| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Chronic Kidney Disease Associated Severe Pruritus |
|
| E.1.1.1 | Medical condition in easily understood language |
| Chronic Kidney Disease Associated Severe Pruritus |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Skin and Connective Tissue Diseases [C17] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 24.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10037087 |
| E.1.2 | Term | Pruritus |
| E.1.2 | System Organ Class | 10040785 - Skin and subcutaneous tissue disorders |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| The primary objective is to evaluate the efficacy of nemolizumab compared to placebo at reducing the intensity of pruritus after a 12-week treatment period in adult hemodialysis subjects with moderate to severe pruritus. |
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| E.2.2 | Secondary objectives of the trial |
| The secondary objectives are to evaluate the safety of nemolizumab compared to placebo, and to assess the pharmacokinetics (PK) and optimal dose in adult hemodialysis subjects with moderate to severe pruritus. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1.Subjects aged ≥ 18 years at the screening visit.
2.Have end-stage kidney disease (ESKD) and have been on hemodialysis three times per week for at least three months prior to the start of screening.
Note 1: Subjects who require an occasional additional hemodialysis treatment to manage fluid overload may be enrolled as long as it is anticipated that no more than one such treatment will be required in any given week.
Note 2: Subjects having received in-home hemodialysis may participate as long as they have switched to in-center hemodialysis at least two weeks prior to screening and plan to remain on in-center hemodialysis for the duration of the study.
3.Hemodialysis subjects meeting the Kidney Outcome Quality Initiative Guidelines of hemodialysis adequacy within 60 days of screening, two:
Single-pool Kt/V measurements of at least 1.2.
4.Pruritus for ≥ three months (documented pruritus with no etiology identified other than CKD by medical record, previous physician’s letter/statement, or written documentation by site investigators based on the medical history obtained from the subject).
5.WI NRS score ≥ 5.0 at the screening and baseline visit. Screening WI NRS score will be determined by a single WI NRS assessment (score ranging from 0 to 10) for the 24-hour period immediately preceding the screening visit. Baseline WI NRS score will be determined based on the weekly average of daily WI NRS scores (score ranging from 0 to 10) during the seven days immediately preceding baseline (rounding is not permitted). A minimum of four daily scores out of the seven days immediately preceding baseline is required for this calculation.
6.Women of childbearing potential (WOCBP) (i.e., fertile, following menarche and until becoming post-menopausal unless permanently sterile) must agree either to commit to true abstinence throughout the study and for 12 weeks after the last study drug injection, when this is in line with the preferred and usual lifestyle of the subject, or to use an adequate and approved method of contraception throughout the study and for 12 weeks after the last study injection.
Adequate and approved methods of contraception applicable for the subject and/or her partner are defined below:
Progestogen-only oral hormonal contraception.
Combination of male condom with cap, diaphragm, or sponge with spermicide (double-barrier methods).
Note: “Double barrier methods” refers to simultaneous use of a physical barrier by each partner. Use of a single barrier method (e.g., condom) together with a spermicide is not acceptable.
Combined (estrogen- and progestogen-containing) oral, intravaginal, or transdermal hormonal contraception.
Injectable or implanted hormonal contraception.
Intrauterine devices or intrauterine hormone releasing system.
Bilateral tubal ligation or tube insert (such as the Essure system) at least three months before the study.
Bilateral vasectomy of partner at least three months before the study.
7.Women are considered to be of non-childbearing potential if they meet one of the following criteria:
Absence of menstrual bleeding for one year prior to screening without any other medical reason, confirmed with follicle stimulating hormone (FSH) level in the postmenopausal range.
Documented hysterectomy, bilateral salpingectomy, or bilateral oophorectomy at least three months before screening.
Note: Bilateral tubal ligation is not accepted as reason for non-childbearing potential.
8.Subject willing and able to comply with all time commitments and procedural requirements of the clinical study protocol.
9.Understands and signs an informed consent form (ICF) before any investigational procedure(s) are performed.
