| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Moderate to severe atopic dermatitis (AD) |
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| E.1.1.1 | Medical condition in easily understood language |
| Atopic dermatitis is also known as atopic eczema. It is a type of inflammation of the skin that results in itchy, red, swollen, and cracked skin. |
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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 | 100000004858 |
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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 |
| To compare the efficacy of abrocitinib 200 mg once daily (QD) versus dupilumab (as per label guidelines) in adult participants on background topical therapy with moderate to severe atopic dermatitis (AD). |
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| E.2.2 | Secondary objectives of the trial |
• To compare the efficacy of abrocitinib 200 mg once daily versus dupilumab on additional efficacy endpoints in adult participants on background topical therapy with moderate to severe atopic dermatitis (AD).
• To compare the efficacy of abrocitinib 200 mg once daily versus dupilumab on additional efficacy endpoints in adult participants on background topical therapy with moderate to severe atopic dermatitis (AD). |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Participants are eligible to be included in the study only if all of the following criteria apply:
Age
1. Participants must be 18 years of age or older inclusive, at the time of signing the informed consent.
Type of Participant and Disease Characteristics
2. Participants who meet all of the following atopic dermatitis criteria:
• Clinical diagnosis of chronic atopic dermatitis (also known as atopic eczema) for at least 6 months prior to Day 1 and has confirmed atopic dermatitis at the screening and baseline visits according to Hanifin and Rajka criteria for AD. Refer to Appendix 9.
• Documented recent history (within 6 months before the screening visit) of inadequate response to treatment with medicated topical therapy for AD for at least 4 consecutive weeks, or who have required systemic therapies for control of their disease within the past year. NOTE: Medicated topical therapy is defined as a topical product that contains an active pharmaceutical ingredient indicated for the treatment of AD (irrespective of whether it is an over the counter [OTC] or prescribed product).
• Moderate to severe AD (BSA ≥ 10%, IGA ≥ 3, EASI ≥ 16, and PP-NRS severity score ≥ 4 on the day of the baseline visit).
Sex
3. Male or Female
Contraceptive use by men or women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies.
a. Male participants:
No contraceptive measures are required.
b. Female participants:
A female participant is eligible to participate if she is not pregnant or breastfeeding, and at least one of the following conditions applies:
• Is not a woman of childbearing potential (WOCBP) (see definition in Section 10.4.3)
OR
•Is a WOCBP and using a contraceptive method that is highly effective (with a failure rate of <1% per year), as described below, during the intervention period and for at least 28 days after the last dose of study intervention, which corresponds to the time needed to eliminate any reproductive safety risk of the study intervention(s). If a highly effective method that is user dependent is chosen, a second effective method of contraception, as described below, must also be used. The investigator should evaluate the effectiveness of the contraceptive method in relationship to the first dose of study intervention.
The investigator is responsible for review of medical history, menstrual history, and recent sexual activity to decrease the risk for inclusion of a woman with an early undetected pregnancy.
4. Capable of giving signed informed consent as described in Appendix 1 which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol.
5. For the treatment of AD, the participant may use low- or medium-potency medicated and non-medicated topical therapy, with response to treatment remaining inadequate at baseline. The participant must also be willing and able to comply with standardized background topical therapy, as per protocol guidelines Section 6.5.1, throughout the remainder of the study.
6. Participants willing and able to comply with scheduled visits, treatment plan, laboratory tests, lifestyle considerations, and other study procedures.
7. Participants must agree to avoid prolonged exposure to the sun and to refrain from the use of tanning booths, sun lamps, and other sources of ultraviolet light during the study.
8. If participants are receiving concomitant medications for any reason other than AD, these participants must be on a stable regimen, which is defined as not starting a new drug or changing dosage within 7 days or 5 half-lives (whichever is longer) prior to Day 1. Administration of these stable regimen concomitant medications will be allowed to continue throughout the study.
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| E.4 | Principal exclusion criteria |
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions
1. Other acute or chronic medical condition including laboratory abnormality that may increase the risk associated with study participation or study intervention administration or may interfere with the interpretation of study results and, in the judgement of the investigator, would make the participant inappropriate for entry into this study.
2. The participant should have a risk assessment done by a qualified mental health professional (MHP) to assess whether it is safe to participate in the trial if the participant’s responses on any of the screening instruments or other screening information indicate:
• Suicidal ideation associated with actual intent and a method or plan in the past year: “Yes” answers on items 4 or 5 of the Columbia Suicide Severity Rating Scale (C-SSRS).
• Previous history of suicidal behaviors in the past 5 years: “Yes” answer (for events that occurred in the past 5 years) to any of the suicidal behavior items of the C-SSRS.
• Any lifetime history of serious or recurrent suicidal behavior (non-suicidal self-injurious behavior is not a trigger for a risk assessment unless in the investigator’s judgement it is indicated).
• Clinically significant depression: Patient Health Questionnaire 8 items (PHQ-8) when the total score is ≥15.
• The presence of any current major psychiatric disorder that is not explicitly permitted in the inclusion/exclusion criteria.
• In the investigator’s judgment a risk assessment or exclusion is required.
3. Have increased risk of developing venous thromboembolism, e.g. deep vein thrombosis or pulmonary embolism:
•History of venous thromboembolism, or
•First-degree relative with unprovoked venous thromboembolism (i.e. without known underlying cause such as trauma, surgery, immobilization, prolonged travel, pregnancy, hormone use, or plaster cast), that would suggest participant is at increased risk of inherited coagulation disorder (e.g. Factor V Leiden).
