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NCT02308111: COBALT

Phase 4 Study of Obeticholic Acid Evaluating Clinical Outcomes in Patients With Primary Biliary Cholangitis

Terminated Phase 4 Results posted Last updated 9 March 2023
What this trial tests

Phase 4 trial testing Obeticholic Acid (OCA) in Liver Cirrhosis, Biliary in 334 participants. Terminated before completion.

Timeline
26 December 2014
Primary endpoint
23 December 2021
23 December 2021

Quick facts

Lead sponsorIntercept Pharmaceuticals
PhasePhase 4
StatusTerminated
Study typeINTERVENTIONAL
Allocationrandomized
Designparallel
Maskingquadruple
Primary purposetreatment
Enrollment334
Start date26 December 2014
Primary completion23 December 2021
Estimated completion23 December 2021
Sites181 locations across Hong Kong, Italy, Finland, Poland, South Korea, Denmark, New Zealand, Netherlands

Drugs / interventions tested

Conditions studied

Sponsor

Intercept Pharmaceuticals — full company profile →

Who can join

18 and older, any sex, with Liver Cirrhosis, Biliary. Patients with the condition only — healthy volunteers not accepted.

Results — posted to ClinicalTrials.gov

Per-arm endpoint measurements with 95% confidence intervals where reported. Source: trial results section.

Time to the First Occurrence of Composite Endpoint Primary · Time to first occurrence from date of randomization until the time to accrue approximately 127 primary endpoint events (up to 7 years)

To assess the effect of OCA, compared to placebo in conjunction with the established local standard of care, on clinical outcomes in participants with PBC as measured by time to the first occurrence of any of the following adjudicated events, derived as a composite event endpoint of death, liver transplant, model of end-stage liver disease (MELD) ≥15, uncontrolled ascites, or hospitalization for new onset or recurrence of variceal bleed, hepatic encephalopathy (as defined by a West Haven score of \>=2), or spontaneous bacterial peritonitis. The clinical events distribution was estimated using

25th Percentile
GroupValue95% CI
Obeticholic Acid1092670 – 1464
Placebo970688 – 1342
50th Percentile
GroupValue95% CI
Obeticholic AcidNA1910 – NA
PlaceboNANA – NA
Time to the First Occurrence of Primary Clinical Event (Expanded Endpoint) Primary · Time to first occurrence from date of randomization until the time to accrue approximately 127 primary endpoint events (up to 7 years)

Primary clinical outcome event is the first occurrence of the following events: death, liver transplant, MELD score \>=15 (MELD-Na score \>=12 baseline), MELD-Na score \>=15 (MELD-Na score \<12 baseline), hospitalization for new onset or recurrence of variceal bleed, hepatic encephalopathy, spontaneous bacterial peritonitis (confirmed by diagnostic paracentesis), or bacterial empyema, uncontrolled or refractory ascites (requiring large volume paracentesis), portal hypertension syndromes, progression to decompensated liver disease, and progression to clinical evidence of portal hypertension wit

25th Percentile
GroupValue95% CI
Obeticholic Acid370261 – 638
Placebo450358 – 569
50th Percentile
GroupValue95% CI
Obeticholic Acid18271198 – NA
Placebo1102841 – NA
Time To First Occurrence Of Severe Decompensating Events of Expanded Composite Endpoint Secondary · Time to first occurrence from date of randomization until the date of first documented progression or date of death from any cause, whichever came first (up to 7 years)

The first occurrence of the key secondary clinical event refers to the first occurrence of the following events: death, liver transplant, MELD-Na score \>=15 if MELD-Na\< 12 at baseline, MELD score \>=15 if MELD-Na \>=12 at baseline, uncontrolled or refractory ascites, portal hypertension syndromes (hepatorenal syndrome, portopulmonary syndrome, hepatopulmonary syndrome) or hospitalization for new onset or recurrence of variceal bleed, hepatic encephalopathy, spontaneous bacterial peritonitis, or bacterial empyema. The clinical events distribution was estimated using the Kaplan-Meier methodolo

25th Percentile
GroupValue95% CI
Obeticholic Acid1092670 – 1408
Placebo929679 – 1342
50th Percentile
GroupValue95% CI
Obeticholic AcidNA1910 – NA
PlaceboNANA – NA
Time To Liver Transplant Or Death (All-cause) Secondary · Time to first occurrence from date of randomization until the date of first documented liver transplant or date of death from any cause (up to 7 years)

The effect of OCA compared to placebo on time to liver transplant or death (all-cause) was assessed. The events distribution was estimated using the Kaplan-Meier methodology. Point estimates and 95% CIs for the clinical events distribution percentiles (25th and 50th) are provided.

