E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
|
E.1.1.1 | Medical condition in easily understood language |
Dermatomyositis is a rare inflammatory disease marked by muscle weakness and a distinctive severe skin rash |
|
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 | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10012503 |
E.1.2 | Term | Dermatomyositis |
E.1.2 | System Organ Class | 10040785 - Skin and subcutaneous tissue disorders |
|
E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
STAGE 1 (complete): •To evaluate the efficacy of PF-06823859 in adult participants with moderate to severe DM.
STAGE 2: •To estimate the efficacy of PF-06823859 in adult participants with moderate to severe DM across two stages.
AMENDED STAGE 2: •To estimate the efficacy of PF-06823859 in adult participants with moderate to severe DM across Stage 1 and Stage 2.
STAGE 3: •To evaluate the safety and tolerability of PF-06823859 in adult DM participants with moderate to severe active muscle disease |
|
E.2.2 | Secondary objectives of the trial |
STAGE 1 (complete): •To evaluate the efficacy of PF-06823859 over time. •To determine the safety, and tolerability, of PF-06823859.
STAGE 2: •To estimate the efficacy of PF-06823859 overtime across two Stages. •To determine the safety, and tolerability, of PF-06823859 across two Stages.
AMENDED STAGE 2: •To estimate the efficacy of PF-06823859 over time across Stage 1 and Stage 2. •To determine the safety, and tolerability, of PF-06823859 across Stage 1 and Stage 2.
STAGE 3: •To evaluate the efficacy of PF-06823859 over time in adult DM participants with moderate active muscle disease |
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
STAGE 1 and 2: 3. Cutaneous Dermatomyositis Disease Area and Severity Index (CDASI) Activity Score, v2-a (See Appendix 2) (Activity ≥14, and have failed at least 1 standard of care systemic treatment, (eg, corticosteroids). 5. Participant has had a standard work up for dermatomyositis (prior to) baseline. a. Stable interstitial lung disease related to DM that is not severe in the opinion of the investigator is allowed, ie, no supplemental oxygen permitted. b. If their DM diagnosis is within 2 years of the screening visit, then they must have completed either: • Age appropriate malignancy screening eg, computerized tomography, (CT) of the chest/abdomen/pelvis if indicated; or • PET CT of chest/abdomen/pelvis at least once by the baseline visit. 6. Willing to provide 6 skin punch biopsies; (4) skin punch biopsies at pre-dose Day 1, Visit 2, and (2) skin punch biopsies at Week 12. 7. Male participants able to father children and female participants of childbearing potential must agree to use 2 highly effective methods of contraception throughout the duration of the study, including the follow-up period until the end of study. 8. Female participants of non-childbearing potential must meet at least 1 of the following criteria: a. 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 with a serum follicle-stimulating hormone (FSH) level confirming the postmenopausal state; b. Have undergone a documented hysterectomy and/or bilateral oophorectomy; c. Have medically confirmed ovarian failure. All other female participants (including female participants with tubal ligations) are considered to be of childbearing potential.
Amended STAGE 2: If a participant meets eligibility for both the Stage 2, (skin focused cohort) and the Stage 3, (muscle disease cohort) the patient should be placed in the Stage 3 muscle disease cohort. All inclusion criteria is the same as Stage 1 and Stage 2 with the exception to Inclusion Criteria #6. 6. Willing to provide at least (8) vs. 6 skin punch biopsies; (4) skin punch biopsies at pre-dose Day 1 Visit 2, (2) skin punch biopsies at Week 12, Visit 6 and (2) skin punch biopsies at Week 24 Visit 9.
STAGE 3: 3. Meets one of the following two criteria: • MMT-8 ≤ 136/150 and PhGA, VAS ≥ 3 cm (0-10 cm) by visual analog scale (VAS) (Appendix 21) • Sum of PhGA, VAS, PtGA, and extramuscular global assessment VAS scores (Appendix 20) is ≥ 10 cm (0-10 cm) VAS for each) 4. Participant has failed at least two or more adequate courses of an immunosuppressive agent or immunomodulatory agent, including IVIG, at a dose known to be effective for rheumatologic diseases. 5. Participant has had a standard work up for dermatomyositis (prior to) baseline. a. Stable interstitial lung disease related to DM that is not severe in the opinion of the investigator is allowed, ie, no supplemental oxygen permitted. completed either: • Age appropriate malignancy screening eg, computerized tomography, (CT) of the chest/abdomen/pelvis if indicated; or • PET CT of chest/abdomen/pelvis at least once by the baseline visit. 6. Male participants able to father children and female participants of childbearing potential must agree to use 2 highly effective methods of contraception throughout the duration of the study, including the follow-up period until the end of study. 7. Female participants of non-childbearing potential must meet at least 1 of the following criteria: a. 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 with a serum follicle-stimulating hormone (FSH) level confirming the postmenopausal state; b. Have undergone a documented hysterectomy and/or bilateral oophorectomy; c. Have medically confirmed ovarian failure. d. All other female participants (including female participants with tubal ligations) are considered to be of childbearing potential.
