Primary Biliary Cholangitis
Conditions
Keywords
PBC, Primary Biliary Cholangitis (PBC)
Brief summary
A 52-week, placebo-controlled, randomized, Phase 3 study to evaluate the safety and efficacy of seladelpar in subjects with primary biliary cholangitis (PBC) and an inadequate response to or intolerance to ursodeoxycholic acid (UDCA) The participants might enter the ongoing open-label safety study (NCT03301506) following this double-blind study.
Detailed description
Primary: * To evaluate the safety and effect on cholestasis of two seladelpar regimens (5 mg/day titrated to 10 mg/day and 10 mg/day) over 52 weeks of treatment compared to placebo Key Secondary: * To evaluate the effect of seladelpar on normalization of alkaline phosphatase (AP) levels * To evaluate the effect of seladelpar on pruritus
Interventions
DRUGseladelpar 5-10 mg
Seladelpar 5 mg for 6 months and then titrating up to 10 mg based on tolerability and response for remainder of double-blind period. After completion of the 1-year double-blind period subjects will be offered the opportunity to enter an open label long term safety study. Subjects will continue the seladelpar dose (5 or 10 mg) received during the double-blinded study
DRUGseladelpar 10 mg
Seladelpar 10 mg for double-blind period. After completion of the 1-year double-blind period subjects will be offered the opportunity to enter an open label safety study. Subjects will continue the seladelpar dose (10 mg) received during the double-blinded study
DRUGPlacebo
One capsule daily for double-blind period. After completion of the 1-year double-blind period subjects will be offered the opportunity to enter an open label long term safety study. Subjects on placebo will be re-randomized to initiate seladelpar at 5 or 10 mg once daily
Sponsors
Gilead Sciences
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
1. Must have given written informed consent (signed and dated) and any authorizations required by local law 2. 18 to 75 years old (inclusive) 3. Male or female with a diagnosis of PBC, by at least two of the following criteria: * History of AP above ULN for at least six months * Positive anti-mitochondrial antibody (AMA) titers (\>1/40 on immunofluorescence or M2 positive by enzyme linked immunosorbent assay \[ELISA\]) or positive PBC-specific antinuclear antibodies * Documented liver biopsy result consistent with PBC 4. On a stable and recommended dose of UDCA for the past twelve months OR intolerant to UDCA (last dose of UDCA \> 3 months prior to Screening) 5. AP ≥ 1.67 × ULN 6. Females of reproductive potential must use at least one barrier contraceptive and a second effective birth control method during the study and for at least 90 days after the last dose. Male subjects who are sexually active with female partners of reproductive potential must use barrier contraception and their female partners must use a second effective birth control method during the study and for at least 90 days after the last dose
Exclusion criteria
1. Previous exposure to seladelpar (MBX-8025) 2. A medical condition, other than PBC, that in the investigator's opinion would preclude full participation in the study or confound its results (e.g., cancer) 3. AST above 3 × ULN 4. ALT above 3 × ULN 5. Total bilirubin above 2.0 × ULN 6. Advanced PBC as defined by the Rotterdam criteria (albumin below LLN AND total bilirubin above 1 × ULN) 7. Creatine kinase (CK) above 1.0 × ULN 8. eGFR below 60 mL/min/1.73 m2 (calculated by MDRD formula) 9. International normalized ratio (INR) above 1.0 × ULN 10. Platelet count below 100 × 103/µL 11. Presence of clinically significant hepatic decompensation, including: * History of liver transplantation, current placement on liver transplantation list, or current MELD score ≥ 15 * Complications of portal hypertension, including known esophageal varices, history of variceal bleeds or related interventions (e.g., transjugular intrahepatic portosystemic shunt placement), relevant ascites, hepatic encephalopathy * Cirrhosis with complications, including history or presence of spontaneous bacterial peritonitis 12. Other chronic liver diseases: * Current features of auto-immune hepatitis as determined by the investigator based on immunoserology, liver biochemistry and histology * Primary sclerosing cholangitis determined by presence of diagnostic cholangiographic findings * History or clinical evidence of alcoholic liver disease * History or clinical evidence of alpha-1-antitrypsin deficiency * Biopsy confirmed nonalcoholic steatohepatitis * History or evidence of Gilbert' Syndrome with elevated total bilirubin * History or evidence of hemochromatosis * Hepatitis B defined as presence of hepatitis B surface antigen (HBsAg) * Hepatitis C defined as presence of HCV RNA 13. Known history of HIV 14. Evidence of significant alcohol consumption 15. Evidence of drug abuse 16. Subjects with inadequate response to obeticholic acid (OCA) or intolerance to OCA: OCA must be discontinued 30 days prior to Screening 17. Use of colchicine, methotrexate, azathioprine, or long-term systemic corticosteroids (\> 2 weeks) within two months prior to Screening 18. Use of fibrates within 30 days prior to Screening 19. Use of simvastatin within 7 days prior to Screening 20. Use of an experimental or unapproved treatment for PBC within 30 days prior to Screening 21. Use of experimental or unapproved immunosuppressant within 30 days prior to Screening 22. Treatment with any other investigational therapy or device within 30 days or within five half-lives, whatever is longer, prior to Screening 23. For females, pregnancy or breast-feeding 24. Any other condition(s) that would compromise the safety of the subject or compromise the quality of the clinical study, as judged by the investigator
