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Combination Obeticholic Acid (OCA) and Statins for Monitoring of Lipids (CONTROL) (CONTROL)

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ClinicalTrials.gov Identifier: NCT02633956
Recruitment Status : Completed
First Posted : December 17, 2015
Results First Posted : June 4, 2018
Last Update Posted : June 4, 2018
Sponsor:
Information provided by (Responsible Party):
Intercept Pharmaceuticals

Brief Summary:
This Phase 2, double-blind, randomized, placebo-controlled, multicenter study, with an open-label long-term safety extension (LTSE), will evaluate the effect of Obeticholic Acid, and the subsequent addition of statin therapy, on lipoprotein metabolism in subjects with nonalcoholic steatohepatitis (NASH) with fibrosis stage 1 to 4, but no evidence of hepatic decompensation.

Condition or disease Intervention/treatment Phase
Nonalcoholic Steatohepatitis Drug: Obeticholic Acid Drug: Atorvastatin Drug: Placebo Phase 2

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 84 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: A Phase 2, Randomized, Double Blind, Placebo Controlled Clinical Study Investigating the Effects of Obeticholic Acid and Atorvastatin Treatment on Lipoprotein Metabolism in Subjects With Nonalcoholic Steatohepatitis
Actual Study Start Date : December 4, 2015
Actual Primary Completion Date : March 21, 2017
Actual Study Completion Date : March 12, 2018


Arm Intervention/treatment
Experimental: 5 mg Obeticholic Acid
5 mg Obeticholic Acid daily for the double-blind treatment period. 10 mg Atorvastatin titrating to 20mg.
Drug: Obeticholic Acid
Once a day (QD) by mouth (PO)
Other Names:
  • OCA
  • 6alpha-ethylchenodeoxycholic acid (6-ECDCA)
  • INT-747

Drug: Atorvastatin

Initiate treatment with Atorvastatin at Week 4 visit with a dose of 10 mg once daily (QD) by mouth (PO).

Increase Atorvastatin to 20 mg once daily (QD) by mouth (PO) at Week 8 visit if 10 mg daily is tolerated.

Atorvastatin may be titrated up or down at Week 12 visit as clinically indicated.


Experimental: 10 mg Obeticholic Acid
10 mg Obeticholic Acid daily for the double-blind treatment period. 10 mg Atorvastatin titrating to 20mg.
Drug: Obeticholic Acid
Once a day (QD) by mouth (PO)
Other Names:
  • OCA
  • 6alpha-ethylchenodeoxycholic acid (6-ECDCA)
  • INT-747

Drug: Atorvastatin

Initiate treatment with Atorvastatin at Week 4 visit with a dose of 10 mg once daily (QD) by mouth (PO).

Increase Atorvastatin to 20 mg once daily (QD) by mouth (PO) at Week 8 visit if 10 mg daily is tolerated.

Atorvastatin may be titrated up or down at Week 12 visit as clinically indicated.


Experimental: 25 mg Obeticholic Acid
25 mg Obeticholic Acid daily for the double-blind treatment period. 10 mg Atorvastatin titrating to 20mg.
Drug: Obeticholic Acid
Once a day (QD) by mouth (PO)
Other Names:
  • OCA
  • 6alpha-ethylchenodeoxycholic acid (6-ECDCA)
  • INT-747

Drug: Atorvastatin

Initiate treatment with Atorvastatin at Week 4 visit with a dose of 10 mg once daily (QD) by mouth (PO).

Increase Atorvastatin to 20 mg once daily (QD) by mouth (PO) at Week 8 visit if 10 mg daily is tolerated.

Atorvastatin may be titrated up or down at Week 12 visit as clinically indicated.


Placebo Comparator: Placebo
One tablet daily for the double-blind treatment period. 10 mg Atorvastatin titrating to 20mg.
Drug: Atorvastatin

Initiate treatment with Atorvastatin at Week 4 visit with a dose of 10 mg once daily (QD) by mouth (PO).

