Primary Biliary Cirrhosis
Conditions
Keywords
Primary Biliary Cholangitis, Primary Biliary Cirrhosis, PBC, Cirrhosis, Liver
Brief summary
The main objectives of the study were to assess the effects of Obeticholic Acid (OCA) on serum alkaline phosphatase (ALP) and total bilirubin, together as a composite endpoint and on safety in participants with primary biliary cirrhosis (PBC).
Detailed description
The study included 2 phases: a 12-month randomized, double-blind (DB), placebo-controlled, parallel group phase, followed by a long-term safety extension (LTSE) phase up to 5 years. Participants from the 12-month DB phase, including those who received placebo, were eligible to participate in the open-label LTSE phase. The Month 12 visit from the DB phase served as the Day 1 visit of the LTSE phase. After completion of the 12-month DB phase all participants were offered the opportunity to enter an open-label LTSE for up to 5 years beginning at 5 mg OCA. Data for the LTSE phase is reported by the randomized dose group assigned in the DB phase.
Interventions
OCA was administered orally once daily and provided in tablet form in 2 strengths: 5 mg and 10 mg.
DRUGPlacebo
Matching placebo tablets were administered orally once daily.
Sponsors
Intercept Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Definite or probable PBC diagnosis (consistent with American Association for the Study of Liver Disease \[AASLD\] and European Association for Study of the Liver \[EASL\] Practice Guidelines; \[Lindor 2009; EASL 2009\]), as demonstrated by the presence of ≥ 2 of the following 3 diagnostic factors: * History of elevated alkaline phosphatase (ALP) levels for at least 6 months * Positive antimitochondrial antibodies (AMA) titer or if AMA negative or in low titer (\<1:80) PBC specific antibodies (anti-GP210 and/or anti-SP100 and/or antibodies against the major M2 components (pyruvate dehydrogenase complex-E2 \[PDC-E2\], 2-oxo-glutaric acid dehydrogenase complex) * Liver biopsy consistent with PBC 2. At least 1 of the following qualifying biochemistry values: * ALP ≥ 1.67x upper limit of normal (ULN) * Total bilirubin \> ULN but \< 2x ULN 3. Age ≥ 18 years 4. Taking ursodeoxycholic acid (UDCA) for at least 12 months (stable dose for ≥ 3 months) prior to Day 0, or unable to tolerate UDCA (no UDCA for ≥ 3 months) prior to Day 0. 5. Contraception: Female participants must be postmenopausal, surgically sterile, or if premenopausal, be prepared to use ≥ 1 effective (≤ 1% failure rate) method of contraception during the trial and for 30 days after the end of treatment (EOT) visit. Effective methods of contraception are considered to be: * Hormonal (for example, contraceptive pill, patch, intramuscular implant or injection); or * Double barrier method, that is, (a) condom (male or female) or (b) diaphragm, with spermicide; or * Intrauterine device (IUD); or * Vasectomy (partner); or * Sexual abstinence 6. Must provide written informed consent and agree to comply with the trial protocol.
Exclusion criteria
1. History or presence of other concomitant liver diseases including: * Hepatitis C virus (HCV) infection; participants with active hepatitis B (HBV) infection will be excluded, however, participants who have seroconverted (hepatitis B surface antigen \[Hbs Ag\] and hepatitis B e antigen \[Hbe Ag\] negative) may be included after consultation with the medical monitor. * Primary sclerosing cholangitis (PSC) * Alcoholic liver disease * Definite autoimmune liver disease or overlap hepatitis * Nonalcoholic steatohepatitis (NASH) * Gilbert's Syndrome (due to interpretability of bilirubin levels) 2. Presence of clinical complications of PBC or clinically significant hepatic decompensation, including: * History of liver transplantation, current placement on a liver transplant list or current Model for End Stage Liver Disease (MELD) score ≥ 15 * Portal hypertension with complications, including: known gastric or large esophageal varices, poorly controlled or diuretic resistant ascites, history of variceal bleeds or related therapeutic or prophylactic interventions (for example, beta blockers, insertion of variceal bands or transjugular intrahepatic portosystemic shunt \[TIPS\]), or hepatic encephalopathy * Cirrhosis with complications, including history or presence of: spontaneous bacterial peritonitis, hepatocellular carcinoma, bilirubin \> 2x ULN * Hepatorenal syndrome (type I or II) or Screening serum creatinine \> 2 mg/deciliter dL) (178 micromole \[µmol\])/liter \[L\]) 3. Participants with severe pruritus or those requiring systemic treatment for pruritus (for example, with bile acid sequestrants \[BAS\] or rifampicin) within 2 months of Day 0 will be excluded 4. Administration of the following medications is prohibited as specified below: * Prohibited 6 months prior to Day 0 and throughout the trial (that is, to last dose and/or EOT): azathioprine, colchicine, cyclosporine, methotrexate, mycophenolate mofetil, pentoxifylline; fenofibrate or other fibrates; budesonide and other systemic corticosteroids; potentially hepatotoxic drugs (including α-methyl-dopa, sodium valproic acid, isoniazide, or nitrofurantoin) * Prohibited 12 months prior to Day 0 and throughout the trial (that is, to last dose and/or EOT): antibodies or immunotherapy directed against interleukins or other cytokines or chemokines 5. Participants