| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| E.1.1.1 | Medical condition in easily understood language |
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| 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 | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10037084 |
| E.1.2 | Term | Prurigo nodularis |
| E.1.2 | System Organ Class | 10040785 - Skin and subcutaneous tissue disorders |
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| 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 assess the long-term safety of nemolizumab (CD14152) in subjects with prurigo nodularis (PN). |
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| E.2.2 | Secondary objectives of the trial |
| The secondary objective is to assess the long-term efficacy of nemolizumab (CD14152) in subjects with PN. |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Individuals must meet all of the following criteria at screening and baseline, as applicable, to be included in the study (individuals reentering from the phase 3b durability study RD.06.SPR.203890 must meet all inclusion criteria at re-entry Week R0):
1. Subjects who may benefit from study participation in the opinion of the investigator and participated in a prior nemolizumab study for PN including:
a. Subjects who completed the treatment period in a phase 3 pivotal study (RD.06.SPR.202685 or RD.06.SPR.203065) and enroll within 56 days
OR
b. Subjects who were previously randomized in the nemolizumab phase 2a PN study (RD.03.SPR.115828).
c. Subjects who completed through Week 24 of the phase 3b durability study (RD.06.SPR.203890) or who exit the study due to relapse may be eligible to reenter in the LTE study within 28 days of exiting the durability study (selected countries/ selected sites)
2. Female subjects of childbearing potential (ie, fertile, following menarche and until becoming post-menopausal unless permanently sterile) must agree to use an adequate and approved method of contraception throughout the study and for 12 weeks after the last study drug injection.
Adequate and approved methods of contraception applicable for the subject and/or her partner are defined below:
• True abstinence, when in line with the preferred and usual lifestyle of the subject. Periodic abstinence (eg, calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception
• Progestogen-only oral hormonal contraception
• Combination of male condom with cap, diaphragm, or sponge with spermicide (double barrier methods) (*In Germany only, double barrier methods are not considered an adequate and approved method of contraception)
Note: “Double barrier methods” refers to simultaneous use of a physical barrier by each partner. Use of a single barrier method (eg, 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 3 months before the study
• Bilateral vasectomy of partner at least 3 months before the study
3. Female subjects of non-childbearing potential must meet one of the following criteria:
• Absence of menstrual bleeding for 1 year prior to screening without any other medical reason, confirmed with follicle stimulating hormone (FSH) level in the postmenopausal range
OR
• Documented hysterectomy, bilateral salpingectomy, or bilateral oophorectomy at least 3 months before the study.
4. Subject willing and able to comply with all of the time commitments and procedural requirements of the clinical study protocol, including periodic weekly recordings by the subject using an electronic handheld device provided for this study.
5. Understand and sign an informed consent form before any investigational procedure(s) are performed. |
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| E.4 | Principal exclusion criteria |
Individuals meeting any of the following criteria at screening or baseline are ineligible to participate in this study (individuals re-entering from the phase 3b durability study RD.06.SPR.203890 meeting any of the following criteria at the re-entry Week R0 visit are ineligible):
1. Subjects who, during their participation in a prior nemolizumab study, experienced an AE which in the opinion of the investigator could indicate that continued treatment with nemolizumab may present an unreasonable risk for the subject.
2. Body weight < 30 kg;
3. Having received any of the treatments listed in Table 7 in the protocolwithin the specified timeframe before the baseline or re-entry Week R0 visit.
4. Pregnant women (positive pregnancy test result at screening, baseline or re-entry Week R0 visit), breastfeeding women, or women planning a pregnancy during the clinical study;
5. Any medical or psychological condition that may put the subject at significant risk according to the investigator’s judgment, if he/she participates in the clinical study, or may interfere with study assessments (eg, poor venous access or needle-phobia).
6. Planning or expected to have a major surgical procedure during the clinical study.
7. Subjects unwilling to refrain from using prohibited medications during the clinical study.
8. History of alcohol or substance abuse within 6 months of the screening or re-entry Week R0 visit.
9. Subjects with a history of asthma meeting 1 or more of the following criteria:
a. Had an exacerbation of asthma requiring hospitalization in the preceding 12 months.
b. Reporting asthma that has not been well-controlled (ie, symptoms occurring on >2 days per week, nighttime awakenings 2 or more times per week, or some interference with normal activities) during the preceding 3 months.
c. Asthma Control Test (ACT) ≤19 (only for subjects with a history of asthma) at screening and baseline.
d. Peak expiratory flow (PEF) <80% of the predicted value at screening and baseline.
10. Subjects with a current medical history of chronic obstructive pulmonary disease and/or chronic bronchitis.
11. Cutaneous infection within 1 week before the baseline visit, any infection requiring treatment with oral or parenteral antibiotics, antivirals, antiparasitics or antifungals within 2 weeks before the aseline visit, or any confirmed or suspected coronavirus disease (COVID)-19 infection within 2 weeks before the screening or baseline visit. Subjects may be rescreened once the infection has resolved. Resolution of COVID-19 infection can be confirmed by recovery
assessment methods, as described in Section 8.4.2 of the protocol.
12. Positive serology results (hepatitis B surface antigen [HBsAg] or hepatitis B core antibody [HBcAb], hepatitis C (HCV) antibody with positive confirmatory test for HCV (eg, polymerase chain reaction
[PCR]), or or human immunodeficiency virus antibody) at screening.
13. Chronic pruritus resulting from another active condition than PN, such as but not limited to scabies, lichen simplex chronicus, psoriasis, atopic dermatitis, contact dermatitis, acne, folliculitis, lichen planus, habitual picking/excoriation disorder, sporotrichosis, bullous autoimmune disease, end-stage renal disease, or cholestatic liver disease (eg, primary biliary cirrhosis), or diabetes mellitus or thyroid disease that is not adequately treated, as per standard of care;
14. History of or current confounding skin condition (eg, Netherton syndrome, cutaneous T-cell lymphoma [mycosis fungoides or Sezary syndrome], chronic actinic dermatitis, dermatitis herpetiformis).