Increase Atorvastatin to 20 mg once daily (QD) by mouth (PO) at Week 8 visit if 10 mg daily is tolerated.

Atorvastatin may be titrated up or down at Week 12 visit as clinically indicated.


Drug: Placebo
Once a day (QD) by mouth (PO)




Primary Outcome Measures :
  1. The Effect of Obeticholic Acid on Low-density Lipoprotein (LDL) Concentration (Least Squares Mean Change From Baseline at Week 16) [ Time Frame: Baseline and Week 16 ]
    The effect of Obeticholic Acid on LDL metabolism in subjects with biopsy confirmed nonalcoholic steatohepatitis (NASH) and the ability of atorvastatin to modulate this effect as measured by change (least squares mean) from baseline at week 16 in LDL concentration

  2. The Effect of Obeticholic Acid on LDL Particle Size (Least Squares Mean Change From Baseline at Week 16) [ Time Frame: Baseline and Week 16 ]
    The effect of Obeticholic Acid on LDL metabolism in subjects with biopsy confirmed NASH and the ability of atorvastatin to modulate this effect as measured by change from baseline (least squares mean) at week 16 in LDL particle size. It is LDL particle diameter size (nm) that is reported.

  3. The Effect of Obeticholic Acid on LDL Particle Concentration (Total) (Least Squares Mean Change From Baseline at Week 16) [ Time Frame: Baseline and Week 16 ]
    The effect of Obeticholic Acid on LDL metabolism in subjects with biopsy confirmed nonalcoholic NASH and the ability of atorvastatin to modulate this effect as measured by change (least squares mean) from baseline at week 16 in LDL particle concentration (total)



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 85 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Age ≥18 years
  2. Histologic evidence of NASH, as assessed by central reading of a liver biopsy obtained no more than 1 year prior to randomization, defined by the presence of all 3 key histological features of NASH with a score of at least 1 for each and a combined score of 4 or greater out of a possible 8 points according to NASH Clinical Research Network (CRN) criteria.
  3. Histologic evidence of fibrosis stage 1 to stage 4 (as defined by NASH CRN scoring of fibrosis) without any evidence of hepatic decompensation.
  4. If subject has type 2 diabetes, is on stable dose of anti-diabetic medication (except thiazolidinediones [TZDs]) for ≥3 months prior to Day 1.
  5. Is either not taking or is on stable doses of TZDs and/or Vitamin E for ≥6 months prior to Day 1.
  6. Contraception: Female subjects of childbearing potential must use ≥1 effective method of contraception during the study and until 30 days following the last dose of investigational product. Effective methods of contraception are considered to be the following: barrier method, ie, condom (male or female) with spermicide or diaphragm with spermicide, intrauterine device, vasectomy (partner), hormonal (eg, contraceptive pill, patch, intramuscular implant or injection), abstinence (defined as refraining from heterosexual intercourse).
  7. Must provide written informed consent and agree to comply with the study protocol, including adherence to protocol-described statin withdrawal and statin therapy.

Exclusion Criteria:

  1. Current or history of significant alcohol consumption for a period of more than 3 consecutive months within 1 year prior to Screening Visit 1 (significant alcohol consumption is defined as more than 2 units/day in females and more than 4 units/day in males, on average)
  2. Prior intolerance to treatment with atorvastatin or other 3-hydroxy-3-methyl-glutaryl (HMG) Coenzyme A reductase inhibitors (including but not limited to rhabdomyolysis).
  3. LDL cholesterol ≥190 mg/dL and already on statin therapy at Screening Visit 1.
  4. LDL cholesterol >200 mg/dL at any Screening Visit in subjects who are not on statin therapy, or at Screening Visit 2 in statin washout subjects.
  5. Planned change in diet or exercise habits during participation in the double-blind period, or a significant weight change of >5% in the prior 6 months.
  6. Subjects who have undergone gastric bypass procedures (gastric lap band is acceptable) or ileal resection or plan to undergo either of these procedures.
  7. History of biliary diversion
  8. Uncontrolled diabetes defined as HbA1c ≥9.5% within 60 days prior to randomization (Day 1).
  9. Administration of any of the following medications as specified below:

