Atopic Dermatitis

This is a randomized, double blind, placebo controlled, parallel group, Phase 3 study to evaluate the efficacy and safety of PF 04965842 in adolescent participants 12 to <18 years of age with moderate to severe AD.

PF-04965842

PF-04965842

film-coated tablet

100
200

Primary Outcome Measures :
-Percentage of Participants Achieving Investigator's Global Assessment (IGA) Response of 'Clear' (0) or 'Almost Clear' (1) and ≥2 Points Improvement From Baseline at Week 12 [ Time Frame: Baseline to Week 12 ]
The IGA of Atopic Dermatitis (AD) was scored on a 5-point scale (0-4), reflecting a global consideration of the erythema, induration and scaling. The overall severity of AD was assessed according to the 5-point scale: 0=Clear, 1=Almost Clear, 2=Mild, 3=Moderate, and 4=Severe. Participants who withdrew from the study were counted as non-responder.

-Percentage of Participants Achieving Eczema Area and Severity Index (EASI) Response ≥ 75% Improvement From Baseline at Week 12 [ Time Frame: Baseline to Week 12 ]
The EASI quantifies the severity of AD based on both severity of lesion clinical signs and the percent of body surface area (BSA) affected. The EASI score can vary in increments of 0.1 and range from 0.0 to 72.0, with higher scores representing greater severity of AD. Participants who withdrew from the study were counted as non-responder.

. Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria apply:
Age
1. Participant must be 12 to < 18 years of age, inclusive, at the time of signing the
informed consent.
Type of Participant and Disease Characteristics
2. Participants who meet the following AD criteria:
 Clinical diagnosis of chronic moderate-to-severe AD (also known as atopic
eczema) for at least 1 year prior to Day 1 and has confirmed AD at the screening
and baseline visits according to Hanafin and Rajka criteria for AD20 (see
Appendix 10).
 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 BSA  10%, IGA  3, EASI  16, Peak Pruritus
NRS 4 at the baseline visit).
3. 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) at least twice daily, without
other active ingredients indicated to treat AD, or other additives which could affect
AD (eg, hyaluronic acid, urea, ceramide or filaggrin degradation products), 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.
4. 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.
5. 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.
Weight
6. Body weight  40 kg. The body weight threshold may be revised after interim PK
data from adolescents in study B7451012 have been evaluated by the E-DMC. Study
sites will be notified of the revised body weight threshold, if applicable.
Sex
7. Male or Female
Contraception 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 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 Appendix 4)
OR
 Is a WOCBP (all female participants, regardless of whether or not they have
experienced/reported menarche, are considered WOCBP unless they are
permanently sterile or confirmed infertile). A WOCBP who is sexually active
must use a contraceptive method that is highly effective, with a failure rate of
<1%, as described in Appendix 4 during the intervention period and for at
least 28 days after the last dose of study intervention. The investigator should
evaluate the effectiveness of the contraceptive method in relationship to the first
dose of study intervention.
 A WOCBP must have a negative highly sensitive (Appendix 2) serum pregnancy
test at the screening visit. A urine pregnancy test with a sensitivity of at least
25 mIU/mL, will be performed before the first dose of study intervention and at
every site visit including the EOT and follow-up visits to confirm the subject has
not become pregnant. If a urine test cannot be confirmed as negative (eg, an
ambiguous result), a serum pregnancy test is required. In such cases, the
participant must be excluded from participation if the serum pregnancy result is
positive.
 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.
Informed Consent
8. Capable of giving signed informed consent/assent as described in Appendix 1 which
includes compliance with the requirements and restrictions listed in the informed
consent form (ICF) and in this protocol.
9. Willing and able to comply with scheduled visits, treatment plan, laboratory tests and
other study procedures.

Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions
1. Other acute or chronic medical or 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 judgment of the investigator, would make the participant 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) (Section 8.2.9.1);
 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 recurrent suicidal behavior;
 Suicidal behaviors questionnaire – revised (SBQ-R) total score 8
(Section 8.2.9.2);
 Clinically significant depression: patient health questionnaire-8 items
(PHQ-8) total score 15 (Section 8.2.9.3);
 The presence of any significant impairment from a psychiatric disorder
and/or one 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. 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.
5. 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.
6. 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 (Section 8.2.8.1).
 For China, Taiwan and countries where Hepatitis B viral
deoxyribonucleic acid (HBV DNA) testing is required: Participants
who are hepatitis B surface antigen negative (HBsAg-), hepatitis B
core antibody positive (HBcAb+), and hepatitis B surface antibody
positive (HBsAb+) will have reflex testing for HBV DNA.
Participants who have HBV DNA above lower limit of quantification
(LLQ) will be excluded. Participants who are HBV DNA negative or
below LLQ may be randomized.
 For Japan only: Participants with negative results for HBsAg, HBcAb
and HBsAb may be eligible. Participants who are HBsAg negative,
HBcAb negative and HBsAb positive and provide documentation of
prior HBV vaccination may be eligible and will not require HBV DNA
monitoring during the study. Participants who are HBsAg negative,
HBcAb negative and HBsAb positive without documentation of prior
HBV vaccination AND participants who are HBsAg negative, HBcAb
positive, and HBsAb positive at screening will have reflex testing for
HBV DNA. Participants who are HBV DNA negative or below LLQ
may be randomized but will have repeat HBV DNA testing at Week
12 (or Early Termination).
 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.
7. 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.
8. Have a known immunodeficiency disorder or a first-degree relative with a
hereditary immunodeficiency.
9. 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.
10. 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 In-Tube test (QFT-G) or positive
Mantoux/Purified Protein Derivative (PPD)/ tuberculin skin test (if
appropriate per Section 8.2.4) performed at or within the 12 weeks prior to
Day 1 is exclusionary; a negative test is required for eligibility. QFT-G is
the preferred testing method. If the QFT-G test cannot be performed, or if
the results cannot be determined by the reference laboratory to be either
positive or negative, then participants may be screened using the PPD test
with approval of the Pfizer clinician.
 For Japan only: While QuantiFERON is the preferred testing
method, the T-SPOT.TB test is also permitted. Borderline results
from the T-SPOT.TB test should be considered exclusionary. If the
test results are indeterminate, the test should be repeated. If the result
of the repeat test is indeterminate, then participants may be screened
using Mantoux/PPD skin testing following consultation and agreement
with the Pfizer Medical Monitor. See Section 8.2.4.
 It is recommended that participants 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.
A QFT-G or PPD skin test is not required if the subject has previously
received a documented adequate course of therapy for either latent or
active TB infection.
 A negative QFT-G, T-SPOT
.TB test (Japan only) or PPD 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 X-ray (or chest computed tomography scan, or magnetic resonance
imaging [MRI]) taken at screening with changes suggestive of active TB
infection as determined by a qualified radiologist. Chest X-ray or other
appropriate imaging is recommended for adolescents per local
standard/guidelines, 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.
Prior/Concomitant Therapy
11. Require treatment with prohibited concomitant medication(s) (Section 6.5.2
and Appendix 7) or have received a prohibited concomitant medication within
the specified time frame prior to the first dose of study medication.
12. Receiving anti-coagulants or medications known to cause thrombocytopenia,
(unless considered safe to stop and washout for the duration of the study).
13. Vaccinated or exposed to a live or attenuated vaccine within the 6 weeks prior
to the first dose of study intervention, or is expected to be vaccinated or to
have household exposure to these vaccines during treatment or during the
6 weeks following discontinuation of study intervention.
14. Participants without documented evidence of having received at least one dose
of the varicella vaccine in countries where the vaccine is approved and
standard of care or those who do not have evidence of prior exposure to
varicella zoster virus (VZV) based on serological testing (ie, varicella zoster
virus immunoglobulin G antibody [VZV IgG Ab]) at screening.
15. Participants who have received prior treatment with any JAK inhibitors.
16. Have received any of the following treatment regimens specified in the
timeframes outlined below:
Within 1 year of first dose of study intervention:
 Prior treatment with non B cell-specific lymphocyte depleting agents/therapies
(eg, alemtuzumab [CAMPATH
], alkylating agents [eg, cyclophosphamide or
chlorambucil], total lymphoid irradiation, etc.). Participants 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 study intervention:
 Other biologics: within 12 weeks of first dose of study intervention or 5 half-lives
(if known), whichever is longer.
Within 4 weeks of first dose of study intervention:
 Use of oral immunosuppressive drugs (eg, cyclosporine A [CsA], azathioprine,
methotrexate, systemic corticosteroids, mycophenolate-mofetil, IFN-) within
4 weeks of first dose of study intervention or within 5 half-lives (if known),
whichever is longer;
NOTE: Corticosteroid inhalers and intranasal sprays are permissible for
participants receiving a stable dose.
NOTE: Ophthalmic corticosteroids are permissible for participants receiving a
stable dose.
 Use of CYP2C9 and CYP2C19 inducers within 5 half-lives of the inducer plus
28 days of first dose of study intervention. 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 study intervention.
 Phototherapy narrowband UVB (NB-UVB) or broad band 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 study intervention:
 Medicated topical therapy that could affect AD (eg, corticosteroids, calcineurin
inhibitors, tars, antibiotic creams, topical antihistamines).
Prior/Concurrent Clinical Study Experience
17. 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.
18. 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 clinician (or designee).
Participants cannot participate in studies of other investigational or
experimental therapies or procedures at any time during their participation in
this study.
Diagnostic assessments
19. ANY of the following abnormalities in the 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);
20. A Screening 12-lead electrocardiogram (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.
21. 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.
22. Have undergone significant trauma or major surgery within 1 month of the
first dose of study intervention.
23. 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 participants who are Pfizer employees, including their family
members, directly involved in the conduct of the study.
24. See Appendix 11 for additional exclusion criteria for the vaccine sub-study.