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Double-blind, Placebo-controlled study to confirm the superiority of MR13A9 to placebo, and followed by extension, open-label treatment to confirm long-term safety of MA13A9 in hemodialysis patients with pruritus.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| MR13A9/MR13A9 | Experimental | Patients are administered MR13A9 for 6 weeks (double-blind period), followed by MR13A9 for 52 weeks (open-label period). |
|
| Placebo/MR13A9 | Placebo Comparator | Patients are administered Placebo for 6 weeks (double-blind period), followed by MR13A9 for 52 weeks (open-label period). |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| MR13A9 | Drug | Intravenous administration |
| |
| Measure | Description | Time Frame |
|---|---|---|
| Change From Baseline in the Mean NRS Score at Week 4 | The change from baseline in the mean NRS score at each time point was calculated using an MMRM with the change from baseline in the mean NRS score at each time point as an objective variable, group, time point, and group-by-time point interaction as fixed effects, mean NRS score at baseline and presence or absence of prior treatment with nalfurafine hydrochloride as dynamic allocation factors as a covariate, and subjects as a random effect for data up to Week 4 of the double-blind period in FAS. Looking back on the period between the time of awakening on the previous day of assessment and the time of awakening on the day of assessment (including sleeping hours) once daily, subjects will assess the NRS score for the most severe itching by themselves. The most severe itching within the day will be assessed in integer on a scale ranging from 0 to 10, where 0 represents no itching and 10 represents worst itching imaginable. | 4 weeks |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Yoshitaka Shimizu | Kissei Pharmaceutical Co., Ltd. | Study Director |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Research Site | Multiple Locations | Japan |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 38320524 | Derived | Narita I, Tsubakihara Y, Takahashi N, Ebata T, Uchiyama T, Marumo M, Okamura S, Gejyo F; MR13A9-5 Trial Investigators. Difelikefalin for Hemodialysis Patients with Pruritus in Japan. NEJM Evid. 2023 Nov;2(11):EVIDoa2300094. doi: 10.1056/EVIDoa2300094. Epub 2023 Oct 17. |
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Previously treated hemodialysis patients with pruritus were enrolled in a 1:1 ratio to either MR13A9 0.5 μg/kg group or Placebo group. Subjects who received placebo in the double-blind period received MR13A9 0.5 μg/kg in the extension period.
Two hundred thirty subjects were screened. A total of 178 subjects included in the study and were randomly assigned to the study drug. The number of subjects in the double-blind period (6 weeks) was 178. The number of subjects who transitioned to the extension period (52 weeks) was 168. The number of subjects who completed Week 58 was 122.
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| ID | Title | Description |
|---|---|---|
| FG000 | Double Blind Period: MR13A9 0.5 μg/kg Group | MR13A9 was injected into the venous line of the dialysis circuit at the end of each dialysis session for 6 weeks (3 times weekly, 18 times in total). The dose of the study drug was determined according to mentioned below based on the subject's dry weight before dialysis on the start day of the screening period.
|
| FG001 | Double Blind Period: Placebo Group | Placebo was injected into the venous line of the dialysis circuit at the end of each dialysis session for 6 weeks (3 times weekly, 18 times in total). The dose of the study drug was determined according to mentioned below based on the subject's dry weight before dialysis on the start day of the screening period.
|
| FG002 | Entire Study: MR13A9/MR13A9 Group | [Double-blind period (6 weeks)] The subjects in this group received the investigational drug for 6 weeks as the MR13A9 0.5 μg/kg group. [Extension period (52 weeks)] The study drug was injected into the venous line of the dialysis circuit at the end of each dialysis session for 52 weeks (3 times weekly, 156 times in total). The dose of the study drug was determined according to mentioned below, and the dose of the study drug from Week 6 to immediately before Week 34 will be determined based on the subject's dry weight before dialysis at Week 6. The dose of the study drug after Week 34 will be determined based on the subject's dry weight before dialysis at Week 34. The study drug (MR13A9) will not be administered at Week 58.
|
| FG003 | Entire Study: Placebo/MR13A9 Group | [Double-blind period (6 weeks)] The subjects in this group received the investigational drug for 6 weeks as the Placebo group. [Extension period (52 weeks)] The study drug was injected into the venous line of the dialysis circuit at the end of each dialysis session for 52 weeks (3 times weekly, 156 times in total). The dose of the study drug was determined according to mentioned below, and the dose of the study drug from Week 6 to immediately before Week 34 will be determined based on the subject's dry weight before dialysis at Week 6. The dose of the study drug after Week 34 will be determined based on the subject's dry weight before dialysis at Week 34. The study drug (MR13A9) will not be administered at Week 58.
