Clinical trial NCT05011305: Saroglitazar Magnesium for the Treatment of Nonalcoholic Steatohepatitis with Fibrosis
Official title: A Phase 2b, Prospective, Multicenter, Randomized, Double-blind, Placebo-controlled Study to Evaluate Efficacy and Safety of Saroglitazar Magnesium in Subjects with Nonalcoholic Steatohepatitis and Fibrosis
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE2
Conditions: Nonalcoholic Steatohepatitis
Fibrosis
Keywords: Saroglitazar Magnesium
Nonalcoholic Steatohepatitis
NASH
Fibrosis
Lead sponsor: Zydus Therapeutics Inc.
Sponsor class: INDUSTRY
First posted: 2021-08-18
Enrollment: 180
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: 180 subjects randomized in a 1:1:1 ratio to Saroglitazar 2 mg, Saroglitazar 4 mg or Placebo.
Primary purpose: TREATMENT

Brief summary: Saroglitazar Magnesium for the Treatment of Nonalcoholic Steatohepatitis

Detailed description: A Phase 2b, Prospective, Multicenter, Randomized, Double-blind, Placebo-controlled Study to Evaluate Efficacy and Safety of Saroglitazar Magnesium in Subjects with Nonalcoholic Steatohepatitis and Fibrosis.

Eligibility criteria: Inclusion Criteria:

* Males or females, between 18 and 75 years of age, both inclusive at screening.
* BMI ≤45 kg/m²
* Histological confirmation of NASH with liver fibrosis by central pathologist on a diagnostic liver biopsy with a NAS ≥4 with at least one-point score in each of the three components of the NAFLD activity score \[NAS\] (steatosis scored 0-3, ballooning degeneration scored 0-2, and lobular inflammation scored 0-3) and NASH by pattern recognition Note: The biopsy must not have been performed more than 24 weeks before randomization.
* The subjects must have a stable body weight (no more than 5% change) between the time of biopsy and randomization.
* Fibrosis stage 2 and 3, according to the NASH CRN fibrosis staging, reported by central pathologist.
* If the subjects have type 2 diabetes mellitus, then it must be moderately controlled with HbA1c ≤ 9.5% and on a stable dose of permitted anti-diabetic medication for at least 90 days before screening until randomization.
* If the subjects are taking vitamin E \> 400 IU/day, then it must be on a stable dose for at least 24 weeks prior to screening or, if a historical biopsy is used, at least 24 weeks prior to baseline liver biopsy until randomization.
* Must provide written informed consent and agree to comply with the trial protocol.

Exclusion Criteria:

* Consumption of \>2 units of alcohol per day (\>14 units per week) if male and \>1 units of alcohol per day (\>7 units per week) if female for at least 12 consecutive weeks within 5 years before screening (Note: 1 unit = 12 ounces of beer, 4 ounces of wine or 1 ounce of spirits/hard liquor)
* History or presence of other concomitant liver diseases at screening:

  1. Chronic hepatitis B (HBV) or hepatitis C virus (HCV) infection (However, If the subject has been treated for the HCV infection and has been cured at least 5 years from screening, such subjects can be enrolled in the study)
  2. Primary biliary cholangitis (PBC)
  3. Primary sclerosing cholangitis (PSC)
  4. Definite autoimmune liver disease or overlap syndrome
  5. Alcoholic liver disease
  6. Hemochromatosis
  7. Wilsons disease
  8. Alpha-1 antitrypsin deficiency
* Subject with known cirrhosis, either based on histology, clinical criteria or any non-invasive diagnostic modality, within 24 weeks prior to the randomization.
* Evidence of portal hypertension (low platelet count, esophageal varices, ascites, history of hepatic encephalopathy, splenomegaly) at screening.
* Treatment with glucagon-like peptide-1 receptor agonists (GLP-1RAs), sodium glucose cotransporter- 2 (SGLT-2) inhibitors, and dipeptidyl peptidase 4 inhibitors (gliptins) unless stable for 120 days prior to screening or, if a historical biopsy is used, from 120 days prior to baseline liver biopsy until randomization.
* Use of concurrent medications prior to screening including:

  1. Anti-NASH therapy(s) including S-adenosyl methionine (SAMe), ursodeoxycholic acid (UDCA), and obeticholic acid in the period from 90 days prior to screening or, if a historical biopsy is used, from 90 days prior to baseline liver biopsy until randomization. For resmetirom; 120 days prior to screening or if a historical biopsy is used, from 120 days prior to baseline liver biopsy until randomization.
  2. Antidiabetic mediation which may impact NASH histology including thiazolidinediones (pioglitazone, rosiglitazone) in the period from 90 days prior to screening or, if a historical biopsy is used, from 90 days prior to baseline liver biopsy until randomization.
  3. Immune modulatory agents including anti-TNF-α therapies (infliximab, adalimumab, etanercept) or anti-integrin therapy (namixilab) in the period from 28 days prior to screening or if a historical biopsy is used from 28 days prior to baseline liver biopsy until randomization.
  4. Any treatment or anticipated initiation (intended use for more than 14 consecutive days) of medications known to have an effect on steatosis (e.g. treatment with corticosteroids \[topical and inhaled are allowed\]), methotrexate, tamoxifen, valproic acid, amiodarone or tetracycline, estrogens in doses higher than used in oral contraceptives, vitamin A, L-asparaginase, valproate, chloroquine, or antiretroviral drugs in the period from 28 days prior to screening or, if a historical biopsy is used, from 28 days prior to baseline liver biopsy until randomization.
  5. Treatment with orlistat, zonisamide, topiramate, phentermine, lorcaserin, bupropion, or naltrexone alone, or in combination or any other medication, that could promote weight loss, in the opinion of the investigator, in the period from 28 days prior to screening or if a historical biopsy is used from 28 days prior to baseline liver biopsy until randomization.
* Changing doses of statins (simvastatin, pitavastatin, pravastatin, atorvastatin, fluvastatin, lovastatin, rosuvastatin) or fibrates (clofibrate, Fenofibrate) in the 90 days preceding screening until randomization.
* Use of drugs that are known CYP2C8 inhibitors/substrate in the 28 days preceding screening until randomization.
* History of liver transplant
* Any weight reduction surgery in the 2 years prior to screening or planned during the study (weight reduction surgery is disallowed during the study), and malabsorptive weight loss surgery (Rouxen-Y or distal gastric bypass) at any time prior to screening.

Note: Lap banding, if the band has been removed \>6 months before baseline liver biopsy, or intragastric balloon, if the balloon has been removed \> 6 months before baseline liver biopsy, is allowed.

* Type 1 diabetes mellitus
* History of stomach or intestinal surgery or resection within the six months prior to screening that would potentially alter absorption and/or excretion of orally administered drugs as judged by the investigator.
* Unstable cardiovascular disease, including:

  1. unstable angina, (i.e., new or worsening symptoms of coronary heart disease) in the 90 days before screening and throughout the screening period; acute coronary syndrome in the 24 weeks before screening and throughout the screening period;
  2. acute myocardial infarction in the 90 days before screening and throughout the screening period; or heart failure of New York Heart Association class (III - IV), worsening congestive heart failure, or coronary artery intervention, in the 24 weeks before screening and throughout the screening period.
  3. history of unstable cardiac dysrhythmias
  4. uncontrolled hypertension at screening
  5. stroke or transient ischemic attack in the 24 weeks before screening
* History of myopathies or evidence of active muscle disease demonstrated by CPK ≥ 5 times ULN at screening.
* For subjects with elevated baseline ALT, AST, or ALP; ALT, AST, or ALP exceeding by more than 50% at Visit 2 reading compared to Visit 1 Note: If the ALT, AST or ALP values at Visit 2 exceed by more than 50% from Visit 1, then a third value will be measured to assess for the trend. If the third value shows continued increase ≥ 10%, then subject is considered ineligible for randomization.
* Any of the following laboratory values at screening:

  1. Hemoglobin \<9 g/dL
  2. WBC count \<2.5 × 103/µL
  3. Neutrophil count \<1.5 × 103/µL
  4. Platelets \<140 × 103/µL \[if low platelet count is due to reasons other than liver disease as assessed by a hematologist, participants may be eligible if the platelet count is \> 75 x 103/µL\] as per investigator's discretion\]
  5. INR ≥ 1.3 (in the absence of anticoagulants)
  6. Total bilirubin \> ULN except in Gilbert's syndrome. In subjects with known Gilbert's syndrome, direct bilirubin \> 2 x ULN
  7. Albumin \<3.5 g/dL
  8. eGFR \<60 mL/min/1.73 m2
  9. ALP ≥ 2x ULN
  10. ALT or AST ≥ 250 U/L
* Participation in any other therapeutic clinical study and on active treatment in the past 90 days of the screening.
* History of benign or malignant bladder tumors, and/or hematuria or has current hematuria except due to a urinary tract infection.
* History of malignancy in the past 5 years and/or active neoplasm with the exception of resolved superficial nonmelanoma skin cancer.
* Known allergy, sensitivity or intolerance to the study drug, comparator or formulation ingredients.
* Pregnancy-related exclusions, including:

  1. Pregnant/lactating female (including positive pregnancy test at screening)
  2. Pregnancy should be avoided by male and female participants 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
* 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)
* Receiving an elemental diet or parenteral nutrition.
* Chronic pancreatitis or pancreatic insufficiency.

