A Study In Adults With Moderate To Severe Dermatomyositis

Study Overview
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Brief Summary
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A Study looking at Investigational drug and Placebo administered to adult Patients with moderate to severe Dermatomyositis

Official Title
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A PHASE 2 DOUBLE-BLIND, RANDOMIZED, PLACEBO-CONTROLLED STUDY TO EVALUATE THE EFFICACY, SAFETY, AND TOLERABILITY OF PF-06823859 IN ADULT SUBJECTS WITH DERMATOMYOSITIS

Conditions
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Dermatomyositis

Intervention / Treatment
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* Drug: PF-06823859 low
* Drug: Placebo Arm
* Drug: PF-06823859 high


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria for Patients with Skin Predominant Activity: Must have CDASI Activity score of greater than or equal to 14, and have failed at least 1 standard of care systemic treatment, (eg, corticosteroids). Confirmation of DM by the investigator and two of the following: Gottron's papules; Gottron's sign; Heliotrope eruption; Nailfold changes, (dilated capillary loops, capillary dropout, cuticular hypertrophy and/or rugged cuticles; Photodistributed violaceous erythema, (skin that is exposed to sunlight and appears purplish/reddish, and patchy in appearance; Positive DM serology - Post DM diagnosis; standard of care workup for DM must have been completed prior to entry into this research study. Willing to provide 8 biopsies during the course of the research study Inclusion Criteria for Patients with Muscle Predominant Activity: MMT-8 ≤136/150 and PhGA, VAS ≥3 cm (0-10 cm) by visual analog scale (VAS) Sum of PhGA, VAS, PtGA, and extramuscular global assessment VAS scores is ≥10 cm (0-10 cm) VAS for each. 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. Exclusion Criteria for Patients with Skin Predominant Activity: Investigator site staff or members of their family. Acute and Chronic present medical conditions Intake of greater than 15 mg of prednisone or equivalent per day Pregnant or breastfeeding females. Fertile men and women who will not comply with the use of 2 effective birth control methods as per the research protocol Have required management of acute or chronic infections Have pre existing demyelinating disorder such as multiple sclerosis, or other severe neurological deficits. Clinically significant lab abnormalities Any health condition that may be worsened by immunosuppression Exclusion Criteria for Patients with Muscle Predominant Activity: Similar to patients with skin predominant activity; Intake of >20 mg oral prednisone/day, or equivalent

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo ARM<br> | Drug: Placebo Arm<br>* Placebo contains histidine, sucrose, PS80, ethylene diamine, and triacetic acid<br>|
| Experimental: PF-06823859 ARM high<br> | Drug: PF-06823859 high<br>* A humanized immunoglobulin neutralizing antibody<br>|
| Experimental: PF-06823859 ARM low<br> | Drug: PF-06823859 low<br>* A humanized immunoglobulin neutralizing antibody<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Cutaneous Dermatomyositis Disease Area and Severity Index (CDASI) Activity Score at Week 12 (Stage 1, Stage 2 and Amended Stage 2) | The treatment effect was defined as the difference (mean chg from baseline at Week12 in the active treatment group minus that in the placebo group) in the mean change of CDASI activity score from baseline at Week 12. The score (range: 0-100) consists of the extent score (ES), Gottorn hands score (GHS), peringual score (PS) and allopecia score (AS). ES (range: 0-90) was obtained by summing up scores for the total erythema (ER [0-45], redness of the skin or mucous membranes), scaling (SC [0-30], peeling of the skin) and erosion/ulceration (EU [0-15], presence of the deeper wound). Total ER, SC and EU scores were calculated as a sum of the contributions from 15 individual areas of the body. GHS characterizes papules (swellings) on hand and is a sum of the papule's characterization score (0-6) and ulceration score (0-1). PS (0-2) characterizes abnormalities around nails. The AS (0-1) characterizes hair loss. Higher scores indicate greater disease severity. | Baseline and Week 12 | 
| Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAE) (Stage 3) | Adverse event (AE) was any untoward medical occurrence in a participant temporally associated with the use of study intervention, whether or not considered related to the study intervention. SAE was any untoward medical occurrence that at any dose resulted in any of following outcomes/deemed significant for any other reason: death; initial /prolonged inpatient hospitalization; life-threatening; persistent or significant disability/incapacity; congenital anomaly/birth defect and suspected transmission via a Pfizer product of an infectious agent, pathogenic or non-pathogenic. AEs included both serious (if occurred) and all non-serious adverse events. TEAEs are events between first dose of study drug and up to Week 40 that were absent before treatment or that worsened relative to pretreatment state. | Up to Week 40 | 
| Number of Participants With Clinically Significant Laboratory Abnormalities (Stage 3) | Hemoglobin(HGB),hematocrit,erythrocytes(ery.),HDL cholesterol(chl.)<0.8*lower limit of normal(LLN);reticulocytes (ret.), ret./ery.(%)<0.5*LLN,>1.5*upper limit of normal (ULN);ery. mean corpuscular(EMC) volume,EMC HGB concentration,potassium,chloride,calcium,bicarbonate<0.9*LLN,>1.1*ULN;platelets<0.5*LLN,>1.75*ULN; leukocytes(leu.),glucose<0.6*LLN,>1.5*ULN;lymphocytes(lym.), lym./leu.(%),neutrophils (neu.), neu./leu.(%), protein,albumin<0.8*LLN,>1.2*ULN;basophils(bas.), bas./leu.(%), eosinophils(eos.), eos./leu., monocytes(mon.), mon./leu.(%), urate>1.2*ULN;bilirubin (total, direct,indirect)>1.5*ULN;aspartate/alanine aminotransferase,gamma glutamyl transferase,lactate dehydrogenase,alkaline phosphatase>3.0*ULN;urea nitrogen,creatinine,triglycerides, chl.>1.3*ULN; sodium <0.95*LLN,>1.05*ULN; creatine kinase >2.0*ULN;Urine: pH<4.5,>8;glucose, ketones,protein, HGB,urobilinogen,bilirubin,nitrite,leukocyte esterase>=1;ery., leu.>= 20;hyaline casts>1;bacteria>20. | Up to Week 40 | 
| Number of Participants With Vital Sign Abnormalities (Stage 3) | Abnormality in vital signs: Sitting pulse rate <40 beats per minute (bpm) to >120 bpm, sitting diastolic blood pressure (DBP) < 50 millimeter of mercury (mmHg), sitting systolic blood pressure (SBP) <90 mmHg. | Baseline up to Week 40 | 
| Number of Participants With Electrocardiogram (ECG) Abnormalities (Stage 3) | ECG abnormalities criteria included: 1) QTc interval adjusted according to Fridericia formula (QTcF) (msec): >450, >480, >500, increase from baseline >=30, increase from baseline >=60; 2) Pulse rate (PR) (msec): >=300, change from baseline (Chg) >=25% or 50%; 3) QT (msec): >=500; 4) QRS (msec): >=200, Chg >=25% or 50%. Categories, with at least 1 participant having ECG abnormality in any of the reporting arms, were reported in this outcome measure. | Baseline up to Week 40 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With TEAEs and SAEs (Stage 1 and Stage 2) | AE was any untoward medical occurrence in a participant temporally associated with the use of study intervention, whether or not considered related to the study intervention. SAE was any untoward medical occurrence that at any dose resulted in any of following outcomes/deemed significant for any other reason: death; initial /prolonged inpatient hospitalization; life-threatening; persistent or significant disability/incapacity; congenital anomaly/birth defect and suspected transmission via a Pfizer product of an infectious agent, pathogenic or non-pathogenic. AEs included both serious (if occurred) and all non-serious adverse events. TEAEs are events between first dose of study drug and up to Week 28 that were absent before treatment or that worsened relative to pretreatment state. | Up to Week 28 | 