4. A current or past medical history of conditions associated with thrombocytopenia, coagulopathy, or platelet dysfunction.
5. Receiving anti-coagulants or medications known to cause thrombocytopenia (unless considered safe to stop and washout for the duration of the study).
6. Currently have active forms of other inflammatory skin diseases (ie, not AD) or have evidence of skin conditions (eg, psoriasis, seborrheic dermatitis, Lupus) at the time of Day 1 that would interfere with evaluation of AD or response to treatment.
7. Have a history of any lymphoproliferative disorder such as Epstein Barr virus (EBV), related lymphoproliferative disorder, history of lymphoma, leukemia, or signs or symptoms suggestive of current lymphatic or lymphoid disease.
8. Infection history:
• Have a history of systemic infection requiring hospitalization, parenteral antimicrobial therapy, or as otherwise judged clinically significant by the investigator within 6 months prior to Day 1;
• Have a known helminth infection;
• Have active chronic or acute skin infection requiring treatment with systemic antimicrobials within 2 weeks prior to Day 1, or superficial skin infections within 1 week prior to Day 1;
• A participant known to be infected with human immunodeficiency virus (HIV), Hepatitis B, or Hepatitis C.
• Participants who are hepatitis B surface antigen (HBsAg) negative, hepatitis B core antibody (HBcAb) positive, and hepatitis B surface antibody (HBsAb) positive at Screening will have reflex testing for hepatitis B Virus (HBV) deoxyribose nucleic acid (DNA). Participants who have HBV DNA above the lower limit of quantification (LLQ) are excluded. Participants who have HBV DNA negative or below LLQ may be randomized but will have HBV DNA testing repeated at Week 16 and Week 26 End of Treatment (EOT) visit, or Early Discontinuation (ED) visit, whichever is sooner.
• Have a history (single episode) of disseminated herpes zoster or disseminated herpes simplex, or a recurrent (more than one episode of) localized, dermatomal herpes zoster.
9. Have a known immunodeficiency disorder or a first-degree relative with a hereditary immunodeficiency.
10. Have a history of alcohol or substance abuse within 6 months prior to Day 1 that in the opinion of the investigator will preclude participation in the study.
11. Have any malignancies or have a history of malignancies with the exception of adequately treated or excised non-metastatic basal cell or squamous cell cancer of the skin, or cervical carcinoma in situ.
12. Require treatment with prohibited concomitant medications (refer to Section 6.5) or have received a prohibited concomitant medication within the specified timeframe prior to the first dose of study intervention(s).
Please refer to section 5.2 of the protocol for a complete list of exclusion criteria.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
• Response based on achieving at least a 4-point improvement in the severity of Peak Pruritus Numerical Rating Scale (PP-NRS4) from baseline at Week 2.
• Response based on achieving the Eczema Area and Severity Index (EASI)-90 (≥90% improvement from baseline) at Week 4.
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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) |
Key Secondary Endpoints :
• Response based on achieving the Eczema Area and Severity Index (EASI)-90 (≥90% improvement from baseline) at Week 16.
Secondary Endpoints:
•Response based on achieving a ≥90% improvement in the EASI total score (EASI-90) at all other scheduled time points up to Week 26;
•Response based on achieving a ≥75% improvement in the EASI total score (EASI-75) at all scheduled time points up to Week 26;
•Response based on Investigator’s Global Assessment (IGA) score of clear (0) or almost clear (1) (on a 5 point scale) and a reduction from baseline of ≥2 points at all scheduled time points up to Week 26;
•Response based on achieving at least a 4-point improvement in the severity of PP-NRS4 from baseline at all scheduled time points except Week 2;
•Time from baseline to achieve at least a 4-point improvement in the severity of PP-NRS4 scale;
•Percent Change from Baseline in the % Body Surface Area (BSA) affected at all scheduled time points;
•Percent Change from Baseline in the SCORing Atopic Dermatitis (SCORAD) at all scheduled time points;
•Change from baseline in the Hospital Anxiety and Depression Scale (HADS) at all scheduled time points;
•Change from baseline in Dermatology Life Quality Index (DLQI) at all scheduled time points;
•Change from baseline in EuroQol Quality of Life 5-Dimension 5-Level Scale (EQ-5D-5L) at all scheduled time points;
•Change from baseline in Patient-Oriented Eczema Measure (POEM) at all scheduled time points;
•Change from baseline in Medical Outcomes Study –Sleep Scale (MOSSleep Scale) at all scheduled time points;
•Change from baseline in Skin Pain NRS at all scheduled time points;
•Medicated topical background therapy-free days.
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Variable. Please see section 3.0 of the protocol for the defined time points. |
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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 | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| 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 | Yes |
| E.8.1.7.1 | Other trial design description |
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| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| 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.8.4.1 | Number of sites anticipated in Member State concerned | 5 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 51 |
| 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 |
| Australia |
| Canada |
| Chile |
| Korea, Republic of |
| Taiwan |
| United States |
| Bulgaria |
| Finland |
| Germany |
| Hungary |
| Italy |
| Latvia |
| Poland |
| Slovakia |
| 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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| The end of the study is defined as the date of the last visit of the last participant in the study or last scheduled procedure shown in the Schedule of Activities for the last participant in the trial globally. |
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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 | |
| E.8.9.1 | In the Member State concerned months | 11 |
| E.8.9.1 | In the Member State concerned days | 7 |
| 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 | 4 |
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