25th Percentile
GroupValue95% CI
Obeticholic Acid15801275 – NA
Placebo18031206 – NA
50th Percentile
GroupValue95% CI
Obeticholic AcidNANA – NA
PlaceboNANA – NA
Time to First Occurrence of Fatal Event (All-Cause) Secondary · Time to first occurrence from date of randomization until the date of death from any cause (up to 7 years)

The results represent the ratio of OCA to placebo. The fatal events distribution was estimated using the Kaplan-Meier methodology. Point estimates and 95% CIs for the fatal events distribution percentiles (25th and 50th) are provided

25th Percentile
GroupValue95% CI
Obeticholic AcidNANA – NA
PlaceboNANA – NA
50th Percentile
GroupValue95% CI
Obeticholic AcidNANA – NA
PlaceboNANA – NA
Time to First Occurrence of Liver Transplant Secondary · Time to first occurrence from date of randomization until the date of first documented liver transplant or date of death from any cause (up to 5 years)

The effect of OCA compared to placebo on time to occurrence of a liver transplant was assessed. The results represented the ratio of OCA to placebo. A hazard ratio \<1 indicated an advantage for OCA. The event of interest was summarized through Cumulative Incidence Function (CIF) estimate at 5 years.

GroupValue95% CI
Obeticholic Acid0.180.11 – 0.26
Placebo0.160.09 – 0.23
Time to First Occurrence of Hospitalization Due to Hepatic Events Secondary · Time to first occurrence from date of randomization until the date of hospitalization, liver transplant or death from any cause, whichever came first (up to 5 years)

Hospitalization events include new onset or recurrent variceal bleed, hepatic encephalopathy (as defined by a West Haven score of \>=2), spontaneous bacterial peritonitis (confirmed by diagnostic paracentesis OR presence of \>250/mm\^3 polymorph leucocytes \[PMNs\] in the ascitic fluid), bacterial empyema is confirmed by diagnostic thoracentesis OR presence of \>250/mm\^3 PMNs in the pleural fluid. The event of interest was summarized through CIF estimate at 5 years.

GroupValue95% CI
Obeticholic Acid0.110.06 – 0.17
Placebo0.180.10 – 0.26
Time to First Occurrence of Uncontrolled or Refractory Ascites Secondary · Time to first occurrence from date of randomization until the date of first documented uncontrolled or refractory ascites, liver transplant or date of death from any cause, whichever came first (up to 5 years)

Uncontrolled or refractory ascites are defined as diuretic-resistant ascites requiring large-volume paracentesis. The effect of OCA compared to placebo on time to the first occurrence of uncontrolled or refractory ascites was assessed. The event of interest was summarized through CIF estimate at 5 years.

GroupValue95% CI
Obeticholic Acid0.020.01 – 0.05
Placebo0.040.01 – 0.08
Time to First Occurrence of MELD Score ≥15 Secondary · Time to first occurrence from date of randomization until the date of first documented MELD Score ≥15, liver transplant or date of death from any cause, whichever came first (up to 5 years)

The MELD score is useful in assessing participants with significant decompensation. The MELD score is now used by the United Network for Organ Sharing in the United States and Eurotransplants to manage organ allocation for liver transplantation. The MELD score is derived from the participant's serum total bilirubin, serum creatinine, and International Normalized Ratio (INR), as appropriate, to predict survival. The MELD score ranges from 6 to 40. The higher the score, the more likely a participant will receive a liver from a deceased donor when an organ becomes available. The event of interest

GroupValue95% CI
Obeticholic Acid0.130.07 – 0.19
Placebo0.180.11 – 0.25
Time To Development Of Varix/Varices Secondary · Time to first occurrence from date of randomization until the date of first documented development of varix/varices, liver transplant or death from any cause, whichever came first (up to 5 years)

The effect of OCA compared to placebo on time to development of varix/varices was assessed. The event of interest was summarized through CIF estimate at 5 years.

