Atopic Dermatitis

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).

PF-04965842

PF-04965842

film-coated tablet

100

Primary Outcome Measures :
Percentage of Participants Achieving Investigator's Global Assessment (IGA) Response of Clear (0) or Almost Clear (1) and a Reduction of Greater Than or Equal to (>=) 2 Points From Baseline at Week 12 [ Time Frame: Baseline (the last measurement prior to first dosing on Day 1), Week 12 ]
IGA assessed severity of atopic dermatitis (AD) on a 5 point scale (0 to 4, higher scores indicate more severity). Scores: 0= clear, no inflammatory signs of AD; 1= almost clear, AD not fully cleared- light pink residual lesions (except post-inflammatory hyperpigmentation), just perceptible erythema, papulation/induration lichenification, excoriation, and no oozing/crusting; 2= mild AD with light red lesions, slight but definite erythema, papulation/induration, lichenification, excoriation and no oozing/crusting; 3= moderate AD with red lesions, moderate erythema, papulation/induration, lichenification, excoriation and slight oozing/crusting; 4= severe AD with deep dark red lesions, severe erythema, papulation/induration, lichenification, excoriation and moderate to severe oozing/crusting. Assessment excluded scalp, palms and sole.

Percentage of Participants Achieving Eczema Area and Severity Index (EASI) Response >=75 Percent (%) Improvement From Baseline at Week 12 [ Time Frame: Baseline, Week 12 ]
EASI evaluates severity of participants with AD (excluded scalp, palms, soles) based on severity of AD clinical signs and % of body surface area (BSA) affected. Severity of clinical signs of AD (erythema, induration/papulation, excoriation and lichenification) scored separately for each of 4 body regions (head and neck, upper limbs, trunk [including axillae and groin] and lower limbs [including buttocks]) on 4-point scale: 0= absent; 1= mild; 2= moderate; 3= severe. EASI area score was based upon % BSA with AD in body region: 0 (0%), 1 (>0 to <10%), 2 (10 to <30%), 3 (30 to <50%), 4 (50 to <70%), 5 (70 to <90%) and 6 (90 to 100%). Total EASI score =0.1*Ah*(Eh+Ih+Exh+Lh) + 0.2*Au*(Eu+Iu+ExU+Lu) + 0.3*At*(Et+It+Ext+Lt) + 0.4*Al*(El+Il+Exl+Ll); A = EASI area score; E = erythema; I = induration/papulation; Ex = excoriation; L = lichenification; h = head and neck; u = upper limbs; t = trunk; l = lower limbs. Total EASI score ranged from 0.0 to 72.0, higher scores = greater severity of AD.

Inclusion Criteria
Subjects must meet all of the following inclusion criteria to be eligible for enrollment into the
study:
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.

