The Efficacy, Safety and Tolerability of Oral LPCN 1144 in Subjects With Nonalcoholic Steatohepatitis
Condition: Nonalcoholic Steatohepatitis (NASH)
MeSH terms: Fatty Liver; Non-alcoholic Fatty Liver Disease
Intervention: LPCN 1144 Formulation A; LPCN 1144 Formulation B; Placebo
Intervention description: Oral LPCN 1144 Formulation A capsule, total daily dose of 450 mg testosterone undecanoate administered as 225 mg testosterone undecanoate twice daily (BID).; Oral LPCN 1144 + d-alpha tocopherol total daily dose of 450 mg testosterone undecanoate + 476 mg d-alpha tocopherol administered as 225 mg testosterone undecanoate + 238 mg d-alpha tocopherol BID; Oral matching placebo capsule administered as BID
Intervention MeSH terms: Tocopherols; alpha-Tocopherol; Methyltestosterone; Testosterone; Testosterone undecanoate; Testosterone enanthate; Testosterone 17 beta-cypionate
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: Randomized in 1:1:1 ratio to receive one of the following treatments:
Treatment A: Oral LPCN 1144 Formulation A
Treatment B: Oral LPCN 1144 Formulation B
Treatment C: Oral matching placebo
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking description: Subjects meeting the enrollment criteria will be randomly assigned to one of the three treatment arms. The randomization will be carried out by central assignment. The study is a blinded study; therefore all the randomization codes will be centrally maintained and no data from the randomization will be available to Sponsor, contract research organization (CRO) operations team, medical monitors, monitors or any site staff.
Enrollment: 56.0
Sex: Male
Minimum age: 18 Years
Maximum age: 80 Years
Healthy volunteers: No

Summary:

      This is a Phase 2, randomized, double-blind, placebo controlled, three arm study in adult men
      with biopsy confirmed NASH. The study is aimed at evaluating efficacy and tolerability of
      LPCN 1144 in adult men with NASH.
    

Eligibility criteria:

        Inclusion Criteria:

          1. Male between 18 and 80 years of age, inclusive.

          2. Subject with histologic evidence of NASH upon central read of a liver biopsy.

             i. A historical biopsy no more than 4 months before Screening may be considered for
             use with medical monitor approval if the following criteria are met:

               -  Stable weights between the time of the biopsy and Screening. Stable weight is
                  defined as no more than a 5% change.

               -  Is either not taking or is on a stable dose of Thiazolidinedione(TZDs)/glitazones
                  for 3 months before Day 1.

          3. Background therapy for other ongoing chronic conditions, and weight should be stable
             for at least 3 months before trial enrollment. Stable weight is defined as no more
             than a 5% change.

          4. Judged to be in good general health as determined by the investigator at screening.

        Exclusion Criteria:

          1. Significant alcohol consumption more than 30 g/day on average, either currently or for
             a period of more than 3 consecutive months in the 5 years prior to screening.

          2. Inability to reliably quantify alcohol intake.

          3. Biochemical, clinical or histologic evidence of cirrhosis on liver biopsy (stage 4
             fibrosis).

          4. Evidence of other causes of chronic liver disease including alcoholic liver disease,
             viral hepatitis, primary biliary cirrhosis, primary sclerosing cholangitis, autoimmune
             hepatitis, Wilson's disease, hemochromatosis, alpha-1 antitrypsin deficiency, human
             immunodeficiency virus, etc.

          5. Suspected or proven liver cancer.

          6. Clinically significant abnormal laboratory value, in the opinion of the investigator,
             in serum chemistry, hematology, or urinalysis including but not limited to:

               -  Hematocrit > upper limits of normal (ULN)

               -  Hemoglobin > ULN

               -  Prostate-specific antigen (PSA) > 4 ng/mL

               -  Serum aspartate aminotransferase (AST) or alanine transaminase (ALT) > 200 IU/L

               -  Serum alkaline phosphatase (ALP) > 2 x ULN

               -  Serum creatinine of 2.0 mg/dL or greater

               -  Total bilirubin > ULN

               -  International normalized ratio (INR) ≥ 1.3.

               -  Prolactin > ULN

          7. Subjects with evidence of worsening liver function based on the two initial laboratory
             values used to establish the screening / baseline values.

          8. Model for End-Stage Liver Disease (MELD) score greater than 12

          9. Subjects with a documented history of Gilbert's syndrome

         10. Evidence of portal hypertension (e.g., low platelet counts, esophageal varices,
             ascites, history of hepatic encephalopathy, splenomegaly).

         11. Use of drugs historically associated with NAFLD (amiodarone, methotrexate, systemic
             glucocorticoids, tetracyclines, tamoxifen, estrogens, anabolic steroids, valproic
             acid, other known hepatotoxins) for more than 2 weeks in the 2 years prior to
             randomization.

         12. Subjects who are not on a stable dose of lipid-lowering drugs, diabetic and / or
             hypertensive medication in the 3 months prior to biopsy or the 3 months prior to
             randomization

         13. Any over-the-counter medication or herbal remedy that is being taken with an intent to
             improve hyperlipidemia must be stable for at least 3 months prior to randomization and
             through the end of the study.

         14. Vitamin E supplementation of greater than 100 IU/day, unless completed adequate
             washout for at least 4 weeks prior to Day 1 or biopsy if one is required.

         15. Inability to safely obtain a liver biopsy.

         16. History of total parenteral nutrition in the year prior to screening.

         17. History of bariatric surgery or currently undergoing evaluation for bariatric surgery.

         18. History of gastric surgery, vagotomy, bowel resection or any surgical procedure that
             might interfere with gastrointestinal motility, pH or absorption.

         19. History of biliary diversion.

         20. Known positivity for antibody to Human Immunodeficiency Virus (HIV).

         21. Known heart failure of New York Heart Association class 3 or 4.

         22. Active, serious medical disease with likely life-expectancy less than 5 years.

         23. History of current or suspected prostate or breast cancer.

         24. History of diagnosed, severe, untreated, obstructive sleep apnea.

         25. Active substance abuse in the year prior to screening.

         26. History of significant sensitivity or allergy to any androgens, including
             testosterone, or product excipients

         27. History of seizures or convulsions, including alcohol or drug withdrawal seizures.
             Childhood seizures are not exclusionary.

         28. Use of known strong inhibitors (e.g., ketoconazole) or inducers (e.g., dexamethasone,
             phenytoin, rifampin, carbamazepine) of cytochrome P450 3A (CYP3A) within 30 days prior
             to study drug administration and through the end of the study.

         29. Subjects who are currently receiving any androgens (testosterone or other androgens or
             androgen supplements). Subjects who are on testosterone may be eligible for the study
             following an adequate washout (12 weeks following intramuscular androgen injections; 4
             weeks following topical or buccal androgens; 3 weeks following oral androgens).

         30. Use of any investigational drug within 5 half-lives of the last dose or in the past 6
             months prior to Study Day -2 without PI and/or Sponsor approval.

         31. Receipt of any drug by injection within 30 days or 10 half-lives (whichever is longer)
             prior to study drug administration without PI and/or Sponsor approval. Insulin,
             allergy shots, and vaccines are allowed.

         32. Subject who is not willing to use adequate contraception for the duration of the
             study.

         33. Any other condition, which in the opinion of the investigator would impede compliance
             or hinder completion of the study.

         34. Failure to give informed consent.