15. Subjects with active atopic dermatitis (signs and symptoms other
than dry skin) in the last 3 months;
16. Neuropathic and psychogenic pruritus, such as but not limited to notalgia paresthetica, brachioradial pruritus, small fiber neuropathy, skin picking syndrome, or delusional parasitosis.
17. History of lymphoproliferative disease or history of malignancy of any organ system within the last 5 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.
18. History of hypersensitivity (including anaphylaxis) to an immunoglobulin (plasma-derived or recombinant) product (eg, monoclonal antibody) or to any of the study drug excipients.
19. Current active or latent tuberculosis (TB) infection or history of either untreated or inadequately treated active or latent TB according to the local applicable guidelines;
20. Known or suspected immunosuppression or unusually frequent, recurrent, severe, or prolonged infections as per investigator judgment.
For the complete list of the exclusion criteria please refer to the study protocol.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Incidence and severity of adverse events (AEs), including AEs of special interest, treatment-emergent AEs, and serious AEs.
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
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| E.5.2 | Secondary end point(s) |
Efficacy Endpoints:
• Proportion of subjects with an IGA success (defined as IGA of 0 [Clear] or 1 [Almost clear]) at each visit up to Week 184
• Proportion of subjects with an improvement of ≥4 from baseline in PP NRS up to Week 184
• Proportion of subjects with low disease activity state (ie, IGA ≤2) at each visit up to Week 184
• Percentage of pruriginous lesions with excoriations/crusts (PAS item 5a) at each visit up to Week 184
• Percentage of healed prurigo lesions (PAS item 5b) at each visit up to Week 184
• Change from baseline in number of lesions in representative area (PAS item 4) at each visit up to Week 184
• Proportion of subjects with PP NRS <2 up to Week 184
• Absolute and percent change from baseline in PP NRS up to Week 184
• Proportion of subjects with AP NRS <2 up to Week 52
• Proportion of subjects with an improvement of ≥4 from baseline in AP NRS up to Week 52
• Absolute and percent change from baseline in AP NRS up to Week 52
• Proportion of subjects with an improvement of ≥4 from baseline in Sleep Disturbance (SD) NRS up to Week 184
• Absolute and percent change from baseline in SD NRS up to Week 184
• Change from baseline in PN-associated pain frequency up to Week 184
• Change from baseline in PN-associated pain intensity up to Week 184
• Proportion of subjects reporting low disease activity (clear, almost clear, or mild) based on Patient Global Assessment of Disease (PGAD) at each visit up to Week 52
• Proportion of subjects satisfied with study treatment (good, very good, or excellent) based on Patient Global Assessment of Treatment (PGAT) at each visit up to Week 52
• Proportion of subjects with an improvement of ≥4 from baseline in Dermatology Life Quality Index (DLQI) up to Week 184
• Change from baseline in EuroQoL 5-Dimension (EQ-5D) up to Week 184
• Time to permanent study drug discontinuation
• Time to rescue therapy use
• Proportion of subjects receiving any rescue treatment by rescue treatment
For subjects who re-entered from durability study (RD.06.SPR.203890):
• Proportion of subjects with an Investigator Global Assessment (IGA) success (defined as IGA of 0 [Clear] or 1 [Almost clear]) at each visit up to Week R132 by treatment and overall [relapsed, non-relapsed subjects]
• Proportion of subjects with an improvement of =4 from re-entry baseline in Peak Pruritus numeric rating scale (PP NRS) up to Week R132 by treatment and overall [relapsed subjects]
• Proportion of subjects with an improvement of =4 from baseline in Peak Pruritus numeric rating scale (PP NRS) up to Week R132 by treatment and overall [non-relapsed subjects]
• Proportion of subjects with recapture of clinical response, defined as: Investigator Global Assessment (IGA) success and an improvement of =4 from re entry baseline in Peak Pruritus numeric rating scale (PP NRS) up to Week R132 by treatment and overall [relapsed subjects]
• Proportion of subjects with maintenance of clinical response, defined as: Investigator Global Assessment (IGA) success and an improvement of =4 from baseline in Peak Pruritus numeric rating scale (PP NRS) up to Week R132 by treatment and overall [non-relapsed subjects]
• Proportion of subjects with an improvement =4 from baseline in Sleep Disturbance numeric rating scale (SD NRS) up to Week R132 by treatment and overall [relapsed and non-relapsed subjects]
• Proportion of subjects with an improvement =4 from baseline in Dermatology Life Quality Index (DLQI) up to Week R132 by treatment and overall [relapsed and non-relapsed subjects]
• Time to recapture of clinical response for relapsed subjects who received placebo in the durability study (RD.06.SPR.203890)
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| As specified within the list of endpoints |
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| 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 | Yes |
| 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 |
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| 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) | No |
| 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 | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
| Placebo used for blinded dosing at Day 1/baseline/re-entry Week R0 visit only to maintain the blind |
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| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 1 |
| 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 | 24 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 84 |
| 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 |
| Switzerland |
| Canada |
| Korea, Republic of |
| United Kingdom |
| United States |
| Austria |
| Belgium |
| Denmark |
| France |
| Germany |
| Hungary |
| Italy |
| Netherlands |
| Poland |
| Spain |
| Sweden |
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| 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
|
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 6 |
| E.8.9.1 | In the Member State concerned months | 3 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 6 |
| E.8.9.2 | In all countries concerned by the trial months | 9 |
| E.8.9.2 | In all countries concerned by the trial days | 20 |
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