who have previously participated in a clinical trial of OCA will not be allowed to participate 6. History or presence of clinically concerning cardiac arrhythmias likely to affect survival during the trial, or prolongation of Screening (pretreatment) QT or QTc interval of \> 500 milliseconds (msec) 7. If female: known pregnancy, or has a positive urine pregnancy test (confirmed by a positive serum pregnancy test), or lactating 8. Known history of human immunodeficiency virus (HIV) infection 9. Presence of any other disease or condition that is interfering with the absorption, distribution, metabolism, or excretion of drugs including bile salt metabolism in the intestine. Participants with inflammatory bowel disease or who have undergone gastric bypass procedures will be excluded (gastric lap band is acceptable). 10. Medical conditions that may cause nonhepatic increases in ALP (for example, Paget's disease) or which may diminish life expectancy to \< 2 years, including known cancers (except carcinomas in situ or other stable, relatively benign conditions such as chronic lymphatic leukemia) 11. Other clinically significant medical conditions that are not well controlled or for which medication needs are anticipated to change during the trial 12. Anticipated changes to current concomitant medications during the course of the trial 13. History of alcohol abuse, defined as consumption of more than 210 mL of alcohol per week (that is, the equivalent of fourteen 4-ounce (125 mL) glasses of wine or fourteen 12 ounce cans/bottles of beer), or other substance abuse within 1 year prior to Day 0 14. Participation in another investigational drug, biologic, or medical device trial within 30 days prior to Screening 15. History of noncompliance with medical regimens, or participants who are considered to be potentially unreliable 16. Blood or plasma donation within 30 days prior to Day 0 17. Mental instability or incompetence, such that the validity of informed consent or compliance with the trial is uncertain
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| DB Phase: Composite Endpoint Alkaline Phosphatase (ALP) And Total Bilirubin, 10 mg OCA Versus Placebo | DB Month 12 | Percentage of participants at Month 12 with ALP \< 1.67 x upper limit of normal (ULN) and total bilirubin ≤ ULN and ALP decrease of ≥ 15% from baseline. |
| LTSE Phase: Composite Endpoint ALP And Total Bilirubin | Baseline (DB Month 12), LTSE Months 24, 36, 48, and 60 | Percentage of participants at Months 24, 36, 48, and 60 with ALP \< 1.67x ULN and total bilirubin ≤ ULN and ALP decrease of ≥ 15% from baseline. DB Month 12 is the baseline for the LTSE phase. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| DB Phase: ALP Absolute Change From Baseline To Month 12 | Baseline, DB Month 12 | Blood samples were evaluated for ALP levels. ALP Absolute Change From Baseline (ALP at Month 12 - ALP at Baseline) is presented. |
| DB Phase: Total Bilirubin Absolute Change From Baseline To Month 12 | Baseline, DB Month 12 | Blood samples were evaluated for bilirubin levels. Total bilirubin absolute change from baseline (total bilirubin at Month 12 - total bilirubin at Baseline) is presented. |
| DB Phase: Direct Bilirubin Absolute Change From Baseline To Month 12 | Baseline, DB Month 12 | Blood samples were evaluated for bilirubin levels. Direct bilirubin absolute change from baseline (direct bilirubin at Month 12 - direct bilirubin at Baseline) is presented. |
| DB Phase: Alanine Aminotransferase (ALT) Absolute Change From Baseline To Month 12 | Baseline, DB Month 12 | Blood samples were evaluated for ALT levels. ALT absolute change from baseline (ALT at Month 12 - ALT at Baseline) is presented. |
| DB Phase: Composite Endpoint ALP And Total Bilirubin, 10 mg Versus Placebo | DB Month 6 | Percentage of participants at Month 6 with ALP \< 1.67x ULN and total bilirubin ≤ ULN and ALP decrease of ≥ 15% from baseline. |
| DB Phase: Gamma-glutamyltransferase (GGT) Absolute Change From Baseline To Month 12 | Baseline, DB Month 12 | Blood samples were evaluated for GGT levels. GGT absolute change from baseline (GGT at Month 12 - GGT at Baseline) is presented. |
| LTSE Phase: ALP Levels | LTSE Day 0 and LTSE Months 12, 24, 36, 48, and 60 | Blood samples were evaluated for ALP levels. |
| LTSE Phase: ALP Change From DB Baseline | DB Baseline, LTSE Months 12, 24, 36, 48, and 60 | Blood samples were evaluated for ALP levels. ALP Change From Baseline (ALP at LTSE Months 12, 24, 36, 48, and 60 - ALP at Baseline) is presented. DB baseline is the mean of all available evaluations prior to DB treatment. |
| DB Phase: Aspartate Aminotransferase (AST) Absolute Change From Baseline To Month 12 | Baseline, DB Month 12 | Blood samples were evaluated for AST levels. AST absolute change from baseline (AST at Month 12 - AST at Baseline) is presented. |
| DB Phase: Composite Endpoint ALP And Total Bilirubin, 5-10 mg Versus Placebo | DB Month 12 | Percentage of participants at Month 12 with ALP \< 1.67x ULN and total bilirubin ≤ ULN and ALP decrease of ≥ 15% from baseline. |
Countries
Australia, Austria, Belgium, Canada, France, Germany, Italy, Netherlands, Poland, Spain, Sweden, United Kingdom, United States
Participant flow
Recruitment details
Recruitment into hospitals and physicians' clinics started January 2012 and completed December 2012.