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| E.4 | Principal exclusion criteria |
1.Body weight < 30 kg.
2.Pruritus caused by a concomitant condition unrelated to ESKD.
3.Localized itch of only the palms of the hands and/or soles of the feet.
4.Pruritus present only during hemodialysis session.
5.History of or anticipated non-compliance with hemodialysis.
6.New York Heart Association Class IV symptoms or myocardial infarction within three months prior to screening.
7.History of stroke or transient ischemic attack within six months prior to screening.
8.Subjects meeting one or more of the following criteria at screening or baseline:
a.Had an exacerbation of asthma requiring hospitalization in the preceding 12 months.
b.Reporting asthma that has not been well-controlled during the preceding three months.
c.Asthma Control Test (ACT) ≤ 19 (only for subjects with a history of asthma).
d.Peak expiratory flow (PEF) < 80% of the predicted value.
9.Cutaneous infection within one week before the baseline visit, any infection requiring treatment with oral or parenteral antibiotics, antivirals, antiparasitics or antifungals within two weeks before the baseline visit.
10.Any confirmed or suspected coronavirus disease (COVID-19) infection within two weeks before the screening or baseline visit. Subjects may be rescreened after the infection has resolved. Resolution of COVID-19 infection can be confirmed by recovery assessment methods, as described in the protocol.
11.Positive serology results (hepatitis B surface antigen [HbsAg] or hepatitis B core antibody [HbcAb], hepatitis C [HCV] antibody with positive confirmatory test for hepatitis C virus [HCV] (e.g., HCV polymerase chain reaction [PRC]), or human immunodeficiency virus [HIV] antibody) at the screening visit.
Note: Subjects with a positive HbcAb and a negative HbsAg can be included in this clinical study if hepatitis B surface antibody is positive
. Subjects who are positive for HCV antibody and negative for HCV RNA may be enrolled.
In the event of rescreening, the serology tests results (e.g., HBV, HCV, HIV) from the previous screening can be used by the investigator to assess the eligibility of rescreened subjects if those tests were performed within six weeks prior to the baseline visit.
12.Known active or untreated latent tuberculosis (TB) infection or history of either untreated or inadequately treated active or latent TB according to the local applicable guidelines.
Note: Subjects who have a documented history of completion of an appropriate TB treatment regimen for latent or active TB with no history of re-exposure to TB since their treatment was completed are eligible to participate in the study.
13.Known or suspected immunosuppression beyond that expected due to end-stage kidney disease and its comorbidities or unusually frequent, recurrent, severe, or prolonged infections as per investigator judgment.
14.History of lymphoproliferative disease or history of malignancy of any organ system within the last five years, except for (1) basal cell carcinoma, squamous cell carcinoma in situ (Bowen’s disease), or carcinomas in situ of the cervix that have been treated and have no evidence of recurrence in the last 12 weeks before the baseline visit, or (2) actinic keratoses that have been treated.
15.Pregnant women, breastfeeding women, or women planning a pregnancy during the clinical study.
16.In the opinion of the investigator the subject has any medical or psychological condition that could pose undue risk to the subject, prevent study completion, or adversely affect the validity or interpretability of the study measurements or interfered with study assessments.
17.Any clinically relevant laboratory abnormalities, such as but not limited to elevated alanine aminotransferase (ALT) or aspartate aminotransferase (AST) (> 3 × upper limit of normal [ULN]) in combination with elevated bilirubin
(> 2 × ULN), during the screening period that may put the subject at significant risk according to the investigator’s judgment, if he/she participates in the clinical study.
18.Planned or expected major surgical procedure during the clinical study, including a scheduled kidney transplant during the study. Subjects on a kidney transplant waiting list with no scheduled transplant date are not excluded.
19.Has not adhered to the restrictions in the selected medications and dialysis procedures prior to screening or is not expected to be compliant with restrictions during the study.
