| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| E.1.1.1 | Medical condition in easily understood language |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Immune System Diseases [C20] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 19.0 |
| E.1.2 | Level | SOC |
| E.1.2 | Classification code | 10021428 |
| E.1.2 | Term | Immune system disorders |
| E.1.2 | System Organ Class | 10021428 - Immune system disorders |
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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 |
| The primary objective of this study is to evaluate the efficacy of 4 QD dose levels (10, 30, 100, and 200 mg) of PF-04965842 relative to placebo in adult subjects with moderate to severe atopic dermatitis, using the Investigator’s Global Assessment (IGA). |
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| E.2.2 | Secondary objectives of the trial |
- To evaluate the effect of PF-0465842 on additional efficacy endpoints and patient reported outcomes over time in adult subjects with moderate to severe atopic dermatitis.
- To evaluate the safety and tolerability of PF-0465842 over time in adult subjects with moderate to severe atopic dermatitis.
EXPLORATORY OBJECTIVES:
- To assess pharmacodynamic and disease-related biomarkers over time.
- To characterize pharmacokinetics of PF-04965842 over 12 weeks. |
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| 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 between 18-75 years of age, inclusive, at time of informed consent.
3. Subjects who are willing and able to comply with scheduled visits, treatment plan, laboratory tests and other study procedures.
4. Male subjects able to father children and female subjects of childbearing potential and at risk for pregnancy must agree to use a highly effective method of contraception (per Section 4.4.2) throughout the study and for at least 28 days after the last dose of assigned treatment.
Female subjects who are not of childbearing potential (eg, 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; status may be confirmed by having a serum follicle stimulating hormone (FSH) level confirming the post-menopausal state.
5. Must have the following atopic dermatitis criteria:
a. Have a 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 (Hanifin and Rajka criteria of AD refer to Appendix 2) at the Screening visit.
b. Have inadequate response to treatment with topical medications given for at least 4 weeks, or for whom topical treatments are otherwise medically inadvisable (eg, because of important side effects or safety risks) within 12 months of the first dose of study drug.
c. Moderate to severe AD (affected BSA >=10 %, IGA >=3, and EASI >=12 at the screening and baseline visits).
6. 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.
7. 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. Subject must be willing to stay on a stable regimen during the duration of the study. |
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| E.4 | Principal exclusion criteria |
(For more and complete information please refer to Protocol section 4.2)
1. Severe acute or chronic medical or psychiatric condition or laboratory abnormality.
...
4. Have received any of the following treatment regiments specified in the timeframes outlined below:
• Within 6 months of first dose of study drug: Any cell-depleting agents including but not limited to rituximab.
• Within 12 weeks of first dose of study drug: A) Any studies with JAK inhibitors. B) Other biologics: within 12 weeks of first dose of study drug or 5 half-lives (if known), whichever is longer.
• Within 8 weeks of first dose of study drug: Participation in other studies involving investigational drug(s) within 8 weeks of first dose of study drug or within 5 half-lives (if known), whichever is longer.
• Within 6 weeks of first dose of study drug: Have been vaccinated with live or attenuated live vaccine.
• Within 4 weeks of first dose of study drug: A) Use of oral immune suppressants within 4 weeks of first dose of study drug or within 5 half-lives (if known), whichever is longer. B) Phototherapy (NB-UVB) or broad band phototherapy. C) Regular use (more than 2 visits per week) of a tanning booth/parlor.
• Within 1 week of first dose of study drug: A) Topical treatments that could affect atopic dermatitis. Note: Corticosteroid inhalers and intranasal sprays are allowed for stable asthma patients. B) Herbal medications with unknown properties or known beneficial effects for AD.
...
17. History of human immunodeficiency virus (HIV) or positive HIV serology at screening,
18. Infected with hepatitis B or hepatitis C viruses.
19. Have evidence of active or latent or inadequately treated infection with Mycobacterium tuberculosis (TB) as defined by the following:
a. 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 is exclusionary; a negative test is required for eligibility. 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 7.3.5 for requirements for Mantoux/PPD tuberculin skin testing. A QFT-G or Mantoux/PPD tuberculin skin test is not required if the subject has previously received a documented adequate course of therapy for either latent or active TB infection or is currently receiving a documented adequate treatment for latent TB infection;
b. A history of either untreated or inadequately treated latent or active TB infection;
c. If a subject has previously received an 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, neither a QFT-G test nor a Mantoux/PPD tuberculin skin test is needed, but a chest radiograph(s) (per local standard/guidelines) must be obtained if not performed within 12 weeks prior to Day 1. To be considered eligible for the study, the radiograph(s) must be negative for active tuberculosis infection as determined by a qualified radiologist. Documentation of adequate treatment for TB and negative chest radiograph(s) results must be obtained prior to Day 1. 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;
d. A subject who is currently being treated for active TB infection is to be excluded.