Pre-assignment details
Screening interim allowed for pre-randomization eligibility assessment of 1 to 8 weeks. A total of 217 participants were randomized into the double-blind phase of the study, however, 216 received treatment with study drug. One randomized participant discontinued prior to receiving any study drug.
Participants by arm
| Arm | Count |
|---|---|
| DB OCA 5-10 mg OCA 5 mg for 6 months and then titrating up to 10 mg based on tolerability and response for remaining 6 months of the DB phase.
After completion of the 12-month DB phase participants were offered the opportunity to enter an open-label LTSE for up to 5 years beginning at 5 mg OCA, and then the dose could be titrated up. Initially, participants were allowed to titrate to doses up to 25 mg, however, the maximum dose was then limited to 10 mg. | 70 |
| DB OCA 10 mg OCA 10 mg 12 months during the DB phase. After completion of the 12-month DB phase participants were offered the opportunity to enter an open-label LTSE for up to 5 years beginning at 5 mg OCA, and then the dose could be titrated up. Initially, participants were allowed to titrate to doses up to 25 mg, however, the maximum dose was then limited to 10 mg. | 73 |
| DB Placebo Matching placebo for 12 months during the DB phase. After completion of the 12-month DB phase participants were offered the opportunity to enter an open-label LTSE for up to 5 years beginning at 5 mg OCA, and then the dose could be titrated up. Initially, participants were allowed to titrate to doses up to 25 mg, however, the maximum dose was then limited to 10 mg. | 73 |
| Total | 216 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| DB Phase | Adverse Event | 4 | 8 | 2 | 0 | 0 | 0 |
| DB Phase | Death | 1 | 0 | 0 | 0 | 0 | 0 |
| DB Phase | Withdrawal by Subject | 2 | 1 | 1 | 0 | 0 | 0 |
| LTSE Phase | Adverse Event of Pruritus | 0 | 0 | 0 | 1 | 5 | 2 |
| LTSE Phase | Death | 0 | 0 | 0 | 0 | 1 | 0 |
| LTSE Phase | Liver Transplantation | 0 | 0 | 0 | 0 | 0 | 1 |
| LTSE Phase | Lost to Follow-up | 0 | 0 | 0 | 1 | 3 | 2 |
| LTSE Phase | Other Clinical/ Laboratory Adverse Event | 0 | 0 | 0 | 2 | 4 | 6 |
| LTSE Phase | Pregnancy | 0 | 0 | 0 | 1 | 0 | 0 |
| LTSE Phase | Principal Investigator Decision | 0 | 0 | 0 | 1 | 1 | 3 |
| LTSE Phase | Protocol Violation | 0 | 0 | 0 | 0 | 0 | 1 |
| LTSE Phase | Withdrawal by Subject | 0 | 0 | 0 | 3 | 3 | 6 |
Baseline characteristics
| Characteristic | DB OCA 5-10 mg | DB OCA 10 mg | DB Placebo | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 10 Participants | 17 Participants | 13 Participants | 40 Participants |
| Age, Categorical Between 18 and 65 years | 60 Participants | 56 Participants | 60 Participants | 176 Participants |
| Age, Continuous | 55.8 years STANDARD_DEVIATION 10.53 | 56.2 years STANDARD_DEVIATION 11 | 55.5 years STANDARD_DEVIATION 10.03 | 55.8 years STANDARD_DEVIATION 10.48 |
| Alanine Aminotransferase (ALT) (U/L) | 61.56 U/L STANDARD_DEVIATION 39.037 | 56.31 U/L STANDARD_DEVIATION 39.741 | 55.99 U/L STANDARD_DEVIATION 30.312 | 57.9 U/L STANDARD_DEVIATION 36.498 |
| Alkaline Phosphatase (U/L) | 325.87 U/L STANDARD_DEVIATION 116.238 | 316.34 U/L STANDARD_DEVIATION 103.881 | 327.49 U/L STANDARD_DEVIATION 115.014 | 323.19 U/L STANDARD_DEVIATION 111.375 |
| Aspartate Aminotransferase (AST) (U/L) | 52.25 U/L STANDARD_DEVIATION 25.289 | 50.49 U/L STANDARD_DEVIATION 31.1 | 48.79 U/L STANDARD_DEVIATION 22.449 | 50.49 U/L STANDARD_DEVIATION 26.456 |
| Direct Bilirubin (umol/L) | 4.398 umol/L STANDARD_DEVIATION 4.528 | 4.868 umol/L STANDARD_DEVIATION 4.473 | 5.469 umol/L STANDARD_DEVIATION 6.214 | 4.919 umol/L STANDARD_DEVIATION 5.138 |
| Gamma-Glutamyltransferase (GGT) (U/L) | 252.83 U/L STANDARD_DEVIATION 167.038 | 261.07 U/L STANDARD_DEVIATION 207.396 | 309.58 U/L STANDARD_DEVIATION 449.356 | 274.79 U/L STANDARD_DEVIATION 302.673 |