| Number of Participants With TEAEs and SAEs (Amended Stage 2) | AE was any untoward medical occurrence in a participant temporally associated with the use of study intervention, whether or not considered related to the study intervention. SAE was any untoward medical occurrence that at any dose resulted in any of following outcomes/deemed significant for any other reason: death; initial /prolonged inpatient hospitalization; life-threatening; persistent or significant disability/incapacity; congenital anomaly/birth defect and suspected transmission via a Pfizer product of an infectious agent, pathogenic or non-pathogenic. AEs included both serious (if occurred) and all non-serious adverse events. TEAEs are events between first dose of study drug and up to Week 40 that were absent before treatment or that worsened relative to pretreatment state. | Up to Week 40 | 
| Number of Participants With Clinically Significant Laboratory Abnormalities (Stage 1 and Stage 2) | HGB,hematocrit,ery.,HDL chl.<0.8*LLN;ret., ret./ery. (%)<0.5*LLN,>1.5*ULN;EMC volume,EMC HGB,EMC HGB concentration,potassium,chloride,calcium,bicarbonate<0.9*LLN,>1.1*ULN;platelets<0.5*LLN,>1.75*ULN;leu.,glucose<0.6*LLN,>1.5*ULN;lym., lym./leu.(%), neu., neu./leu. (%), protein,albumin <0.8*LLN,>1.2*ULN;bas., bas./leu.(%), eos., eos./leu., mon., mon./leu.(%), urate >1.2*ULN;bilirubin (total, direct, indirect)>1.5*ULN;aspartate/alanine aminotransferase, gamma glutamyl transferase, lactate dehydrogenase, alkaline phosphatase>3.0*ULN;urea nitrogen, creatinine, triglycerides, chl.>1.3*ULN; sodium <0.95*LLN,>1.05*ULN; creatine kinase >2.0*ULN;Urine: pH<4.5,>8;glucose, ketones, protein, HGB, urobilinogen,bilirubin,nitrite,leukocyte esterase>=1;ery., leu.>= 20;hyaline casts>1;bacteria>20. Clinical significance of laboratory parameters was determined at the investigator's discretion. | Up to Week 28 | 
| Number of Participants With Clinically Significant Laboratory Abnormalities (Amended Stage 2) | HGB,hematocrit,ery.,HDL chl.<0.8*LLN;ret., ret./ery. (%)<0.5*LLN,>1.5*ULN;EMC volume,EMC HGB,EMC HGB concentration,potassium,chloride,calcium,bicarbonate<0.9*LLN,>1.1*ULN;platelets<0.5*LLN,>1.75*ULN;leu.,glucose<0.6*LLN,>1.5*ULN;lym., lym./leu.(%), neu., neu./leu. (%), protein,albumin <0.8*LLN,>1.2*ULN;bas., bas./leu.(%), eos., eos./leu., mon., mon./leu.(%), urate >1.2*ULN;bilirubin (total, direct, indirect)>1.5*ULN;aspartate/alanine aminotransferase, gamma glutamyl transferase, lactate dehydrogenase, alkaline phosphatase>3.0*ULN;urea nitrogen, creatinine, triglycerides, chl.>1.3*ULN; sodium <0.95*LLN,>1.05*ULN; creatine kinase >2.0*ULN;Urine: pH<4.5,>8;glucose, ketones, protein, HGB, urobilinogen,bilirubin,nitrite,leukocyte esterase>=1;ery., leu.>= 20;hyaline casts>1;bacteria>20. Clinical significance of laboratory parameters was determined at the investigator's discretion. | Up to Week 40 | 
| Number of Participants With Vital Sign Abnormalities (Stage 1 and Stage 2) | Abnormality in vital signs: Sitting pulse rate <40 bpm to >120 bpm, sitting DBP < 50 mmHg, sitting SBP <90 mmHg. | Up to Week 28 | 
| Number of Participants With Vital Sign Abnormalities (Amended Stage 2) | Abnormality in vital signs: Sitting pulse rate <40 bpm to >120 bpm, sitting DBP < 50 mmHg, sitting SBP <90 mmHg. | Up to Week 40 | 
