A Study to Assess the Efficacy, Safety and Tolerability of Oral LPCN 1144 in Subjects With Nonalcoholic Steatohepatitis (NASH)

Overview

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.

Full Title of Study: “A Phase 2, Randomized Double-Blind, Placebo-Controlled, Multi-Center Study to Assess the Efficacy, Safety and Tolerability of Oral LPCN 1144 in Subjects With Nonalcoholic Steatohepatitis (NASH)”

Study Type

  • Study Type: Interventional
  • Study Design
    • Allocation: Randomized
    • Intervention Model: Parallel Assignment
    • Primary Purpose: Treatment
    • Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
  • Study Primary Completion Date: June 2020

Detailed Description

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. The study will be conducted across multiple centers in the United States.

Approximately 75 subjects will be 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

Subjects will undergo a screening period to determine study eligibility. As a part of screening, liver biopsies will be performed for subjects who have not had a liver biopsy within 6 months of Day 1, and fat fraction will be measured by MRI-PDFF in all subjects. Adult male subjects with histologic evidence of NASH will be enrolled into the study.

Eligible subjects will be randomized to one of the three treatment arms. The treatment phase will be for a duration of 36-weeks with assessments of liver biopsies, hepatic fat fraction, liver enzymes, lipid levels and other safety parameters. Safety and tolerability will be assessed throughout the study.

Interventions

  • Drug: LPCN 1144 Formulation A
    • Oral LPCN 1144 Formulation A capsule, total daily dose of 450 mg testosterone undecanoate administered as BID (225 mg testosterone undecanoate per dose)
  • Drug: LPCN 1144 Formulation B
    • Oral LPCN 1144 Formulation B capsule, total daily dose of 450 mg testosterone undecanoate administered as BID (225 mg testosterone undecanoate per dose)
  • Drug: Placebo
    • Oral matching placebo capsule administered as BID

Arms, Groups and Cohorts

  • Experimental: Treatment A
    • LPCN 1144 Formulation A
  • Experimental: Treatment B
    • LPCN 1144 Formulation B
  • Placebo Comparator: Treatment C
    • Placebo

Clinical Trial Outcome Measures

Primary Measures

  • Change in hepatic fat fraction based on MRI-PDFF measurements in LPCN 1144 treated subjects compared to placebo.
    • Time Frame: Baseline to Week 12

Secondary Measures

  • Change in NASH activity evaluated via a standardized scoring of liver biopsies at baseline and after 36 weeks of treatment in LPCN 1144 treated subjects compared to placebo.
    • Time Frame: Baseline to Week 36
  • Relative change in hepatic fat fraction based on MRI-PDFF measurements in LPCN 1144 treated subjects compared to placebo.
    • Time Frame: Baseline to week 12
  • Change in hepatic fat fraction based on MRI-PDFF measurements in LPCN 1144 treated subjects compared to placebo.
    • Time Frame: Baseline to Week 36
  • Relative change in hepatic fat fraction based on MRI-PDFF measurements in LPCN 1144 treated subjects compared to placebo.
    • Time Frame: Baseline to Week 36
  • NAFLD resolution of subjects who at baseline are at least 5% with a decrease to less than 5% at end of study in LPCN 1144 treated subjects compared to placebo.
    • Time Frame: Baseline to Week 36
  • Resolution of NASH on overall histopathological reading in LPCN 1144 treated subjects compared to placebo. Resolution of NASH is defined as NAS score of 0-1 for inflammation, 0 for ballooning, and any value for steatosis.
    • Time Frame: Baseline to Week 36
  • Resolution of NASH on overall histopathological reading and no worsening of liver fibrosis on NASH CRN fibrosis score in LPCN 1144 treated subjects compared to placebo..
    • Time Frame: Baseline to Week 36
  • Change in fibrosis score via NASH Clinical Research Network fibrosis score (0-4) of liver biopsies in LPCN 1144 treated subjects compared to placebo.
    • Time Frame: Baseline to Week 36
    • Lower score indicates improvement in fibrosis
  • Improvement in liver fibrosis greater than or equal to one stage (NASH Clinical Research Network fibrosis score, 0-4) in LPCN 1144 treated subjects compared to placebo..
    • Time Frame: Baseline to Week 36
    • Lower score indicates improvement in fibrosis
  • Improvement in liver fibrosis greater than or equal to one stage (NASH Clinical Research Network fibrosis score, 0-4) and no worsening of NASH (defined as no increase in NAFLD Activity Score (0-8)) in LPCN 1144 treated subjects compared to placebo.
    • Time Frame: Baseline to Week 36
    • Lower score indicates improvement on both scales
  • Change in insulin resistance (assessed by Homeostasis Model Assessment (HOMA)) in LPCN 1144 treated subjects compared to placebo.
    • Time Frame: Baseline to Week 36
  • Changes in liver enzymes aspartate transaminase (AST), (alanine transaminase (ALT), alkaline phosphatase (ALP), gamma-glutamyltransferase (GGT), Total Bilirubin (TB) and Creatine Kinase (CK) in LPCN 1144 treated subjects compared to placebo.
    • Time Frame: Baseline to Week 36
  • Changes in non-invasive markers of fibrosis and steatosis in LPCN 1144 treated subjects compared to placebo.
    • Time Frame: Baseline to Week 36
  • Changes in serum lipid profile parameters (LDL, HDL, and triglycerides) in LPCN 1144 treated subjects compared to placebo.
    • Time Frame: Baseline to Week 36
  • Changes in Functional Activity (NHANES Physical Activity and Physical Fitness – PAQ, 2017) in LPCN 1144 treated subjects compared to placebo.
    • Time Frame: Baseline to Week 36
  • Changes in weight (kg) in LPCN 1144 treated subjects compared to placebo.
    • Time Frame: Baseline to Week 36
  • Changes in body mass index (BMI) in LPCN 1144 treated subjects compared to placebo.
    • Time Frame: Baseline to Week 36
  • Changes in waist circumference (cm) in LPCN 1144 treated subjects compared to placebo.
    • Time Frame: Baseline to Week 36
  • Changes in waist to hip ratio (each measured in cm) in LPCN 1144 treated subjects compared to placebo.
    • Time Frame: Baseline to Week 36
  • Changes in measurements of triceps skin fold thickness (mm) and upper arm circumference (mm) in LPCN 1144 treated subjects compared to placebo.
    • Time Frame: Baseline to Week 36

Participating in This Clinical Trial

Inclusion Criteria

1. Adult male subject with histologic evidence of NASH upon central read of a liver biopsy obtained no more than 6 months before Day 1 defined by NASH activity score (NAS) greater than or equal to 4 with at least 1 point each in inflammation and ballooning. Subjects who have had a biopsy more than 3 months before trial enrollment should have stable weights between the time of the biopsy and trial initiation. Stable weight is defined as no more than a 5% change.

2. For subjects with a historical biopsy, is either not taking or is on stable doses of TZDs/glitazones or vitamin E (d-alpha tocopherol) 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. A previous historical diagnosis of hypogonadism or low testosterone 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 > ULN
  • Hemoglobin > ULN
  • PSA > 4 ng/mL
  • Serum AST or ALT > 200 IU/L
  • Serum ALP > 2 x ULN
  • Serum creatinine of 2.0 mg/dL or greater
  • 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 with bilirubin outside the normal reference range.

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. Inability to safely obtain a liver biopsy.

14. History of total parenteral nutrition in the year prior to screening.

15. History of bariatric surgery or currently undergoing evaluation for bariatric surgery.

16. History of gastric surgery, cholecystectomy, vagotomy, bowel resection or any surgical procedure that might interfere with gastrointestinal motility, pH or absorption.

17. History of biliary diversion.

18. Known positivity for antibody to Human Immunodeficiency Virus (HIV).

19. Known heart failure of New York Heart Association class 3 or 4.

20. Active, serious medical disease with likely life-expectancy less than 5 years.

21. History of current or suspected prostate or breast cancer.

22. History of diagnosed, severe, untreated, obstructive sleep apnea.

23. Active substance abuse in the year prior to screening.

24. History of significant sensitivity or allergy to any androgens, including testosterone, or product excipients

25. Participation in an investigational new drug trial in the 30 days prior to randomization without the approval of the PI and/or Sponsor.

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.

28. Use of known 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. 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.

31. Use of any drug within 5 half-lives of the last dose in the past 6 months prior to Study Day -2 without PI and/or Sponsor approval.

32. Any contraindications to a MRI scan (i.e. subjects with non-removable ferromagnetic implants, pacemakers, aneurysm clips or other foreign bodies), and/or subjects with claustrophobic symptoms and/or inability to fit into an MRI scanner.

33. 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.

34. Subject who is not willing to use adequate contraception for the duration of the study.

35. Any other condition, which in the opinion of the investigator would impede compliance or hinder completion of the study.

36. Failure to give informed consent.

Gender Eligibility: Male

Minimum Age: 18 Years

Maximum Age: 80 Years

Are Healthy Volunteers Accepted: No

Investigator Details

  • Lead Sponsor
    • Lipocine Inc.
  • Provider of Information About this Clinical Study
    • Sponsor
  • Overall Contact(s)
    • Nachiappan Chidambaram, 8018819495, nc@lipocine.com

Clinical trials entries are delivered from the US National Institutes of Health and are not reviewed separately by this site. Please see the identifier information above for retrieving further details from the government database.

At TrialBulletin.com, we keep tabs on over 200,000 clinical trials in the US and abroad, using medical data supplied directly by the US National Institutes of Health. Please see the About and Contact page for details.