| Race/Ethnicity, Customized Asian | 1 participants | 1 participants | 1 participants | 3 participants |
| Race/Ethnicity, Customized Black or African American | 1 participants | 1 participants | 1 participants | 3 participants |
| Race/Ethnicity, Customized Other | 1 participants | 1 participants | 5 participants | 7 participants |
| Race/Ethnicity, Customized White | 67 participants | 70 participants | 66 participants | 203 participants |
| Region of Enrollment Australia | 5 participants | 1 participants | 3 participants | 9 participants |
| Region of Enrollment Austria | 2 participants | 0 participants | 1 participants | 3 participants |
| Region of Enrollment Belgium | 2 participants | 9 participants | 5 participants | 16 participants |
| Region of Enrollment Canada | 2 participants | 2 participants | 4 participants | 8 participants |
| Region of Enrollment France | 0 participants | 0 participants | 1 participants | 1 participants |
| Region of Enrollment Germany | 8 participants | 11 participants | 9 participants | 28 participants |
| Region of Enrollment Italy | 11 participants | 10 participants | 11 participants | 32 participants |
| Region of Enrollment Netherlands | 3 participants | 7 participants | 6 participants | 16 participants |
| Region of Enrollment Poland | 4 participants | 6 participants | 4 participants | 14 participants |
| Region of Enrollment Spain | 4 participants | 2 participants | 3 participants | 9 participants |
| Region of Enrollment Sweden | 3 participants | 1 participants | 0 participants | 4 participants |
| Region of Enrollment United Kingdom | 8 participants | 5 participants | 9 participants | 22 participants |
| Region of Enrollment United States | 18 participants | 19 participants | 17 participants | 54 participants |
| Sex: Female, Male Female | 65 Participants | 63 Participants | 68 Participants | 196 Participants |
| Sex: Female, Male Male | 5 Participants | 10 Participants | 5 Participants | 20 Participants |
| Total Bilirubin (umol/L) | 10.192 umol/L STANDARD_DEVIATION 5.549 | 11.278 umol/L STANDARD_DEVIATION 6.634 | 11.757 umol/L STANDARD_DEVIATION 7.227 | 11.088 umol/L STANDARD_DEVIATION 6.522 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk |
|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 64 / 70 | 64 / 73 | 62 / 73 | 61 / 63 | 62 / 64 | 64 / 66 | 187 / 193 |
| serious Total, serious adverse events | 11 / 70 | 8 / 73 | 3 / 73 | 30 / 63 | 19 / 64 | 20 / 66 | 69 / 193 |
Outcome results
Primary
DB Phase: Composite Endpoint Alkaline Phosphatase (ALP) And Total Bilirubin, 10 mg OCA Versus Placebo
Percentage of participants at Month 12 with ALP \< 1.67 x upper limit of normal (ULN) and total bilirubin ≤ ULN and ALP decrease of ≥ 15% from baseline.
Time frame: DB Month 12
Population: Intent-to-Treat Population: All participants who were randomized and received at least 1 dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| DB OCA 10 mg | DB Phase: Composite Endpoint Alkaline Phosphatase (ALP) And Total Bilirubin, 10 mg OCA Versus Placebo | 47 percentage of participants |
| DB Placebo | DB Phase: Composite Endpoint Alkaline Phosphatase (ALP) And Total Bilirubin, 10 mg OCA Versus Placebo | 10 percentage of participants |
Comparison: H0: The response rates are equal between placebo and 10 mg OCA. H1: The response rates are different between placebo and 10 mg OCA.p-value: <0.0001Cochran-Mantel-Haenszel
Primary
LTSE Phase: Composite Endpoint ALP And Total Bilirubin
Percentage of participants at Months 24, 36, 48, and 60 with ALP \< 1.67x ULN and total bilirubin ≤ ULN and ALP decrease of ≥ 15% from baseline. DB Month 12 is the baseline for the LTSE phase.