GroupValue95% CI
Obeticholic Acid0.070.03 – 0.12
Placebo0.090.04 – 0.17
Time To Liver-Related Death Secondary · Time to first occurrence from date of randomization until the date of first liver-related or non-liver- related death, whichever came first (up to 5 years)

The effect of OCA compared to placebo on time to liver-related death was assessed. The event of interest was summarized through CIF estimate at 5 years.

GroupValue95% CI
Obeticholic Acid0.030.01 – 0.07
Placebo0.040.01 – 0.09
Time To Liver-Related Death Or Liver Transplant Secondary · Time to first occurrence from date of randomization until the date of liver transplant, liver-related death or non-liver-related death from any cause, whichever came first (up to 5 years)

The effect of OCA compared to placebo on time to liver-related death or liver transplant was assessed. The event of interest was summarized through CIF estimate at 5 years.

GroupValue95% CI
Obeticholic Acid0.200.13 – 0.29
Placebo0.190.12 – 0.27

Adverse events — posted to ClinicalTrials.gov

Time frame: Baseline up to the last IP dose plus 30 days and prior to commercial OCA initiation date, approximately 7 years. Reporting threshold: 5%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

Obeticholic Acid
Serious: 53/168 (32%)
Deaths: 16/168
Placebo
Serious: 53/166 (32%)
Deaths: 12/166

Serious adverse events (128 terms)

ReactionSystemObeticholic AcidPlacebo
Oesophageal varices haemorrhageGastrointestinal disorders
Hepatic encephalopathyNervous system disorders
AscitesGastrointestinal disorders
Gastrointestinal haemorrhageGastrointestinal disorders
Urinary tract infectionInfections and infestations
UrosepsisInfections and infestations
Small intestinal obstructionGastrointestinal disorders
SepsisInfections and infestations
Hepatic cirrhosisHepatobiliary disorders
Hepatic failureHepatobiliary disorders
CholecystitisHepatobiliary disorders
Acute respiratory failureRespiratory, thoracic and mediastinal disorders
Pleural effusionRespiratory, thoracic and mediastinal disorders
Cerebrovascular accidentNervous system disorders
Hip fractureInjury, poisoning and procedural complications
Disease progressionGeneral disorders
Oedema peripheralGeneral disorders
Thrombotic thrombocytopenic purpuraBlood and lymphatic system disorders
Coronary artery diseaseCardiac disorders
Breast cancerNeoplasms benign, malignant and unspecified (incl cysts and polyps)
Hepatocellular carcinomaNeoplasms benign, malignant and unspecified (incl cysts and polyps)
Acute kidney injuryRenal and urinary disorders
PruritusSkin and subcutaneous tissue disorders
Abdominal herniaGastrointestinal disorders
Abdominal painGastrointestinal disorders
Other adverse events (42 terms — click to expand)

ReactionSystemObeticholic AcidPlacebo
PruritusSkin and subcutaneous tissue disorders
Oedema peripheralGeneral disorders
Urinary tract infectionInfections and infestations
ArthralgiaMusculoskeletal and connective tissue disorders
Varices oesophagealGastrointestinal disorders
DiarrhoeaGastrointestinal disorders
Abdominal pain upperGastrointestinal disorders
NauseaGastrointestinal disorders
FatigueGeneral disorders
Blood bilirubin increasedInvestigations
HeadacheNervous system disorders
Abdominal painGastrointestinal disorders
AscitesGastrointestinal disorders
ConstipationGastrointestinal disorders
NasopharyngitisInfections and infestations
InsomniaPsychiatric disorders
Abdominal distensionGastrointestinal disorders
DyspnoeaRespiratory, thoracic and mediastinal disorders
Portal hypertensive gastropathyGastrointestinal disorders
VomitingGastrointestinal disorders
Upper respiratory tract infectionInfections and infestations
DizzinessNervous system disorders
CoughRespiratory, thoracic and mediastinal disorders
AnaemiaBlood and lymphatic system disorders
PyrexiaGeneral disorders
Back painMusculoskeletal and connective tissue disorders
Muscle spasmsMusculoskeletal and connective tissue disorders
Gastrooesophageal reflux diseaseGastrointestinal disorders
SinusitisInfections and infestations
OsteoporosisMusculoskeletal and connective tissue disorders
Oropharyngeal painRespiratory, thoracic and mediastinal disorders
HyperbilirubinaemiaHepatobiliary disorders
RashSkin and subcutaneous tissue disorders
BronchitisInfections and infestations
InfluenzaInfections and infestations
JaundiceHepatobiliary disorders
DyspepsiaGastrointestinal disorders
Pain in extremityMusculoskeletal and connective tissue disorders
Hepatic encephalopathyNervous system disorders
Hepatic cirrhosisHepatobiliary disorders

