| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Moderate to severe atopic dermatitis (AD) |
|
| 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. |
|
| 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 | 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 |
| To compare the efficacy of 100 mg and 200 mg once daily (QD) of PF 04965842 versus placebo in adult subjects on background topical therapy with moderate to severe atopic dermatitis (AD). |
|
| E.2.2 | Secondary objectives of the trial |
To compare the efficacy of PF 04965842 versus dupilumab in terms of attaining a clinically significant improvement in the severity of pruritus for adult subjects on background topical therapy with moderate to severe AD.
To estimate the difference in efficacy measures between two doses of PF 04965842 and dupilumab for adult subjects on background topical therapy with moderate to severe AD.
To estimate the effect of PF 04965842 on additional efficacy endpoints and patient reported outcomes over time in adult subjects on background topical therapy with moderate to severe AD.
To estimate the effect of PF 04965842 on additional efficacy endpoints and patient reported outcomes over time in adult subjects on background topical therapy with moderate to severe AD. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Evidence of a personally signed and dated informed consent document indicating that the subject has been informed of all pertinent aspects of the study.
2. Male or female subjects aged 18 years or older at the time of informed consent.
3. Meet all the following atopic dermatitis criteria:
• Clinical diagnosis of chronic atopic dermatitis (also known as atopic eczema) for at least 1 year prior to Day 1 and has confirmed atopic dermatitis at the screening and baseline visits according to Hanifin and Rajka criteria for AD17 (see Appendix 2).
• 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 weeks, or who have required systemic therapies for control of their disease.
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 (affected body surface area (BSA) ≥ 10%, IGA ≥ 3, EASI ≥ 16, and Pruritus NRS severity score ≥ 4 on the day of the baseline visit).
4. During the last 7 days prior to Day 1, for the treatment of AD, the subject must have used only non medicated topical therapy (ie, emollient) without other active ingredients indicated to treat AD, or other additives which could affect AD (eg, hyaluronic acid, urea, ceramide or filaggrin degradation products) at least twice daily, with response to treatment remaining inadequate at baseline. The subject must also be willing and able to comply with standardized background topical therapy, as per protocol guidelines (Section 5.8.1), throughout the remainder of the study.
5. Willing and able to comply with scheduled visits, treatment plan, laboratory tests and other study procedures.
6. Female subjects who are of childbearing potential must not be intending to become pregnant, currently pregnant, or lactating. The following conditions apply:
a. Female subjects of childbearing potential must have a confirmed negative pregnancy test prior to randomization;
b. Female subjects of childbearing potential must agree to use a highly effective method of contraception (as per Section 4.4.1) for the duration of the active treatment period and for at least 28 days after the last dose of investigational product.
NOTE: Sexual abstinence, defined as completely and persistently refraining from all heterosexual intercourse (including during the entire period of risk associated with study treatments) may obviate the need for contraception ONLY if this is the preferred and usual lifestyle of the subject.
7. Female subjects of non childbearing potential must meet at least 1 of the following criteria:
• Have undergone a documented hysterectomy and/or bilateral oophorectomy;
• Have medically confirmed ovarian failure; or
• Achieved postmenopausal status, defined as follows: cessation of regular menses for at least 12 consecutive months with no alternative pathological or physiological cause and have a serum follicle stimulating hormone (FSH) level confirming the postmenopausal state.
All other female subjects (including female subjects with tubal ligations) are considered to be of childbearing potential.
8. Must agree to avoid prolonged exposure to the sun and not to use tanning booths, sun lamps or other ultraviolet light sources during the study.
9. If receiving concomitant medications for any reason other than AD, 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 and through the duration of the study. |
|
| E.4 | Principal exclusion criteria |
1. Other acute or chronic medical or psychiatric condition including recent (within the past year) or active suicidal ideation or behavior or laboratory abnormality that may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the subject inappropriate for entry into this study.
2. Any psychiatric condition including recent or active suicidal ideation or behavior that meets any of the following criteria:
• 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) (Appendix 15);
• 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;
• Clinically significant depression: patient health questionnaire – 8 items (PHQ 8) total score ≥ 15 (Appendix 16);
• The presence of any current major psychiatric disorder that is not explicitly permitted in the inclusion/exclusion criteria;
• In the opinion of the investigator or Pfizer (or designee) exclusion is required.
3. A current or past medical history of conditions associated with thrombocytopenia, coagulopathy or platelet dysfunction.
4. Receiving anti coagulants or medications known to cause thrombocytopenia, (unless considered safe to stop and washout for the duration of the study).
5. 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 atopic dermatitis or response to treatment.
6. Vaccinated or exposed to a live or attenuated vaccine within the 6 weeks prior to the first dose of investigational product, or is expected to be vaccinated or to have household exposure to these vaccines during treatment or during the 6 weeks following discontinuation of investigational product.
7. Subjects who have received prior treatment with any JAK inhibitors.
8. Previous treatment with dupilumab and/or a history of hypersensitivity, intolerance, adverse event, or allergic reaction associated with prior exposure to dupilumab’s excipients.
