| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Moderate-to-Severe Atopic Dermatitis |
|
| E.1.1.1 | Medical condition in easily understood language |
| Moderate-to-Severe Atopic Dermatitis |
|
| 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 | 100000004858 |
|
| 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 investigate the efficacy of nemolizumab administered in combination with topical background therapy (topical corticosteroids [TCS] with or without topical calcineurin inhibitors [TCI]) in adult subjects with moderate-to-severe atopic dermatitis (AD) who are not adequately controlled with or are not advised to use oral cyclosporine A (CsA) for medical reasons. |
|
| E.2.2 | Secondary objectives of the trial |
The secondary objective is to investigate the safety of nemolizumab in adult subjects with moderate-to-severe AD who are not adequately controlled with or are not advised to use oral CsA for medical
reasons. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Subjects aged ≥ 18 years at the screening visit.
2. Chronic AD for at least 2 years before the screening visit and confirmed according to American Academy of Dermatology Consensus Criteria at the time of the screening visit.
3. EASI score ≥ 20 at both the screening and baseline visits. Subjects with an EASI score of 18-19 at the screening visit only may be reevaluated once within 48 hours.
4. IGA score ≥ 3 (based on the IGA scale ranging from 0 to 4, in which 3 is moderate and 4 is severe) at both the screening and baseline visits.
5. AD involvement ≥ 10% of BSA at both the screening and baseline visits.
6. PP NRS score of at least 4.0 at the screening and baseline visit. The
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. The baseline PP NRS score will be determined based on the average of the daily PP NRS scores
(score ranging from 0 to 10) during the 7 days immediately preceding
baseline (rounding is not permitted). A minimum of 4 daily scores out of the 7 days immediately preceding baseline is required for this calculation.
7. Documented history of one of the following:
a. Previously exposed to CsA:
1) Inadequate response to CsA with previous exposure (defined as flare of AD during CsA tapering from a maximum of 6 weeks of high dose [5 mg/kg/day] to maintenance dose [2 to 3 mg/kg/day] or a flare after a minimum of 3 months on maintenance dose). Flare is defined as increase in signs and/or symptoms leading to escalation of therapy (ie, increase in dose, switch to a higher-potency TCS, or start of another systemic nonsteroidal immunosuppressive drug).
or
2) Previous requirement for CsA at doses > 5 mg/kg/day, or duration
beyond those specified in the prescribing information (> 1 year).
or
3) Intolerance and/or unacceptable toxicity (eg, elevated creatinine, elevated liver function tests, uncontrolled hypertension, paresthesia, headache, nausea, hypertrichosis) with previous CsA exposure.
b. CsA is medically inadvisable:
1) medical contraindications (e.g. uncontrolled hypertension on medication).
or
2) use of prohibited concomitant medications (e.g. statins, digoxin, macrolide antibiotics, barbiturates, anti-seizure drugs, nonsteroidal anti-inflammatory drugs, diuretics, angiotensin-converting-enzyme inhibitors, St John’s Wort, etc.).
or
3) increased susceptibility to CsA-induced renal damage (elevated creatinine) and/or liver damage (elevated function tests).
or
4) increased risk of serious infections.
or
5) hypersensitivity to CsA active substance or excipients.
Acceptable documentation includes patient records with information on CsA prescription and treatment outcome, other prohibitive medications/medical history, or written documentation of the conversation with the subject’s treating physician, if different than the investigator, as applicable.
8. Documented history by a physician (within 6 months before the screening visit) of inadequate response to topical medications or use of systemic therapies for control of the disease.
Inadequate response to TCS treatment (with or without TCI) is defined as inability to achieve good disease control defined as mild disease or better (eg, IGA ≤ 2) after use of at least a moderate potency TCS as recommended by the product prescribing information. TCS may be used with or without TCIs.
If documentation is not acceptable, subjects may be rescreened after such documentation is obtained.
9. Agree to apply a moisturizer throughout the study from the screening visit; agree to apply an authorized TCS, with or without TCI, from the screening visit and throughout the study as determined appropriate by the investigator.
Full list of inclusion criteria is included within the protocol. |
|
| E.4 | Principal exclusion criteria |
1.Body weight < 30 kg.