    • Prohibited 30 days prior to Day 1:

      • bile acid sequestrants (BAS) including cholestyramine and its derivatives, colesevelam, colestipol, or
      • omega-3 fatty acid-containing dietary supplements
    • Prohibited 3 months prior to Day 1:

      • nicotinic acid and derivatives, ezetimibe
      • any prescription or over-the-counter (OTC) medication or herbal remedy with putative NASH efficacy (except Vitamin E or TZDs)
      • ursodeoxycholic acid
      • fenofibrate or other fibrates
      • any OTC or health food used to treat lipids including plant sterols and berberine
    • Prohibited 6 months prior to Day 1:

      • azathioprine, colchicine, cyclosporine, methotrexate, mycophenolate, mofetil, pentoxifylline; budesonide and other systemic corticosteroids, or
      • potentially hepatotoxic drugs (including α-methyl-dopa, sodium valproic acid, isoniazide, or nitrofurantoin)
    • Prohibited 12 months prior to Day 1:

      • antibodies or immunotherapy directed against interleukins, or
      • other cytokines or chemokines
  10. Evidence of other forms of chronic liver disease including but not limited to:

    • Positive test result at Screening for hepatitis B surface antigen
    • Active hepatitis C virus (HCV) infection (positive for HCV ribonucleic acid [RNA] at Screening) or history of positive HCV RNA test result
    • Primary biliary cirrhosis, primary sclerosing cholangitis, autoimmune hepatitis or overlap syndrome
    • Alcoholic liver disease
    • Wilson's disease or hemochromatosis or iron overload
    • Alpha-1-antitrypsin (A1AT) deficiency
    • Prior known drug-induced liver injury within 5 years before Day 1
    • Known or suspected hepatocellular carcinoma
  11. History of liver transplant, current placement on a liver transplant list, or current Model for End-Stage Liver Disease (MELD) score >12. Subjects who are placed on a transplant list despite relatively early disease stage (eg, per regional guidelines) may be eligible as long as they do not meet any of the other exclusion criteria
  12. Presence of hepatic decompensation, including:

    • Gastroesophageal varices
    • Ascites
    • Hepatic encephalopathy
    • Spontaneous bacterial peritonitis
    • Hepatorenal or hepatopulmonary syndromes
  13. Total bilirubin ≥2x upper limit of normal (ULN) at any Screening Visit (subjects with Gilbert's syndrome may be enrolled despite a total bilirubin level >2x ULN if their conjugated bilirubin is <2x ULN)
  14. Creatine phosphokinase >5x ULN at Screening Visit 2
  15. Serum creatinine ≥1.5 mg/dL at any Screening Visit
  16. Serum alanine aminotransferase (ALT) >300 U/L at any Screening Visit
  17. Platelet count <75,000/mm3 at any Screening Visit
  18. Known positivity for human immunodeficiency virus (HIV) infection
  19. Subjects with recent history (within 1 year of randomization) of cardiovascular disease or with history or planned cardiovascular interventions to treat atherosclerotic cardiovascular disease
  20. Other concomitant disease, malignancy, or condition likely to significantly decrease life expectancy to <5 years, including known cancers (except carcinomas in situ or other stable, relatively benign conditions such as chronic lymphocytic leukemia) and moderate to severe congestive heart failure.
  21. Known substance abuse, including inhaled or injected drugs in the year before Screening.
  22. For female subjects: pregnancy, planned or potential for pregnancy and unwillingness to use effective birth control during the study, or breastfeeding
  23. Participation in a clinical research study with any investigational product being evaluated for the treatment of diabetes or NASH in the 6 months before Day 1.
  24. Receipt of any investigational product not being evaluated for the treatment of diabetes or NASH from Screening Visit 1 to Day 1, within 30 days prior to Day 1, or within 5 half-lives of the compound before Day 1 (whichever was longer)
  25. Previous exposure to Obeticholic Acid
  26. History of known or suspected clinically significant hypersensitivity to Obeticholic Acid or any of its components
  27. Mental instability or incompetence, such that the validity of informed consent or ability to be compliant with the study is uncertain
  28. Any other condition which, in the opinion of the Investigator, would impede compliance or hinder completion of the study
  29. Acute cholecystitis or acute biliary obstruction