9. Participation in other studies involving investigational drug(s) within 8 weeks or within 5 half lives (if known) whichever is longer, prior to study entry and/or during study participation.
NOTE: Any investigational or experimental therapy taken or procedure performed for AD, psoriasis, psoriatic arthritis or rheumatoid arthritis in the previous 1 year should be discussed with the Pfizer Medical Monitor (or designee). Subjects cannot participate in studies of other investigational or experimental therapies or procedures at any time during their participation in this study.
10. Have received any treatment regimens specified in the timeframes outlined in the protocol (secton 4.2)
11. 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.
12. Infection history (please refer to protocol section 4.2)
13. 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.
14. A Screening 12 lead ECG that demonstrates clinically significant abnormalities requiring treatment (eg, acute myocardial infarction, serious tachy or brady arrhythmias) or that are indicative of serious underlying heart disease (eg, cardiomyopathy, major congenital heart disease, low voltage in all leads, Wolff Parkinson White syndrome) or criteria associated with Q wave interval (QT)/ Fridericia corrected Q wave interval (QTcF) abnormalities (please refer to protocol section 4.2)
15. Have a known immunodeficiency disorder or a first degree relative with a hereditary immunodeficiency.
16. 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.
17. Require treatment with prohibited concomitant medication(s) (Section 5.8.2 and Appendix 3) or have received a prohibited concomitant medication within the specified timeframe prior to the first dose of investigational product.
18. Have evidence of active or latent or inadequately treated infection with Mycobacterium tuberculosis (TB) (please refer to protocol section 4.2)
Please refer to protocol section 4.2 for a full list of exclusion criteria.
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
• Response based on achieving the Investigator's Global Assessment (IGA) of clear (0) or almost clear (1) (on a 5 point scale) and a reduction from baseline (pre dose Day 1) of ≥ 2 points at Week 12;
• Response based on achieving the Eczema Area and Severity Index (EASI) 75 (≥ 75% improvement from baseline) at Week 12. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
• Response based on achieving at least 4 points improvement in the severity of Pruritus Numerical Rating Scale (NRS) from baseline at Week 2.
• Response based on achieving the IGA of clear (0) or almost clear (1) (on a 5 point scale) and a reduction from baseline of ≥ 2 points at Week 16;
• Response based on achieving EASI 75 (≥ 75% improvement from baseline) at Week 16.
Secondary Efficacy Endpoints:
• Response based on achieving the IGA of clear (0) or almost clear (1) (on a 5 point scale) and ≥ 2 point reduction from baseline at all scheduled time points except Week 12 and Week 16;
• Response based on achieving a ≥ 75% improvement in the EASI total score (EASI 75) at all scheduled time points except Week 12 and Week 16;
• Response based on achieving a ≥ 50%, ≥ 90%, and 100% improvement in the EASI total score (EASI 50, EASI 90, and EASI-100) at all scheduled time points;
• Response based on achieving at least 4 points improvement in the severity of Pruritus NRS from baseline at all scheduled time points except Week 2;
• Time from baseline to achieve at least 4 points improvement in the severity of Pruritus NRS scale;
• Change from baseline in the percentage Body Surface Area (BSA) affected at all scheduled time points;
• Change from baseline of Patient Global Assessment (PtGA) at all scheduled time points;
• Change from baseline in Dermatology Life Quality Index (DLQI) at all scheduled time
• 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 Hospital Anxiety and Depression Scale (HADS) at all scheduled time points;
• Change from baseline in Patient Oriented Eczema Measure (POEM) at all scheduled time points;
• Change from baseline in Pruritus and Symptoms Assessment for Atopic Dermatitis (PSAAD) total score at all scheduled time points;
• Response based on a ≥ 50% and ≥ 75% improvement in SCORAD (SCORAD50, SCORAD75) from baseline at all scheduled time points;
• Change from baseline at all scheduled time points in SCORAD subjective assessments of itch and sleep loss;
• Steroid free days at Week 16.
Safety Endpoints:
• Incidence of treatment emergent adverse event (AE)s;
• Incidence of serious adverse event (SAE)s and AEs leading to discontinuation;
• Incidence of clinical abnormalities and change from baseline in clinical laboratory values, electrocardiogram (ECG) measurements, and vital signs.
Exploratory Endpoints:
• Response based on achieving at least 4 points improvement in the Night Time Itch Scale, for severity and frequency, from baseline at all scheduled time points;
• Time from baseline to achieve at least 4 points improvement in the Night Time Itch Scale for severity and frequency.
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Individual timepoints are included in each bullet point above. |
|
| 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 | 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 |
|
| 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 | 5 |
| 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 | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 76 |
| 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 |
| Austria |
| Bulgaria |
| Canada |
| Czech Republic |
| France |
| Germany |
| Hungary |
| Italy |
| Korea, Republic of |
| Latvia |
| Mexico |
| Poland |
| Slovakia |
| Spain |
| Sweden |
| Taiwan |
| United Kingdom |
| United States |
|
| 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 0 |
| E.8.9.1 | In the Member State concerned months | 9 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 0 |
| E.8.9.2 | In all countries concerned by the trial months | 9 |
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