Most-reported serious reactions: Oesophageal varices haemorrhage, Hepatic encephalopathy, Ascites, Gastrointestinal haemorrhage, Urinary tract infection, Urosepsis, Small intestinal obstruction, Sepsis.

Data from ClinicalTrials.gov NCT02308111 adverse events section.

Sponsor's own description

Primary Biliary Cholangitis (PBC) is a serious, life-threatening, bile acid related liver disease of unknown cause. Without treatment, it frequently progresses to liver fibrosis and eventual cirrhosis requiring liver transplantation or resulting in death. The investigational drug, Obeticholic Acid (OCA) is a modified bile acid and FXR agonist that is derived from the primary human bile acid chenodeoxycholic acid. The key mechanisms of action of OCA, including its choleretic, anti-inflammatory, and anti-fibrotic properties, underlie its hepatoprotective effects and result in attenuation of injury and improved liver function in a cholestatic liver disease such as PBC. The study will assess the effect of OCA compared to placebo, combined with stable standard care, on clinical outcomes in PBC participants.

Publications & conference data

8 peer-reviewed publications reference this trial (live from Europe PMC):

  1. Bile acid metabolism and signaling in health and disease: molecular mechanisms and therapeutic targets.
    Fleishman JS, Kumar S. · · 2024 · cited 267× · PMID 38664391 · DOI 10.1038/s41392-024-01811-6
  2. A randomized trial of obeticholic acid monotherapy in patients with primary biliary cholangitis.
    Kowdley KV, Luketic V, Chapman R, Hirschfield GM, et al · · 2018 · cited 213× · PMID 29023915 · DOI 10.1002/hep.29569
  3. Farnesoid X receptor (FXR): Structures and ligands.
    Jiang L, Zhang H, Xiao D, Wei H, et al · · 2021 · cited 173× · PMID 33995909 · DOI 10.1016/j.csbj.2021.04.029
  4. Novel therapeutic targets for cholestatic and fatty liver disease.
    Trauner M, Fuchs CD. · · 2022 · cited 141× · PMID 34615727 · DOI 10.1136/gutjnl-2021-324305
  5. Current understanding of primary biliary cholangitis.
    Tanaka A. · · 2021 · cited 102× · PMID 33264835 · DOI 10.3350/cmh.2020.0028
  6. Bile acids and their receptors: modulators and therapeutic targets in liver inflammation.
    Bertolini A, Fiorotto R, Strazzabosco M. · · 2022 · cited 99× · PMID 35415765 · DOI 10.1007/s00281-022-00935-7
  7. Gut-liver axis signaling in portal hypertension.
    Simbrunner B, Mandorfer M, Trauner M, Reiberger T. · · 2019 · cited 82× · PMID 31660028 · DOI 10.3748/wjg.v25.i39.5897
  8. Clinical Advancements in the Targeted Therapies against Liver Fibrosis.
    Bansal R, Nagórniewicz B, Prakash J. · · 2016 · cited 72× · PMID 27999454 · DOI 10.1155/2016/7629724

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Drug Landscape aggregates and links these public records for informational use only. Always verify against the primary source before clinical or regulatory decisions. Canonical URL: https://druglandscape.com/trial/NCT02308111.

Primary sources · FDA · ClinicalTrials.gov · EMA · SEC EDGAR · ChEMBL · Wikidata · full sourcing