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02633956


Locations
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United States, Arizona
St. Joseph's Hospital and Medical Center
Phoenix, Arizona, United States, 85013
United States, California
Scripps Clinic
La Jolla, California, United States, 92037
Inland Empire Liver Foundation
Rialto, California, United States, 92377
United States, Florida
Nature Coast Clinical Research
Inverness, Florida, United States, 34452
University of Miamai, Schiff Center for Liver Diseases
Miami, Florida, United States, 33136
South Florida Center of Gastroenterology
Wellington, Florida, United States, 33414
Florida Medical Clinic, P.A.
Zephyrhills, Florida, United States, 33542
United States, Hawaii
The Queen's Medical Center - Liver Center
Honolulu, Hawaii, United States, 96813
United States, Maryland
Mercy Medical Center, Institute for Digestive Health & Liver Disease
Baltimore, Maryland, United States, 21202
United States, Missouri
Kansas City Research Institute
Kansas City, Missouri, United States, 64131
St. Louis University
Saint Louis, Missouri, United States, 63104
United States, North Carolina
Duke University Medical Center
Durham, North Carolina, United States, 27710
Cumberland Research Associates, LLC
Fayetteville, North Carolina, United States, 28304
United States, Ohio
Consultants for Clinical Research
Cincinnati, Ohio, United States, 45249
United States, Pennsylvania
Thomas Jefferson University
Philadelphia, Pennsylvania, United States, 19107
United States, Rhode Island
University Gastroenterology Liver Center
Providence, Rhode Island, United States, 02905
United States, South Carolina
Medical University of South Carolina
Charleston, South Carolina, United States, 29425
United States, Tennessee
ClinSearch
Chattanooga, Tennessee, United States, 37421
United States, Texas
Texas Clinical Research Institute, LLC
Arlington, Texas, United States, 76012
Liver Associates of Texas, P.A.
Houston, Texas, United States, 77030
American Research Corporation at the Texas Liver Institute
San Antonio, Texas, United States, 78215
United States, Virginia
McGuire DVAMC
Richmond, Virginia, United States, 23249
Sponsors and Collaborators
Intercept Pharmaceuticals
Investigators
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Study Director: David Shapiro, MD Intercept Pharmaceuticals
  Study Documents (Full-Text)

Documents provided by Intercept Pharmaceuticals:
Study Protocol  [PDF] December 19, 2016
Statistical Analysis Plan  [PDF] June 20, 2017


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Responsible Party: Intercept Pharmaceuticals
ClinicalTrials.gov Identifier: NCT02633956     History of Changes
Other Study ID Numbers: 747-209
First Posted: December 17, 2015    Key Record Dates
Results First Posted: June 4, 2018
Last Update Posted: June 4, 2018
Last Verified: May 2018

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Intercept Pharmaceuticals:
Non-alcoholic Fatty Liver Disease
NAFLD
Fatty Liver Disease
NASH

Additional relevant MeSH terms:
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Fatty Liver
Non-alcoholic Fatty Liver Disease
Liver Diseases
Digestive System Diseases
Atorvastatin
Chenodeoxycholic Acid
Anticholesteremic Agents
Hypolipidemic Agents
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Lipid Regulating Agents
Hydroxymethylglutaryl-CoA Reductase Inhibitors
Enzyme Inhibitors
Cathartics
Gastrointestinal Agents