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Response to Composite Endpoint of ALP <1.67 × Upper Limit of Normal [ULN], ≥15% Reduction in ALP, and Total Bilirubin ≤ ULN) at Month 3 | Month 3 | Percentage of Participants with Response to Composite Endpoint of ALP \<1.67 × Upper Limit of Normal \[ULN\], ≥15% reduction in ALP, and total bilirubin ≤ ULN) at Month 3. The mITT analysis set included all randomized subjects who received at least one study drug dose. The primary endpoint was analyzed using Cochran-Mantel-Haenszel (CMH) test adjusted for both randomization stratification variables (ALP level: \<350 U/L and 2:350 U/L; pruritus NRS: \<4 and 2:4). The CMH tests were performed for the comparison of 10 mg versus placebo and 5 mg/10 mg versus placebo separately. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Response Defined by Normalized Alkaline Phosphatase Levels at Month 3 | Month 3 | The response was defined by normalized ALP levels (ALP ≤1.0 × ULN) at endpoint. The mITT analysis set included all randomized subjects who received at least one study drug dose. |
| Change From Baseline in Pruritus NRS for Subjects With Baseline NRS ≥4 at Month 3 | Month 3 | Pruritus Numerical Rating Scale (NRS) used to rate the intensity of the worst itching you experienced in the past 24 hours from no itching to worst possible itching by selecting a number from 0 to 10 on Itch Scale. Zero means no itching and 10 means worst imaginable itching. The analysis will be limited to those subjects in the mITT analysis set with a baseline NRS ≥ 4. |
Countries
Argentina, Australia, Austria, Belgium, Canada, Chile, France, Germany, Greece, Hungary, Israel, Italy, Mexico, Netherlands, New Zealand, Poland, Romania, Russia, Serbia, South Korea, Spain, United Kingdom, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Seladelpar 5-10 mg seladelpar 5-10 mg: Seladelpar 5 mg for 6 months and then titrating up to 10 mg based on tolerability and response for remainder of double-blind period. After completion of the 1-year double-blind period subjects will be offered the opportunity to enter an open label long term safety study. Subjects will continue the seladelpar dose (5 or 10 mg) received during the double-blinded study | 89 |
| Seladelpar 10 mg seladelpar 10 mg: Seladelpar 10 mg for double-blind period. After completion of the 1-year double-blind period subjects will be offered the opportunity to enter an open label safety study. Subjects will continue the seladelpar dose (10 mg) received during the double-blinded study | 89 |
| Placebo Placebo: One capsule daily for double-blind period. After completion of the 1-year double-blind period subjects will be offered the opportunity to enter an open label long term safety study. Subjects on placebo will be re-randomized to initiate seladelpar at 5 or 10 mg once daily | 87 |
| Total | 265 |
Baseline characteristics
| Characteristic | Seladelpar 5-10 mg | Seladelpar 10 mg | Placebo | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 14 Participants | 16 Participants | 14 Participants | 44 Participants |
| Age, Categorical Between 18 and 65 years | 75 Participants | 73 Participants | 73 Participants | 221 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 4 Participants | 8 Participants | 5 Participants | 17 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 4 Participants | 2 Participants | 7 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 83 Participants | 77 Participants | 80 Participants | 240 Participants |
| Sex: Female, Male Female | 82 Participants | 83 Participants | 85 Participants | 250 Participants |
| Sex: Female, Male Male | 7 Participants | 6 Participants | 2 Participants | 15 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 89 | 0 / 89 | 0 / 87 |
| other Total, other adverse events | 55 / 89 | 58 / 89 | 62 / 87 |
| serious Total, serious adverse events | 3 / 89 | 1 / 89 | 3 / 87 |
Outcome results
Primary
Percentage of Participants With Response to Composite Endpoint of ALP <1.67 × Upper Limit of Normal [ULN], ≥15% Reduction in ALP, and Total Bilirubin ≤ ULN) at Month 3
Percentage of Participants with Response to Composite Endpoint of ALP \<1.67 × Upper Limit of Normal \[ULN\], ≥15% reduction in ALP, and total bilirubin ≤ ULN) at Month 3. The mITT analysis set included all randomized subjects who received at least one study drug dose. The primary endpoint was analyzed using Cochran-Mantel-Haenszel (CMH) test adjusted for both randomization stratification variables (ALP level: \<350 U/L and 2:350 U/L; pruritus NRS: \<4 and 2:4). The CMH tests were performed for the comparison of 10 mg versus placebo and 5 mg/10 mg versus placebo separately.