Exclusion Criteria
Subjects with any of the following characteristics/conditions will not be included in the
study:
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 of the following treatment regimens specified in the timeframes
outlined below:
Within 1 year of first dose of investigational product:
 Prior treatment with non B cell-specific lymphocyte depleting agents/therapies
(eg, alemtuzumab [CAMPATH
], alkylating agents [eg, cyclophosphamide or
chlorambucil], total lymphoid irradiation, etc.). Subjects who have received
rituximab or other selective B lymphocyte depleting agents (including
experimental agents) are eligible if they have not received such therapy for at
least 1 year prior to study baseline and have normal cluster of differentiation (CD)
19/20+ counts by fluorescence-activated cell sorting (FACS) analysis.
Within 12 weeks of first dose of investigational product:
 Other biologics: within 12 weeks of first dose of investigational product or
5 half-lives (if known), whichever is longer.
Within 4 weeks of first dose of investigational product:
 Use of oral immunosuppressive drugs (eg, cyclosporine A [CsA], azathioprine,
methotrexate, systemic corticosteroids, mycophenolate-mofetil, IFN-) within
4 weeks of first dose of investigational product or within 5 half-lives (if known),
whichever is longer.
NOTE: Corticosteroid inhalers and intranasal sprays are permissible for subjects
receiving a stable dose.
NOTE: Ophthalmic corticosteroids are permissible for subjects receiving a stable
dose.
 Use of CYP2C9 and CYP2C19 inducers within 5 half-lives of the inducer plus
28 days of first dose of investigational product. For example, the average half-life
of Carbamazepine after repeat dosing is 15 hours. The washout period is
calculated as the sum of 5 half-lives (approximately 3 days) and an additional
28 days for a total of 31 days prior to the first dose of investigational product.
 Phototherapy narrowband UVB (NB-UVB) or broadband phototherapy.
 Regular use (more than 2 visits per week) of a tanning booth/parlor
 Herbal medications with unknown properties or known beneficial effects for AD.
Within 1 week of first dose of investigational product:
 Medicated topical therapy that could affect atopic dermatitis (eg, corticosteroids,
calcineurin inhibitors, tars, antibiotic creams, topical antihistamines).
NOTE: Non-medicated topical therapy (ie, emollients), as detailed in Section 5.8.1
are permitted.
Within 1 week of first dose of investigational product:
 Use of CYP2C9 and CYP2C19 inhibitors within 1 week of first dose of
investigational product or within 5 half-lives (if known) of the inhibitor,
whichever is longer.
 Anti-platelet drugs.
NOTE: low dose acetyl salicylic acid (100 mg QD) is permitted, for the purpose of
cardiovascular prophylaxis, at the discretion of the investigator.
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:
a. 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;
b. Have a known helminth infection;
c. 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;
d. A subject known to be infected with Human Immunodeficiency Virus (HIV),
Hepatitis B, or Hepatitis C (Section 7.6.2);
e. 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.
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.
For Czech Republic only, exclusion criterion 13 states:
A history of alcohol or substance abuse within 12 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 including:
 A marked prolongation of QTcF interval (>450 milliseconds [ms]) on the
screening ECG.
 A history of additional risk factors for Torsade de Pointes (TdP) (eg, heart failure,
hypokalemia, family history of Long QT Syndrome).
 Use of concomitant medications that prolong the QT/QTcF interval.
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) as evidenced by any of the following:
 A positive QuantiFERON
-TB Gold (QFT-G) In-Tube test or positive
Mantoux/Purified Protein Derivative (PPD) tuberculin skin test performed at or
within the 12 weeks prior to Day 1.
 It is recommended that subjects with a history of Bacille Calmette Guérin (BCG)
vaccination be tested with the QFT-G test since the Mantoux/PPD tuberculin skin
test may be positive due to vaccination. See Section 7.3.4 for requirements for
Mantoux/PPD tuberculin skin testing.
 A negative QFT-G or Mantoux/PPD tuberculin skin test is required unless the
subject has previously received a documented adequate course of therapy for
either latent (9 months of isoniazid in a locale where rates of primary multi-drug
TB resistance are <5% or an acceptable alternative regimen) or active (acceptable multi-drug regimen) TB infection. If the current incidence rates of multi-drug
resistant TB infection in the locale are unavailable, an adequate treatment regimen
should be defined as the regimen recommended by the health ministry or expert
panel in the locale.
 Chest radiograph (or chest Computed Tomography (CT) scan, if available) taken
at screening with changes suggestive of active tuberculosis (TB) infection as
determined by a qualified radiologist. A chest X-ray is required, unless
previously performed and documented within 12 weeks prior to Study Day 1.
 A history of either untreated or inadequately treated latent or active TB infection.
 A subject who is currently being treated for active TB infection is to be excluded.
19. ANY of the following abnormalities in clinical laboratory tests at screening, as
assessed by the study-specific laboratory and confirmed by a single repeat, if deemed
necessary:
 Absolute neutrophil count of <1.2 x 109
/L (<1200/mm3
);
 Hemoglobin <10.0 g/dL or hematocrit <30%;
 Platelet count of <150 x 109
/L (<150,000/mm3
);
 Absolute lymphocyte count of <0.50 x 109
/L (<500/mm3
);
NOTE: In the Czech Republic only an Absolute lymphocyte count of <0.75 x 109
/L
(<500/mm3
) is exclusionary.
 Estimated Creatinine Clearance <40 mL/min based on the age appropriate
calculation, or serum creatinine >1.5 times the upper limit of normal (ULN);
 Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) values
>2 times the ULN;
 Total bilirubin 1.5 times the ULN; subjects with a history of Gilbert’s syndrome
may have a direct bilirubin measured and would be eligible for this study
provided the direct bilirubin is  ULN.
20. In the opinion of the investigator or sponsor, have any uncontrolled clinically
significant laboratory abnormality that would affect interpretation of study data or the
subject’s participation in the study.
21. Have undergone significant trauma or major surgery within 1 month of the first dose
of investigational product.
22. Investigator site staff members directly involved in the conduct of the study and their
family members, site staff members otherwise supervised by the investigator, or
subjects who are Pfizer employees, including their family members, directly involved
in the conduct of the study.