20.Requiring rescue therapy for pruritus during the screening period or expected to require rescue therapy within 4 weeks following the baseline visit.
21.Previous treatment with nemolizumab.
22.History of hypersensitivity to an immunoglobulin product or to any of the study drug excipients.
23.Currently participating or participated in any other study of an investigational drug or device, within the past four weeks before the screening visit.
24.History of alcohol or substance abuse within six months of the screening visit.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Data of both nemolizumab groups (30 mg and 60 mg) and placebo group and comparisons versus placebo group of both nemolizumab groups will be presented.
In adult hemodialysis patients with chronic kidney disease and associated moderate to severe pruritus, 2 nemolizumab dosing schedules[1] compared to placebo by the difference in proportions of responders where response is defined as an improvement from baseline of WI NRS ≥ 4 at Week 12 without use of rescue therapies and without treatment discontinuation due to lack of efficacy or AE/death related to
study drug. Treatment: Conditions: initial dose of nemolizumab (60 mg) or placebo at baseline, then nemolizumab (30 mg or 60 mg) or placebo Q4W at Weeks 4 and 8 via subcutaneous injection.
Population: adult hemodialysis patients with chronic kidney disease and associated moderate to severe pruritus (will be estimated in the (Intent-to-
Treat analysis set).
Variable: a binary composite response where: Responder is defined as an improvement ≥ 4 in WI NRS from baseline at Week 12 without use of rescue therapies and without treatment discontinuation due to lack of efficacy or AE/death related to study drug.
Non-responder is defined as an improvement < 4 in WI NRS from baseline at Week 12 or use of rescue therapies or treatment
discontinuation due to lack of efficacy or AE/death related to study drug.
Strategies for Intercurrent Events: A composite strategy was chosen for the use of rescue therapies and treatment discontinuation due to lack of
efficacy or AE/death related to study drug; in case of use of rescue
therapies or treatment discontinuation due to lack of efficacy or
AE/death related to study drug, subjects will be considered as treatment failures in the binary composite response. In the case of treatment discontinuation, for any other reason, a treatment policy strategy will be used and observed after discontinuation data (if available) will be used.
Summary measure: treatment difference of nemolizumab from placebo in proportions of responders. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
1.Proportion of subjects with an improvement of WI NRS ≥ 3 from baseline at Week 12.
2.Proportion of subjects with an improvement of WI NRS ≥ 4 from baseline at Week 4.
3.Proportion of subjects with an improvement of SD NRS ≥ 4 from baseline at Week 12.
4.Proportion of subjects with an improvement of WI NRS ≥ 3 from baseline at Week 4.
5.Proportion of subjects with an improvement of SD NRS ≥ 4 from baseline at Week 4.
6.Change from baseline in Skindex 10 score at Week 12.
7.Change from baseline in ItchyQoL score at Week 12.
8.Change from baseline in Hospital Anxiety and Depression Scale (HADS) depression subscale at Week 12.
9.Change from baseline in Hospital Anxiety and Depression Scale (HADS) anxiety subscale at Week 12.
10.Change from baseline in EQ-5D-5L at Week 12.
11.Percent change from baseline in WI NRS score at Week 12.
12.Percent change from baseline in WI NRS score at Week 4.
13.Percent change from baseline in SD NRS score at Week 12.
14.Percent change from baseline in SD NRS score at Week 4.
15.Time to onset of effect on pruritus from baseline (defined as the day when the weekly average of WI NRS shows a change from baseline ≥ 4).
16.Proportion of subjects with an improvement of WI NRS ≥ 4 from baseline at Week 1.
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Week 1 or Week 4 or Week 12 |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
|
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 3 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 7 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 16 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| United States |
| Hungary |
| Poland |
| Spain |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
| Last Patient Last Visit (LPLV) Follow-up included |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | 4 |
| E.8.9.1 | In the Member State concerned days | 11 |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 11 |
| E.8.9.2 | In all countries concerned by the trial days | 14 |
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