Time frame: Baseline (DB Month 12), LTSE Months 24, 36, 48, and 60
Population: All participants who received at least 1 dose of OCA in the open-label safety extension phase and had an assessment at the specified timepoint.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| DB OCA 10 mg | LTSE Phase: Composite Endpoint ALP And Total Bilirubin | Baseline (Double-blind Month 12) | 51 percentage of participants |
| DB OCA 10 mg | LTSE Phase: Composite Endpoint ALP And Total Bilirubin | LTSE Month 12 | 55 percentage of participants |
| DB OCA 10 mg | LTSE Phase: Composite Endpoint ALP And Total Bilirubin | LTSE Month 24 | 60 percentage of participants |
| DB OCA 10 mg | LTSE Phase: Composite Endpoint ALP And Total Bilirubin | LTSE Month 36 | 48 percentage of participants |
| DB OCA 10 mg | LTSE Phase: Composite Endpoint ALP And Total Bilirubin | LTSE Month 48 | 52 percentage of participants |
| DB OCA 10 mg | LTSE Phase: Composite Endpoint ALP And Total Bilirubin | LTSE Month 60 | 48 percentage of participants |
| DB Placebo | LTSE Phase: Composite Endpoint ALP And Total Bilirubin | LTSE Month 60 | 52 percentage of participants |
| DB Placebo | LTSE Phase: Composite Endpoint ALP And Total Bilirubin | LTSE Month 36 | 51 percentage of participants |
| DB Placebo | LTSE Phase: Composite Endpoint ALP And Total Bilirubin | Baseline (Double-blind Month 12) | 56 percentage of participants |
| DB Placebo | LTSE Phase: Composite Endpoint ALP And Total Bilirubin | LTSE Month 24 | 61 percentage of participants |
| DB Placebo | LTSE Phase: Composite Endpoint ALP And Total Bilirubin | LTSE Month 12 | 58 percentage of participants |
| DB Placebo | LTSE Phase: Composite Endpoint ALP And Total Bilirubin | LTSE Month 48 | 55 percentage of participants |
| LTSE OCA (DB Placebo) | LTSE Phase: Composite Endpoint ALP And Total Bilirubin | LTSE Month 12 | 41 percentage of participants |
| LTSE OCA (DB Placebo) | LTSE Phase: Composite Endpoint ALP And Total Bilirubin | LTSE Month 24 | 54 percentage of participants |
| LTSE OCA (DB Placebo) | LTSE Phase: Composite Endpoint ALP And Total Bilirubin | LTSE Month 36 | 49 percentage of participants |
| LTSE OCA (DB Placebo) | LTSE Phase: Composite Endpoint ALP And Total Bilirubin | LTSE Month 60 | 50 percentage of participants |
| LTSE OCA (DB Placebo) | LTSE Phase: Composite Endpoint ALP And Total Bilirubin | LTSE Month 48 | 60 percentage of participants |
| LTSE OCA (DB Placebo) | LTSE Phase: Composite Endpoint ALP And Total Bilirubin | Baseline (Double-blind Month 12) | 9 percentage of participants |
| Overall LTSE OCA | LTSE Phase: Composite Endpoint ALP And Total Bilirubin | LTSE Month 48 | 56 percentage of participants |
| Overall LTSE OCA | LTSE Phase: Composite Endpoint ALP And Total Bilirubin | LTSE Month 60 | 50 percentage of participants |
| Overall LTSE OCA | LTSE Phase: Composite Endpoint ALP And Total Bilirubin | LTSE Month 12 | 51 percentage of participants |
| Overall LTSE OCA | LTSE Phase: Composite Endpoint ALP And Total Bilirubin | LTSE Month 36 | 49 percentage of participants |
| Overall LTSE OCA | LTSE Phase: Composite Endpoint ALP And Total Bilirubin | Baseline (Double-blind Month 12) | 38 percentage of participants |
| Overall LTSE OCA | LTSE Phase: Composite Endpoint ALP And Total Bilirubin | LTSE Month 24 | 58 percentage of participants |
Secondary
DB Phase: Alanine Aminotransferase (ALT) Absolute Change From Baseline To Month 12
Blood samples were evaluated for ALT levels. ALT absolute change from baseline (ALT at Month 12 - ALT at Baseline) is presented.
Time frame: Baseline, DB Month 12
Population: Intent-to-Treat Population: All participants who were randomized and received at least 1 dose of study drug and had an assessment at the specified timepoint.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| DB OCA 10 mg | DB Phase: Alanine Aminotransferase (ALT) Absolute Change From Baseline To Month 12 | -21.26 U/L | Standard Error 3.27 |
| DB Placebo | DB Phase: Alanine Aminotransferase (ALT) Absolute Change From Baseline To Month 12 | -25.31 U/L | Standard Error 3.35 |
| LTSE OCA (DB Placebo) | DB Phase: Alanine Aminotransferase (ALT) Absolute Change From Baseline To Month 12 | -4.95 U/L | Standard Error 3.32 |
p-value: <0.0001ANCOVA
p-value: <0.0001ANCOVA
Secondary
DB Phase: ALP Absolute Change From Baseline To Month 12
Blood samples were evaluated for ALP levels. ALP Absolute Change From Baseline (ALP at Month 12 - ALP at Baseline) is presented.
