Study of Elafibranor in Patients With Primary Biliary Cholangitis (PBC)

Primary Biliary Cirrhosis Clinical Trial

— ELATIVE  

Official title:

A Double-blind, Randomized, Placebo-Controlled Study and Open-label Long Term Extension to Evaluate the Efficacy and Safety of Elafibranor 80 mg in Patients With Primary Biliary Cholangitis With Inadequate Response or Intolerance to Ursodeoxycholic Acid

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT04526665
• Other study ID #: GFT505B-319-1
• Secondary ID: 2019-004941-34
• Status: Active, not recruiting
• Phase: Phase 3
• Start date: September 24, 2020
• Est. completion date: December 1, 2028

Study information

• Verified date: May 2024
• Source: Ipsen
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The participants of this study will have confirmed Primary Biliary Cholangitis (PBC) with inadequate response or intolerance to ursodeoxycholic acid (which is a medication used in the management and treatment of cholestatic liver disease).

PBC is a slowly progressive disease characterized by damage of the bile ducts in the liver, leading to a buildup of bile acids which causes further damage. The liver damage in PBC may lead to scarring (cirrhosis).

PBC may also be associated with multiple symptoms. Many patients with PBC may require liver transplant or may die if the disease progresses and a liver transplant is not done.

This study has two main parts; the first part will compare a daily dose of elafibranor (the study drug) to a daily dose of placebo (a dummy treatment), and will last between a minimum of one year and a maximum of two years. In the second part, all participants will receive elafibranor, for a period between 4-5 years.

The main aim of this study is to determine if elafibranor is better than placebo at decreasing the levels of a specific blood test (alkaline phosphatase) that provides information about participant's disease. This study will also study the safety of long-term treatment with elafibranor, as well as the impact on symptoms such as pruritus and fatigue.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 161
• Est. completion date: December 1, 2028
• Est. primary completion date: June 1, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 75 Years

Eligibility

Inclusion Criteria

• Males or females age of 18 to 75 years (inclusive)

• Definite or probable PBC diagnosis

• ALP = 1.67x upper limit of normal (ULN)

• Total bilirubin (TB) = 2x ULN

• UDCA for at least 12 months (stable dose = 3 months) prior to screening, or unable to tolerate UDCA treatment (no UDCA for = 3 months) prior to screening (per country standard-of-care dosing)

• Must have PBC Worst Itch NRS collected prior to randomization

• Females participating in this study must be of non-child bearing potential or must be using highly efficient contraception for the full duration of the study and for 1 month after the last drug intake

Exclusion Criteria:

• History or presence of other concomitant liver disease

• Clinically significant hepatic decompensation, including patients with complications of cirrhosis/portal hypertension

• Medical conditions that may cause non-hepatic increases in ALP (e.g., Paget's disease) or which may diminish life expectancy to < 2 years, including known cancers

• Patient has a positive test for HIV Type 1 or 2 at screening, or patient is known to have tested positive for HIV

• Evidence of any other unstable or untreated clinically significant disease

• History of alcohol abuse

• For female patients: known pregnancy or lactating

• Use of fibrates and glitazones within 2 months prior to screening

• Use of OCA, azathioprine, cyclosporine, methotrexate, mycophenolate, pentoxifylline, budesonide and other systemic corticosteroids (parenteral and oral chronic administration only); potentially hepatotoxic drugs

• (including a-methyl-dopa, sodium valproic acid isoniazid, or nitrofurantoin) within 3 months prior to screening

• Use of antibodies or immunotherapy directed against interleukins (ILs) or other cytokines or chemokines within 12 months prior to screening

• For patients with previous exposure to obeticholic acid (OCA), OCA should be discontinued 3 months prior to screening

• Patients who are currently participating in, plan to participate in, or have participated in an investigational drug study or medical device study containing active substance within 30 days or five half-lives, whichever is longer, prior to screening; for patients with previous exposure to seladelpar, seladelpar should be discontinued 3 months prior to screening

• ALT and/or AST values > 5 x ULN

• For patients with AT or TB>ULN at SV1, variability of AT or TB > 40% (see section 3.5.1)

• Albumin<3.0 g/dl

• Severely advanced patients according to Rotterdam criteria (TB > ULN and albumin <LLN)

• INR > 1.3 due to altered hepatic function

• CPK > 2 x ULN

• Screening serum creatinine > 1.5 mg/dl

• Significant renal disease, including nephritic syndrome, chronic kidney disease (defined as patients with markers of kidney failure damage or eGFR < 60 mL/min/1,73 m2) calculated by MDRD

