Effects of ACC Inhibitor on Lipid and Lipoprotein Metabolism

August 19, 2021 updated by: Columbia University

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

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.

Study Overview

Status

Withdrawn

Conditions

Intervention / Treatment

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.

Study Type

Interventional

Phase

  • Phase 1

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 70 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Basic Science
  • Allocation: Non-Randomized
  • Interventional Model: Sequential Assignment
  • Masking: Single

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Active Comparator: PF-0522130
PF-05221304 10 mg daily (two 5mg tablets daily in the morning).
Drug: PF-05221304
PF-05221304 10 mg daily (two 5mg tablets daily in the morning for 6 weeks)
Other Names:
  • PF1304
Placebo Comparator: Placebo
Placebo (two tablets daily in the morning).
Drug: Placebo
Placebo two tablets daily in the morning for 6 weeks
Other Names:
  • Placebo tablets

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Rate of Secretion (also called production-PR) of VLDL TG (mg/kg/day)
Time Frame: Up to 20 weeks
This is also called the production rate of very low density lipoprotein (VLDL) triglycerides (TG).
Up to 20 weeks
Fractional Clearance Rate (FCR) of VLDL TG (pool/day)
Time Frame: Up to 20 weeks
This is obtained from the modeling of enrichment data obtained by mass spectrometry.
Up to 20 weeks

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Columbia University

Collaborators

Pfizer

Investigators

  • Principal Investigator: Henry Ginsberg, MD, Columbia University

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Anticipated)

December 1, 2020

Primary Completion (Actual)

August 19, 2021

Study Completion (Actual)

August 19, 2021

Study Registration Dates

First Submitted

May 15, 2020

First Submitted That Met QC Criteria

May 19, 2020

First Posted (Actual)

May 20, 2020

Study Record Updates

Last Update Posted (Actual)

August 25, 2021

Last Update Submitted That Met QC Criteria

August 19, 2021

Last Verified

August 1, 2021

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • AAAS9106

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

Yes

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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