| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Moderate-to-Severe Atopic Dermatitis |
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| E.1.1.1 | Medical condition in easily understood language |
| Moderate-to-Severe Atopic Dermatitis |
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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 | 21.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10003639 |
| E.1.2 | Term | Atopic dermatitis |
| 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 of the study is to assess the pharmacokinetics (PK) and safety and tolerability of nemolizumab administered concomitantly with topical corticosteroids (TCS) in pediatric subjects with moderate-to-severe atopic dermatitis (AD) not adequately controlled with topical treatments. |
|
| E.2.2 | Secondary objectives of the trial |
| The secondary objective of the study is to assess the efficacy of nemolizumab (CD14152) and to further characterize the relationship between nemolizumab concentrations and clinical efficacy endpoints. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Subjects ≥7 to <12 years of age or ≥2 to <7 years of age at the screening visit.
Note: Subjects aged 2 to 6 years can be enrolled only after the IA - 1.1 and the IDMC has assessed interim safety data from Cohort 1.1 (aged 7 to 11 years) and provided recommendations to the Sponsor, who will then determine the eligibility of this age group for enrollment in the study and confirm the dose. The Sponsor will send a written communication to the sites confirming that the study is open for enrollment of Cohort 2 (aged 2 to 6 years). This cohort must not be enrolled in the study until such communication is received.
2. Chronic AD that has been documented for at least 6 months for subjects aged 2-6 years and at least 1 year for subjects aged 7-11 years before the screening visit and confirmed according to the American Academy of Dermatology Consensus Criteria (Appendix 1) at the time of the screening visit.
3. Eczema Area and Severity Index (EASI) score ≥16 at both screening and baseline visits.
4. Investigator’s Global Assessment (IGA) score ≥3 (based on the IGA scale ranging from 0 to 4, in which 3 is moderate and 4 is severe) at both screening and baseline visits.
5. AD involvement ≥10% of Body Surface Area (BSA) at both screening and baseline visits.
6. Peak (maximum) Pruritus Numeric Rating Scale (PP NRS) score of at least 4.0 at both screening and baseline visits:
• Screening PP NRS score will be determined by a single PP NRS assessment (score ranging from 0 to 10) for the 24-hour period immediately preceding the screening visit.
• Baseline PP NRS score will be determined based on the average of daily PP NRS scores (score ranging from 0 to 10) during the 7 days immediately preceding baseline (rounding not permitted). A minimum of 4 daily scores out of the 7 days immediately preceding baseline is required for this calculation.
7. Documented history by a physician and/or investigator (within 6 months before the screening visit) of inadequate response to existing topical medication or use of systemic therapies for control of the disease.
8. Agree to apply a moisturizer throughout the study from the screening visit daily, and liberally as needed; agree to apply an authorized TCS, with or without TCI, from the screening visit and throughout the study as determined appropriate by the investigator.
9. Any female of childbearing potential (i.e., a subject who has started menstruating) who is, in the opinion of the investigator, sexually active and at risk for pregnancy must be willing and able either to be strictly abstinent or 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 [e.g., calendar, ovulation, symptothermal, post-ovulation methods] and withdrawal are not acceptable methods of contraception.)
• oral hormonal contraception
10. Subject and caregiver willing and able to comply with all of the time commitments and procedural requirements of the clinical trial protocol.
11. Understand and sign an Informed Consent Form (ICF) and Assent Form before any investigational procedures being performed.
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| E.4 | Principal exclusion criteria |
1. Body weight <10 kg.
2. Child in Care: a child who has been placed under the control or protection of an agency, organization, institution or entity by the courts, the government or a government body, acting in accordance with powers conferred on them by law or regulation.
3. Subjects meeting one or more of the following criteria at screening or baseline:
3a. Had a documented asthma exacerbation requiring hospitalization in the preceding 12 months.
3b. Reporting asthma that has not been well controlled as defined by one or more of the following:
• Daytime asthma symptoms >2 times per week during the preceding 3 months
• Nighttime awakenings with asthma symptoms >2 times per month during the preceding 3 months
• Asthma exacerbation requiring oral corticosteroid use >2 times per year
3c. Childhood Asthma Control Test (cACT) ≤19 (applies only for subjects with a history of asthma aged 7 to 11 years; cACT will not be performed for subjects aged 2 to 6 years).
3d. Peak expiratory flow (PEF) <80% of the predicted value (applies only for subjects aged 7 to 11 years; PEF will not be performed for subjects aged 2 to 6 years).
Note: In the event that PEF is <80% of the predicted value at screening in patients without any history of asthma or in patients with history of asthma but with the cACT score >19, PEF testing can be repeated once within 48 hours.
4. Subjects with a current medical history of chronic bronchitis.
5. Cutaneous infection within 1 week before the baseline visit or any infection requiring treatment with oral or parenteral antibiotics, antivirals, antiparasitics, or antifungals within 2 weeks before the baseline 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 8.3.4.2.
6. Requiring rescue therapy for AD during the run-in period or expected to require rescue therapy within 2 weeks following the baseline visit.
7. Positive serology results for 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 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 trial if hepatitis B surface antibody (HBsAb) is positive (considered immune after a natural infection). Subjects with negative confirmatory test for HCV can be included in this clinical study.
In the event of rescreening, the serology tests results (e.g., HBV, HCV, HIV) from the first screening can be used by the investigator to assess the eligibility of rescreened subjects if those tests were performed within 6 weeks prior to the baseline visit.
8. Current active tuberculosis (TB) or latent TB infection or history of either untreated or inadequately treated latent or active 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.
In the event of rescreening, the TB tests result from the first screening can be used by the investigator to assess the eligibility of rescreened subjects if the test was performed within 6 weeks prior to the baseline visit.
9. History of lymphoproliferative disease or history of malignancy of any organ system within the last 5 years or since birth for subjects <5 years of age.
10. History of hypersensitivity (including anaphylaxis) to an immunoglobulin product (plasma-derived or recombinant, e.g., monoclonal antibody) or to any of the study drug excipients.
11. History of intolerance to low or mid potency TCS or for whom TCS is not advisable (e.g., hypersensitivity to TCS, significant skin atrophy, etc.).
12. Known or suspected immunosuppression.
13. Presence of skin conditions that may interfere with study assessments (e.g., Netherton syndrome, psoriasis, contact dermatitis, chronic actinic dermatitis, dermatitis herpetiformis, erythroderma, ichthyosis, or scabies).
14. Having received any of the following treatments in Table 2 within the specified timeframe before the baseline visit.
Full list of exclusion criteria is included within the protocol.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Pharmacokinetics (PK):
•Nemolizumab serum concentrations at Weeks 4, 8, 12, 16, 32, and 52
•Nemolizumab serum PK parameters estimated with a population PK analysis
Safety:
• Incidence of adverse events (AEs), including treatment-emergent AEs (TEAEs), AEs of special interests (AESIs), AEs leading to discontinuation and serious AEs (SAEs) through the study. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| As specified within the list of endpoints |
|
| E.5.2 | Secondary end point(s) |
Efficacy:
• Absolute and percent change in EASI score from baseline at each visit up to Week 16 and up to Week 52.
• Proportion of subjects achieving 50%, 75% or 90% response in EASI [EASI-50, EASI-75 and EASI-90] at baseline and at each visit up to Week 16 and Week 52.
• IGA success rate (defined as an IGA of 0 [Clear] or 1 [Almost clear] and a ≥2-point improvement from baseline) at each visit up to Week 16 and up to Week 52.
• Change in BSA involvement of AD, reported as a percentage of all major body sections combined, from baseline at each visit up to Week 16 and up to Week 52.
• Absolute and percent change in weekly average of peak pruritus NRS (PP NRS) score from baseline at each visit up to Week 16 and up to Week 52.
• Proportion of subjects with an improvement of ≥4 from baseline in weekly average of PP NRS at visit up to Week 16 and Week 52.
• Absolute and percent change in weekly average of average pruritus NRS score from baseline at each visit and up to Week 16 and up Week 52.
• Absolute and percent change in weekly sleep disturbance NRS score from baseline at each visit up to Week 16 and up to Week 52.
• Proportion of subjects receiving any rescue therapy by rescue treatment type (e.g., topical, phototherapy, systemic) at any visit during the treatment period.
• Percent change in SCORing Atopic Dermatitis (SCORAD) score from baseline at each visit up to Week 16 and up to Week 52.
• Change in Children’s Dermatology Life Quality Index (cDLQI) for subjects ≥4 years of age from baseline up to Week 16 and up to Week 52.
• Change in Infants’ Dermatitis Quality of Life Index (IDQOL) for subjects <4 years of age from baseline up to Week 16 and up to Week 52.
• Change in Patient-Oriented Eczema Measure (POEM) from baseline up to Week 16 and up to Week 52.
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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 | 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 |
| Immunogenicity, Quality of life |
|
| 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) | No |
| 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 |
| single arm.Subject will be enrolled in 3 cohorts: Cohort 1&1.1: aged 7-11 years, Cohort 2: 2-6 years |
|
| 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 | 6 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 19 |
| 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 |
| Denmark |
| Hungary |
| Poland |
| Spain |
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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 | 3 |
| E.8.9.1 | In the Member State concerned months | 4 |
| E.8.9.1 | In the Member State concerned days | 27 |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 9 |
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