| Number of Participants With ECG Abnormalities (Stage 1 and Stage 2) | ECG abnormalities criteria included: 1) QTc interval adjusted according to Fridericia formula (QTcF) (msec): >450, >480, >500, increase from baseline >=30, increase from baseline >=60; 2) Pulse rate (PR) (msec): >=300, change from baseline (Chg) >=25% or 50%; 3) QT (msec): >=500; 4) QRS (msec): >=200, Chg >=25% or 50%. Categories, with at least 1 participant having ECG abnormality in any of the reporting arms, were reported in this outcome measure. | Up to Week 28 | 
| Number of Participants With ECG Abnormalities (Amended Stage 2) | ECG abnormalities criteria included: 1) QTc interval adjusted according to Fridericia formula (QTcF) (msec): >450, >480, >500, increase from baseline >=30, increase from baseline >=60; 2) Pulse rate (PR) (msec): >=300, change from baseline (Chg) >=25% or 50%; 3) QT (msec): >=500; 4) QRS (msec): >=200, Chg >=25% or 50%. Categories, with at least 1 participant having ECG abnormality in any of the reporting arms, were reported in this outcome measure. | Up to Week 40 | 
| Change From Baseline in CDASI Activity Score at at All Scheduled Timepoints Through Week 12 (Stage 1, Stage 2 and Amended Stage 2) | The treatment effect was defined as the difference (mean change from baseline at Weeks 1, 4, 8 in the active treatment group minus the mean change from baseline at Weeks 1, 4, 8 in the placebo group) in the mean change of CDASI activity score from baseline at scheduled timepoints. The score (range: 0-100) consists of the ES, GHS, PS and AS. ES (range: 0-90) was obtained by summing up scores for the total erythema (ER [0-45], redness of the skin or mucous membranes), scaling (SC [0-30], peeling of the skin) and erosion/ulceration (EU [0-15], presence of the deeper wound). Total ER, SC and EU scores were calculated as a sum of the contributions from 15 individual areas of the body. GHS characterizes papules (swellings) on hand and is a sum of the papule's characterization score (0-6) and ulceration score (0-1). PS (0-2) characterizes abnormalities around nails. The AS (0-1) characterizes hair loss. Higher scores indicate greater disease severity. | Baseline, Week 1, Week 4, and Week 8 (except for Week 12 which is a primary outcome measure) | 
| Change From Baseline in CDASI Activity Score at All Scheduled Timepoints Through Week 12 (Stage 3) | The treatment effect was defined as the difference (mean change from baseline at Weeks 1, 4, 8,12 in the active treatment group minus the mean change from baseline at Weeks 1, 4, 8, 12 in the placebo group) in the mean change of CDASI activity score from baseline at scheduled timepoints. The score (range: 0-100) consists of the ES, GHS, PS and AS. ES (range: 0-90) was obtained by summing up scores for the total erythema (ER [0-45], redness of the skin or mucous membranes), scaling (SC [0-30], peeling of the skin) and erosion/ulceration (EU [0-15], presence of the deeper wound). Total ER, SC and EU scores were calculated as a sum of the contributions from 15 individual areas of the body. GHS characterizes papules (swellings) on hand and is a sum of the papule's characterization score (0-6) and ulceration score (0-1). PS (0-2) characterizes abnormalities around nails. The AS (0-1) characterizes hair loss. Higher scores indicate greater disease severity. | Baseline, Week 1, Week 4, Week 8 and Week 12 | 
| Absolute Values of CDASI Activity Score at All Scheduled Timepoints Through Week 12 (All Stages) | The CDASI activity score (range: 0-100) consists of the ES, GHS, PS and AS. ES (range: 0-90) was obtained by summing up scores for the total erythema (ER [0-45], redness of the skin or mucous membranes), scaling (SC [0-30], peeling of the skin) and erosion/ulceration (EU [0-15], presence of the deeper wound). Total ER, SC and EU scores were calculated as a sum of the contributions from 15 individual areas of the body. GHS characterizes papules (swellings) on hand and is a sum of the papule's characterization score (0-6) and ulceration score (0-1). PS (0-2) characterizes abnormalities around nails. The AS (0-1) characterizes hair loss. Higher scores indicate greater disease severity. | Baseline, Week 1, Week 4, Week 8 and Week 12 | 