|
| Title | Milestones | Reasons Not Completed | ||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Double-blind Period (6 Weeks) |
|
| ||||||||||||||||||
| Extension Period (52 Weeks) |
|
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| ID | Title | Description |
|---|---|---|
| BG000 | MR13A9 0.5 μg/kg Group | The study drug was injected into the venous line of the dialysis circuit at the end of each dialysis session for 6 weeks (3 times weekly, 18 times in total). The dose of the study drug (MR13A9) was determined according to mentioned below based on the subject's dry weight before dialysis on the start day of the screening period.
|
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | ||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Change From Baseline in the Mean NRS Score at Week 4 | The change from baseline in the mean NRS score at each time point was calculated using an MMRM with the change from baseline in the mean NRS score at each time point as an objective variable, group, time point, and group-by-time point interaction as fixed effects, mean NRS score at baseline and presence or absence of prior treatment with nalfurafine hydrochloride as dynamic allocation factors as a covariate, and subjects as a random effect for data up to Week 4 of the double-blind period in FAS. Looking back on the period between the time of awakening on the previous day of assessment and the time of awakening on the day of assessment (including sleeping hours) once daily, subjects will assess the NRS score for the most severe itching by themselves. The most severe itching within the day will be assessed in integer on a scale ranging from 0 to 10, where 0 represents no itching and 10 represents worst itching imaginable. | Posted | Mean | Standard Error | points | 4 weeks |
|
Up to Week 58 (6-week Double Blind Treatment Period and 52-week Extension Period)
Adverse Events were not collected separately for the Extension Period, but rather were pre-specified to be collected for the separate "MR-MR Group" and "P-MR Group" Arms/Groups separately for the Double Blind Period and for the entire study. Therefore, we have presented separate Arms/Groups for the Double-Blind Period (data monitored/assessed over 6 weeks), and the Entire Study Period (data monitored/assessed over 58 weeks)
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Double Blind Period: MR13A9 0.5 μg/kg Group | MR13A9 was injected into the venous line of the dialysis circuit at the end of each dialysis session for 6 weeks (3 times weekly, 18 times in total). The dose of the study drug was determined according to mentioned below based on the subject's dry weight before dialysis on the start day of the screening period.
|
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Immune thrombocytopenia | Blood and lymphatic system disorders | MedDRA version 23.1 | Systematic Assessment |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Constipation | Gastrointestinal disorders | MedDRA version 23.1 | Systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Clinical Development Division | Kissei Pharmaceutical Co., Ltd | Email olly | rinsyousiken@pharm.kissei.co.jp |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot | Yes | No | No | Study Protocol | Oct 28, 2020 | Mar 26, 2025 | Prot_000.pdf |
| SAP | No | Yes | No | Statistical Analysis Plan | Oct 24, 2022 | Mar 26, 2025 | SAP_001.pdf |
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| Placebo |
| Drug |
Intravenous administration |
|
| Lack of Efficacy |
|
| Protocol Violation |
|
| 4 consecutive missed doses of the study drug |
|
| COMPLETED |
|
| NOT COMPLETED |
|
|
| BG001 | Placebo Group | The study drug was injected into the venous line of the dialysis circuit at the end of each dialysis session for 6 weeks (3 times weekly, 18 times in total). |
| BG002 | Total | Total of all reporting groups |
| Participants |
|
| Age, Continuous | Mean | Standard Deviation | years |
|
| Age, Customized | Median | Inter-Quartile Range | years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Ethnicity (NIH/OMB) | Count of Participants | Participants |
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| Race (NIH/OMB) | Count of Participants | Participants |
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| Region of Enrollment | Number | participants |
|
| Dry Weight at the start of Screening | Mean | Standard Deviation | kg |
|
| Hemodialysis History | Mean | Standard Deviation | years |
|
| Disease Duration of Itch | Mean | Standard Deviation | years |
|
| Average NRS Score | Looking back on the period between the time of awakening on the previous day of assessment and the time of awakening on the day of assessment (including sleeping hours) once daily, subjects will assess the NRS score for the most severe itching by themselves. The most severe itching within the day will be assessed in integer on a scale ranging from 0 to 10, where 0 represents no itching and 10 represents worst itching imaginable. | Mean | Standard Deviation | points |
|
The study drug was injected into the venous line of the dialysis circuit at the end of each dialysis session for 6 weeks (3 times weekly, 18 times in total). The dose of the study drug (MR13A9) was determined according to mentioned below based on the subject's dry weight before dialysis on the start day of the screening period.