Time frame: Baseline, DB Month 12
Population: Intent-to-Treat Population: All participants who were randomized and received at least 1 dose of study drug and had an assessment at the specified timepoint.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| DB OCA 10 mg | DB Phase: ALP Absolute Change From Baseline To Month 12 | -112.51 U/L | Standard Error 14.36 |
| DB Placebo | DB Phase: ALP Absolute Change From Baseline To Month 12 | -129.90 U/L | Standard Error 14.6 |
| LTSE OCA (DB Placebo) | DB Phase: ALP Absolute Change From Baseline To Month 12 | -14.42 U/L | Standard Error 14.74 |
p-value: <0.0001ANCOVA
p-value: <0.0001ANCOVA
Secondary
DB Phase: Aspartate Aminotransferase (AST) Absolute Change From Baseline To Month 12
Blood samples were evaluated for AST levels. AST absolute change from baseline (AST at Month 12 - AST at Baseline) is presented.
Time frame: Baseline, DB Month 12
Population: Intent-to-Treat Population: All participants who were randomized and received at least 1 dose of study drug and had an assessment at the specified timepoint.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| DB OCA 10 mg | DB Phase: Aspartate Aminotransferase (AST) Absolute Change From Baseline To Month 12 | -13.03 U/L | Standard Error 4.17 |
| DB Placebo | DB Phase: Aspartate Aminotransferase (AST) Absolute Change From Baseline To Month 12 | -15.00 U/L | Standard Error 4.28 |
| LTSE OCA (DB Placebo) | DB Phase: Aspartate Aminotransferase (AST) Absolute Change From Baseline To Month 12 | 1.04 U/L | Standard Error 4.22 |
p-value: 0.0003ANCOVA
p-value: <0.0001ANCOVA
Secondary
DB Phase: Composite Endpoint ALP And Total Bilirubin, 10 mg Versus Placebo
Percentage of participants at Month 6 with ALP \< 1.67x ULN and total bilirubin ≤ ULN and ALP decrease of ≥ 15% from baseline.
Time frame: DB Month 6
Population: Intent-to-Treat Population: All participants who were randomized and received at least 1 dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| DB OCA 10 mg | DB Phase: Composite Endpoint ALP And Total Bilirubin, 10 mg Versus Placebo | 51 percentage of participants |
| DB Placebo | DB Phase: Composite Endpoint ALP And Total Bilirubin, 10 mg Versus Placebo | 7 percentage of participants |
Comparison: H0: The response rates are equal between placebo and 10 mg OCA. H1: The response rates are different between placebo and 10 mg OCA.p-value: <0.0001Cochran-Mantel-Haenszel
Secondary
DB Phase: Composite Endpoint ALP And Total Bilirubin, 5-10 mg Versus Placebo
Percentage of participants at Month 6 with ALP \< 1.67x ULN and total bilirubin ≤ ULN and ALP decrease of ≥ 15% from baseline.
Time frame: DB Month 6
Population: Intent-to-Treat Population: All participants who were randomized and received at least 1 dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| DB OCA 10 mg | DB Phase: Composite Endpoint ALP And Total Bilirubin, 5-10 mg Versus Placebo | 34 percentage of participants |
| DB Placebo | DB Phase: Composite Endpoint ALP And Total Bilirubin, 5-10 mg Versus Placebo | 7 percentage of participants |
Comparison: H0: The response rates are equal between placebo and 5-10 mg OCA. H1: The response rates are different between placebo and 5-10 mg OCA.p-value: <0.0001Cochran-Mantel-Haenszel
Secondary
DB Phase: Composite Endpoint ALP And Total Bilirubin, 5-10 mg Versus Placebo
Percentage of participants at Month 12 with ALP \< 1.67x ULN and total bilirubin ≤ ULN and ALP decrease of ≥ 15% from baseline.
Time frame: DB Month 12
Population: Intent-to-Treat Population: All participants who were randomized and received at least 1 dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| DB OCA 10 mg | DB Phase: Composite Endpoint ALP And Total Bilirubin, 5-10 mg Versus Placebo | 46 percentage of participants |
| DB Placebo | DB Phase: Composite Endpoint ALP And Total Bilirubin, 5-10 mg Versus Placebo | 10 percentage of participants |
Comparison: H0: The response rates are equal between placebo and 5-10 mg OCA. H1: The response rates are different between placebo and 5-10 mg OCA.p-value: <0.0001Cochran-Mantel-Haenszel
Secondary
DB Phase: Direct Bilirubin Absolute Change From Baseline To Month 12
Blood samples were evaluated for bilirubin levels. Direct bilirubin absolute change from baseline (direct bilirubin at Month 12 - direct bilirubin at Baseline) is presented.
