ENHANCE: Seladelpar in Subjects With Primary Biliary Cholangitis (PBC) and an Inadequate Response to or an Intolerance to Ursodeoxycholic Acid (UDCA)

Primary Biliary Cholangitis Clinical Trial

Official title:

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 an Intolerance to Ursodeoxycholic Acid (UDCA)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03602560
• Other study ID #: CB8025-31735
• Status: Completed
• Phase: Phase 3
• Start date: October 1, 2018
• Est. completion date: February 16, 2020

Study information

• Verified date: July 2022
• Source: CymaBay Therapeutics, Inc.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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

Recruitment information / eligibility

• Status: Completed
• Enrollment: 265
• Est. completion date: February 16, 2020
• Est. primary completion date: February 16, 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 75 Years

Eligibility

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

Related Conditions & MeSH terms

• Cholangitis
• Liver Cirrhosis, Biliary
• Primary Biliary Cholangitis

Intervention

Drug:
• 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
• 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
• 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

Locations

Country	Name	City	State
Argentina	Fundación Sanatorio Güemes	Buenos Aires	Ciudad Autónoma De BuenosAires
Argentina	Hospital Universitario Austral	Pilar	Buenos Aires
Argentina	DIM Clínica Privada	Ramos Mejía
Argentina	Hospital Provincial Del Centenario	Rosario	Santa Fe
Australia	St Vincents Hospital Melbourne	Fitzroy	Victoria
Australia	The Canberra Hospital	Garran	Australian Capital Territory
Australia	Royal Brisbane & Women's Hospital	Herston	Queensland
Australia	Royal Melbourne Hospital	Parkville	Victoria
Australia	Royal Perth Hospital	Perth	Western Australia
Austria	LKH-Universitätsklinikum Klinikum Graz	Graz
Austria	Salzburger Landeskliniken	Salzburg
Austria	Medizinische Universitat Wien	Vienna	Wien
Austria	Klinikum Wels-Grieskirchen GmbH	Wels
Belgium	UZ Antwerpen	Edegem	Antwerpen
Belgium	UZ Gent	Gent	Oost-Vlaanderen
Belgium	UZ Leuven	Leuven	Vlaams Brabant
Canada	University of Calgary Medicine	Calgary	Alberta
Canada	McGill University Health Centre (MUHC)	Montréal	Quebec
Canada	University Health Network	Toronto	Ontario
Canada	Toronto Digestive Disease Associates Inc	Vaughan	Ontario
Canada	University of Manitoba	Winnipeg	Manitoba
Chile	Centro Clinico Mediterraneo	La Serena
Chile	Pontificia Universidad Catolica de Chile	Santiago	Región-MetropolitanadeSantiago
Chile	Centro de Investigaciones Clínicas Vina del Mar	Viña Del Mar
France	Hôpital Jean Verdier	Bondy
France	CHU de GRENOBLE	Grenoble
France	Hôpital Saint Antoine	Paris
Germany	Charité - Universitätsmedizin Berlin	Berlin
Germany	Universitätsklinikum Erlangen	Erlangen
Germany	ifi-Institute for Interdisciplinary Medicine	Hamburg
Germany	Gastroenterologische Gemeinschaftspraxis Herne	Herne	Nordrhein-Westfalen
Germany	Gastroenterologisch Hepatologisches Zentrum Kiel	Kiel	Schleswig-Holstein
Germany	Uniklinik Köln	Köln	Nordrhein-Westfalen
Germany	Universitatsklinikum Leipzig	Leipzig
Germany	Universitätsklinikum Tübingen	Tübingen	Baden-Württemberg
Greece	University General Hospital of Heraklion	Heraklion
Greece	University General Hospital of Larissa	Larissa
Greece	University General Hospital of Patras	Patras
Hungary	Budai Hepatológiai Centrum	Budapest
Hungary	Debreceni Egyetem Klinikai Kozpont	Debrecen
Hungary	Somogy Megyei Kaposi Mór Oktató Kórház	Kaposvár
Hungary	Szegedi Tudomanyegyetem Szent-Gyorgyi Albert Klinikai Kozpont	Szeged	Csongrád
Israel	Hillel Yaffe Medical Center	Hadera
Israel	Carmel Medical Center	Haifa
Israel	Rambam Health Corporation	Haifa
Israel	Hadassah Medical Center	Jerusalem
Israel	The Galilli Medical Center	Nahariya