|
| OG001 | Placebo Group | The study drug was injected into the venous line of the dialysis circuit at the end of each dialysis session for 6 weeks (3 times weekly, 18 times in total). |
|
|
|
| 0 |
| 89 |
| 7 |
| 89 |
| 27 |
| 89 |
| EG001 | Double Blind Period: Placebo Group | Placebo was injected into the venous line of the dialysis circuit at the end of each dialysis session for 6 weeks (3 times weekly, 18 times in total). The dose of the study drug was determined according to mentioned below based on the subject's dry weight before dialysis on the start day of the screening period.
| 1 | 89 | 10 | 89 | 24 | 89 |
| EG002 | Entire Study: MR-MR Group | [Double-blind period (6 weeks)] The subjects in this group received the investigational drug for 6 weeks as the MR13A9 0.5 μg/kg group. [Extension period (52 weeks)] The study drug was injected into the venous line of the dialysis circuit at the end of each dialysis session for 52 weeks (3 times weekly, 156 times in total). The dose of the study drug was determined according to mentioned below, and the dose of the study drug from Week 6 to immediately before Week 34 will be determined based on the subject's dry weight before dialysis at Week 6. The dose of the study drug after Week 34 will be determined based on the subject's dry weight before dialysis at Week 34. The study drug (MR13A9) will not be administered at Week 58.
| 2 | 85 | 33 | 85 | 74 | 85 |
| EG003 | Entire Study: P-MR Group | [Double-blind period (6 weeks)] The subjects in this group received the investigational drug for 6 weeks as the Placebo group. [Extension period (52 weeks)] The study drug was injected into the venous line of the dialysis circuit at the end of each dialysis session for 52 weeks (3 times weekly, 156 times in total). The dose of the study drug was determined according to mentioned below, and the dose of the study drug from Week 6 to immediately before Week 34 will be determined based on the subject's dry weight before dialysis at Week 6. The dose of the study drug after Week 34 will be determined based on the subject's dry weight before dialysis at Week 34. The study drug (MR13A9) will not be administered at Week 58.
| 2 | 83 | 38 | 83 | 74 | 83 |
| Nephrogenic anaemia | Blood and lymphatic system disorders | MedDRA version 23.1 | Non-systematic Assessment |
|
| Acute myocardial infarction | Cardiac disorders | MedDRA version 23.1 | Non-systematic Assessment |
|
| Angina pectoris | Cardiac disorders | MedDRA version 23.1 | Non-systematic Assessment |
|
| Angina unstable | Cardiac disorders | MedDRA version 23.1 | Non-systematic Assessment |
|
| Cardiac failure | Cardiac disorders | MedDRA version 23.1 | Non-systematic Assessment |
|
| Cardiac failure acute | Cardiac disorders | MedDRA version 23.1 | Non-systematic Assessment |
|
| Coronary artery stenosis | Cardiac disorders | MedDRA version 23.1 | Non-systematic Assessment |
|
| Myocardial ischaemia | Cardiac disorders | MedDRA version 23.1 | Non-systematic Assessment |
|
| Paroxysmal atrioventricular block | Cardiac disorders | MedDRA version 23.1 | Non-systematic Assessment |
|
| Sinus tachycardia | Cardiac disorders | MedDRA version 23.1 | Non-systematic Assessment |
|
| Cataract | Eye disorders | MedDRA version 23.1 | Non-systematic Assessment |
|
| Anal prolapse | Gastrointestinal disorders | MedDRA version 23.1 | Non-systematic Assessment |
|
| Colitis ischaemic | Gastrointestinal disorders | MedDRA version 23.1 | Non-systematic Assessment |
|
| Diverticular perforation | Gastrointestinal disorders | MedDRA version 23.1 | Non-systematic Assessment |
|
| Enterocolitis | Gastrointestinal disorders | MedDRA version 23.1 | Non-systematic Assessment |
|
| Gastric polyps | Gastrointestinal disorders | MedDRA version 23.1 | Non-systematic Assessment |
|
| Gastric ulcer haemorrhage | Gastrointestinal disorders | MedDRA version 23.1 | Non-systematic Assessment |
|
| Gastrointestinal haemorrhage | Gastrointestinal disorders | MedDRA version 23.1 | Non-systematic Assessment |
|
