Phase 3 Study of Difelikefalin in Haemodialysis Chinese Adult Subjects With Moderate-to-Severe Pruritus

Vifor Fresenius Medical Care Renal Pharma260 enrolled

Overview

This a multicentre study that consists of a 12-week double-blind period, and an optional 14-week open-label extension period and a 1-week follow-up period.

Total study duration for a single subject is 31 to 32 weeks with a 4-week screening period, a 12-week double-blind period, a 14-week optional open-label extension period, and a 1-week follow-up period. For subjects not participating in the open-label extension period, the total study duration is 17 weeks. Difelikefalin will be administered in the double-blind and open-label period 3 times a week at the end of each dialysis session. The total dose of the investigational product will be determined based on the subject's prescription dry body weight. The primary objective of the study is: To evaluate the efficacy of difelikefalin 0.5 μg/kg compared to placebo in reducing the intensity of itch in HD Chinese subjects with moderate-to-severe pruritus.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

QUADRUPLE

Enrollment

260

Conditions

Uremic Pruritus

Interventions

Difelikefalin InjectionDRUG

Participants receive Difelikefalin three times a week (0.5 micrograms/kg dry body weight). Difelikefalin is administered by intravenous bolus injection into the venous line of the dialysis circuit at the end of each dialysis.

Placebo InjectionDRUG

Participants receive Placebo three times a week (0.5 micrograms/kg dry body weight). Placebo is administered by intravenous bolus injection into the venous line of the dialysis circuit at the end of each dialysis.

Eligibility

Sex: ALLMin age: 18 YearsMax age: 85 Years

Medical Language ↔ Plain English

Inclusion Criteria: * Subjects with chronic kidney disease (CKD) on HD 3 times weekly for ≥12 weeks prior to the informed consent procedure (including the date of informed consent) who can continue HD without changing its frequency or method. * If female, is not pregnant, or nursing. * If female: 1. Is surgically sterile; or 2. Has been amenorrhoeic for at least 1 year and is over the age of 55 years; or 3. Has a negative serum pregnancy test within 7 days before first dose of investigational product and agrees to use acceptable contraceptive measures (e.g., hormonal contraceptives, barrier with spermicide, intrauterine device, vasectomised partner, or abstinence) from the time of informed consent until 7 days after the last dose of investigational product. * If male, agrees not to donate sperm after the first dose of investigational product administration until 7 days after the last dose of investigational product, and agrees to use a condom with spermicide or abstain from heterosexual intercourse during the study until 7 days after the last dose of investigational product. * Subjects with a prescription dry body weight between 40 and 100 kg, inclusive. Exclusion Criteria: * Planned or anticipated to receive a kidney transplant during the study. * Has localised itch restricted to the palms of the hands. * Has pruritus only during the dialysis session * Subjects with severe hepatic impairment (Child-Pugh Class C) or concurrent hepatic cirrhosis. * Subject is receiving ongoing ultraviolet B treatment and anticipates receiving such treatment during the study. * Significant systolic or diastolic heart failure (e.g., New York Heart Association Class IV congestive heart failure) * Subjects with concurrent malignancy except excised basal cell or squamous cell carcinoma of the skin, or carcinoma in situ that has been excised or resected completely. * Known or suspected history of alcohol, narcotic, or other drug abuse, or substance dependence within 12 months prior to screening. * Severe mental illness or cognitive impairment (e.g., dementia) or other concurrent mental disorder that, in the opinion of the Investigator, would compromise the validity of study measurements. * Any other relevant acute or chronic medical or neuropsychiatric condition within 3 months prior to screening (e.g., diagnosis of encephalopathy, coma, delirium). * New or change of treatment received for itch including antihistamines and corticosteroids (oral, IV, or topical) within 14 days prior to screening. * New or change of prescription for opioids, gabapentin, or pregabalin within 14 days prior to screening. * Subject is receiving prohibited medication (e.g., nalfurafine hydrochloride, opioid antagonists)

Locations (35)

Investigator Site 25

Outcomes

Primary Outcomes

Change From Baseline in the Weekly Mean of the Daily 24-hour WI-NRS Score at Week 4 of the DB Period

On a daily basis, participants recorded the intensity of the worst itching they experienced over the past 24 hours using a numerical rating scale (NRS) scale from 0 to 10, where 0 represents "no itching" and 10 was "worst itching imaginable". A higher score indicated a more severe outcome. The weekly mean of the daily values of the daily 24-hour WI-NRS was calculated for the analysis. The least square (LS) means of change from baseline to Week 4 in the weekly mean of the daily 24-hour WI-NRS score was estimated using the mixed model repeated measures (MMRM) method. The MMRM model included use of prior anti-itch medication (yes/no), presence of specific medical conditions at baseline (yes/no), treatment, visit, and treatment-by-visit-interaction as fixed categorical effects and baseline WI-NRS score as fixed continuous effects.

Time frame: From Baseline to Week 4

Secondary Outcomes

Percentage of Participants Achieving Greater Than or Equal to (>=) 3-point Improvement From Baseline With Respect to the Weekly Mean of the Daily 24-hour WI-NRS in the DB Period

On a daily basis, participants recorded the intensity of the worst itching they experienced over the past 24 hours using a NRS scale from 0 to 10, where 0 represents "no itching" and 10 was "worst itching imaginable". A higher score indicated a more severe outcome. The weekly mean of the daily values of the daily 24-hour WI-NRS was calculated for the analysis. Missing weekly mean WI-NRS data were imputed using missing at random (MAR) multiple imputation (MI) approach, assuming that participants who do not have weekly mean WI-NRS score at a timepoint would have similar weekly mean WI-NRS scores as other participants in their respective treatment arm who have complete data. The percentage of participants were estimated using a logistic regression model with terms for treatment group, baseline WI-NRS score, use of anti-itch medication during the week prior to randomisation, and the presence of specific medical conditions at baseline.

Time frame: From Baseline, and at Weeks 4, 8, and 12

Percentage of Participants Achieving at Least 4-point Improvement From Baseline With Respect to the Weekly Mean of the Daily 24-hour WI-NRS in the DB Period

Data from ClinicalTrials.gov

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Investigator Site 01

Beijing, China

Investigator Site 07

Beijing, China

Investigator Site 26

Changsha, China

Investigator Site 06

Guangzhou, China

Investigator Site 12

Jiaxing, China

Investigator Site 02

Lanzhou, China

Investigator Site 34

Mianyang, China

Investigator Site 03

Nanjing, China

Investigator Site 10

Nanjing, China

...and 25 more locations

Time frame: From Baseline, and at Weeks 4, 8, and 12

Change From Baseline in the Weekly Mean of the 24-hour WI-NRS Score at Each Week of the DB Period

On a daily basis, participants recorded the intensity of the worst itching they experienced over the past 24 hours using a NRS scale from 0 to 10, where 0 represents "no itching" and 10 was "worst itching imaginable". A higher score indicated a more severe outcome. The weekly mean of the daily values was calculated for the analysis. The weekly mean of the daily values of the daily 24-hour WI-NRS was calculated for the analysis. The MMRM model included use of prior anti-itch medication (yes/no), presence of specific medical conditions at baseline (yes/no), treatment, visit, and treatment-by-visit-interaction as fixed categorical effects and baseline WI-NRS score as fixed continuous effects.

Time frame: From Baseline to Weeks 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12

Change From Baseline in Itch-related Quality-of-life (QoL) as Assessed by the 5-D Itch Scale Total Score (DB Period)

The 5-D itch scale is a questionnaire where participants assess the 5 dimensions of itch (degree, duration, direction, disability, and distribution). The scores of each of the 5 domains are achieved separately and then summed together to obtain a total 5-D score. 5-D itch scale scores can potentially range between 5 (no pruritus) and 25 (most severe pruritus) where a higher score indicates a more severe outcome. The LS means of change from baseline in itch-related QoL as assessed by the 5-D itch scale total score was estimated using the MMRM method. The MMRM model included use of prior anti-itch medication (yes/no), presence of specific medical conditions at baseline (yes/no), treatment sequence, visit, and treatment sequence-by-visit-interaction as fixed categorical effects and baseline 5-D Itch score (total score) as fixed continuous effects.

Time frame: From Baseline to Weeks 4, 8, and 12

Change From Baseline in Itch-related QoL as Assessed by the 5-D Itch Scale Total Score (OLE Period)

Time frame: From Baseline to OLE Period - Weeks 4, 8, 12, and 14

Change From Baseline in Itch-related QoL as Assessed by the Skindex-10 Scale Total Score (DB Period)

The Skindex-10 scale is a questionnaire that measures QoL in relationship to the itch intensity. Participants are asked the question "During the past week, how often have you been bothered by" and respond by filling in 1 of 7 circles numbered from 0 (labelled with the anchor phrase "never bothered") to 6 (labelled as "always bothered") for each of the 10 questions. The total score is the sum of the numeric value of each answered question. Here, a higher score indicated a severe outcome. The LS means of change from baseline in itch-related QoL as assessed by the Skindex-10 scale total score was estimated using the MMRM method. The MMRM model included use of prior anti-itch medication (yes/no), presence of specific medical conditions at baseline (yes/no), treatment, visit, and treatment-by-visit-interaction as fixed categorical effects and baseline skindex-10 scale score (total score) as fixed continuous effects.

Time frame: From Baseline to Weeks 4, 8, and 12

Change From Baseline in Itch-related QoL as Assessed by the Skindex-10 Scale Total Score (OLE Period)

Time frame: From Baseline to OLE Period - Weeks 4, 8, 12, and 14

Patient Global Impression of Change

The Patient Global Impression of Change is a global participant reported outcome measure that assesses the change in itch (no change, improvement or worsening) overall relative to the start of the study. The scale has only 1 item, and the participant was asked to mark the category that best describes the change in itch ranging from "Very Much Improved" to "Very Much Worse". Number of participants within all individual categories are reported here.

Time frame: At Week 12

Number of Participants With Adverse Events (AEs)

Time frame: Up to Week 27 (12 weeks in DB + 14 weeks in OLE +1 week of follow up)

Number of Participants With Clinically Significant Abnormal 12-lead Electrocardiogram (ECG)

Time frame: Up to Week 27 (12 weeks in DB + 14 weeks in OLE +1 week of follow up)

Number of Participants With Clinically Relevant Change From Baseline in Vital Signs and Laboratory Evaluations

Time frame: From baseline to Week 27 (12 weeks in DB + 14 weeks in OLE +1 week of follow up)