20. 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 <2.5 x 109/L (<2500/mm3).
• Hemoglobin <10.0 g/dL or hematocrit <30%;
• Platelet count below the lower limit of normal (LLN) at Screening;
• Absolute lymphocyte count of <0.5 x 109 /L (<500/mm3);
• Estimated Creatinine Clearance <40 mL/min based on the age appropriate calculation, or serum creatinine >1.5 times the upper limit of normal (ULN);
• AST or 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;
• 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.
... |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| Proportion of subjects achieving the IGA for clear (0) or almost clear (1) and > = 2 points improvement from baseline at Week 12. The baseline will be defined as the IGA score on Day 1 pre-dose. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Proportion of subjects achieving the IGA for clear (0) or almost clear (1) and > = 2 points improvement from baseline at Week 12. The baseline will be defined as the IGA score on Day 1 pre-dose. |
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| E.5.2 | Secondary end point(s) |
- Efficacy Endpoints: Baseline is defined as the score for each assessment on Day 1 pre-dose.
Key Secondary Efficacy Endpoint: Percent change from baseline in the eczema area and severity index (EASI) Total score at Week 12.
Secondary Efficacy Endpoints:
* Proportion of subjects achieving the IGA for clear (0) or almost clear (1) and >=2 points improvement from baseline at all scheduled time points except Week 12.
* Percent change from baseline in the EASI total score at all scheduled time points except Week 12.
* Proportion of subjects achieving >=3 points improvement in the pruritus numerical rating scale (NRS) from baseline at all scheduled time points.
* Percent change from baseline in the pruritus NRS from baseline at all scheduled time points.
* Proportion of subjects achieving >=2 points improvement in the IGA from baseline at all scheduled time points.
* Proportion of subjects achieving a >=50%, 75% and 90% improvement in the EASI Total score (EASI50, EASI75, EASI90) at all scheduled time points.
* Change from baseline in affected body surface area (BSA) at all scheduled time points.
* Change from baseline in SCORing atopic dermatitis (SCORAD) at all scheduled time points.
* Proportion of subjects achieving a >=50% and 75% improvement in SCORAD (SCORAD50, SCORAD75) from baseline at all scheduled time points.
- Safety Endpoints:
Incidence of treatment-emergent adverse events.
Incidence of specific clinical laboratory abnormalities (anemia, neutropenia, thrombocytopenia, lymphopenia, lipid profile, liver function tests [LFTs]).
- Patient-Reported Outcome (PRO) Endpoints: Baseline is defined as the score for each assessment on Day 1 pre-dose.
* Change from baseline in Pruritus NRS score at all scheduled time points.
* Proportion of subjects with patient global assessment (PtGA) of AD of clear (0) or almost clear (1) and >=2 points improvement from baseline at all scheduled time points.
* Change from baseline in dermatology life quality index (DLQI) total score at all scheduled time points.
* Change from baseline in patient Oriented Eczema Measure (POEM) at all scheduled time points.
* Change from baseline in the hospital and anxiety depression scale (HADS) at all scheduled time points.
- Exploratory Endpoints:
* Change from baseline in pharmacodynamic and disease-related protein and/or nucleic acid biomarkers over time, including but not limited to: IP-10 (CXCL10), hsCRP, CCL17 (TARC), IL-31, total IgE, eosinophil counts, lymphocyte subsets (T, B and NK cells and T cell subtypes).
* Plasma concentrations of PF-04965842.
* Change from baseline in the PSAAD over time (baseline is defined as the average score pre-dose). |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Please refer to Schedule of Activities of the protocol.
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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 | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| 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) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| 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 | 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 | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 11 |
| 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 |
| United States |
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| E.8.7 | Trial has a data monitoring committee | No |
| 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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| End of trial (EoT) in a Member State (MS) of the EU: time at which it is deemed that a sufficient number of subjects have been recruited and completed the study as stated in the regulatory and ethics applications in the MS. Poor recruitment (recruiting less than the anticipated number in the CTA) by a MS is not a reason for premature termination but is considered a normal conclusion to the study in that Member State. EoT in all other participating countries: last subject last visit (LSLV). |
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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 | 1 |
| E.8.9.1 | In the Member State concerned months | 5 |
| E.8.9.1 | In the Member State concerned days | 0 |
| 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 | 5 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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