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

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

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.

Study Overview

• Status: Completed
• Conditions: Uremic Pruritus
• Intervention / Treatment: Drug: Nalbuphine HCL ER

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 22
• Phase: Phase 1

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Inclusion Criteria:

For Hemodialysis Patients Only

1. 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).
2. Subjects who experience at least mild intermittent pruritus.
3. Non-reactive serology for hepatitis B, hepatitis C, and human immunodeficiency virus (HIV) antibody screens.
4. Adequate venous access.
5. Hemoglobin concentration at Screening > 9 g/dL.

For Healthy Subjects Only

1. Subjects are demographically comparable to the ESRD subjects.

   1. Gender matched 100%
   2. Age ± 10 years
   3. Body mass index (BMI) ± 15%
2. Clinical chemistry within normal range.

For Hemodialysis Patients and Healthy Subjects

1. Written informed consent must be obtained before any assessment is performed.
2. Male or female between the ages of 18 and 70 years, inclusive.

Exclusion Criteria:

For Hemodialysis Patients Only

1. Patients who had a significant alteration in dialysis regimen within 2 weeks of the Screening Visit.
2. An alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) concentration > 2x the upper limit of the normal range (ULN) at Screening.
3. A serum total bilirubin > 1.8x ULN.
4. Patients who require peritoneal dialysis.
5. 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

1. Subjects with a positive drug screen at Screening and Day -1 without a prescription.
2. Known hypersensitivity or allergy to nalbuphine or vehicle components.
3. Known drug allergy to opioids.
4. History of drug dependency, opioid abuse, or emotional instability deemed clinically significant per investigator review.
5. Women with a positive pregnancy test
6. Lactating females.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

3

Arms and Interventions

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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Trevi Therapeutics
• Collaborators: Davita Clinical Research
• Investigators: Study Director: Thomas Sciascia, Trevi Therapeutics

Study record dates

Study Major Dates

• Study Start: April 1, 2013
• Primary Completion (Actual): November 1, 2013
• Study Completion (Actual): November 1, 2013

Study Registration Dates

• First Submitted: February 13, 2015
• First Submitted That Met QC Criteria: February 20, 2015
• First Posted (Estimate): February 26, 2015

Study Record Updates

• Last Update Posted (Actual): August 3, 2020
• Last Update Submitted That Met QC Criteria: July 30, 2020
• Last Verified: July 1, 2020

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Skin Diseases; Skin Manifestations; Pruritus; Physiological Effects of Drugs; Central Nervous System Depressants; Peripheral Nervous System Agents; Analgesics; Sensory System Agents; Analgesics, Opioid; Narcotics; Nalbuphine
• Other Study ID Numbers: TR01