Time frame: Baseline, DB Month 12
Population: Intent-to-Treat Population: All participants who were randomized and received at least 1 dose of study drug and had an assessment at the specified timepoint.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| DB OCA 10 mg | DB Phase: Direct Bilirubin Absolute Change From Baseline To Month 12 | -0.13 umol/L | Standard Error 0.52 |
| DB Placebo | DB Phase: Direct Bilirubin Absolute Change From Baseline To Month 12 | -0.49 umol/L | Standard Error 0.54 |
| LTSE OCA (DB Placebo) | DB Phase: Direct Bilirubin Absolute Change From Baseline To Month 12 | 1.89 umol/L | Standard Error 0.53 |
p-value: <0.0001ANCOVA
p-value: <0.0001ANCOVA
Secondary
DB Phase: Gamma-glutamyltransferase (GGT) Absolute Change From Baseline To Month 12
Blood samples were evaluated for GGT levels. GGT absolute change from baseline (GGT at Month 12 - GGT at Baseline) is presented.
Time frame: Baseline, DB Month 12
Population: Intent-to-Treat Population: All participants who were randomized and received at least 1 dose of study drug and had an assessment at the specified timepoint.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| DB OCA 10 mg | DB Phase: Gamma-glutamyltransferase (GGT) Absolute Change From Baseline To Month 12 | -140.83 U/L | Standard Error 24.7 |
| DB Placebo | DB Phase: Gamma-glutamyltransferase (GGT) Absolute Change From Baseline To Month 12 | -176.66 U/L | Standard Error 25.58 |
| LTSE OCA (DB Placebo) | DB Phase: Gamma-glutamyltransferase (GGT) Absolute Change From Baseline To Month 12 | 6.70 U/L | Standard Error 25.56 |
p-value: <0.0001ANCOVA
p-value: <0.0001ANCOVA
Secondary
DB Phase: Total Bilirubin Absolute Change From Baseline To Month 12
Blood samples were evaluated for bilirubin levels. Total bilirubin absolute change from baseline (total bilirubin at Month 12 - total bilirubin at Baseline) is presented.
Time frame: Baseline, DB Month 12
Population: Intent-to-Treat Population: All participants who were randomized and received at least 1 dose of study drug and had an assessment at the specified timepoint.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| DB OCA 10 mg | DB Phase: Total Bilirubin Absolute Change From Baseline To Month 12 | -0.33 umol/L | Standard Error 0.68 |
| DB Placebo | DB Phase: Total Bilirubin Absolute Change From Baseline To Month 12 | -0.90 umol/L | Standard Error 0.71 |
| LTSE OCA (DB Placebo) | DB Phase: Total Bilirubin Absolute Change From Baseline To Month 12 | 1.98 umol/L | Standard Error 0.7 |
p-value: 0.0004ANCOVA
p-value: <0.0001ANCOVA
Secondary
LTSE Phase: ALP Change From DB Baseline
Blood samples were evaluated for ALP levels. ALP Change From Baseline (ALP at LTSE Months 12, 24, 36, 48, and 60 - ALP at Baseline) is presented. DB baseline is the mean of all available evaluations prior to DB treatment.
Time frame: DB Baseline, LTSE Months 12, 24, 36, 48, and 60
Population: All participants who received at least 1 dose of OCA in the open-label safety extension phase and had an assessment at the specified timepoint.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| DB OCA 10 mg | LTSE Phase: ALP Change From DB Baseline | Month 48 | -118.23 U/L | Standard Deviation 101.527 |
| DB OCA 10 mg | LTSE Phase: ALP Change From DB Baseline | Month 60 | -118.99 U/L | Standard Deviation 147.126 |
| DB OCA 10 mg | LTSE Phase: ALP Change From DB Baseline | Month 36 | -100.98 U/L | Standard Deviation 109.952 |
| DB OCA 10 mg | LTSE Phase: ALP Change From DB Baseline | Month 24 | -120.86 U/L | Standard Deviation 96.614 |
| DB OCA 10 mg | LTSE Phase: ALP Change From DB Baseline | Month 12 | -106.63 U/L | Standard Deviation 98.448 |
| DB Placebo | LTSE Phase: ALP Change From DB Baseline | Month 36 | -84.65 U/L | Standard Deviation 137.293 |
| DB Placebo | LTSE Phase: ALP Change From DB Baseline | Month 48 | -101.50 U/L | Standard Deviation 91.335 |
| DB Placebo | LTSE Phase: ALP Change From DB Baseline | Month 24 | -102.52 U/L | Standard Deviation 79.413 |
| DB Placebo | LTSE Phase: ALP Change From DB Baseline | Month 12 | -104.39 U/L | Standard Deviation 82.496 |
| DB Placebo | LTSE Phase: ALP Change From DB Baseline | Month 60 | -117.49 U/L | Standard Deviation 95.587 |
| LTSE OCA (DB Placebo) | LTSE Phase: ALP Change From DB Baseline | Month 60 | -119.52 U/L | Standard Deviation 108.949 |
| LTSE OCA (DB Placebo) | LTSE Phase: ALP Change From DB Baseline | Month 24 | -100.99 U/L | Standard Deviation 87.181 |
| LTSE OCA (DB Placebo) | LTSE Phase: ALP Change From DB Baseline | Month 48 | -115.51 U/L | Standard Deviation 106.774 |
| LTSE OCA (DB Placebo) | LTSE Phase: ALP Change From DB Baseline | Month 12 | -104.36 U/L | Standard Deviation 83.074 |
| LTSE OCA (DB Placebo) | LTSE Phase: ALP Change From DB Baseline | Month 36 | -112.73 U/L | Standard Deviation 89.661 |
| Overall LTSE OCA | LTSE Phase: ALP Change From DB Baseline | Month 48 | -111.49 U/L | Standard Deviation 99.433 |
| Overall LTSE OCA | LTSE Phase: ALP Change From DB Baseline | Month 12 | -105.13 U/L | Standard Deviation 87.882 |
| Overall LTSE OCA | LTSE Phase: ALP Change From DB Baseline | Month 24 | -108.34 U/L | Standard Deviation 87.98 |
| Overall LTSE OCA | LTSE Phase: ALP Change From DB Baseline | Month 36 | -98.96 U/L | Standard Deviation 114.635 |
| Overall LTSE OCA | LTSE Phase: ALP Change From DB Baseline | Month 60 | -118.74 U/L | Standard Deviation 121.391 |
Secondary
LTSE Phase: ALP Levels
Blood samples were evaluated for ALP levels.