| Absolute Values of CDASI Damage Score at All Scheduled Timepoints Through Week 12 (All Stages) | The Damage Score (DS) was calculated as a sum of the total poilkiloderma score (POLS), total calcinosis score (CALS) and Gotorn's hands damage score (GHDS). The POLS characterizes specific dispigmentation in the particulal area and calcinosis score characterizes calcification of the skin in the particular area. The POLS and the CALS are summed up over 15 individual areas in the body and each of them has range 0-15. The GHDS has the range 0-2 so that the DS has the range 0-32. Higher scores indicate greater disease severity. | Baseline, Week 1, Week 4, Week 8 and Week 12 | 
| Absolute Values for Total Improvement Score (TIS) at Week 12 and Intermediate Scheduled Time Points (Stage 3) | The TIS was the sum of all 6 improvement scores where higher score indicates worse status (PhGA [from the MDAAT, 0-20 scale], PtGA [0-10 scale], MMT [0-35 scale], HAQ-DI [0-10 scale], muscle enzymes [0-7.5 scale], and extramuscular global assessment [0-20 scale]) associated with the change in each core set measure. A total improvement score between 0 and 100 corresponded to the degree of improvement, with higher scores corresponding to a greater degree of improvement: of ≥20 represented minimal improvement, a score of ≥40 represented moderate improvement, and a score of ≥60 represented major improvement. | Week 4, Week 8 and Week 12 | 
| Change From Baseline in the Core Set Measures (CSM) of the TIS (Global Disease Activity [PhGA] and Extramuscular Global Assessment [EmGA]) (Stage 3) | PhGA: assessment of the severity of disease by the physician. The physician used the visual analog scale and put a mark on 0 cm (best) -10 cm (worst) scale where higher score indicated worse status. EmGA: overall evaluation of disease activity in all extramuscular systems using visual analog scale 0 cm (best) -10 cm (worst) scale where higher score indicated worse status. | Baseline, Week 4, Week 8 and Week 12 | 
| Change From Baseline in the CSM of the TIS (PtGA) (Stage 3) | PtGA: assessment of the severity of disease by the participant/participant's guardian, using a visual analog scale from 0 mm (no evidence of disease activity) to 100 mm (extremely active or severe disease activity). Higher score indicated worse status. | Baseline, Week 4, Week 8 and Week 12 | 
| Change From Baseline in the CSM of the TIS (MMT8 and HAQ01-HAQ-DI) (Stage 3) | Manual Muscle Testing-8 designated muscle groups (MMT-8): was a set of 8 designated muscles tested unilaterally generally on right side (left side used unless right side cannot be used). Potential score range was from 0 to 80, where higher scores denoted better health status. HAQ-DI: contained eight sections (including dressing & grooming, arising, eating, walking, hygiene, grip, reach, and activities). Each section had multiple questions that the participant used to rank their functionality and ranged from 0 to 3 where 0 = without any difficulty and 3 = unable to do. For each participant, the average ranking was calculated for each of the eight sections. HAQ-DI had a score range of 0 to 3, where higher score reflected worse status. | Week 4, Week 8 and Week 12 | 
| Change From Baseline in the CSM of the TIS (Aldolase and Creatine Kinase) (Stage 3) | The LS mean (with 90% CI) of CSM of the TIS (aldolase and creatine kinase) at weeks 4, 8, 12 were presented. | Baseline, Week 4, Week 8 and Week 12 |