[See section 4 of the Protocol for the full list of Inclusion Criteria] |
|
E.4 | Principal exclusion criteria |
STAGE 1 AND STAGE 2: 2. 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 participant inappropriate for entry into this study. 7. Abnormal labs: • Hemoglobin <10 g/dL; • Neutrophils <1.0 x 109/L; • Lymphocytes <500 cells/uL; • Platelets <75 x 109/L; • Creatinine clearance <60 ml/min according to modified Cockcroft-Gault equation; • Alkaline phosphatase >2.5 x upper normal limit; • Total bilirubin ≥1.5 x upper limit of normal. Note: Elevation of aspartate aminotransferase (AST), alanine aminotransferase(ALT), lactate dehydrogenase (LDH) , creatinine kinase (CK) or aldolasedue to muscle involvement (in the opinion of the investigator) are allowed if gamma glutamyl transferase, GGT <1.5 upper limit normal. 12. Have received the following within 60 days of Day 1: • Any intra muscular (IM) or IV steroid injection. • Tofacitinib or any other Janus kinase (JAK) inhibitors. • Any change in dose of an immunosuppressive/immunomodulatory or antimalarial agent. Dose must be stable for 60 days prior to Day 1 and remain stable through Week 12. • Inhaled immunosuppressive agents can be used during the study however must be on a stable dose 60 days prior to Day 1 and remain stable through Week 12. (Immunosuppressive ophthalmic drops are allowed without any restrictions). • Disease -modifying antirheumatic drugs (DMARD)s, (methotrexate, sulfasalazine, hydroxychloroquine, and leflunomide). Less frequently used medications include gold salts, azathioprine, and cyclosporine. Dose must be stable for 60 days prior to Day 1 and remain stable through Week 12. • Participants may be on one of the following cytotoxic agents: methotrexate, azathioprine, leflunomide, mycophenolate, or 6 MP, but not on any combination of these cytotoxic agents. Use of IV or IM antibacterials, antivirals, antifungals, or anti-parasitic agents within 60 days of Day 1. Substitution of IM agents for oral agents because of gastro intestinal, (GI) intolerance may be acceptable, as long as it does not otherwise meet the criteria for a serious infection (requires hospitalization or use of other IV antibiotics) (See exclusion #24). 25. Have acute coronary syndrome (eg, myocardial infarction, unstable angina pectoris) or any history of significant cerebrovascular disease within 24 weeks of screening. A screening 12-lead electrocardiogram (ECG) that demonstrates clinically significant abnormalities requiring treatment (eg, acute myocardial infarction, serious tachy- or brady- arrhythmias) or that is indicative of serious underlying heart disease Wolff-Parkinson-White syndrome). 26. Have cancer or a history of cancer within 5 years of screening (other than adequately treated cutaneous basal cell, squamous cell carcinoma, or carcinoma in situ of the uterine cervix with no evidence of recurrence within the previous 5 years).
Amended STAGE 2: All exclusion criteria is the same as Stage 1 and Stage 2 with the exception of Exclusion Criterion #7 Abnormal labs and Exclusion Criterion #12 Exclusion Criterion #7: • Hemoglobin <9 g/dL; • Creatinine clearance <50 mL/min according to modified Cockcroft-Gault equation. Exclusion Criterion #12: • Any change in dose of an immunosuppressive/immunomodulatory or antimalarial agent. Dose must be stable for 60 days prior to Day 1 and remain stable through Week 24.
STAGE 3: 5. Drug induced myopathy, metabolic myopathy, muscular dystrophy, cancer associated DM, mixed connective tissue disease-associated DM, (eg, overlap syndrome) and polymyositis. 6. Significant concurrent disease or conditions other than DM that may influence response to the study drug or safety. 18. Active bacterial, viral, fungal, mycobacterial or other infections (including but not limited to tuberculosis [TB] and atypical mycobacterial disease, granulomatous disease on chest x-ray). History of recurrent bacterial, viral, fungal, mycobacterial or other infections (including but not limited to TB and atypical mycobacterial disease, granulomatous disease on chest x-ray) that would substantially increase the risk to the participant if he or she participates in the study. 33. Participant has severe muscle damage defined as a global muscle damage score >5 on a 10cm VAS scale which is a component on the Myositis Damage Index (MDI) Appendix 23
[See section 4 of the Protocol for the full list of Exclusion Criteria] |
|
E.5 End points |
E.5.1 | Primary end point(s) |
STAGE 1, STAGE 2 AND AMENDED STAGE 2 •Change from baseline in CDASI activity score at Week 12.
STAGE 3 •Incidence of adverse events (AEs) laboratory abnormalities, changes in vital signs, and electrocardiogram (ECG) findings.
|
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
E.5.2 | Secondary end point(s) |
STAGE 1, STAGE 2 AND AMENDED STAGE 2 •Absolute values and change from baseline of CDASI activity and CDASI damage scores at all scheduled time points. (Exception: The change from baseline in CDASI activity score at Week 12 is a primary endpoint). •Incidence of adverse events (AEs) laboratory abnormalities, changes in vital signs, and electrocardiogram (ECG) findings.
STAGE 3 •Total Improvement Score (TIS) at Week 12 and intermediate scheduled time points •Change from baseline in the core Set Measures (CSM) of the TIS including PGA, PtGA, MMT, HAQ-DI, muscle enzymes, and extra-muscular activity, (MDAAT) •Absolute values and change from baseline of CDASI activity and CDASI damage scores at all scheduled time points. |
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
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 | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
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) | 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 | No |
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 | 3 |
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 | 18 |
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 |
United States |
Germany |
Hungary |
Italy |
Poland |
Spain |
|
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
|
Last participant last visit (LSLV) is defined as the date the investigator reviews the last participant’s final safety data and determines that no further evaluation is required for the participant to complete the trial. |
|
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 | 1 |
E.8.9.1 | In the Member State concerned days | 14 |
E.8.9.2 | In all countries concerned by the trial years | 4 |
E.8.9.2 | In all countries concerned by the trial months | 4 |
E.8.9.2 | In all countries concerned by the trial days | 9 |