Israel	Chaim Sheba Medical Center	Ramat Gan
Israel	Kaplan Medical Center	Re?ovot
Israel	Tel Aviv Sourasky Medical Center	Tel Aviv
Italy	Azienda Ospedaliera Universitaria Careggi	Firenze
Italy	ASST Santi Paolo e Carlo - Azienda Universitaria-Polo Universitario San Paolo	Milano
Italy	Ospedale Civile di Baggiovara	Modena
Italy	Azienda Ospedaliera Di Padova	Padova
Italy	ASST di Monza - Azienda Ospedaliera San Gerardo	Rozzano
Korea, Republic of	Pusan National University Hospital	Busan
Korea, Republic of	Kyungpook National University Hospital	Daegu
Korea, Republic of	Seoul National University Bundang Hospital	Seongnam-si	Gyeonggido
Korea, Republic of	Gangnam Severance Hospital, Yonsei University Health System	Seoul
Korea, Republic of	Inje University Ilsan Paik Hospital	Seoul
Korea, Republic of	Seoul National University Hospital	Seoul
Korea, Republic of	Severance Hospital Yonsei University Health System	Seoul
Korea, Republic of	The Catholic University of Korea, Seoul St. Mary's Hospital	Seoul
Mexico	Consultorio Medico - Distrito Federal	Ciudad de Mexico
Mexico	Consultorio de la Doctora Maria Sarai Gonzalez Huezo	Metepec
Mexico	Centro de Diabetes y Obesidad Graber	Pachuca de Soto	Hidalgo
Netherlands	Radboud Universitair Medisch Centrum	Nijmegen	Gelderland
New Zealand	Christchurch Hospital	Christchurch	South Island
New Zealand	Dunedin Hospital	Dunedin	South Island
New Zealand	Waikato Hospital	Hamilton
Poland	Wojewodzki Szpital Obserwacyjno-Zakazny im. Tadeusza Browicza w Bydgoszczy	Bydgoszcz	Kujawsko-pomorskie
Poland	Samodzielny Publiczny Szpital Kliniczny Nr 7 Slaskiego Uniwersytetu Medycznego w Katowicach	Katowice	Slaskie
Poland	Wojewodzki Szpital Zespolony w Kielcach	Kielce
Poland	SP ZOZ Szpital Uniwersytecki w Krakowie	Kraków
Poland	ID Clinic	Myslowice
Poland	Centrum Onkologii Instytut im. Marii Sklodowskiej-Curie	Warszawa	Mazowieckie
Romania	Colentina Clinical Hospital	Bucharest
Romania	Fundeni Clinical Institute	Bucharest
Romania	Sana Monitoring SRL	Bucharest
Romania	Pius Brinzeu Emergency Clinical County Hospital	Timisoara	Timis
Russian Federation	Peoples Friendship University of Russia	Moscow	Moskva
Russian Federation	City Hospital #31	St. Petersburg
Russian Federation	Ulyanovsk Regional Clinical Hospital	Ulyanovsk
Serbia	Clinical Hospital Centar Zvezdara	Belgrade
Serbia	KBC Zemun	Belgrade
Spain	Hospital Clinic de Barcelona	Barcelona
Spain	Hospital Universitario Germans Trias i Pujol	Barcelona
Spain	Hospital Universitario Vall d'Hebrón - PPDS	Barcelona
Spain	Hospital Universitario La Paz	Madrid
Spain	Hospital Universitario Ramon y Cajal	Madrid
Spain	Hospital Universitario Puerta de Hierro - Majadahonda	Majadahonda	Madrid
Spain	Hospital Universitario Virgen de la Victoria	Málaga
Spain	Hospital Universitario Virgen del Rocio	Sevilla
Spain	Hospital Clinico Universitario de Valencia	Valencia
Spain	Hospital Universitari i Politecnic La Fe de Valencia	Valencia
United Kingdom	University Hospital Birmingham	Birmingham
United Kingdom	Hull and East Yorkshire Hospitals NHS Trust	Hull
United Kingdom	Barts Health NHS Trust, Royal London Hospital, Ambrose King Centre	London
United Kingdom	Kings College Hospital	London
United Kingdom	Royal Free London NHS Foundation Trust	London
United Kingdom	The Newcastle Upon Tyne Hospital NHS Foundation Trust	Newcastle
United Kingdom	University of Nottingham	Nottingham
United Kingdom	Plymouth Hospitals NHS Trust	Plymouth
United Kingdom	Queen Alexandra Hospital	Portsmouth	Hampshire
United Kingdom	Singleton Hospital	Swansea
United States	Asheville Gastroenterology Associates, a Division of Digestive Health Partners, P.A.	Asheville	North Carolina
United States	Digestive Healthcare of Georgia	Atlanta	Georgia
United States	Univeristy of Colorado Denver and Hospital	Aurora	Colorado
United States	Northeast Clinical Research Center, LLC	Bethlehem	Pennsylvania
