Efficacy and Safety of MT-9938 for Treatment of Uremic Pruritus in Subjects With End-stage Renal Disease Receiving Hemodialysis

Study Overview
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Brief Summary
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This study is being conducted to investigate the efficacy of MT-9938 compared with placebo after 2 weeks, to continue to evaluate efficacy for an additional 6 weeks, and to explore the effect of a reduction in itching intensity on health-related Quality of Life(QoL) domains, especially those which recent research suggests have a positive correlation with overall survival for this patient group. The study will consist of the following phases: Screening (1 to 2 weeks), Run in (1 week), double-blind Treatment (8 weeks), Washout (1 week) culminating in a Follow-up Visit (1 week after the last dose).

Detailed Description
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This study has been terminated because of insufficient patient recruitment. There were no safety concerns.

Official Title
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A Phase 2, Randomized, Double-blind, Placebo-controlled, Fixed-dose, Parallel-group, Multicenter, Efficacy, and Safety Study of MT-9938 for Treatment of Uremic Pruritus in Subjects With End-stage Renal Disease Receiving Hemodialysis

Conditions
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Uremic Pruritus

Intervention / Treatment
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* Drug: Nalfurafine hydrochloride(MT-9938) 2.5μg
* Drug: Nalfurafine hydrochloride(MT-9938) 5μg
* Drug: Nalfurafine hydrochloride(MT-9938) 10μg
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: On stable hemodialysis for at least 3 months Has stable functioning arteriovenous fistula, graft or other venous access Has continued (uncontrolled) uremic pruritus despite standard of care in the institution Has severe pruritus, as determined by a qualifying score of ≥3 on the Itch Severity Score Scale (0 to 4) either day or night during the week prior to Screening Visit Has no known drug addiction to any prescription, nonprescription, herbal or natural drugs, and successfully passes a drug screen test Women and men whose partners are of childbearing potential agree to practice the medically acceptable methods of birth control and agree to continue with the regimen throughout the duration of the study Capable of understanding and responding to the subject questionnaires, understands the purpose and risks of the study, and has given written informed consent Has rated his/her NRS score each day for at least 5 days out of the 7 days of the Run-in Phase Has severe pruritus, as determined by qualifying mean worst NRS score in a day of ≥5 (on 11 point NRS) at the end of the 1-week Run-in Phase Exclusion Criteria: Current, clinically significant medical comorbidities Abnormal liver dysfunction Pruritus attributed mainly to any disease unrelated to kidney disease Calcium x phosphorus product >80 mg2/dL2 or hemoglobin <7 g/dL or parathyroid hormone levels >1000 pg/mL at Screening Received ultraviolet B treatment within 30 days prior to Screening Started or changed psychotropic medication within 14 days prior to Screening Is receiving opioid antagonists or opioid agonists within 7 days prior to Screening and not willing to abstain from these medications during the study. Started or changed medications, creams or emollients including over-the-counter oil bath treatment for relief of pruritus within 7 days prior to Screening Has known hypersensitivity to opioids or the study drug ingredients Is currently participating in an investigational drug or device clinical study or was participating in such a study within 30 days prior to the start of Screening Female subject who is known to be pregnant or nursing Is considered not suitable for inclusion in the study in the opinion of Investigator Has current suicidal ideation with some intent to act or with specific plan and intent or had suicidal behavior at any time in subject's life

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

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
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: MT-9938 2.5μg<br> | Drug: Nalfurafine hydrochloride(MT-9938) 2.5μg<br>* 2.5 μg (2capsules) once daily for 8 weeks<br>|
| Active Comparator: MT-9938 5μg<br> | Drug: Nalfurafine hydrochloride(MT-9938) 5μg<br>* 5 μg (2capsules) once daily for 8 weeks<br>|
| Active Comparator: MT-9938 10μg<br> | Drug: Nalfurafine hydrochloride(MT-9938) 10μg<br>* 10 μg (2capsules) once daily for 8 weeks<br>|
| Placebo Comparator: Placebo<br> | Drug: Placebo<br>* Placebo (2capsules) once daily for 8 weeks<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Worst-itching 11-point Numerical Rating Scale (NRS) | The subject indicated the number on the line from left (0:no itching) to right (10:worst itch I have ever experienced). Assessments was made twice daily using an electronic Patient Reported Outcomes (ePRO) device from the Screening Visit to the Follow-up Visit (Week 9). The 2 daily assessments was separated by 12 h, at approximately 8 am and at approximately 8 pm. Subjects selected the number that best described the worst itch during the day (assessed at approximately 8 pm) or during the night (assessed at approximately 8 am). The day or night score, whichever was greater, was used to calculate the weekly average score and changes from baseline (average over the Run-in Phase [Days -7 to -1]) score in weekly average at 2, 4 and 8 weeks as specified in the protocol are reported. Amount of change score of plus indicates worsening, and minus indicates improvement. | 2 weeks, 4 weeks and 8 week | 
| Change From Baseline in Worst-itching Visual Analog Scale (VAS) | The subject placed a single vertical mark on the line of a VAS corresponding to degree of itching intensity from left (no itching) to right (worst itch I have ever experienced). The VAS represents a 100 mm line. It consists of 101 selectable regions and the subject's score on the VAS will correspond to the region (0 to 100) selected on the line. Assessments was made twice daily using an ePRO device from the Screening Visit to the Follow-up Visit (Week 9). The 2 daily assessments was separated by 12 h, in the morning at approximately 8 am and in the night at approximately 8 pm. Subjects put a single vertical mark on the line to show the intensity of your worst itching during the day or during the night. The day or night score, whichever was greater, was used to calculate the weekly average score and changes from baseline in weekly average at 2, 4 and 8 weeks as specified in the protocol are reported. Amount of change score of plus indicates worsening, and minus indicates improvement. | 2 weeks, 4 weeks and 8 weeks | 
| Change From Baseline in Itch Severity Score | The subject performed an assessment on day and nighttime symptoms of itch and effect of itch on sleep using a 5-point ordinal scale of itchiness (0 = none, 1 = mild, 2 = Moderate, 3=Severe, 4 = very severe). Assessments was made during each dialysis treatment (3x/week) and recorded on paper from the Screening Visit to the Follow-up Visit (Week 9). Change from Baseline (average over the Run-in Phase [Days -7 to -1]) in Weekly Averages of Itch Severity Score were assessed and score at 2, 4 and 8 weeks as specified in the protocol are reported. Amount of change score of plus indicates worsening, and minus indicates improvement. | 2 weeks, 4 weeks and 8 weeks | 
| Change From Baseline in Sleep Quality Assessment | The PSQI has a minimum possible score of 0 (better sleep quality) and a maximum possible score of 10 (worse sleep quality). Subjects was asked to rate their sleep experience during the previous week. Pittsburgh Sleep Quality Index (PSQI) modified assessment was made during the dialysis treatment 1x/week every week and recorded on paper from the Screening Visit to the Follow-up Visit (Week 9).Change from Baseline (the Run-in Phase [Days -7 to -1]) were assessed and score at 2, 4 and 8 weeks as specified in the protocol are reported. Amount of change score of plus indicates worsening, and minus indicates improvement. | 2 weeks, 4 weeks and 8 weeks | 
| Change From Baseline in QoL Assessment (Skindex-10) | The Skindex-10 has a minimum possible score of 0 (itching not bothersome) and a maximum possible score of 60 (itching very bothersome). The Skindex-10 is a self-administered questionnaire used to evaluate the health-related QoL in UP. It is comprised of 10 questions, adopted for pruritus from the Skindex-16, a widely used instrument for a variety of skin disease. Subjects was asked to identify on paper at Baseline and Weeks 2, 4, and 8 (EOT) what has bothered them most during the past week by marking along a scale 0 to 6 boxes from never bothered to always bothered. Change from Baseline (the Run-in Phase [Days -7 to -1]) were assessed. Amount of change score of plus indicates worsening, and minus indicates improvement. | 2 weeks, 4 weeks and 8 weeks | 
| The Mean Value in Treatment Satisfaction (Patient's Global Impression of Change ) | The PGIC has a minimum possible score of 1 (very much improved) and a maximum possible score of 7 (very much worse). Subjects was asked to use a categorical scale with 7 categories to describe their global impression of change (PGIC) with study drug treatment. Subjects recorded their impression of change on paper at Weeks 2, 4, and 8 (EOT). Although the change from baseline (run-in phase [Days -7 to -1]) was specified as an outcome in this study, it was not calculated because the target enrollment was not met and no meaningful statistical analysis could be expected. Therefore, the mean value of patients at each point is shown instead. | 2 weeks, 4 weeks and 8 weeks | 
| Change From Baseline in QoL Assessment (5-D-Itch Scale) | The 5-D-Itch scale has a minimum possible score of 5 (better) and a maximum possible score of 25 (worse). Subjects was asked to assess QoL by means of the 5D-Itch-Scale at Baseline, Weeks 2, 4, and 8 (EOT). The 5D-Itch Scale is a 5-item (duration, degree, direction, disability, and distribution) multidimensional measure of pruritus itch. Change from Baseline (the Run-in Phase [Days -7 to -1]) were assessed. Amount of change score of plus indicates worsening, and minus indicates improvement. | 2 weeks, 4 weeks and 8 weeks | 
| The Number of Patients in Excoriation | Investigator and/or the designated medically qualified staff assessed the subject's excoriation at Baseline, and weekly thereafter, by completing the subject's answers to the following questions: Excoriation present? Yes/No If yes, please rate the severity: Mild/Moderate/Severe Although the change from baseline (run-in phase [Days -7 to -1]) was specified as an outcome in this study, it was not calculated because the target enrollment was not met and no meaningful statistical analysis could be expected. Therefore, the number of patients at each point is shown instead. | 2 weeks, 4 weeks and 8 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Adverse Events as a Measure of Safety and Tolerability | The number of subjects with at least 1 treatment-emergent adverse event (TEAE). Please see the adverse event table for specific. | 8 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Pruritus, Renal dialysis, Receptors, Opioid, kappa, Sleep Disorders, Quality of Life