Time frame: LTSE Day 0 and LTSE Months 12, 24, 36, 48, and 60
Population: All participants who received at least 1 dose of OCA in the open-label safety extension phase and had an assessment at the specified timepoint.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| DB OCA 10 mg | LTSE Phase: ALP Levels | LTSE Day 0 | 218.69 U/L | Standard Deviation 100.328 |
| DB OCA 10 mg | LTSE Phase: ALP Levels | LTSE Month 12 | 209.49 U/L | Standard Deviation 93.157 |
| DB OCA 10 mg | LTSE Phase: ALP Levels | LTSE Month 24 | 195.14 U/L | Standard Deviation 80.361 |
| DB OCA 10 mg | LTSE Phase: ALP Levels | LTSE Month 36 | 204.52 U/L | Standard Deviation 68.019 |
| DB OCA 10 mg | LTSE Phase: ALP Levels | LTSE Month 48 | 189.75 U/L | Standard Deviation 55.929 |
| DB OCA 10 mg | LTSE Phase: ALP Levels | LTSE Month 60 | 200.90 U/L | Standard Deviation 97.475 |
| DB Placebo | LTSE Phase: ALP Levels | LTSE Month 60 | 191.37 U/L | Standard Deviation 62.404 |
| DB Placebo | LTSE Phase: ALP Levels | LTSE Month 36 | 214.66 U/L | Standard Deviation 158.831 |
| DB Placebo | LTSE Phase: ALP Levels | LTSE Day 0 | 191.24 U/L | Standard Deviation 61.381 |
| DB Placebo | LTSE Phase: ALP Levels | LTSE Month 24 | 194.57 U/L | Standard Deviation 66.593 |
| DB Placebo | LTSE Phase: ALP Levels | LTSE Month 12 | 198.68 U/L | Standard Deviation 75.799 |
| DB Placebo | LTSE Phase: ALP Levels | LTSE Month 48 | 192.00 U/L | Standard Deviation 59.761 |
| LTSE OCA (DB Placebo) | LTSE Phase: ALP Levels | LTSE Month 12 | 226.28 U/L | Standard Deviation 105.404 |
| LTSE OCA (DB Placebo) | LTSE Phase: ALP Levels | LTSE Month 24 | 215.99 U/L | Standard Deviation 83.469 |
| LTSE OCA (DB Placebo) | LTSE Phase: ALP Levels | LTSE Month 36 | 205.37 U/L | Standard Deviation 65.206 |
| LTSE OCA (DB Placebo) | LTSE Phase: ALP Levels | LTSE Month 60 | 209.38 U/L | Standard Deviation 82.24 |
| LTSE OCA (DB Placebo) | LTSE Phase: ALP Levels | LTSE Month 48 | 198.70 U/L | Standard Deviation 65.551 |
| LTSE OCA (DB Placebo) | LTSE Phase: ALP Levels | LTSE Day 0 | 317.79 U/L | Standard Deviation 139.666 |
| Overall LTSE OCA | LTSE Phase: ALP Levels | LTSE Month 48 | 193.38 U/L | Standard Deviation 60.17 |
| Overall LTSE OCA | LTSE Phase: ALP Levels | LTSE Month 60 | 200.94 U/L | Standard Deviation 83.436 |
| Overall LTSE OCA | LTSE Phase: ALP Levels | LTSE Month 12 | 211.47 U/L | Standard Deviation 92.439 |
| Overall LTSE OCA | LTSE Phase: ALP Levels | LTSE Month 36 | 208.27 U/L | Standard Deviation 107.114 |
| Overall LTSE OCA | LTSE Phase: ALP Levels | LTSE Day 0 | 243.75 U/L | Standard Deviation 118.91 |
| Overall LTSE OCA | LTSE Phase: ALP Levels | LTSE Month 24 | 201.47 U/L | Standard Deviation 77.117 |