprotein Metabolism
Official Title  ICMJE 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
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
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: Single (Participant)
Primary Purpose: Basic Science
Condition  ICMJE
  • NASH (Nonalcoholic Steatohepatitis)
  • NAFLD (Nonalcoholic Fatty Liver Disease)
Intervention  ICMJE
  • Drug: PF-05221304
    PF-05221304 10 mg daily (two 5mg tablets daily in the morning for 6 weeks)
    Other Name: PF'1304
  • Drug: Placebo
    Placebo two tablets daily in the morning for 6 weeks
Study Arms  ICMJE
  • Active Comparator: PF-0522130
    PF-05221304 10 mg daily (two 5mg tablets daily in the morning).
    Intervention: Drug: PF-05221304
  • Placebo Comparator: Placebo
    Placebo (two tablets daily in the morning).
    Intervention: Drug: Placebo
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Not yet recruiting
Estimated Enrollment  ICMJE
 (submitted: May 19, 2020)
8
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE September 2022
Estimated Primary Completion Date March 2022   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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).
  • NAFLD will be defined as liver fat ?8% by MRI-proton density fat fraction (PDFF) and a FibroScanTM of Controlled Attenuation Parameter (CAP) >280 db/m and >7 kilopascals (kPa); both performed after a 4 hr fast and will be otherwise stable, including:
  • Alanine aminotransferase (ALT) > ULN but < 5x ULN.
  • 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 ? lower level normal (LLN) (155,000/mm3).
  • Albumin ? LLN (3.0 g/L).
  • International Normalized Ration (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 (glucagon like peptide-1 (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 aspirin (ASA) daily.
  • Treatment with immunomodulators.
  • Drugs associated with acute pancreatitis as asparaginase, azathioprine, didanosine, mercaptourinol, mesalamine, opiates, pentamidine, pentavalent antimonials, valproic acid, and rifampin.
  • Organic-anion-transporting polypeptides (OATP) inhibitors such as gemfibrozil and cyclosporine (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).
  • Drugs substrates for cytochromes P450 (CYP)3A4/5 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.
Sex/Gender  ICMJE
Sexes Eligible for Study:All
Ages  ICMJE 18 Years to 70 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Henry Ginsberg, MD212-305-9562[email protected]
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04395950
Other Study ID Numbers  ICMJE AAAS9106
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD:No
Responsible Party Henry N. Ginsberg, Columbia University
Study Sponsor  ICMJE Henry N. Ginsberg
Collaborators  ICMJE Pfizer
Investigators  ICMJE
Principal Investigator:Henry Ginsberg, MDColumbia University Irving Medical Center
PRS Account Columbia University
Verification Date May 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP