The Efficacy, Safety and Tolerability of Oral LPCN 1144 in Subjects With Nonalcoholic Steatohepatitis

Study Overview
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Brief Summary
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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.

Detailed Description
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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 magnetic resonance imaging derived proton density fat fraction (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.

Official Title
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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)

Conditions
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Nonalcoholic Steatohepatitis (NASH)

Intervention / Treatment
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* Drug: LPCN 1144 Formulation A
* Drug: LPCN 1144 Formulation B
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male between 18 and 80 years of age, inclusive. 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. 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. Judged to be in good general health as determined by the investigator at screening. Exclusion Criteria: 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. Inability to reliably quantify alcohol intake. Biochemical, clinical or histologic evidence of cirrhosis on liver biopsy (stage 4 fibrosis). 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. Suspected or proven liver cancer. 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 Subjects with evidence of worsening liver function based on the two initial laboratory values used to establish the screening / baseline values. Model for End-Stage Liver Disease (MELD) score greater than 12 Subjects with a documented history of Gilbert's syndrome Evidence of portal hypertension (e.g., low platelet counts, esophageal varices, ascites, history of hepatic encephalopathy, splenomegaly). 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. 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 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. 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. Inability to safely obtain a liver biopsy. History of total parenteral nutrition in the year prior to screening. History of bariatric surgery or currently undergoing evaluation for bariatric surgery. History of gastric surgery, vagotomy, bowel resection or any surgical procedure that might interfere with gastrointestinal motility, pH or absorption. History of biliary diversion. Known positivity for antibody to Human Immunodeficiency Virus (HIV). Known heart failure of New York Heart Association class 3 or 4. Active, serious medical disease with likely life-expectancy less than 5 years. History of current or suspected prostate or breast cancer. History of diagnosed, severe, untreated, obstructive sleep apnea. Active substance abuse in the year prior to screening. History of significant sensitivity or allergy to any androgens, including testosterone, or product excipients History of seizures or convulsions, including alcohol or drug withdrawal seizures. Childhood seizures are not exclusionary. 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. 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). 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. 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. Subject who is not willing to use adequate contraception for the duration of the study. Any other condition, which in the opinion of the investigator would impede compliance or hinder completion of the study. Failure to give informed consent.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional 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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment A<br>LPCN 1144 Formulation A | Drug: LPCN 1144 Formulation A<br>* Oral LPCN 1144 Formulation A capsule, total daily dose of 450 mg testosterone undecanoate administered as 225 mg testosterone undecanoate twice daily (BID).<br>* Other names: testosterone undecanoate;|
| Experimental: Treatment B<br>LPCN 1144 Formulation B | Drug: LPCN 1144 Formulation B<br>* 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<br>* Other names: testosterone undecanoate with d-alpha tocopherol;|
| Placebo Comparator: Treatment C<br>Placebo | Drug: Placebo<br>* Oral matching placebo capsule administered as BID<br>* Other names: Oral placebo;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Absolute Change in Hepatic Fat Fraction Based on MRI-PDFF Measurements in LPCN 1144 Treated Subjects Compared to Placebo. | The change in magnetic resonance imaging derived proton fat fraction (MRI-PDFF) from baseline to week 12 in LPCN 1144 treated subjects and subjects given placebo. | Baseline and Week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Relative Change in MRI-PDFF Measurements in LPCN 1144 Treated Subjects Compared to Placebo. | Requirement for inclusion in analysis was having a baseline hepatic fat fraction ≥ 5% based on MRI-PDFF. | Baseline and week 12 | 
| Number of Participants With Resolution of NASH on Overall Histopathological Reading in LPCN 1144 Treated Subjects Compared to Placebo | Resolution of nonalcoholic steatohepatitis (NASH) is defined as the nonalcoholic fatty liver disease activity score (NAS) score of 0-1 for inflammation, 0 for ballooning, and any value for steatosis. These data are based on the NASH-clinical research network (CRN) histology scoring system. The range of scores are as follows (with higher scores equating to a more pathological feature): Steatosis 0-3, inflammation 0-3, ballooning 0-2, fibrosis state 0-4, and NAS 0-8. | Baseline and Week 36 | 
| Number of Subjects Achieving Resolution of NASH on Overall Histopathological Reading and no Worsening of Liver Fibrosis 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. These data are based on the NASH-CRN histology scoring system. The range of scores are as follows (with higher scores equating to a more pathological feature): Steatosis 0-3, inflammation 0-3, ballooning 0-2, fibrosis state 0-4, and NAS 0-8. No worsening was defined as a score in fibrosis equal to, or lower, than baseline. | Baseline and Week 36 | 
| Number of Subjects With Improvement in NASH Evaluated by Paired Biopsies Analysis and no Worsening of Liver Fibrosis in LPCN 1144 Treated Subjects Compared to Placebo. | Paired biopsies are randomly assigned A or B and are scored by a blinded pathologist as better, worse or same for change in fibrosis, steatosis, inflammation, and ballooning. Improvement in NASH requires no worsening of fibrosis, an improvement in ballooning or inflammation, and no worsening of ballooning or inflammation. Assessment of better or same is considered as no worsening. | Baseline and week 36 | 
| Change in the Mean Score of NAS Components at Baseline and After 36 Weeks of Treatment in LPCN 1144 Treated Subjects Compared to Placebo. | These data are based on the NASH-CRN histology scoring system. The range of scores are as follows (with higher scores equating to a more pathological feature): Steatosis 0-3, inflammation 0-3, ballooning 0-2, fibrosis state 0-4, and NAS 0-8. | Baseline and Week 36 | 
| Number of Subjects With an Improvement in Liver Fibrosis Greater Than or Equal to One Stage and no Worsening of NASH in LPCN 1144 Treated Subjects Compared to Placebo. | These data are based on the NASH-CRN histology scoring system. The range of scores are as follows (with higher scores equating to a more pathological feature): Steatosis 0-3, inflammation 0-3, ballooning 0-2, and fibrosis stage 0-4. Improvement in liver fibrosis was defined as an improvement in fibrosis greater than or equal to one stage using the NASH CRN fibrosis score with no worsening of ballooning, inflammation, or steatosis. | Baseline and Week 36 | 
| Number of Subjects With Improvement in Fibrosis Evaluated by Paired Biopsies Analysis and no Worsening of NASH in LPCN 1144 Treated Subjects Compared to Placebo | Paired biopsies are randomly assigned A or B and are scored by a blinded pathologist as better, worse or same for change in fibrosis, steatosis, inflammation, and ballooning. Improvement in fibrosis requires a better score in fibrosis and no worsening of ballooning or inflammation. Assessment of better or same is considered as no worsening. | Baseline to week 36 | 
| Number of Subjects With Improvement in Fibrosis Evaluated Via FibroNest Scores | Improvement in Fibrosis is defined as improvement in parenchymal tissue normalized phenotypic fibrosis composite value compared to baseline. FibroNest is an image analysis system for the assessment of the severity and progression of fibrosis in NASH, produced by PharmaNest LLC. | Baseline and week 36 | 
| Relative Change in Appendicular Lean Muscle Mass | Relative change in appendicular lean muscle mass measured by dual-energy absorptiometry (DXA) in LPCN 1144 treated subjects compared to Placebo. Data were last observation carried forward. | Baseline and 36 weeks | 
| Relative Change in Whole Body Fat Mass | Relative change in whole body fat mass measured by dual-energy absorptiometry (DXA) in LPCN 1144 treated subjects compared to Placebo. Data were last observation carried forward. | Baseline and week 36 | 
| Mean Change From Baseline in Liver Enzymes in LPCN 1144 Treated Subjects Compared to Placebo. | Liver enzymes analyzed were aspartate transaminase (AST), alanine transaminase (ALT), alkaline phosphatase (ALP), and gamma-glutamyltransferase (GGT) | Baseline and Week 36 | 
| Mean Changes in Serum Lipid Profile Parameters in LPCN 1144 Treated Subjects Compared to Placebo. | Lipid profile parameters included total cholesterol, low-density lipoprotein (LDL), high-density lipoprotein (HDL), and triglycerides. | Baseline and Week 36 |