| Haematemesis | Gastrointestinal disorders | MedDRA version 23.1 | Non-systematic Assessment |
|
| Inguinal hernia | Gastrointestinal disorders | MedDRA version 23.1 | Non-systematic Assessment |
|
| Malaise | General disorders | MedDRA version 23.1 | Non-systematic Assessment |
|
| Pyrexia | General disorders | MedDRA version 23.1 | Non-systematic Assessment |
|
| Cholangitis acute | Hepatobiliary disorders | MedDRA version 23.1 | Non-systematic Assessment |
|
| Cholecystitis acute | Hepatobiliary disorders | MedDRA version 23.1 | Non-systematic Assessment |
|
| Hepatic function abnormal | Hepatobiliary disorders | MedDRA version 23.1 | Non-systematic Assessment |
|
| Liver injury | Hepatobiliary disorders | MedDRA version 23.1 | Non-systematic Assessment |
|
| Anaphylactic shock | Immune system disorders | MedDRA version 23.1 | Non-systematic Assessment |
|
| Appendicitis | Infections and infestations | MedDRA version 23.1 | Non-systematic Assessment |
|
| Bacteraemia | Infections and infestations | MedDRA version 23.1 | Non-systematic Assessment |
|
| COVID-19 pneumonia | Infections and infestations | MedDRA version 23.1 | Non-systematic Assessment |
|
| Cellulitis | Infections and infestations | MedDRA version 23.1 | Non-systematic Assessment |
|
| Gastroenteritis | Infections and infestations | MedDRA version 23.1 | Non-systematic Assessment |
|
| Pneumonia | Infections and infestations | MedDRA version 23.1 | Non-systematic Assessment |
|
| Renal cyst infection | Infections and infestations | MedDRA version 23.1 | Non-systematic Assessment |
|
| Sepsis | Infections and infestations | MedDRA version 23.1 | Non-systematic Assessment |
|
| Shunt infection | Infections and infestations | MedDRA version 23.1 | Non-systematic Assessment |
|
| Tuberculosis | Infections and infestations | MedDRA version 23.1 | Non-systematic Assessment |
|
| Urinary tract infection | Infections and infestations | MedDRA version 23.1 | Non-systematic Assessment |
|
| Cataract operation complication | Injury, poisoning and procedural complications | MedDRA version 23.1 | Non-systematic Assessment |
|
| Contusion | Injury, poisoning and procedural complications | MedDRA version 23.1 | Systematic Assessment |
|
| Shunt aneurysm | Injury, poisoning and procedural complications | MedDRA version 23.1 | Non-systematic Assessment |
|
| Shunt occlusion | Injury, poisoning and procedural complications | MedDRA version 23.1 | Non-systematic Assessment |
|
| Shunt stenosis | Injury, poisoning and procedural complications | MedDRA version 23.1 | Non-systematic Assessment |
|
| Blood pressure decreased | Investigations | MedDRA version 23.1 | Non-systematic Assessment |
|
| Decreased appetite | Metabolism and nutrition disorders | MedDRA version 23.1 | Non-systematic Assessment |
|
| Diabetes mellitus | Metabolism and nutrition disorders | MedDRA version 23.1 | Non-systematic Assessment |
|
| Lumbar spinal stenosis | Musculoskeletal and connective tissue disorders | MedDRA version 23.1 | Non-systematic Assessment |
|
| Osteonecrosis | Musculoskeletal and connective tissue disorders | MedDRA version 23.1 | Non-systematic Assessment |
|
| Spinal stenosis | Musculoskeletal and connective tissue disorders | MedDRA version 23.1 | Non-systematic Assessment |
|
| Spondylitis | Musculoskeletal and connective tissue disorders | MedDRA version 23.1 | Non-systematic Assessment |
|
| Chronic myeloid leukaemia | Neoplasms benign, malignant and unspecified (incl cysts and polyps) | MedDRA version 23.1 | Non-systematic Assessment |
|
| Clear cell renal cell carcinoma | Neoplasms benign, malignant and unspecified (incl cysts and polyps) | MedDRA version 23.1 | Non-systematic Assessment |
|
| Gastric cancer | Neoplasms benign, malignant and unspecified (incl cysts and polyps) | MedDRA version 23.1 | Non-systematic Assessment |
|
| Renal cancer | Neoplasms benign, malignant and unspecified (incl cysts and polyps) | MedDRA version 23.1 | Non-systematic Assessment |
|
| Brain stem infarction | Nervous system disorders | MedDRA version 23.1 | Non-systematic Assessment |