2.One or more of the following criteria at screening or baseline:
a. Exacerbation of asthma requiring hospitalization in the preceding 12 months.
b. 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).
d. Peak expiratory flow (PEF) < 80% of the predicted value.
Note: In the event that PEF is < 80% of the predicted value at the screening visit, PEF testing can be repeated once within 48 hours:
•For subjects without a history of asthma
•For subjects with a history of asthma but if the ACT score is >19 at screening
3. Current medical history of chronic obstructive pulmonary disease and/or chronic bronchitis.
4. 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 baseline visit, or any confirmed or suspected coronavirus disease 2019 (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 can be confirmed by recovery assessment methods, as described in the protocol.
Note: Subjects with chronic, stable use of prophylactic treatment for recurrent herpes viral infection can be included in this clinical study.
5. Positive serology results (hepatitis B surface antigen [HBsAg] or hepatitis B core antibody [HBcAb], hepatitis C [HCV] antibody with positive HCV RNA, or human immunodeficiency virus [HIV] antibody) at the screening visit.
Note: Subjects with a positive HBcAb and a negative HBsAg can be included if the hepatitis B surface antibody is positive (considered immune after a natural infection). Subjects who are positive for HCV antibody and negative for HCV RNA may be enrolled.
In the event of rescreening, the serology tests results (eg, 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.
6. 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.
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 test results 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.
7. Known or suspected immunosuppression or unusually frequent, recurrent, severe, or prolonged infections as per investigator judgment.
8. 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.
9. Presence of confounding skin conditions that may interfere with study assessments (eg, Netherton syndrome, psoriasis, cutaneous T-cell lymphoma [mycosis fungoides or Sezary syndrome], contact dermatitis, chronic actinic dermatitis, dermatitis herpetiformis).
10. Pregnant women (positive serum pregnancy test result at the screening visit or positive urine pregnancy test [UPT] at the baseline visit), breastfeeding women, or women planning a pregnancy during the clinical study.
11. Any medical or psychological condition or 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, or may interfere with study assessments (eg, poor venous access or needle-phobia).
12. Planned or expected major surgical procedure during the clinical study.
Full list of exclusion criteria is included within the protocol. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Proportion of subjects with EASI-75 (≥ 75% improvement in EASI from
baseline) at Week 16
Proportion of subjects with an improvement of PP NRS ≥ 4 at Week 16 |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
• Percent change from baseline in EASI at each visit through Week 16
• Proportion of subjects with at least 50%, 75%, or 90% improvement from baseline in EASI (EASI-50, EASI-75, and EASI-90) at each visit through Week 16.
• Percent change from baseline in PP NRS at each visit through Week 16.
• Proportion of subjects with an improvement of PP NRS ≥ 4 at Week 1, Week 2, and each visit through Week 16.
• Proportion of subjects with PP NRS < 2 at each visit through Week 16.
• Proportion of subjects with an Investigator Global Assessment (IGA) success (defined as an IGA of 0 [clear] or 1 [almost clear] and a ≥ 2-point reduction from baseline) at each visit through Week 16.
• Proportion of subjects with EASI-75 and improvement of PP NRS ≥ 4 at each visit through Week 16.
• Proportion of subjects with IGA success and improvement of PP NRS ≥ 4 at each visit through Week 16.
• Proportion of subjects with an improvement of sleep disturbance NRS (SD NRS) ≥ 4 at each visit through Week 16.
• Percent change from baseline in SD NRS at each visit through Week 16.
• Percent change from baseline in SCORing Atopic Dermatitis (SCORAD) and its components at each visit through Week 16.
• Change from baseline in percent of body surface area (BSA) affected by AD at each visit through Week 16.
• Proportion of subjects with prior CsA use achieving EASI-75 at each visit through Week 16.
• Change from baseline in individual components of the EASI (averaged across body regions) at each visit through Week 16.
• Change from baseline in AD-associated pain frequency through Week 16.
• Change from baseline in AD-associated pain intensity through Week 16.
• Incidence of rescue therapy use through Week 16.
• Change from baseline in percentage of itch-free days (based on PP NRS = 0/1) through Week 1 |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| 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 | No |
| 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) | 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 | 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 | 2 |
| 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.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 70 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| 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 | |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
| 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 | 7 |
| E.8.9.2 | In all countries concerned by the trial days | 13 |
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