Time frame: Month 3
Population: mITT Population. The Modified Intent-to-Treat (mITT) set includes any subject who is randomized into the study and receives at least one dose of study drug.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Seladelpar 5-10 mg | Percentage of Participants With Response to Composite Endpoint of ALP <1.67 × Upper Limit of Normal [ULN], ≥15% Reduction in ALP, and Total Bilirubin ≤ ULN) at Month 3 | 32 Participants |
| Seladelpar 10 mg | Percentage of Participants With Response to Composite Endpoint of ALP <1.67 × Upper Limit of Normal [ULN], ≥15% Reduction in ALP, and Total Bilirubin ≤ ULN) at Month 3 | 43 Participants |
| Placebo | Percentage of Participants With Response to Composite Endpoint of ALP <1.67 × Upper Limit of Normal [ULN], ≥15% Reduction in ALP, and Total Bilirubin ≤ ULN) at Month 3 | 7 Participants |
p-value: <0.0001Cochran-Mantel-Haenszel
p-value: <0.0001Cochran-Mantel-Haenszel
Secondary
Change From Baseline in Pruritus NRS for Subjects With Baseline NRS ≥4 at Month 3
Pruritus Numerical Rating Scale (NRS) used to rate the intensity of the worst itching you experienced in the past 24 hours from no itching to worst possible itching by selecting a number from 0 to 10 on Itch Scale. Zero means no itching and 10 means worst imaginable itching. The analysis will be limited to those subjects in the mITT analysis set with a baseline NRS ≥ 4.
Time frame: Month 3
Population: mITT Population. The Modified Intent-to-Treat (mITT) set includes any subject who is randomized into the study and receives at least one dose of study drug.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Seladelpar 5-10 mg | Change From Baseline in Pruritus NRS for Subjects With Baseline NRS ≥4 at Month 3 | -1.95 score on a scale | Standard Deviation 2.226 |
| Seladelpar 10 mg | Change From Baseline in Pruritus NRS for Subjects With Baseline NRS ≥4 at Month 3 | -3.01 score on a scale | Standard Deviation 1.952 |
| Placebo | Change From Baseline in Pruritus NRS for Subjects With Baseline NRS ≥4 at Month 3 | -1.44 score on a scale | Standard Deviation 1.831 |
p-value: 0.016495% CI: [-2.87, -0.3]ANCOVA
p-value: 0.478195% CI: [-1.77, 0.84]ANCOVA
Secondary
Percentage of Participants With Response Defined by Normalized Alkaline Phosphatase Levels at Month 3
The response was defined by normalized ALP levels (ALP ≤1.0 × ULN) at endpoint. The mITT analysis set included all randomized subjects who received at least one study drug dose.
Time frame: Month 3
Population: mITT Population. The Modified Intent-to-Treat (mITT) set includes any subject who is randomized into the study and receives at least one dose of study drug.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Seladelpar 5-10 mg | Percentage of Participants With Response Defined by Normalized Alkaline Phosphatase Levels at Month 3 | 3 Participants |
| Seladelpar 10 mg | Percentage of Participants With Response Defined by Normalized Alkaline Phosphatase Levels at Month 3 | 15 Participants |
| Placebo | Percentage of Participants With Response Defined by Normalized Alkaline Phosphatase Levels at Month 3 | 0 Participants |
p-value: <0.0001Cochran-Mantel-Haenszel
p-value: 0.0839Cochran-Mantel-Haenszel