|
| Cerebral infarction | Nervous system disorders | MedDRA version 23.1 | Non-systematic Assessment |
|
| Status epilepticus | Nervous system disorders | MedDRA version 23.1 | Non-systematic Assessment |
|
| Aspiration | Respiratory, thoracic and mediastinal disorders | MedDRA version 23.1 | Non-systematic Assessment |
|
| Pneumonia aspiration | Respiratory, thoracic and mediastinal disorders | MedDRA version 23.1 | Non-systematic Assessment |
|
| Respiratory failure | Respiratory, thoracic and mediastinal disorders | MedDRA version 23.1 | Non-systematic Assessment |
|
| Skin ulcer | Skin and subcutaneous tissue disorders | MedDRA version 23.1 | Non-systematic Assessment |
|
| Large intestinal polypectomy | Surgical and medical procedures | MedDRA version 23.1 | Non-systematic Assessment |
|
| Aortic stenosis | Vascular disorders | MedDRA version 23.1 | Non-systematic Assessment |
|
| Hypertension | Vascular disorders | MedDRA version 23.1 | Non-systematic Assessment |
|
| Peripheral arterial occlusive disease | Vascular disorders | MedDRA version 23.1 | Non-systematic Assessment |
|
| Cardiac failure congestive | Cardiac disorders | MedDRA version 23.1 | Non-systematic Assessment |
|
| Diarrhoea | Gastrointestinal disorders | MedDRA version 23.1 | Non-systematic Assessment |
|
| Haemorrhoids | Gastrointestinal disorders | MedDRA version 23.1 | Non-systematic Assessment |
|
| Nausea | Gastrointestinal disorders | MedDRA version 23.1 | Non-systematic Assessment |
|
| Vomiting | Gastrointestinal disorders | MedDRA version 23.1 | Non-systematic Assessment |
|
| Pyrexia | General disorders | MedDRA version 23.1 | Non-systematic Assessment |
|
| Vaccination site pain | General disorders | MedDRA version 23.1 | Non-systematic Assessment |
|
| Gastroenteritis | Infections and infestations | MedDRA version 23.1 | Non-systematic Assessment |
|
| Nasopharyngitis | Infections and infestations | MedDRA version 23.1 | Non-systematic Assessment |
|
| Pneumonia | Infections and infestations | MedDRA version 23.1 | Non-systematic Assessment |
|
| Contusion | Injury, poisoning and procedural complications | MedDRA version 23.1 | Non-systematic Assessment |
|
| Fall | Injury, poisoning and procedural complications | MedDRA version 23.1 | Non-systematic Assessment |
|
| Shunt stenosis | Injury, poisoning and procedural complications | MedDRA version 23.1 | Non-systematic Assessment |
|
| Skin abrasion | Injury, poisoning and procedural complications | MedDRA version 23.1 | Non-systematic Assessment |
|
| Vaccination complication | Injury, poisoning and procedural complications | MedDRA version 23.1 | Non-systematic Assessment |
|
| Wound | Injury, poisoning and procedural complications | MedDRA version 23.1 | Non-systematic Assessment |
|
| Diabetes mellitus | Metabolism and nutrition disorders | MedDRA version 23.1 | Non-systematic Assessment |
|
| Arthralgia | Musculoskeletal and connective tissue disorders | MedDRA version 23.1 | Non-systematic Assessment |
|
| Back pain | Musculoskeletal and connective tissue disorders | MedDRA version 23.1 | Non-systematic Assessment |
|
| Myalgia | Musculoskeletal and connective tissue disorders | MedDRA version 23.1 | Non-systematic Assessment |
|
| Pain in extremity | Musculoskeletal and connective tissue disorders | MedDRA version 23.1 | Non-systematic Assessment |
|
| Dizziness | Nervous system disorders | MedDRA version 23.1 | Non-systematic Assessment |
|
| Headache | Nervous system disorders | MedDRA version 23.1 | Non-systematic Assessment |
|
| Insomnia | Psychiatric disorders | MedDRA version 23.1 | Non-systematic Assessment |
|
| Eczema | Skin and subcutaneous tissue disorders | MedDRA version 23.1 | Non-systematic Assessment |
|
| Hyperkeratosis | Skin and subcutaneous tissue disorders | MedDRA version 23.1 | Non-systematic Assessment |
|
| Dialysis hypotension | Vascular disorders | MedDRA version 23.1 | Non-systematic Assessment |
|
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