Effects of ACC Inhibitor on Lipid and Lipoprotein Metabolism
NCT04395950
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- 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.
- 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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| 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 |
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| Intervention ICMJE |
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| Study Arms ICMJE |
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| Publications * |
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* 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 | 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:
Exclusion Criteria:
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| Sex/Gender ICMJE |
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| Ages ICMJE | 18 Years to 70 Years (Adult, Older Adult) | ||||
| Accepts Healthy Volunteers ICMJE | No | ||||
| Contacts ICMJE |
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| 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 |
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| IPD Sharing Statement ICMJE |
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| Responsible Party | Henry N. Ginsberg, Columbia University | ||||
| Study Sponsor ICMJE | Henry N. Ginsberg | ||||
| Collaborators ICMJE | Pfizer | ||||
| Investigators ICMJE |
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| 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 | |||||