• Platelet count < 150 x 103/µL

• AFP > 20 ng/mL with 4-phase liver CT or MRI imaging suggesting presence of liver cancer

• Known hypersensitivity to the investigational product or to any of the formulation excipients of the elafibranor or placebo tablet Mental instability or incompetence, such that the validity of informed consent or ability to be compliant with the study is uncertain

Related Conditions & MeSH terms

• Cholangitis
• Liver Cirrhosis, Biliary
• Primary Biliary Cirrhosis

Intervention

Drug:
• Elafibranor 80mg
Elafibranor 80mg daily
• Placebo
Placebo daily for double blind period and elafibranor 80 mg daily fo the open label period.

Locations

Country	Name	City	State
Argentina	Hospital Alemán	Caba	Buenos Aires
Argentina	Hospital Británico de Buenos Aires	Caba	Buenos Aires
Argentina	Hospital Italiano de Buenos Aires	Caba	Buenos Aires
Argentina	Hospital Espanol De Mendoza	Godoy Cruz	Mendoza
Argentina	Hospital Italiano de La Plata	La Plata	Provincia De Buenos Aires
Argentina	Hospital Provincial del Centenario	Rosario	Santa Fe
Belgium	Hôpital Erasme	Brussels
Belgium	Antwerp University Hospital	Edegem
Belgium	Universitair Ziekenhuis Gent	Gent
Belgium	University Hospital Leuven	Leuven
Brazil	Hospital de Clínicas de Porto Alegre	Porto Alegre	Rio Grande Do Sul
Brazil	Hospital das Clinicas da Faculdade de Medicina da Universidade de Sao Paulo-HCFMUSP	São Paulo	Sao Paulo
Canada	University of Calgary Liver Unit - Heritage Medical Research Clinic (HMRC)	Calgary	Alberta
Canada	Centre de Recherche du Centre Hospitalier de l'Université de Montreal (CRCHUM)	Montréal
Canada	Gordon and Leslie Diamond Health Care Centre, Division of Gastroenterology	Vancouver	British Columbia
Canada	Shared Health Inc.-Operating as Health Sciences Centre-John Buhler Research Centre	Winnipeg	Manitoba
Chile	Hospital de La Serena	La Serena	Coquimbo
Chile	Centro de Investigacion Clinica Universidad Catolica CICUC	Santiago
Chile	Clínica Universidad de los Andes	Santiago
Chile	Hospital Clínico Universidad de Chile	Santiago
Chile	Centro de Investigaciones Clinicas (CIC)	Viña Del Mar	Region De Valparaiso
France	CHU Amiens Picardie	Amiens
France	Hôpital Henri Mondor	Créteil
France	CHU Grenoble Alpes - Hôpital Albert Michallon	Grenoble
France	Centre Hospitalier Régional d'Orléans	Orléans
France	Hôpital Cochin	Paris
France	Hôpital Pitié-Salpétrière	Paris
France	Hôpital Saint-Antoine	Paris
France	Hôpital Haut Lévêque	Pessac
France	Hôpital Robert Debré - CHU de Reims	Reims
France	Hôpitaux Universitaires de Strasbourg - Hôpital de Hautepierre	Strasbourg
Germany	Charite - Universitätsmedizin Berlin- CVK - Medizinische Klinik	Berlin
Germany	Gastro - Sudien	Berlin
Germany	Universitätsklinikum Frankfurt	Frankfurt
Germany	Medizinische Hochschule Hannover	Hannover
Germany	Center for Gastroenterology and Hepatology (GHZ) Kiel	Kiel
Germany	EUGASTRO GmbH	Leipzig
Germany	Universitätsmedizin der Johannes Gutenberg-Universität Mainz	Mainz
Italy	Azienda Ospedaliero-Universitaria di Bologna Policlinico S. Orsola-Malpighi	Bologna
Italy	Azienda Ospedaliera San Paolo, Dipartimento di Scienza della Salute, UO Medicina VI e Pathologia e Gastroenterologia	Milano
Italy	Ospedale Civile di Baggiovara-Struttura Complessa di Medicina ad indririzzo Metabolico Nutrizionale	Modena	Località Baggiovara
Italy	ASST Monza - Ospedale San Gerardo, Gastroenterologia	Monza
Italy	Azienda Ospedale- Università degli Studi di Padova UOC Gastroenterologia	Padova
Italy	Azienda Ospedaliera Universitaria Policlinico P. Giaccone, UOC di Gastroenterologia-Dip.Medicina Interna e Specialistica	Palermo
South Africa	Groote Schuur Hospital, University of Cape Town - Clinical Research Centre	Cape Town	Western Cap
South Africa	Mediclinic Constantiaberg, North Suites	Cape Town
South Africa	Tiervlei Trial Centre	Cape Town	Western Cape
Spain	Hospital Clinic de Barcelona	Barcelona
Spain	Hospital Universitario Vall d'Hebron	Barcelona
Spain	Hospital General Universitario Gregorio Marañón	Madrid
Spain	Hospital Universitario La Paz	Madrid
Spain	Hospital Universitario Puerta de Hierro -Madrid	Madrid
Spain	Complexo Hospitalario Universitario de Pontevedra	Pontevedra
Spain	Hospital Universitario Donostia	San Sebastián
Spain	Hospital Universitario Marqués de Valdecilla	Santander
Spain	Hospital Universitario Virgen del Rocio	Sevilla
Switzerland	Inselspital, Universitätsspital Bern Universitätsklinik für Viszerale chirurgie und Medizin Hepatologie	Bern
Switzerland	Fondazione Epatocentro Ticino	Lugano
Turkey	Hacette Universitesi Hastenesi IC, Hastaliklari Anabilim Dali, Gastronenteroloji Bilim Dali, Mithapasa Cad. Hacettepe Mah.	Ankara