United States	Excel Medical Clinical Trials, LLC	Boca Raton	Florida
United States	Beth Israel Deaconess Medical Center	Boston	Massachusetts
United States	Massachusetts General Hospital	Boston	Massachusetts
United States	Institute for Liver Health	Chandler	Arizona
United States	University of Chicago Medical Center	Chicago	Illinois
United States	UH Cleveland Medical Center	Cleveland	Ohio
United States	Liver Institute at Methodist Dallas	Dallas	Texas
United States	University of Texas Southwestern Medical Center	Dallas	Texas
United States	Duke University Medical Center	Durham	North Carolina
United States	Texas Digestive Disease Consultants	Fort Worth	Texas
United States	Gastro One	Germantown	Tennessee
United States	Penn State Milton S Hershey Medical Center	Hershey	Pennsylvania
United States	American Research Corporation	Houston	Texas
United States	Baylor College of Medicine	Houston	Texas
United States	Indianapolis Gastroenterology Research Foundation	Indianapolis	Indiana
United States	Southern Therapy and Advance Research (STAR) LLC	Jackson	Mississippi
United States	Kansas City Research Institute	Kansas City	Missouri
United States	University of Kansas Hospital	Kansas City	Kansas
United States	GIA Clinical Trials, LLC	Knoxville	Tennessee
United States	Florida Reserach Institute	Lakewood Ranch	Florida
United States	Cedars Sinai Medical Center	Los Angeles	California
United States	Minnesota Gastroenterlogy, P.A.	Maplewood	Minnesota
United States	Schiff Center for Liver Diseases University of Miami	Miami	Florida
United States	University of Minnesota Medical Center, Fairview	Minneapolis	Minnesota
United States	Intermountain Medical Center	Murray	Utah
United States	Vanderbilt University Medical Center	Nashville	Tennessee
United States	Yale School of Medicine Digestive Diseases, Internal Medicine	New Haven	Connecticut
United States	Tulane University School of Medicine	New Orleans	Louisiana
United States	Center for Liver Disease and Transplantation	New York	New York
United States	Concorde Medical Group	New York	New York
United States	Icahn School of Medicine at Mount Sinai	New York	New York
United States	NYU Langone Health	New York	New York
United States	Mary Immaculate Hospital	Newport News	Virginia
United States	Henry Ford Health System	Novi	Michigan
United States	Mayo Clinic Arizona - PPDS	Phoenix	Arizona
United States	University of Pittsburgh Medical Center	Pittsburgh	Pennsylvania
United States	Stanford University School of Medicine	Redwood City	California
United States	Bon Secours Richmond Community Hospital	Richmond	Virginia
United States	University of Rochester Medical Center	Rochester	New York
United States	University of California Davis Medical Center	Sacramento	California
United States	American Research Corporation at Texas Liver Institute	San Antonio	Texas
United States	Pinnacle Clinical Research	San Antonio	Texas
United States	California Pacific Medical Center	San Francisco	California
United States	Swedish Medical Center	Seattle	Washington
United States	Tampa General Medical Group	Tampa	Florida
United States	The Institute for Liver Health-Tucson	Tucson	Arizona
United States	Digestive Health Specialists PA	Tupelo	Mississippi

Sponsors (1)

Lead Sponsor	Collaborator
CymaBay Therapeutics, Inc.

Countries where clinical trial is conducted

United States,  Argentina,  Australia,  Austria,  Belgium,  Canada,  Chile,  France,  Germany,  Greece,  Hungary,  Israel,  Italy,  Korea, Republic of,  Mexico,  Netherlands,  New Zealand,  Poland,  Romania,  Russian Federation,  Serbia,  Spain,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
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.	Month 3
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.	Month 3
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.	Month 3