Phase 1 Study of Nalbuphine HCl ER Tablets in Hemodialysis Patients With Uremic Pruritus

Study Overview
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Brief Summary
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This is a single-center clinical research study with the purpose to evaluate the safety, tolerability, and pharmacokinetics (PK) of nalbuphine HCl ER (extended release) tablets in end-stage renal disease (ESRD) patients receiving hemodialysis (HD) therapy and reporting pruritus.

Detailed Description
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The PK of nalbuphine hemodialysis (HD) patients is unknown and will be investigated under controlled dialysis conditions in the proposed clinical PK study. Nalbuphine is a small molecular weight, water-soluble molecule with low protein binding (approximately 50%) and a large volume of distribution. In addition, its disposition is perfusion-rate limited. In the end-stage renal disease (ESRD) patients on HD, nalbuphine plasma clearance may be impacted, although it is predominantly hepatically cleared in the feces. A dose-escalation design was selected to mimic nalbuphine use in uremic pruritus (UP) patients in subsequent clinical efficacy studies whereby patients will start at a low dose to minimize the AEs such as nausea and vomiting and allow the patients to develop some tolerance to these particular AEs.

Official Title
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A Phase 1, Open-Label, Non-Randomized, Parallel-Group Study to Characterize and Compare the Pharmacokinetics, Safety, and Tolerability of Escalating Oral Doses of Nalbuphine Hydrochloride Extended Release Tablets in End-Stage Renal Disease Patients on Hemodialysis and Matched Healthy Control Subjects

Conditions
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Uremic Pruritus

Intervention / Treatment
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* Drug: Nalbuphine HCL ER


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: For Hemodialysis Patients Only Patients with chronic renal failure who have been receiving chronic in-center HD on an average of 3 times a week for at least 3 months (with Kt/V > 1.1). Subjects who experience at least mild intermittent pruritus. Non-reactive serology for hepatitis B, hepatitis C, and human immunodeficiency virus (HIV) antibody screens. Adequate venous access. Hemoglobin concentration at Screening > 9 g/dL. For Healthy Subjects Only Subjects are demographically comparable to the ESRD subjects. Gender matched 100% Age ± 10 years Body mass index (BMI) ± 15% Clinical chemistry within normal range. For Hemodialysis Patients and Healthy Subjects Written informed consent must be obtained before any assessment is performed. Male or female between the ages of 18 and 70 years, inclusive. Exclusion Criteria: For Hemodialysis Patients Only Patients who had a significant alteration in dialysis regimen within 2 weeks of the Screening Visit. An alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) concentration > 2x the upper limit of the normal range (ULN) at Screening. A serum total bilirubin > 1.8x ULN. Patients who require peritoneal dialysis. Patients who received daily or when necessary (PRN) barbiturates, amphetamines, or opiates within 7 days prior to Check-in. For Healthy Subjects Only 1. Any clinically significant abnormality identified on the physical, ECG, vital sign measurements, or clinical laboratory examinations at Screening or Day -1. For Hemodialysis Patients and Healthy Subjects Subjects with a positive drug screen at Screening and Day -1 without a prescription. Known hypersensitivity or allergy to nalbuphine or vehicle components. Known drug allergy to opioids. History of drug dependency, opioid abuse, or emotional instability deemed clinically significant per investigator review. Women with a positive pregnancy test Lactating females.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1 - Groups 1-3<br>HD patients dosing up to 180mg BID | Drug: Nalbuphine HCL ER<br>* Nalbuphine HCL extended release tablet<br>* Other names: Nalbuphine;|
| Experimental: Cohort 1 - Group 4<br>HD patients dosing up to 240mg BID | Drug: Nalbuphine HCL ER<br>* Nalbuphine HCL extended release tablet<br>* Other names: Nalbuphine;|
| Experimental: Cohort 2<br>Healthy patients dosing up to 180mg BID | Drug: Nalbuphine HCL ER<br>* Nalbuphine HCL extended release tablet<br>* Other names: Nalbuphine;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Steady state PK of nalbuphine HCl ER tablets as a function of dose | Steady state PK of nalbuphine HCl ER tablets following escalating repeated oral doses in ESRD patients receiving HD therapy relative to healthy subjects | Day -1 to 14 Cohort 1 Groups 1-3 and Cohort 2; Day -1 to 17 Cohort 1 Group 4 | 
| Extent of extraction of nalbuphine by measuring nalbuphine in plasma and dialysate during dialysis | Extraction by dialysis was assessed by measuring nalbuphine concentrations in plasma during dialysis obtained from arterial (pre-dialyzer) and venous access ports (post-dialyzer) and by measuring the amount removed in the dialysate during dialysis in the dialysate as a function of dose. | Day -1 to 14 Cohort 1 Groups 1-3; Day -1 to 17 Cohort 1 Group 4 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| VAS measurement of anti-pruritic effects | Visual Analogue Scale (VAS) itch measurement of anti-pruritic effects of nalbuphine HCl ER tablets in HD subjects with pruritus | Day -1 to 19-21 Cohort 1 Groups 1-3; Day -1 to 22-24 Cohort 1 Group 4 |