Turkey	Marmara Universitesi Pendik Egitim ve Arastirma Hastanesi, Gastroentoloji Bilim Dali	Istanbul	Pendik
Turkey	Ege Universitesi Tip Fakultesi Hastanesi	Izmir	Bornova
United Kingdom	Belfast Health and Social Care Trust-Royal Victoria Hospital	Belfast
United Kingdom	Frimley Health NHS Foundation Trust - Frimley Park Hospital	Camberley
United Kingdom	Cambridge University Hospitals NHS Foundation Trust - Addenbrookes Hospital	Cambridge
United Kingdom	Hull University Teaching Hospitals NHS Trust , Hull Royal Infirmary	Hull
United Kingdom	King's College Hospital. King's College NHS Foundation Trust	London
United Kingdom	The Newcastle upon Tyne Hospitals NHS Foundation Trust-Freeman Hospital	Newcastle-upon-Tyne	Newcastle
United Kingdom	Nottingham University Hospitals NHS Trust - Queen's Medical Centre (QMC)	Nottingham
United Kingdom	Plymouth Hospitals NHS Trust, Derriford Hospital	Plymouth
United States	Texas Clinical Research Institute, LLC	Arlington	Texas
United States	Digestive Healthcare of Georgia	Atlanta	Georgia
United States	University of Colorado Denver and Hospital	Aurora	Colorado
United States	Beth Israel Deaconess Medical Center (BIDMC)	Boston	Massachusetts
United States	Massachusetts General Hospital	Boston	Massachusetts
United States	The Institute for Liver Health	Chandler	Arizona
United States	Medical University of South Carolina- College of Medicine	Charleston	South Carolina
United States	University of Virginia Medical Center	Charlottesville	Virginia
United States	Consultants for Clinical Research	Cincinnati	Ohio
United States	University Hospitals Cleveland Medical Center	Cleveland	Ohio
United States	The Ohio State University Wexner Medical Center	Columbus	Ohio
United States	Liver Center of Texas, PLLC	Dallas	Texas
United States	The Liver Institute at Methodist Dallas Medical Center	Dallas	Texas
United States	The University of Texas Southwestern Medical Center-IDS Aston Pharmacy	Dallas	Texas
United States	Duke University Medical Center	Durham	North Carolina
United States	South Denver Gastroenterology, P.C.	Englewood	Colorado
United States	Texas Digestive Disease Consultants dba GI Alliance	Fort Worth	Texas
United States	Investigational Drug Service Pharmacy Penn State Milton S. Hershey Medical Center	Hershey	Pennsylvania
United States	Liver Associates of Texas, P.A.	Houston	Texas
United States	St. Luke's Health-Baylor St Luke's Medical center - Advanced Liver Therapies Research	Houston	Texas
United States	Carolinas Centre for Liver disease/ Atrium Health	Huntersville	North Carolina
United States	Encore Borland-Groover Clinical Research	Jacksonville	Florida
United States	University of Kansas Medical Center	Kansas City	Kansas
United States	Cedars-Sinai Medical Center	Los Angeles	California
United States	Keck Medical Center of USC	Los Angeles	California
United States	Ruane Clinical Research Group Inc.	Los Angeles	California
United States	Schiff Center for Liver Diseases/University of Miami	Miami	Florida
United States	Intermountain Medical Center - Transplant Services	Murray	Utah
United States	Vanderbilt Digestive Disease Center	Nashville	Tennessee
United States	Yale School of Medicine, Digestive Diseases	New Haven	Connecticut
United States	UPMC Center for Liver Diseases	New Hyde Park	New York
United States	Columbia University Medical Center - Center for Liver Disease and Transplantation	New York	New York
United States	NYU Langone Health / NYU Grossman School of Medicine	New York	New York
United States	The New York-Presbyterian Hospital, David H. Koch Center	New York	New York
United States	Maryview Hospital Inc, Bon Secours Liver Institute of Hampton Roads	Newport News	Virginia
United States	Henry Ford Health System	Novi	Michigan
United States	Thomas Jefferson University	Philadelphia	Pennsylvania
United States	Richmond Community Hospital LLC, Bon Secours Liver Institute of Richmond	Richmond	Virginia
United States	Virginia Commonwealth University Clinical Research Services Unit (CRSU)	Richmond	Virginia
United States	University of California, Davis Medical Center	Sacramento	California
United States	Saint Louis University	Saint Louis	Missouri
United States	University of Utah Hospital-Division of Gastroenterology, Hepatology, and Nutrition	Salt Lake City	Utah
United States	American Research Corporation	San Antonio	Texas
United States	California Pacific Medical Center - Sutter Pacific Medical Foundation	San Francisco	California
United States	Liver Institute Northwest	Seattle	Washington
United States	Gastro health & Nutrition-Victoria	Victoria	Texas

Sponsors (1)

Lead Sponsor	Collaborator
Ipsen

Countries where clinical trial is conducted

United States,  Argentina,  Belgium,  Brazil,  Canada,  Chile,  France,  Germany,  Italy,  South Africa,  Spain,  Switzerland,  Turkey,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Percentage of participants with response to treatment measured by the combination levels of Alkaline Phosphate Levels (ALP) and Total Bilirubin (TB)		At Week 52
Secondary	Percentage of participants who normalised ALP levels		At Week 52
Secondary	Change in pruritus from baseline in participants with baseline PBC Worst Itch NRS Score = 4		Through 52 weeks of treatment
Secondary	Change in pruritus from baseline in participants with baseline PBC Worst Itch NRS Score = 4		Through 24 weeks of treatment
Secondary	Change from baseline in ALP levels		At Week 4, 13, 26, 39 and Week 52 and up to a maximum of 6 years
Secondary	Percentage of participants with =10%, =20%, and =40% decrease from Baseline in ALP Levels		From baseline to Week 52 and up to a maximum of 6 years
Secondary	Percentage of Participants with response to treatment	Based on different biochemical response criteria	At Week 52 and up to a maximum of 6 years
Secondary	Change from baseline in PBC risk scores based on United Kingdom (UK)-PBC score.	the UK-PBC risk score estimates the risk that a patient with PBC will require liver transplantation within 5, 10 or 15 years. A high number is indicative of a worse prognosis.	At Week 52 and up to a maximum of 6 years
Secondary	Change from baseline in Global PBC Study Group (GLOBE) score	The GLOBE score is a prognostic tool used to identify patients with PBC who are at higher/lower risk of liver transplant or death. A high number is indicative of a worse prognosis.	At Week 52 and up to a maximum of 6 years
Secondary	Percentage of participants who normalised bilirubin levels		At Week 52 and up to a maximum of 6 years
Secondary	Percentage of participants who normalised albumin levels		At Week 52 and up to a maximum of 6 years
Secondary	Change from baseline in levels of aspartate aminotransferase (AST)		From baseline to Week 52 and up to a maximum of 6 years
Secondary	Change from baseline in levels of alanine aminotransferase (ALT )		From baseline to Week 52 and up to a maximum of 6 years
Secondary	Change from baseline in levels of gamma-glutamyl transferase (GGT)		From baseline to Week 52 and up to a maximum of 6 years
Secondary	Change from baseline in levels of 5'-nucleotidase (5' NT)		From baseline to Week 52 and up to a maximum of 6 years
Secondary	Change from baseline in levels of total and conjugated bilirubin		From baseline to Week 52 and up to a maximum of 6 years
Secondary	Change from baseline in levels of albumin		From baseline to Week 52 and up to a maximum of 6 years
Secondary	Change from baseline in international normalised ratio (INR)		From baseline to Week 52 and up to a maximum of 6 years
Secondary	Change from baseline in fractionated alkaline phosphatase (ALP)		From baseline to Week 52 and up to a maximum of 6 years
Secondary	Change from baseline in levels of high sensitivity C-reactive protein (hsCRP)		From baseline to Week 52 and up to a maximum of 6 years
Secondary	Change from baseline in levels of fibrinogen		From baseline to Week 52 and up to a maximum of 6 years
Secondary	Change from baseline in levels of haptoglobin		From baseline to Week 52 and up to a maximum of 6 years
Secondary	Change from baseline in levels of tumor necrosis factor-alpha (TNF-a)		From baseline to Week 52 and up to a maximum of 6 years
Secondary	Change from baseline in levels of immunoglobulin G (IgG)		From baseline to Week 52 and up to a maximum of 6 years
Secondary	Change from baseline in levels of immunoglobulin M (IgM)		From baseline to Week 52 and up to a maximum of 6 years
Secondary	Change from baseline in enhanced liver fibrosis (ELF) score		From baseline to Week 52 and up to a maximum of 6 years
Secondary	Change from baseline in levels of plasminogen activator inhibitor-1 (PAI-1)		From baseline to Week 52 and up to a maximum of 6 years
Secondary	Change from baseline in levels of transforming growth factor beta (TGF-ß)		From baseline to Week 52 and up to a maximum of 6 years
Secondary	Change from baseline in levels of cytokeratin-18 (CK-18) (M65 and M30)		From baseline to Week 52 and up to a maximum of 6 years
Secondary	Change from baseline in levels of Pro-C3		From baseline to Week 52 and up to a maximum of 6 years
Secondary	Change from baseline in liver stiffness as measured by Transient Elastography (TE)		From baseline to Week 52 and up to a maximum of 6 years
Secondary	Change from baseline in levels of total cholesterol (TC)		From baseline to Week 52 and up to a maximum of 6 years
Secondary	Change from baseline in levels of low density lipoprotein cholesterol (LDL-C)		From baseline to Week 52 and up to a maximum of 6 years
Secondary	Change from baseline in levels of high density lipoprotein cholesterol (HDL-C)		From baseline to Week 52 and up to a maximum of 6 years
Secondary	Change from baseline in calculated very low density lipoprotein cholesterol (VLDL-C)		From baseline to Week 52 and up to a maximum of 6 years
Secondary	Change from baseline in levels of triglycerides (TG)		From baseline to Week 52 and up to a maximum of 6 years
Secondary	Change from baseline in Fasting Plasma Glucose (FPG)		From baseline to Week 52 and up to a maximum of 6 years
Secondary	Change from baseline in levels of individual bile acids		From baseline to Week 52 and up to a maximum of 6 years
Secondary	Change from baseline in levels of 7-a-hydroxy-4-cholesten-3-one (C4)		From baseline to Week 52 and up to a maximum of 6 years
Secondary	Change from baseline in levels of fibroblast growth factor 19 (FGF19)		From baseline to Week 52 and up to a maximum of 6 years
Secondary	Percentage of participants with no worsening of pruritus	Measured by the PBC Worst Itch Numeric Rating Scale (NRS)	From baseline to week 52 and up to a maximum of 6 years
Secondary	Percentage of responders in PBC Worst Itch NRS	Defined as at least 30% reduction from baseline of NRS at week 52 in patients with a baseline NRS = 4	Baseline through 52 weeks and up to a maximum of 6 years
Secondary	Change from baseline in 5D-Itch	Change from baseline in symptoms in terms of 5 domains: degree, duration, direction, disability and distribution.; Patients rate their symptoms over the preceding 2-week period on a 1 to 5 scale, with 5 being the most affected	From baseline to Week 52 and up to a maximum of 6 years
Secondary	Change from baseline in Patient-Reported Outcomes Measurement Information System (PROMIS) Fatigue Short Form 7a	Change from baseline in assessing seven items that measure both the experience of fatigue and the interference of fatigue on daily activities over the past week	From baseline to Week 52 and up to a maximum of 6 years
Secondary	Change from baseline in Epworth Sleepiness Scale (ESS)	Change from baseline in ESS that assesses eight questions asking to rate how likely it is to fall asleep in everyday situations (each question can be scored from 0 to 3 points; '0' indicates no sleepiness, '3' indicates significant sleepiness).It provides a total score which has been shown to relate to the patient's level of daytime sleepiness (total score range 0-24 points).	From baseline to Week 52 and up to a maximum of 6 years
Secondary	Change from baseline in PBC-40	Assesses symptoms across six domains: fatigue, emotional and social, cognitive function, general symptoms and itch. Patients respond on a verbal response scale, depending on the section options range from 'never' / 'not at all' / 'strongly disagree' to 'always' / 'very much'/ 'strongly agree'.; Five items (3/3 in the itch domain and 2/10 in the social domain) also include a 'does not apply' option. A score for each domain is provided (but a total score is not calculated), with each verbal response scale correlating to a score of 1-5 per item (0-5 on items with a 'does not apply' option) with 5 being the most affected. The PBC-40 has a 4-week recall period.	From baseline to Week 52 and up to a maximum of 6 years
Secondary	Change from baseline in health utility	Measured by Euro quality of life (EQ-5D-5L), a 6-item, standardized questionnaire that assesses mobility, self-care, usual activities, pain / discomfort, anxiety / depression, and overall health state	From baseline to Week 52 and up to a maximum of 6 years
Secondary	Change from baseline in levels of type I collagen N-telopeptides (CTXI)		From baseline to Week 52 and up to a maximum of 6 years
Secondary	Change from baseline in levels of procollagen 1 N-terminal propeptide (P1NP)		From baseline to Week 52 and up to a maximum of 6 years
Secondary	Change from baseline in bone mineral density (hip and lumbar) as assessed by DEXA scanning		From baseline to Week 52 and up to a maximum of 6 years
Secondary	Percentage of patients with onset of clinical outcomes		From baseline to Week 52 and up to a maximum of 6 years
Secondary	Number of participants experiencing Adverse Events (AEs), Serious Adverse Events (SAEs) and Adverse Events of Special Interest (AESIs).	An Adverse event (AE) is any untoward medical occurrence, temporally associated with the use of study intervention, whether or not related to the study intervention. AESIs are AEs that may not be serious but are of special importance to a particular drug or class of drugs.	From baseline to Week 52 and up to a maximum of 6 years
Secondary	Number of participants with clinically significant changes in physical examination	Percentage of participants with clinically significant changes in physical examination will be reported. The clinical significance will be graded by the investigator.	From baseline to Week 52 and up to a maximum of 6 years
Secondary	Number of participants with clinically significant Changes in vital signs	Percentage of participants with clinically significant changes in Vital Signs will be reported. The clinical significance will be graded by the investigator.	From baseline to Week 52 and up to a maximum of 6 years
Secondary	Number of participants with clinically significant changes in electrocardiogram (ECG)	Percentage of participants with clinically significant changes in ECG readings will be reported. The clinical significance will be graded by the investigator.	From baseline to Week 52 and up to a maximum of 6 years
Secondary	Number of participants with clinically significant changes in laboratory parameters (blood chemistry and hematology)	Percentage of participants with clinically significant change in laboratory parameters (blood chemistry, hematology and coagulation) will be reported. The clinical significance will be graded by the investigator.	From baseline to Week 52 and up to a maximum of 6 years
Secondary	Number of Participants With Clinically Significant Changes in liver markers		From baseline to Week 52 and up to a maximum of 6 years
Secondary	Number of Participants With Clinically Significant Changes in Renal biomarkers (including urinalysis)		From baseline to Week 52 and up to a maximum of 6 years
Secondary	Number of Participants With Clinically Significant Changes in other biochemical safety markers (e.g. urinary myoglobin)		From baseline to Week 52 and up to a maximum of 6 years
Secondary	Area Under Curve steady state (AUCss) of study drug		After 4 weeks of treatment during the double-blind period
Secondary	Pharmacokinetic (PK) Parameter: Clearance (CL) of study drug	Clearance (CL) is defined as the systemic clearance of the drug following oral administration.	After 4 weeks of treatment during the double-blind period
Secondary	Pharmacokinetic (PK) Parameter: Vz of study drug	Vz is defined as the volume of distribution of the drug after oral administration.	After 4 weeks of treatment during the double-blind period