Clinical trial NCT05133336: Saroglitazar Magnesium for Treatment of Primary Biliary Cholangitis
Official title: A Multicenter, Randomized, Double-blind, Placebo Controlled, Phase 2b/3 Study to Evaluate the Efficacy and Safety of Saroglitazar Magnesium in Subjects With Primary Biliary Cholangitis
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
PHASE3
Conditions: Primary Biliary Cholangitis
Keywords: Saroglitazar Magnesium
Primary Biliary Cholangitis
PBC
Lead sponsor: Zydus Therapeutics Inc.
Sponsor class: INDUSTRY
First posted: 2021-11-24
Enrollment: 196
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Multicenter, Randomized, Double-blind, Placebo controlled, Phase 2b/3 Safety and Efficacy Study . Initially, 192 subjects (64 subjects in each treatment arm) were planned be randomised in a ratio of 1:1:1 in Saroglitazar Magnesium 1 mg, Saroglitazar Magnesium 2 mg, and Placebo arm, respectively. After an optimal dose selection, the subjects are randomised in 2:1 ratio of Saroglitazar Magnesium 1 mg or placebo. There would be approximately 140 evaluable subjects (90 of Saroglitazar 1 mg and 50 of placebo arm)
Primary purpose: TREATMENT

Brief summary: Saroglitazar Magnesium 1 mg and 2 mg tablets for treatment of subjects with Primary Biliary Cholangitis (PBC)

Detailed description: A Multicenter, Randomized, Double-blind, Placebo controlled, Phase 2b/3 Study to Evaluate the Efficacy and Safety of Saroglitazar Magnesium in Subjects with Primary Biliary Cholangitis

Eligibility criteria: Inclusion Criteria:

1. Males or females, between 18 and 75 years of age, both inclusive at screening.
2. Subjects on ursodeoxycholic acid (UDCA) for at least 12 months at a therapeutic dose (at least 13 mg/kg per day) and a stable dose for 6 months prior to Screening Visit and having ALP ≥ 1.67 x ULN.

   OR Subjects who are unable to tolerate UDCA and did not receive UDCA for at least 3 months prior to the date of screening and having ALP ≥ 1.67 x ULN.
3. History of confirmed PBC diagnosis, based on American Association for the Study of Liver Disease \[AASLD\] and European Association for Study of the Liver \[EASL\] Practice Guidelines, as demonstrated by the presence of at least ≥ 2 of the following 3 diagnostic factors:

   * History of elevated ALP levels for at least 6 months prior to screening
   * Positive anti-mitochondrial antibodies (AMA) titer OR positive PBC specific antibodies (anti-GP210 and/or anti-SP100 and/or antibodies against the major M2 components \[PDC-E2, 2-oxo-glutaric acid dehydrogenase complex\]) if AMA is negative
   * Liver biopsy consistent with PBC
4. ALP ≥ 1.67 x ULN at both Visits 1 and 2 and \< 30% variance between the levels from Visit 1 to Visit 2
5. Total bilirubin \< 2 x ULN at screening (Visit 1)
6. Must provide written informed consent and agree to comply with the trial protocol.

Exclusion Criteria:

1. Consumption of 2 standard alcohol drinks per day if male and 1 standard alcohol drink per day if female for at least 3 consecutive months (12 consecutive weeks) within 5 year before screening (Note: 1 unit = 12 ounces of beer, 4 ounces of wine or 1 ounce of spirits/hard liquor).
2. History or presence of other concomitant liver diseases at screening:

   1. Chronic hepatitis B or C virus (HBV, HCV) infection. (Note: However, If the subject has been treated for the HCV infection and has been cured for a duration of more than 2 years from screening, such subjects can be enrolled in the study)
   2. Primary sclerosing cholangitis (PSC).
   3. Alcoholic liver disease.
   4. Autoimmune hepatitis (AIH) indicative of PBC with overlap syndrome.

Note: The Paris criteria are commonly used to define the presence of PBC with features of AIH and have been endorsed by EASL and AASLD. According to these criteria, a diagnosis can be made in a patient with PBC as follows:

At least two of the following:

I. ALP \> 2 x ULN or GGT \> 5 x ULN. II. AMA positive III. Florid bile duct lesion on histology. AND

At least two of the following three features:

I. ALT \> 5 x ULN. II. Immunoglobulin G serum levels \> 2 x ULN or smooth muscle autoantibody positive.

III. Moderate to severe interface hepatitis on histology. e. Hemochromatosis. f. Non-alcoholic steatohepatitis (NASH) on historical biopsy. 3.Cirrhosis with complications, including history or presence of: spontaneous bacterial peritonitis, hepatocellular carcinoma, ascites requiring treatment, encephalopathy, known large esophageal varices or history of variceal bleeding within one year prior to screening or history of hepatorenal syndrome.

5.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.

6.Use of thiazolidinediones or fibrates (within 12 weeks prior to screening). 7.Use of obeticholic acid (OCA), azathioprine, cyclosporine, methotrexate, mycophenolate, pentoxifylline, budesonide and other systemic corticosteroids (Note: Prednisone dose should not be more than 10 mg per day); potentially hepatotoxic drugs (including α-methyl-dopa, sodium valproic acid, isoniazid, or nitrofurantoin) (within 12 weeks prior to screening).

9.History of bowel surgery (gastrointestinal \[bariatric\] surgery in the preceding 1 year or undergoing evaluation for gastrointestinal surgery (bariatric surgery for obesity, extensive small-bowel resection) or orthotopic liver transplant (OLT) or listed for OLT.

10.Type 1 diabetes mellitus. 11.Unstable cardiovascular disease, including:

a. Unstable angina, (i.e., new or worsening symptoms of coronary heart disease in the 12 weeks before screening and throughout the Screening Period), acute coronary syndrome in the 24 weeks before screening and throughout the Screening Period, acute myocardial infarction in the 12 weeks before screening and throughout the Screening Period or heart failure of New York Heart Association class (III - IV) or worsening congestive heart failure, or coronary artery intervention, in the 24 weeks before screening and throughout the Screening Period.

b. History/current unstable cardiac dysrhythmias. c. Uncontrolled hypertension at screening. d. Stroke or transient ischemic attack in the 24 weeks before screening. 12.History of intracranial hemorrhage, arteriovenous malformation, bleeding disorder, coagulation disorders, or screening blood tests that, in the opinion of the Investigator, indicate altered coagulability (e.g., PT, INR, aPTT) at screening.

13.An uncontrolled thyroid disorder

1. Uncontrolled hyperthyroidism: defined as any history of hyperthyroidism that has either not been treated with either radioactive iodine and/or surgery or that has been treated with radioactive iodine and/or surgery, but has required ongoing continuous or intermittent use of thyroid hormone synthesis inhibitors (i.e., methimazole or propylthiouracil) in the 24 weeks before screening.
2. Uncontrolled hypothyroidism: defined as initiation of thyroid hormone replacement therapy or dose adjustment of replacement therapy in the 12 weeks before screening.

   14.History of myopathies or evidence of active muscle disease demonstrated by CPK ≥ 5 x ULN at screening.

   15.Subjects whose ALT, AST, or ALP exceeds by more than 50% on Visit 2 reading compared to Visit 1. Note: If the ALT, AST, or ALP values on Visit 2 exceed by more than 50% from Visit 1, then a third value will be measured (within 1- 2 weeks) to assess for the trend. If the third value shows continued increase ≥ 10%, then subject is considered ineligible for randomization.

   16.Any of the following laboratory values at screening:

a. Platelets \< 50 × 109/L b. Albumin \< 2.8 g/dL c. eGFR \< 45 mL/min/1.73 m2 d. ALP \> 10 x ULN e. ALT or AST \> 250 U/L 17.Participation in another interventional clinical study and receipt of any other investigational medication (within 12 weeks prior to randomization up to end of study).

18.History of malignancy in the past 5 years and/or active neoplasm with the exception of resolved superficial non-melanoma skin cancer.

19.Contraindications to Saroglitazar Magnesium or has any conditions affecting the ability to evaluate the effects of Saroglitazar Magnesium.

20.Known allergy, sensitivity, or intolerance to the study drug, comparator, or formulation ingredients.

21.Pregnancy-related exclusions, including:

a. Pregnant/lactating female (including positive pregnancy test at screening). b. Pregnancy should be avoided by male and female subjects either by true abstinence or the use of an acceptable effective contraceptive measures for the duration of the study and for at least 1 month after the end of the study treatment. Refer Appendix 8 Contraceptive Guidance 22.History or other evidence of severe illness or any other conditions that would make the subject, in the opinion of the Investigator, unsuitable for the study (such as poorly controlled psychiatric disease, HIV, coronary artery disease, or active gastrointestinal conditions that might interfere with drug absorption).

23.Cirrhosis with Child-Pugh-Turcotte (CPT) Class B or C having score of 7 or above at screening 24.Subjects with Model for End Stage Liver Disease (MELD 3.0) score of 12 or above

Primary outcomes:
measure: Proportion of subjects with biochemical response based on the composite endpoints of ALP and total bilirubin
timeFrame: From baseline to week 52
Secondary outcomes:
measure: Proportion of subjects with complete normalization of ALP.
timeFrame: From baseline to week 52
measure: Pruritis assessed by 5 D itch scales
timeFrame: From baseline to Week 24 and Week 52
measure: Proportion of subjects with biochemical response based on the composite endpoints of ALP and total bilirubin
timeFrame: From baseline to Weeks 4, 8, 16, and 24.
measure: Proportion of subjects change from baseline in ALP
timeFrame: From baseline to Weeks 24 and 52.
measure: Quality of life assessed by the PBC 40 questionnaire
timeFrame: From baseline to Weeks 16, 24, and 52.
measure: Improvement in liver stiffness measurement (LSM) of at least 25% relative to baseline assessed by Liver elastography/FibroScan®
timeFrame: From baseline to Weeks 24 and Week 52
measure: To effect on liver enzymes
timeFrame: From baseline at Weeks 16, 24, and 52.
measure: The effect on liver enzymes
timeFrame: From baseline to week 24 and week 52
measure: The effect on lipid parameters
timeFrame: From baseline to weeks 24 and 52
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: Zydus US007
state: Alabama
city: Tucson
country: United States
facility: Zydus US021
state: Arizona
city: Los Angeles
country: United States
facility: Zydus US013
state: California
city: Pasadena
country: United States
facility: Zydus US011
state: California
city: Sacramento
country: United States
facility: Zydus US043
state: California
city: Aurora
country: United States
facility: Zydus US022
state: Colorado
city: New Haven
country: United States
facility: Zydus US037
state: Connecticut
city: Jacksonville
country: United States
facility: Zydus US027
state: Florida
city: Lakewood Ranch
country: United States
facility: Zydus US006
state: Florida
city: Miami
country: United States
facility: Zydus US005
state: Florida
city: Sarasota
country: United States
facility: Zydus US028
state: Florida
city: Tampa
country: United States
facility: Zydus US019
state: Florida
city: Marietta
country: United States
facility: Zydus US020
state: Georgia
city: Indianapolis
country: United States
facility: Zydus US001
state: Indiana
city: Iowa City
country: United States
facility: Zydus US034
state: Iowa
city: Marrero
country: United States
facility: Zydus US036
state: Louisiana
city: Rochester
country: United States
facility: Zydus US023
state: Minnesota
city: Saint Louis
country: United States
facility: Zydus US030
state: Missouri
city: Omaha
country: United States
facility: Zydus US024
state: Nebraska
city: Manhasset
country: United States
facility: Zydus US038
state: New York
city: Rochester
country: United States
facility: Zydus US035
state: New York
city: Charlotte
country: United States
facility: Zydus US002
state: North Carolina
city: Cincinnati
country: United States
facility: Zydus US014
state: Ohio
city: Philadelphia
country: United States
facility: Zydus US015
state: Pennsylvania
city: Houston
country: United States
facility: Zydus US004
state: Texas
city: Houston
country: United States
facility: Zydus US042
state: Texas
city: Murray
country: United States
facility: Zydus US031
state: Utah
city: Charlottesville
country: United States
facility: Zydus US016
state: Virginia
city: Newport News
country: United States
facility: Zydus US041
state: Virginia
city: Richmond
country: United States
facility: Zydus US039
state: Virginia
city: Seattle
country: United States
facility: Zydus US033
state: Washington
city: Buenos Aires
country: Argentina
facility: Zydus AR004
city: Buenos Aires
country: Argentina
facility: Zydus AR009
city: Buenos Aires
country: Argentina
facility: Zydus AR001
city: Buenos Aires
country: Argentina
facility: Zydus AR005
city: Buenos Aires
country: Argentina
facility: Zydus AR013
city: Buenos Aires
country: Argentina
facility: Zydus AR007
city: Buenos Aires
country: Argentina
facility: Zydus AR006
city: Buenos Aires
country: Argentina
facility: Zydus AR012
city: Buenos Aires
country: Argentina
facility: Zydus AR003
city: Santa Fe
country: Argentina
facility: Zydus AR010
city: Reykjavik
country: Iceland
facility: Zydus IS001
city: Adana
country: Turkey
facility: Zydus TR014
city: Altındag
country: Turkey
facility: Zydus TR016
city: Ankara
country: Turkey
facility: Zydus TR004
city: Bursa
country: Turkey
facility: Zydus TR005
city: Cebeci
country: Turkey
facility: Zydus TR017
city: Gaziantep
country: Turkey
facility: Zydus TR008
city: Istanbul
country: Turkey
facility: Zydus TR009
city: Istanbul
country: Turkey
facility: Zydus TR010
city: Istanbul
country: Turkey
facility: Zydus TR003
city: Istanbul
country: Turkey
facility: Zydus TR001
city: Izmir
country: Turkey
facility: Zydus TR002
city: Izmir
country: Turkey
facility: Zydus TR013
city: Kocaeli
country: Turkey
facility: Zydus TR011
city: Melikgazi
country: Turkey
facility: Zydus TR015
city: Mersin
country: Turkey
facility: Zydus TR006
Study officials:
affiliation: Zydus Therapeutics Inc.
name: Deven V Parmar, MD
role: STUDY_DIRECTOR
References: