Uremic Pruritus
Conditions
Keywords
Uremic Pruritus, Chronic kidney disease-associated pruritus, CKD-aP, Difelikefalin
Brief summary
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.
Detailed description
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.
Interventions
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.
DRUGPlacebo Injection
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.
Sponsors
Tigermed Consulting Co., Ltd
Vifor Fresenius Medical Care Renal Pharma
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 85 Years
Healthy volunteers
No
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)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in the Weekly Mean of the Daily 24-hour WI-NRS Score at Week 4 of the DB Period | From Baseline to Week 4 | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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 | From Baseline, and at Weeks 4, 8, and 12 | 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 MAR-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. |
| Change From Baseline in the Weekly Mean of the 24-hour WI-NRS Score at Each Week of the DB Period | From Baseline to Weeks 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12 | 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. |
| Change From Baseline in Itch-related Quality-of-life (QoL) as Assessed by the 5-D Itch Scale Total Score (DB Period) | From Baseline to Weeks 4, 8, and 12 | 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. |
| Change From Baseline in Itch-related QoL as Assessed by the 5-D Itch Scale Total Score (OLE Period) | From Baseline to OLE Period - Weeks 4, 8, 12, and 14 | 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. |
| Change From Baseline in Itch-related QoL as Assessed by the Skindex-10 Scale Total Score (DB Period) | From Baseline to Weeks 4, 8, and 12 | 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. |
| 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 | From Baseline, and at Weeks 4, 8, and 12 | 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. |
| Patient Global Impression of Change | At Week 12 | 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. |
| Number of Participants With Adverse Events (AEs) | 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) | 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 | From baseline to Week 27 (12 weeks in DB + 14 weeks in OLE +1 week of follow up) | — |
| Change From Baseline in Itch-related QoL as Assessed by the Skindex-10 Scale Total Score (OLE Period) | From Baseline to OLE Period - Weeks 4, 8, 12, and 14 | 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. |
Countries
China
Participant flow
Recruitment details
This study was conducted at 35 investigative sites in China.
Pre-assignment details
A total of 291 participants were screened, and 31 of these were screen failures. Of the screened participants, 260 were randomized in the study. Of these 260 participants, 227 completed the double blind (DB) treatment period and 217 of these participants entered the open-label extension (OLE) period of the study.
Participants by arm
| Arm | Count |
|---|---|
| DB Period: Difelikefalin Participants received Difelikefalin injected into the venous line of the dialysis circuit at the end of each dialysis session for up to 12 weeks (3 times weekly, 36 times in total). | 129 |
| DB Period: Placebo Participants received Placebo injected into the venous line of the dialysis circuit at the end of each dialysis session matching to Difelikefalin for up to 12 weeks (3 times weekly, 36 times in total). | 130 |
| Total | 259 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| DB Period | Adverse Event | 4 | 4 |
| DB Period | Lost to Follow-up | 0 | 1 |
| DB Period | Other: Unspecified | 2 | 2 |
| DB Period | Physician Decision | 2 | 0 |
| DB Period | Withdrawal by Subject | 12 | 6 |
| OLE Period | Adverse Event | 3 | 2 |
| OLE Period | Other: Unspecified | 2 | 1 |
| OLE Period | Physician Decision | 1 | 0 |
| OLE Period | Withdrawal by Subject | 5 | 5 |
Baseline characteristics
| Characteristic | Total | DB Period: Difelikefalin | DB Period: Placebo |
|---|---|---|---|
| Age, Continuous | 56.0 years STANDARD_DEVIATION 12.3 | 56.3 years STANDARD_DEVIATION 12.26 | 55.7 years STANDARD_DEVIATION 12.38 |
| Race/Ethnicity, Customized Asian - Chinese | 259 Participants | 129 Participants | 130 Participants |
| Sex: Female, Male Female | 86 Participants | 44 Participants | 42 Participants |
| Sex: Female, Male Male | 173 Participants | 85 Participants | 88 Participants |
| WI-NRS | 7.18 score on a scale STANDARD_DEVIATION 1.268 | 7.35 score on a scale STANDARD_DEVIATION 1.291 | 7.00 score on a scale STANDARD_DEVIATION 1.223 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 129 | 0 / 130 | 0 / 103 | 0 / 113 |
| other Total, other adverse events | 85 / 129 | 66 / 130 | 65 / 103 | 69 / 113 |
| serious Total, serious adverse events | 18 / 129 | 12 / 130 | 19 / 103 | 12 / 113 |
Outcome results
Primary
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
Population: Analysis was performed on the FAS. The FAS included all participants who were randomized to treatment, received at least 1 dose of investigational product and had a non-missing baseline assessment for the weekly mean of the daily 24-hour WI-NRS score. Here, 'overall number of participants analyzed', 'N' = participants with available data for this outcome measure.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| DB Period: Difelikefalin | Change From Baseline in the Weekly Mean of the Daily 24-hour WI-NRS Score at Week 4 of the DB Period | -2.09 score on a scale | Standard Error 0.198 |
| DB Period: Placebo | Change From Baseline in the Weekly Mean of the Daily 24-hour WI-NRS Score at Week 4 of the DB Period | -1.27 score on a scale | Standard Error 0.194 |
Comparison: The null hypothesis in this study was that there was no treatment difference in the primary efficacy analysis of the primary endpoint. The alternative hypothesis was that in participants randomized to difelikefalin there was a significant treatment difference in change in itching compared to participants randomized to placebo. The assessment was based on the mean change from baseline in the weekly mean of the daily 24-hour WI-NRS score at Week 4 of the DB period.p-value: 0.000395% CI: [-1.25, -0.37]MMRM
Secondary
Change From Baseline in Itch-related QoL as Assessed by the 5-D Itch Scale Total Score (OLE 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 OLE Period - Weeks 4, 8, 12, and 14
Population: Analysis was performed on the OLE Safety Analysis Set, which included all participants who received at least 1 dose of IP in the OLE period. Here, 'number analyzed', 'n' = participants with available data for each specified timepoint.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| DB Period: Difelikefalin | Change From Baseline in Itch-related QoL as Assessed by the 5-D Itch Scale Total Score (OLE Period) | Week 4 | -5.0 score on a scale | Standard Error 0.4 |
| DB Period: Difelikefalin | Change From Baseline in Itch-related QoL as Assessed by the 5-D Itch Scale Total Score (OLE Period) | Week 8 | -5.4 score on a scale | Standard Error 0.4 |
| DB Period: Difelikefalin | Change From Baseline in Itch-related QoL as Assessed by the 5-D Itch Scale Total Score (OLE Period) | Week 12 | -5.7 score on a scale | Standard Error 0.41 |
| DB Period: Difelikefalin | Change From Baseline in Itch-related QoL as Assessed by the 5-D Itch Scale Total Score (OLE Period) | Week 14 | -6.2 score on a scale | Standard Error 0.41 |
| DB Period: Placebo | Change From Baseline in Itch-related QoL as Assessed by the 5-D Itch Scale Total Score (OLE Period) | Week 14 | -6.0 score on a scale | Standard Error 0.38 |
| DB Period: Placebo | Change From Baseline in Itch-related QoL as Assessed by the 5-D Itch Scale Total Score (OLE Period) | Week 4 | -5.3 score on a scale | Standard Error 0.38 |
| DB Period: Placebo | Change From Baseline in Itch-related QoL as Assessed by the 5-D Itch Scale Total Score (OLE Period) | Week 12 | -6.0 score on a scale | Standard Error 0.39 |
| DB Period: Placebo | Change From Baseline in Itch-related QoL as Assessed by the 5-D Itch Scale Total Score (OLE Period) | Week 8 | -5.8 score on a scale | Standard Error 0.37 |
Secondary
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
Population: Analysis was performed on FAS. The FAS included all participants who were randomized to treatment, received at least 1 dose of investigational product and had a non-missing baseline assessment for the weekly mean of the daily 24-hour WI-NRS score. Here, 'number analyzed', 'n' = participants with available data for each specified timepoint.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| DB Period: Difelikefalin | Change From Baseline in Itch-related QoL as Assessed by the Skindex-10 Scale Total Score (DB Period) | Week 4 | -9.1 score on a scale | Standard Error 1.46 |
| DB Period: Difelikefalin | Change From Baseline in Itch-related QoL as Assessed by the Skindex-10 Scale Total Score (DB Period) | Week 8 | -11.3 score on a scale | Standard Error 1.51 |
| DB Period: Difelikefalin | Change From Baseline in Itch-related QoL as Assessed by the Skindex-10 Scale Total Score (DB Period) | Week 12 | -10.5 score on a scale | Standard Error 1.59 |
| DB Period: Placebo | Change From Baseline in Itch-related QoL as Assessed by the Skindex-10 Scale Total Score (DB Period) | Week 4 | -5.1 score on a scale | Standard Error 1.43 |
| DB Period: Placebo | Change From Baseline in Itch-related QoL as Assessed by the Skindex-10 Scale Total Score (DB Period) | Week 8 | -7.4 score on a scale | Standard Error 1.48 |
| DB Period: Placebo | Change From Baseline in Itch-related QoL as Assessed by the Skindex-10 Scale Total Score (DB Period) | Week 12 | -9.5 score on a scale | Standard Error 1.55 |
Secondary
Change From Baseline in Itch-related QoL as Assessed by the Skindex-10 Scale Total Score (OLE 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 OLE Period - Weeks 4, 8, 12, and 14
Population: For the OLE period analysis was performed on OLE-SAS, which included all participants who received at least 1 dose of IP in the OLE period. Here, 'number analyzed', 'n' = participants with available data for each specified timepoint.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| DB Period: Difelikefalin | Change From Baseline in Itch-related QoL as Assessed by the Skindex-10 Scale Total Score (OLE Period) | Week 4 | -14.7 score on a scale | Standard Error 1.47 |
| DB Period: Difelikefalin | Change From Baseline in Itch-related QoL as Assessed by the Skindex-10 Scale Total Score (OLE Period) | Week 8 | -15.8 score on a scale | Standard Error 1.49 |
| DB Period: Difelikefalin | Change From Baseline in Itch-related QoL as Assessed by the Skindex-10 Scale Total Score (OLE Period) | Week 12 | -17.5 score on a scale | Standard Error 1.48 |
| DB Period: Difelikefalin | Change From Baseline in Itch-related QoL as Assessed by the Skindex-10 Scale Total Score (OLE Period) | Week 14 | -18.3 score on a scale | Standard Error 1.56 |
| DB Period: Placebo | Change From Baseline in Itch-related QoL as Assessed by the Skindex-10 Scale Total Score (OLE Period) | Week 14 | -15.8 score on a scale | Standard Error 1.48 |
| DB Period: Placebo | Change From Baseline in Itch-related QoL as Assessed by the Skindex-10 Scale Total Score (OLE Period) | Week 4 | -14.1 score on a scale | Standard Error 1.39 |
| DB Period: Placebo | Change From Baseline in Itch-related QoL as Assessed by the Skindex-10 Scale Total Score (OLE Period) | Week 12 | -16.4 score on a scale | Standard Error 1.39 |
| DB Period: Placebo | Change From Baseline in Itch-related QoL as Assessed by the Skindex-10 Scale Total Score (OLE Period) | Week 8 | -15.2 score on a scale | Standard Error 1.41 |
Secondary
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
Population: Analysis was performed on FAS. The FAS included all participants who were randomized to treatment, received at least 1 dose of investigational product and had a non-missing baseline assessment for the weekly mean of the daily 24-hour WI-NRS score. Here, 'number analyzed', 'n' = participants with available data for each specified timepoint.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| DB Period: Difelikefalin | Change From Baseline in Itch-related Quality-of-life (QoL) as Assessed by the 5-D Itch Scale Total Score (DB Period) | Week 4 | -3.3 score on a scale | Standard Error 0.37 |
| DB Period: Difelikefalin | Change From Baseline in Itch-related Quality-of-life (QoL) as Assessed by the 5-D Itch Scale Total Score (DB Period) | Week 8 | -3.9 score on a scale | Standard Error 0.38 |
| DB Period: Difelikefalin | Change From Baseline in Itch-related Quality-of-life (QoL) as Assessed by the 5-D Itch Scale Total Score (DB Period) | Week 12 | -4.3 score on a scale | Standard Error 0.4 |
| DB Period: Placebo | Change From Baseline in Itch-related Quality-of-life (QoL) as Assessed by the 5-D Itch Scale Total Score (DB Period) | Week 4 | -2.5 score on a scale | Standard Error 0.36 |
| DB Period: Placebo | Change From Baseline in Itch-related Quality-of-life (QoL) as Assessed by the 5-D Itch Scale Total Score (DB Period) | Week 8 | -2.8 score on a scale | Standard Error 0.37 |
| DB Period: Placebo | Change From Baseline in Itch-related Quality-of-life (QoL) as Assessed by the 5-D Itch Scale Total Score (DB Period) | Week 12 | -3.6 score on a scale | Standard Error 0.39 |
Secondary
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
Population: Analysis was performed on FAS. The FAS included all participants who were randomized to treatment, received at least 1 dose of investigational product and had a non-missing baseline assessment for the weekly mean of the daily 24-hour WI-NRS score. Here, 'number analyzed', 'n' = participants with available data for each specified timepoint.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| DB Period: Difelikefalin | Change From Baseline in the Weekly Mean of the 24-hour WI-NRS Score at Each Week of the DB Period | Week 2 | -1.37 score on a scale | Standard Error 0.179 |
| DB Period: Difelikefalin | Change From Baseline in the Weekly Mean of the 24-hour WI-NRS Score at Each Week of the DB Period | Week 3 | -1.86 score on a scale | Standard Error 0.188 |
| DB Period: Difelikefalin | Change From Baseline in the Weekly Mean of the 24-hour WI-NRS Score at Each Week of the DB Period | Week 4 | -2.09 score on a scale | Standard Error 0.198 |
| DB Period: Difelikefalin | Change From Baseline in the Weekly Mean of the 24-hour WI-NRS Score at Each Week of the DB Period | Week 5 | -2.35 score on a scale | Standard Error 0.208 |
| DB Period: Difelikefalin | Change From Baseline in the Weekly Mean of the 24-hour WI-NRS Score at Each Week of the DB Period | Week 6 | -2.51 score on a scale | Standard Error 0.216 |
| DB Period: Difelikefalin | Change From Baseline in the Weekly Mean of the 24-hour WI-NRS Score at Each Week of the DB Period | Week 7 | -2.61 score on a scale | Standard Error 0.219 |
| DB Period: Difelikefalin | Change From Baseline in the Weekly Mean of the 24-hour WI-NRS Score at Each Week of the DB Period | Week 8 | -2.71 score on a scale | Standard Error 0.222 |
| DB Period: Difelikefalin | Change From Baseline in the Weekly Mean of the 24-hour WI-NRS Score at Each Week of the DB Period | Week 9 | -2.90 score on a scale | Standard Error 0.223 |
| DB Period: Difelikefalin | Change From Baseline in the Weekly Mean of the 24-hour WI-NRS Score at Each Week of the DB Period | Week 1 | -0.68 score on a scale | Standard Error 0.153 |
| DB Period: Difelikefalin | Change From Baseline in the Weekly Mean of the 24-hour WI-NRS Score at Each Week of the DB Period | Week 10 | -2.97 score on a scale | Standard Error 0.227 |
| DB Period: Difelikefalin | Change From Baseline in the Weekly Mean of the 24-hour WI-NRS Score at Each Week of the DB Period | Week 11 | -3.08 score on a scale | Standard Error 0.228 |
| DB Period: Difelikefalin | Change From Baseline in the Weekly Mean of the 24-hour WI-NRS Score at Each Week of the DB Period | Week 12 | -3.11 score on a scale | Standard Error 0.235 |
| DB Period: Placebo | Change From Baseline in the Weekly Mean of the 24-hour WI-NRS Score at Each Week of the DB Period | Week 11 | -2.16 score on a scale | Standard Error 0.223 |
| DB Period: Placebo | Change From Baseline in the Weekly Mean of the 24-hour WI-NRS Score at Each Week of the DB Period | Week 2 | -0.89 score on a scale | Standard Error 0.175 |
| DB Period: Placebo | Change From Baseline in the Weekly Mean of the 24-hour WI-NRS Score at Each Week of the DB Period | Week 8 | -1.96 score on a scale | Standard Error 0.217 |
| DB Period: Placebo | Change From Baseline in the Weekly Mean of the 24-hour WI-NRS Score at Each Week of the DB Period | Week 3 | -1.08 score on a scale | Standard Error 0.185 |
| DB Period: Placebo | Change From Baseline in the Weekly Mean of the 24-hour WI-NRS Score at Each Week of the DB Period | Week 10 | -2.04 score on a scale | Standard Error 0.222 |
| DB Period: Placebo | Change From Baseline in the Weekly Mean of the 24-hour WI-NRS Score at Each Week of the DB Period | Week 4 | -1.27 score on a scale | Standard Error 0.194 |
| DB Period: Placebo | Change From Baseline in the Weekly Mean of the 24-hour WI-NRS Score at Each Week of the DB Period | Week 12 | -2.16 score on a scale | Standard Error 0.229 |
| DB Period: Placebo | Change From Baseline in the Weekly Mean of the 24-hour WI-NRS Score at Each Week of the DB Period | Week 5 | -1.46 score on a scale | Standard Error 0.204 |
| DB Period: Placebo | Change From Baseline in the Weekly Mean of the 24-hour WI-NRS Score at Each Week of the DB Period | Week 1 | -0.53 score on a scale | Standard Error 0.149 |
| DB Period: Placebo | Change From Baseline in the Weekly Mean of the 24-hour WI-NRS Score at Each Week of the DB Period | Week 6 | -1.55 score on a scale | Standard Error 0.212 |
| DB Period: Placebo | Change From Baseline in the Weekly Mean of the 24-hour WI-NRS Score at Each Week of the DB Period | Week 9 | -2.00 score on a scale | Standard Error 0.218 |
| DB Period: Placebo | Change From Baseline in the Weekly Mean of the 24-hour WI-NRS Score at Each Week of the DB Period | Week 7 | -1.78 score on a scale | Standard Error 0.215 |
Secondary
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)
Population: Analysis was performed on safety analysis set in DB period (DB-SAF). DB-SAF included all randomized participants who received at least 1 dose of investigational product during the DB period. For the OLE period analysis was performed on OLE Safety Analysis Set, which included all participants who received at least 1 dose of IP in the OLE period.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| DB Period: Difelikefalin | Number of Participants With Adverse Events (AEs) | 106 Participants |
| DB Period: Placebo | Number of Participants With Adverse Events (AEs) | 92 Participants |
| OLE Period: Difelikefalin/Difelikefalin | Number of Participants With Adverse Events (AEs) | 82 Participants |
| OLE Period: Placebo/Difelikefalin | Number of Participants With Adverse Events (AEs) | 90 Participants |
Secondary
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)
Population: The DB and OLE SAS consisted of all participants who received at least 1 dose of investigational product during the DB period and OLE period, respectively. Participants were analysed according to the actual treatment received.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| DB Period: Difelikefalin | Number of Participants With Clinically Relevant Change From Baseline in Vital Signs and Laboratory Evaluations | 0 Participants |
| DB Period: Placebo | Number of Participants With Clinically Relevant Change From Baseline in Vital Signs and Laboratory Evaluations | 0 Participants |
Secondary
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)
Population: The DB and OLE SAS consisted of all participants who received at least 1 dose of investigational product during the DB period and OLE period, respectively. Participants were analysed according to the actual treatment received. Here, 'number analyzed', 'n' = participants with available data for each specified timepoint.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| DB Period: Difelikefalin | Number of Participants With Clinically Significant Abnormal 12-lead Electrocardiogram (ECG) | DB period: Week 12 | 41 Participants |
| DB Period: Difelikefalin | Number of Participants With Clinically Significant Abnormal 12-lead Electrocardiogram (ECG) | OLE period: Week 14 | 34 Participants |
| DB Period: Placebo | Number of Participants With Clinically Significant Abnormal 12-lead Electrocardiogram (ECG) | DB period: Week 12 | 48 Participants |
| DB Period: Placebo | Number of Participants With Clinically Significant Abnormal 12-lead Electrocardiogram (ECG) | OLE period: Week 14 | 46 Participants |
Secondary
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
Population: Analysis was performed on FAS. The FAS included all participants who were randomized to treatment, received at least 1 dose of investigational product and had a non-missing baseline assessment for the weekly mean of the daily 24-hour WI-NRS score. Here, 'overall number of participants analyzed', 'N' = participants with available data for the outcome measure.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| DB Period: Difelikefalin | Patient Global Impression of Change | Very Much worse | 0 Participants |
| DB Period: Difelikefalin | Patient Global Impression of Change | Very much improved | 20 Participants |
| DB Period: Difelikefalin | Patient Global Impression of Change | Much improved | 46 Participants |
| DB Period: Difelikefalin | Patient Global Impression of Change | Minimally improved | 22 Participants |
| DB Period: Difelikefalin | Patient Global Impression of Change | No change | 18 Participants |
| DB Period: Difelikefalin | Patient Global Impression of Change | Minimally worse | 2 Participants |
| DB Period: Difelikefalin | Patient Global Impression of Change | Much worse | 2 Participants |
| DB Period: Placebo | Patient Global Impression of Change | Very Much worse | 0 Participants |
| DB Period: Placebo | Patient Global Impression of Change | No change | 24 Participants |
| DB Period: Placebo | Patient Global Impression of Change | Very much improved | 14 Participants |
| DB Period: Placebo | Patient Global Impression of Change | Much worse | 1 Participants |
| DB Period: Placebo | Patient Global Impression of Change | Much improved | 29 Participants |
| DB Period: Placebo | Patient Global Impression of Change | Minimally worse | 2 Participants |
| DB Period: Placebo | Patient Global Impression of Change | Minimally improved | 49 Participants |
Secondary
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
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 MAR-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.
Time frame: From Baseline, and at Weeks 4, 8, and 12
Population: Analysis was performed on FAS. The FAS included all participants who were randomized to treatment, received at least 1 dose of investigational product and had a non-missing baseline assessment for the weekly mean of the daily 24-hour WI-NRS score. Here, 'number analyzed', 'n' = participants with available data for each specified timepoint.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| DB Period: Difelikefalin | 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 | Week 8 | 21.2 percentage of participants |
| DB Period: Difelikefalin | 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 | Week 12 | 29.9 percentage of participants |
| DB Period: Difelikefalin | 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 | Week 4 | 10.9 percentage of participants |
| DB Period: Placebo | 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 | Week 8 | 11.6 percentage of participants |
| DB Period: Placebo | 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 | Week 12 | 19.7 percentage of participants |
| DB Period: Placebo | 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 | Week 4 | 2.2 percentage of participants |
Secondary
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
Population: Analysis was performed on FAS. The FAS included all participants who were randomized to treatment, received at least 1 dose of investigational product and had a non-missing baseline assessment for the weekly mean of the daily 24-hour WI-NRS score. Here, 'number analyzed', 'n' = participants with available data for each specified timepoint.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| DB Period: Difelikefalin | 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 | Week 4 | 21.9 percentage of participants |
| DB Period: Difelikefalin | 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 | Week 8 | 35.8 percentage of participants |
| DB Period: Difelikefalin | 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 | Week 12 | 48.7 percentage of participants |
| DB Period: Placebo | 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 | Week 4 | 8.9 percentage of participants |
| DB Period: Placebo | 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 | Week 8 | 22.3 percentage of participants |
| DB Period: Placebo | 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 | Week 12 | 33.8 percentage of participants |