Ensayos clínicos

Inclusion Criteria:

• Signed written informed consent:
  • Participants must be willing to participate in the study and sign the informed consent form(s) (ICF[s]);
  • Participants (and caregivers as applicable) must be willing and able to complete all study-specific procedures and visits.
• Liver biopsy performed within 6 months (26 weeks) prior to the Screening Period.  Biopsy performed prior to ICF must be available to the central reader prior to randomization. If historical biopsy is not available, a liver biopsy will be performed during the Screening Period. Biopsy must be consistent with NASH, with:
  • A score of at least 1 for each NAS component (steatosis, lobular inflammation, and ballooning), as assessed by the central reader; AND
  • Stage 3 liver fibrosis according to the NASH CRN classification, as assessed by the central reader.
• Participants taking anti-diabetic, anti-obesity, or anti-dyslipidemic medications must have been on stable regimens for at least 3 months (12 weeks) (6 weeks for statins) prior to and during the Screening Period. The investigator may contact the medical monitor regarding the stability of a participant's regimen when determining eligibility for study participation. Participants taking vitamin E at doses ≥800 IU/day must have been on stable doses for at least 6 months (26 weeks) prior to and during the Screening Period.  Vitamin E treatment (≥800 IU/day) must not have been initiated after the qualifying liver biopsy was performed.
• Age and reproductive status:
  • Men or women 18 to 75 (inclusive) years of age;
  • Women of childbearing potential (WOCBPs) must have a negative pregnancy test (minimum sensitivity 25 IU/L or equivalent units of human chorionic gonadotropin) within 24 hours prior to the start of study medication;
  • Women must not be breastfeeding at any time during the study;
  • WOCBPs must agree to follow instructions for method(s) of contraception for the duration of treatment (BMS-986036 or placebo) plus 5 half-lives of study medication (5 days) plus 30 days (duration of ovulatory cycle) for a total of 35 days after the end of the Double-Blind Treatment Period.
  • WOCBPs who are continuously not heterosexually active are exempt from contraceptive requirements but must undergo pregnancy testing.  Investigators will counsel WOCBPs (and/or their caregivers, as applicable) on the importance of pregnancy prevention and the implications of an unexpected pregnancy.  Investigators shall advise on the use of methods of contraception.

Exclusion Criteria:

• Other causes of liver disease (e.g., alcoholic liver disease, hepatitis B virus infection, chronic hepatitis C virus infection (see Appendix 3), autoimmune hepatitis, drug-induced hepatotoxicity, Wilson disease, α-1-antitrypsin deficiency, iron overload, and hemochromatosis).
• Current or past history of HCC.
• Medical conditions:
  • Past or current evidence of hepatic decompensation (e.g., ascites, variceal bleeding, hepatic encephalopathy and/or spontaneous bacterial peritonitis) or liver transplantation;
  • Medical history of gastroesophageal varices, as assessed by the investigator;
  • Recent history (within 2 years prior to the biopsy used to determine eligibility) of drug or alcohol abuse as defined in the Diagnostic and Statistical Manual 5 (DSM-5), Diagnostic Criteria for Drug and Alcohol Abuse (Appendix 4) OR in the investigator’s judgment, a pattern of excessive alcohol consumption ≥ 30 g/day (males) or ≥ 20 g/day (females). This alcohol consumption is equal to approximately 2 alcoholic drinks per day for males, and approximately 1.5 alcoholic drinks per day for females. One alcoholic drink is equal to 12 ounces (355 mL) of 5% alcohol by volume (ABV) beer, 5 ounces (148 mL) of 12% ABV wine, or 1.5 ounces (44.4 mL) of 40% ABV distilled spirits;
  • Use of illicit intravenous drugs within 5 years prior to or during the Screening Period;
  • A urine drug screen result positive for amphetamines, barbiturates, benzodiazepines, cannabinoids, cocaine, methadone, opiates, or phencyclidine during Screening, unless a prescribed drug accounts for the positive test;
  • History of bariatric surgery or intestinal bypass surgery within the 5 years prior to informed consent or planned during the conduct of the study;
  • History of major surgery (i.e., surgery involving a risk to the life of the patient; specifically, an operation upon an organ within the cranium, chest, abdomen, or pelvic cavity) within 6 weeks prior to or during the Screening Period;
  • History of fracture or bone surgery (i.e., hardware placement, joint replacement, bone grafting, or amputation) within 8 weeks prior to or during the Screening Period;
  • History of a blood transfusion within 60 days prior to or during the Screening Period;
  • History of cancer within the last 5 years (other than treated and believed to be cured basal or squamous cell carcinoma of the skin or resected carcinoma of the cervix);
  • History of weight gain/loss ≥ 10% of body weight within 6 months (26 weeks) prior to or during the Screening Period;
  • Uncontrolled hypertension, as defined by systolic blood pressure (SBP) > 160 and/or diastolic blood pressure (DBP) > 100 during Screening, unless discussed with medical monitor. Blood pressure may be rechecked as clinically indicated;
  • QT interval corrected using Fridericia’s formula (QTcF) > 480 msec on 12-lead ECG during Screening, confirmed by repeat ECG 30-60 minutes after the initial ECG;
  • Any acute or chronic cardiovascular condition (e.g., ischemic heart disease, congestive heart failure) considered clinically significant by the investigator;
  • Known immunocompromised status, including but not limited to, individuals who have undergone organ transplantation, who are known to be positive for human immunodeficiency virus, or who have recurrent or chronic systemic bacterial,  fungal, viral or protozoal infections;
  • Major episode of infection requiring hospitalization within 4 weeks prior to or during the Screening Period;
  • Inability to tolerate SC medication;
  • Inability to tolerate venipuncture;
  • Women who are breastfeeding;
• Prior and concomitant therapy:
  • Participants who have taken systemic corticosteroids at a dose exceeding 20 mg/day prednisone or equivalent for more than 7 consecutive days at any time within 3 months (12 weeks) prior to or during the Screening Period;
  • Inability to comply with restrictions and prohibited treatments;
  • Prior exposure to BMS-986036 or other FGF21 analogs;
  • Other investigational agents must be discontinued at least 4 weeks or 5 half-lives before the first dose of study medication, whichever is longer.
• Physical and laboratory test findings:
  • Evidence of organ dysfunction or any clinically significant deviation from normal in physical examination, vital signs, or clinical laboratory determinations beyond what is consistent with the target population;
  • ALT value > 5× the upper limit of normal (ULN) as defined by the central laboratory;
  • AST value > 5× ULN as defined by the central laboratory;
  • Total bilirubin > 1.5 mg/dL (unless the participant has a documented diagnosis of Gilbert’s syndrome);
  • Serum albumin < 3.5 g/ dL;
  • Platelet count < 100 × 103/μL;
  • International normalized ratio (INR) > 1.4, unless due to therapeutic anticoagulation;
  • Fasting plasma glucose < 60 mg/dL (< 3.33 mmol/L) or > 350 mg/dL (> 19.43 mmol/L);
  • Hemoglobin A1c ≥ 10%;
  • Fasting TGs > 500 mg/dL;
  • Estimated Glomerular filtration rate (eGFR) < 30 mL/min/1.73 m2 according to the Modification of Diet in Renal Disease equation;
  • Evidence of significant worsening of ALT, AST or bilirubin during the Screening Period, in the opinion of the investigator or medical monitor m) A centrally read DXA BMD T-Score of -2.5 or less at the femoral neck, total hip, or lumbar spine during Screening (exclusionary only if participant is 40 years of age or older).
• Allergies and adverse drug reactions:
  • History of allergy to FGF21, PEG, or related compounds
  • History of drug-induced liver injury (DILI)
• Other exclusion criteria
  • Prisoners or participants who are involuntarily incarcerated;
    • Note: Under certain specific circumstances, a person who has been imprisoned may be included or permitted to continue as a participant. Strict conditions apply, and sponsor approval is required.
  • Participants who are compulsorily detained for treatment of either a psychiatric or physical (e.g., infectious disease) illness;
  • Any factor that, in the opinion of the investigator, would jeopardize the evaluation or safety of the participant or be associated with poor adherence to the protocol;
  • Participants who are incapable of completing study-related assessments (i.e., participant questionnaires) as they MUST be completed by the participant.

Additional Eligibility Criteria for Participation in the 13C Methacetin Breath Test Assessment:

At sites selected for the 13C methacetin breath test (MBT) Substudy, in addition to the study inclusion and exclusion criteria, to be eligible to participate in the MBT Substudy, the participant must meet the following criteria:

• Participants with an allergy or hypersensitivity to methacetin and its metabolites (i.e., paracetamol) are excluded from participation;
• Participants must agree to not smoke on the day of the breath test prior to the MBT;
• Participants agree to not consume any alcohol or caffeine within 24 hours prior to the MBT.
• Prior and concomitant therapy:
  • Participants taking part in the MBT assessment should not take amiodarone within 30 days prior to the MBT;
  • Participants taking part in the MBT assessment on beta blockers or statins should be on stable doses at least 30 days prior to the MBT;
  • Participants should not take acyclovir, allopurinol, carbamazepine, cimetidine, ciprofloxacin, daidzein (herbal), disulfiram, echinacea, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, montelukast, norfloxacin, phenylpropanolamine, phenytoin, propafenone, rifampin, terbinafine, ticlopidine, thiabendazole, verapamil, zileuton, or any medication that might interfere with methacetin metabolism or might affect cytochrome P450 1A2 (CYP1A2) within 48 hours prior to the MBT;
  • Participants should not take paracetamol (acetaminophen)-related medications within 24 hours prior to the MBT;
  • Participants should not have general anesthesia or sedation within 24 hours prior to the MBT.  If a participant is eligible for the main study but is excluded from the MBT Substudy, they may still participate in the main study.