Primary outcomes:
measure: Resolution of steatohepatitis with no worsening of fibrosis
timeFrame: 52 Weeks/EOT
Secondary outcomes:
measure: Improvement in liver fibrosis with no increase in NAS for ballooning, inflammation or steatosis
timeFrame: Week 52/EOT
measure: 2 points improvement in NAS
timeFrame: Week 52/EOT
measure: Improvement in steatosis, ballooning, inflammation and fibrosis from liver biopsy
timeFrame: Week 52/EOT
measure: Decrease in SAF score on liver biopsy
timeFrame: Week 52/EOT
measure: Histological score changes in steatosis, ballooning, inflammation, and fibrosis
timeFrame: Week 52/EOT
measure: Change in liver enzyme parameters including (ALT, AST, ALP, GGT, total bilirubin, albumin)
timeFrame: Week 52/EOT
measure: Change in non-invasive markers of steatosis
timeFrame: Week 52/EOT
measure: Change in n lipid parameters including (TG, LDLC, TC, HDL-C, non-HDL-C, VLDL-C
timeFrame: Week 52/EOT
measure: Change in body weight (any change from baseline)
timeFrame: Week 52/EOT
measure: Change in insulin resistance marker, HOMA-IR
timeFrame: Week 52/EOT
measure: Change in inflammatory markers including (CK-18 [M30], IL-6, CRP)
timeFrame: Week 52/EOT
measure: Change in glucose homeostasis markers including (HbA1c, FPG)
timeFrame: Week 52/EOT
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: Zydus US032
state: Alabama
city: Homewood
country: United States
facility: Zydus US079
state: Alabama
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state: Arizona
city: Phoenix
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state: Arizona
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state: Arizona
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state: Arizona
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city: Chula Vista
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state: California
city: Fresno
country: United States
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state: California
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state: California
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state: California
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country: United States
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state: California
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state: California
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country: United States
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state: California
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country: United States
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state: California
city: Rancho Cucamonga
country: United States
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state: California
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country: United States
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state: California
city: Aurora
country: United States
facility: Zydus US039
state: Colorado
city: Aventura
country: United States
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state: Florida
city: Clearwater
country: United States
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state: Florida
city: Fort Myers
country: United States
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state: Florida
city: Hallandale Beach
country: United States
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state: Florida
city: Hialeah Gardens
country: United States
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state: Florida
city: Lakeland
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state: Florida
city: Lakewood Ranch
country: United States
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state: Florida
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state: Florida
city: Maitland
country: United States
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state: Florida
city: Maitland
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state: Florida
city: Miami Lakes
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state: Georgia
city: Gainesville
country: United States
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city: Savannah
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country: United States
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state: Indiana
city: West Des Moines
country: United States
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state: Iowa
city: Kansas City
country: United States
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city: Houma
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city: Marrero
country: United States
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city: New Orleans
country: United States
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city: West Monroe
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city: Bethesda
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city: Boston
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city: Burlington
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city: Wyoming
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city: Columbia
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city: Charlotte
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city: Cincinnati
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city: Charleston
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state: Tennessee
city: Nashville
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city: Austin
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city: San Antonio
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state: Texas
city: San Antonio
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state: Texas
city: San Antonio
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state: Texas
city: San Antonio
country: United States
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state: Texas
city: San Antonio
country: United States
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state: Texas
city: San Antonio
country: United States
facility: Zydus US008
state: Texas
city: Waco
country: United States
facility: Zydus US058
state: Texas
city: Waco
country: United States
facility: Zydus US078
state: Texas
city: Wichita Falls
country: United States
facility: Zydus US076
state: Texas
city: Ogden
country: United States
facility: Zydus US088
state: Utah
city: Manassas
country: United States
facility: Zydus US070
state: Virginia
city: Richmond
country: United States
facility: Zydus US082
state: Virginia
city: Richmond
country: United States
facility: Zydus US021
state: Virginia
city: Seattle
country: United States
facility: Zydus US044
state: Washington
city: Seattle
country: United States
facility: Zydus US033
state: Washington
city: Buenos Aires
country: Argentina
facility: Zydus AR004
city: Caba
country: Argentina
facility: Zydus AR001
city: Caba
country: Argentina
facility: Zydus AR013
city: Caba
country: Argentina
facility: Zydus AR007
city: Caba
country: Argentina
facility: Zydus AR006
city: Caba
country: Argentina
facility: Zydus AR005
city: Caba
country: Argentina
facility: Zydus AR008
city: Caba
country: Argentina
facility: Zydus AR012
city: Caba
country: Argentina
facility: Zydus AR003
city: Mar Del Plata
country: Argentina
facility: Zydus AR009
city: Mar Del Plata
country: Argentina
facility: Zydus AR011
city: Ramos Mejía
country: Argentina
facility: Zydus AR002
city: Rosario
country: Argentina
facility: Zydus AR010
city: San Juan
country: Puerto Rico
facility: Zydus US097
city: Adana
country: Turkey
facility: Zydus TR003
city: Ankara
country: Turkey
facility: Zydus TR002
city: Ankara
country: Turkey
facility: Zydus TR001
city: Bursa
country: Turkey
facility: Zydus TR004
city: Gaziantep
country: Turkey
facility: Zydus TR005
city: Istanbul
country: Turkey
facility: Zydus TR009
city: Istanbul
country: Turkey
facility: Zydus TR008
city: İzmir
country: Turkey
facility: Zydus TR007
city: İzmir
country: Turkey
facility: Zydus TR006
city: Kayseri
country: Turkey
facility: Zydus TR011
city: Kocaeli
country: Turkey
facility: Zydus TR010
city: Mersin
country: Turkey
facility: Zydus TR012
city: Rize
country: Turkey
facility: Zydus TR013
city: Trabzon
country: Turkey
facility: Zydus TR014
Study officials:
affiliation: Zydus Therapeutics Inc.
name: Deven V. Parmar, MD, FCP
role: STUDY_DIRECTOR
References: