Dermatomyositis, Polymyositis
Conditions
Keywords
Toll-like Receptor 7, Toll-like Receptor 8, Anti-synthetase syndrome, Idiopathic immune myopathies, Myositis, M5049
Brief summary
The purpose of this study is to evaluate the efficacy and safety of orally administered M5049 in idiopathic inflammatory myopathies, specifically dermatomyositis (DM) and polymyositis (PM) participants for 24 weeks.
Interventions
DRUGM5049 dose
Participants will receive film-coated tablets of M5049 dose orally, twice daily up to 24 weeks.
DRUGPlacebo
Participants will receive placebo matched to M5049 orally, twice daily up to 24 weeks.
Sponsors
EMD Serono Research & Development Institute, Inc.
Merck KGaA, Darmstadt, Germany
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
* Diagnosis of probable or definite DM or PM as per 2017 ACR/EULAR classification criteria, with positive autoantibody status. Anti-synthetase syndrome (ASyS) participants that meet classification criteria are allowed * Active disease on standard of care (SoC), must meet 1 of the criteria within 6 months prior to Screening: Pathological evidence of active myositis in muscle biopsy; Evidence of active myositis by Electromyography (EMG); Magnetic resonance imaging (MRI) with evidence of active myositis; or any muscle enzyme greater than or equal to (\>=) 4 × upper limit of normal (ULN) at time of Screening; Active PM/DM skin rash as per cutaneous dermatomyositis area and severity index-A (CDASI-A) \>= 7 at time of Screening * Minimum disease severity defined by: moderate to severe myopathy with manual muscle testing-8 (MMT-8) \>= 80 and less than or equal to (\<=) 142 AND at least 2 of the following core set measures (CSM) abnormalities: Patient Global Activity (PtGA) \>= 2 centimeters (cm); Physician Global Activity (PGA) derived from myositis disease activity assessment tool (MDAAT) \>= 2 cm; Extramuscular Activity Assessment derived from MDAAT \>2 cm; At least 1 muscle enzyme \> 1.5 times ULN; health assessment questionnaire-disability index (HAQ-DI) \>= 0.25 * Stable doses of oral corticosteroids (CS) and/or maximum of 1 non-corticosteroid immunosuppressive/immunomodulatory medications (methotrexate, 6 mercaptopurine, sulfasalazine, mycophenolate mofetil or sodium, azathioprine, leflunomide, cyclosporine, oral tacrolimus) for DM or PM * Participants have a body mass index (BMI) lower or Equal to 40.0 kilograms per square meter (kg/m\^2) * Other protocol defined inclusion criteria could apply
Exclusion criteria
* Primary diagnosis of inclusion body myositis (IBM), malignancy-associated myositis (defined as diagnosis of myositis within 3 years of cancer), immune mediated necrotizing myopathy (IMNM) with a biopsy characterized as necrotizing biopsy or IMNM with positive anti-signal recognition particle antibody (SRP) or anti 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) auto antibodies. Participants with anti-transcription intermediary factor 1 (TIF1) gamma antibody or newly diagnosed (within 1 year) anti MDAT5 antibody should have had adequate screening for cancer within 12 months of Day 1. Adequate screening of cancer is defined as up-to-date age and gender appropriate screening as per national guidelines * Primary diagnosis of juvenile DM, or adult participants previously diagnosed with juvenile DM * Any other active concurrent connective tissue disease associated with inflammatory myopathy in the Investigator's opinion. Eligibility of participants with diagnosis of concurrent connective tissue disease(s) will be reviewed and approved by an idiopathic inflammatory myopathies (IIM) expert committee * Severe interstitial lung disease defined as supplemental oxygen required at rest, or forced vital capacity (FVC) of \<60 percent (%) predicted. Participants within 1 year of PM/DM diagnosis and anti-MDA5 antibody, should have been evaluated for interstitial lung disease (ILD) with high resolution computed tomography (HRCT) Chest * Any uncontrolled disease (for example \[e.g.\], severe respiratory, cardiovascular, gastrointestinal, neurological, psychiatric, hematological, metabolic \[including thyroiditis with increased/decreased thyroid stimulating hormone (TSH)\], renal \[Estimated glomerular filtration rate \< 40 milliliter per minute/1.73 m\^2 as calculated by the Modification of Diet in Renal Disease equation by the central laboratory\], hepatic, endocrine/reproductive organ disease) other than DM/PM, that in the Investigator's or Sponsor/designee's opinion constitutes an inappropriate risk or contraindication for participation in the study or that could interfere with the study objectives, conduct, or evaluation * Other protocol defined
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| DBPC Period: Number of Participants With Clinically Meaningful Changes From Baseline in Electrocardiograms (ECG) Parameters | Up to Week 26 (Safety follow up) | 12-lead ECG recordings included rhythm, heart rate (as measured by RR interval), PR interval, QRS duration, and QT interval. Number of participants with clinically meaningful changes from baseline in ECG parameters were reported. Clinical meaningfulness was assessed by the investigator. |
| Double Blind Placebo Control Period (DBPC): American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) Total Improvement Score (TIS) at Week 24 | At Week 24 (end of DBPC period) | The ACR/EULAR TIS was derived from evaluation of results from 6 Core Set Measures(CSMs) of myositis disease activity in participants with Dermatomyositis and Polymyositis.TIS was determined by summing scores for each CSM,based on improvement in absolute percent change which is calculated by subtracting the baseline value from the final value,dividing difference by the range, and then multiplying the result by100 and relative weight of each core set measure. The TIS scale ranges from 0 to 100 with thresholds for minimal \[more than or equal to(\>= 20)\],moderate(\>= 40) and major(\>= 60)improvement in combined 6 CSM.The CSMs include,physician global activity visual analogue scale(VAS) score(0-10), patient global activity VAS score(0-10), manual muscle testing-8 score(0-150), health assessment questionnaire-disability index(0-3) along with checks for most abnormal muscle-associated enzymes and extra muscular activity assessment derived using myositis disease activity assessment tool(0-10). |
| DBPC Period: Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Serious TEAEs and Adverse Events of Special Interest (AESIs) | Up to Week 26 (Safety follow up) | An AE was defined as any untoward medical occurrence in a participant administered a pharmaceutical product and which did not necessarily have a causal relationship with this treatment. An AE could therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product or protocol-specified procedure, whether considered related to the medicinal product or protocol-specified procedure. Serious AE was defined AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial/prolonged inpatient hospitalization; congenital anomaly/birth defect. TEAE was defined as events with onset date or worsening during the on-treatment period. TEAEs included serious TEAEs and non-serious TEAEs. Adverse events of special interest (AESI) are serious or non-serious AEs that are of clinical interest and were closely followed. |
| DBPC Period: Number of Participants With Clinically Meaningful Changes From Baseline in Laboratory Parameters | Up to Week 26 (Safety follow up) | Laboratory parameters included hematology, biochemistry, urinalysis and reflex testing for HBV DNA. Number of participants with clinically meaningful changes from baseline in laboratory parameters were reported. Clinical meaningfulness was assessed by the investigator. |
| DBPC Period: Number of Participants With Clinically Meaningful Changes From Baseline in Vital Signs | Up to Week 26 (Safety follow up) | Vital signs included body temperature, systolic and diastolic blood pressure, respiration rate, pulse rate, weight, height and body mass index. Number of participants with clinically meaningful changes from baseline in vital signs were reported. Clinical meaningfulness was assessed by the investigator. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| DBPC Period: Change From Baseline in Extra Muscular Global Assessment From Myositis Disease Activity Assessment Tool (MDAAT) Score | Baseline, Week 4, 8, 12, 16, 20 and 24 | MDAAT was a combined tool capturing physician's assessment of disease activity of various organ systems- constitutional, cutaneous, pulmonary, gastrointestinal, joints and cardiovascular, muscular using: Myositis Intention to Treat Activity Index (MITAX), a scale from 0("Not present in the last 4 weeks") to 4("New - in the last 4 weeks \[compared to the previous 4 weeks\]") and Myositis Disease Activity Assessment Visual Analogue Scales (MYOACT), a 10 cm VAS assessing disease activity in the last 4 weeks of various organ systems from 0 cm("No evidence of disease activity") to 10 cm("Extremely active or severe disease activity"), disease activity being defined as potentially reversible pathology or physiology resulting from the myositis. Left end of line = no evidence of disease activity, midpoint of line = moderate disease activity, and right end of line = extreme or maximum disease activity. An assessment of extramuscular activity assessment was taken from MDAAT using a 10cm VAS scale. |
| DBPC Period: Change From Baseline in Manual Muscle Testing-8 (MMT-8) Score | Baseline, Week 4, 8, 12, 16, 20 and 24 | MMT-8 was an International Myositis Assessment and Clinical Studies (IMACS) Core Set Measure used in the calculation of the IMACS Definition of Improvement (DOI) and ACR/EULAR TIS. It is a set of 8 designated muscles tested unilaterally (generally on right side) -which include 1 axial, 5 proximal (2 upper extremity, 3 lower extremity), and 2 distal muscles (1 upper, 1 lower extremity). Total score for unilateral testing ranges from 0 to 80, and bilateral testing ranges from 0 to 150 with normal strength represented by a higher score at or near the top of the scale. The total score for bilateral testing (item "MMT8 score (0 - 150)" from the MANUAL MUSCLE TESTING-8 (mmt8) form) is used in the derivation of the Total Improvement Score. |
| DBPC Period: Change From Baseline in Health Assessment Questionnaire -Disability Index (HAQ-DI) Score | Baseline, Week 4, 8, 12, 16, 20 and 24 | HAQ-DI was an IMACS Core Set Measure used in the calculation of the IMACS DOI and ACR/EULAR TIS. It is a generic rather than a disease-specific instrument comprised of 8 sections (dressing, arising, eating, walking, hygiene, reach, grip, and activities), with 2 to 3 questions per section. Scoring within each section is from 0 (without any difficulty) to 3 (unable to do). For each section the score given to that section is the worst score within the section. The 8 scores of the 8 sections are summed and divided by 8. Overall score ranges from 0-3. |
| DBPC Period: Relative Change From Baseline in Most Abnormal Muscle-associated Enzyme | Baseline, Week 4, 8, 12, 16, 20 and 24 | For each participant, the most abnormal muscle-associated enzyme was defined as the baseline muscle-associated enzyme with the highest ratio of the observed value to the upper limit of the normal range (ULN) among creatinine kinase, lactate dehydrogenase, aspartate aminotransferase, alanine aminotransferase, and aldolase. The relative abnormality could be expressed as a percentage of ULN, calculated as (enzyme value divided by ULN) multiplied by 100. |
| DBPC Period: Number of Participants Who Achieved International Myositis Assessment and Clinical Studies (IMACS) Response | At Week 16 and 24 | A participant was defined as an International Myositis Assessment and Clinical Studies (IMACS) Responder if 3 of any 6 IMACS Core Set Measures (CSMs) have been improved by more than equal to (\>= 20) percent (%), with no more than 2 IMACS CSMs worse by \>= 25%. The CSMs include, physician global activity visual analogue scale(VAS) score(0-10), patient global activity VAS score(0-10), manual muscle testing-8 score(0-150), health assessment questionnaire-disability index (0-3) along with checks for muscle-associated enzymes and extra muscular activity assessment derived using myositis disease activity assessment tool(0-10). |
| DBPC Period: Change From Baseline in Cutaneous Dermatomyositis Area and Severity Index-A (CDASI-A) and Cutaneous Dermatomyositis Area and Severity Index-D (CDASI-D) Subscale Score | Baseline, Week 4, 8, 12, 16, 20 and 24 | CDASI is a clinician-scored single page instrument that separately measures activity and damage in the skin of DM participants. CDASI has 3 activity measures (CDASI-A: erythema, scale, and erosion/ulceration) and 2 damage measures (CDASI-D: poikiloderma and calcinosis) which are assessed over 15 body areas. In addition, Gottron's papules on the hands, periungual changes and alopecia are evaluated separately both for activity and damage. Activity and Damage Subscale scores range from 0 to 100 and 0 to 32, respectively, where higher scores indicate greater disease severity. |
| DBPC Period: Change From Baseline in Investigator's Global Assessment (IGA) Skin Activity Score | Baseline, Week 4, 8, 12, 16, 20 and 24 | The IGA skin activity is a five-point score that defines the level of disease severity based on overall lesion characteristics where 0 is "clear" and "4" is severe. |
| Open-label Extension (OLE) Period: Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Serious TEAEs and Adverse Events of Special Interest (AESIs) | From start of OLE period (Week 1) up to safety follow up (Week 26) | An AE was defined as any untoward medical occurrence in a participant administered a pharmaceutical product and which did not necessarily have a causal relationship with this treatment. An AE could therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product or protocol-specified procedure, whether considered related to the medicinal product or protocol-specified procedure. Serious AE was defined AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial/prolonged inpatient hospitalization; congenital anomaly/birth defect. TEAE was defined as events with onset date or worsening during the on-treatment period. TEAEs included serious TEAEs and non-serious TEAEs. Adverse events of special interest (AESI) are serious or non-serious AEs that are of clinical interest and were closely followed. |
| OLE Period: Number of Participants With Clinically Meaningful Changes From Baseline in Laboratory Parameters | From start of OLE period (Week 1) up to safety follow up (Week 26) | Laboratory parameters included hematology, biochemistry, urinalysis and reflex testing for HBV DNA. Number of participants with clinically meaningful changes from baseline in laboratory parameters were reported. Clinical meaningfulness was assessed by the investigator. |
| OLE Period: Number of Participants With Clinically Meaningful Changes From Baseline in Electrocardiograms (ECG) Parameters | From start of OLE period (Week 1) up to safety follow up (Week 26) | 12-lead ECG recordings included rhythm, heart rate (as measured by RR interval), PR interval, QRS duration, and QT interval. Number of participants with clinically meaningful changes from baseline in ECG parameters were reported. Clinical meaningfulness was assessed by the investigator. |
| OLE Period: Number of Participants With Clinically Meaningful Changes From Baseline in Vital Signs | From start of OLE period (Week 1) up to safety follow up (Week 26) | Vital signs included body temperature, systolic and diastolic blood pressure, respiration rate, pulse rate, weight, height and body mass index. Number of participants with clinically meaningful changes from baseline in vital signs were reported. Clinical meaningfulness was assessed by the investigator. |
| DBPC Period: Number of Participants With American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) Total Improvement Score (TIS) Greater Than or Equal to (>=) 20, >= 40 and >= 60 | At Week 16 and Week 24 | The ACR/EULAR TIS was derived from evaluation of results from 6 Core Set Measures(CSMs) of myositis disease activity in participants with Dermatomyositis and Polymyositis.TIS was determined by summing scores for each CSM,based on improvement in absolute percent change which is calculated by subtracting the baseline value from the final value,dividing difference by the range, and then multiplying the result by100 and relative weight of each core set measure. The TIS scale ranges from 0 to 100 with thresholds for minimal \[more than or equal to(\>= 20)\],moderate(\>=40) and major(\>=60)improvement in combined 6 CSM.The CSMs include,physician global activity visual analogue scale(VAS) score(0-10), patient global activity VAS score(0-10), manual muscle testing-8 score(0-150), health assessment questionnaire-disability index(0-3) along with checks for most abnormal muscle-associated enzymes and extra muscular activity assessment derived using myositis disease activity assessment tool(0-10). |
| DBPC Period: Participant's Total Improvement Score (TIS) | Week 4, 8, 12, 16, 20 and 24 | The ACR/EULAR TIS was derived from evaluation of results from 6 Core Set Measures(CSMs) of myositis disease activity in participants with Dermatomyositis and Polymyositis.TIS was determined by summing scores for each CSM,based on improvement in absolute percent change which is calculated by subtracting the baseline value from the final value,dividing difference by the range, and then multiplying the result by100 and relative weight of each core set measure. The TIS scale ranges from 0 to 100 with thresholds for minimal \[more than or equal to(\>= 20)\],moderate(\>=40) and major(\>=60)improvement in combined 6 CSM.The CSMs include,physician global activity visual analogue scale(VAS) score(0-10), patient global activity VAS score(0-10), manual muscle testing-8 score(0-150), health assessment questionnaire-disability index(0-3) along with checks for most abnormal muscle-associated enzymes and extra muscular activity assessment derived using myositis disease activity assessment tool(0-10). |
| DBPC Period: Change From Baseline in Physician Global Activity (PGA) Scores From Myositis Disease Activity Assessment Tool (MDAAT) | Baseline, Week 4, 8, 12, 16, 20 and 24 | The Physician's Global Assessment of Disease Activity was an assessment of overall global disease activity by the physician that was taken from Myositis Disease Activity Assessment Tool (MDAAT). Physician rated participant's disease activity on a 0-10 centimeter (cm) visual analog scale (VAS). Extra-muscular activity ranged between 0 and 10, where, 0 cm = absent and 10 cm = maximum disease activity. |
| DBPC Period: Change From Baseline in Patient Global Activity (PtGA) Visual Analog Scale (VAS) Score | Baseline, Week 4, 8, 12, 16, 20 and 24 | PtGA was the assessment of the severity of disease by the participant/participant's guardian, using a VAS from 0 mm (no evidence of disease activity) to 100 mm (extremely active or severe disease activity). Higher score indicated worse status. |
Countries
Czechia, Greece, Italy, Poland, Spain, United Kingdom, United States
Contacts
STUDY_DIRECTORMedical Responsible
Merck Healthcare KGaA, Darmstadt, Germany, an affiliate of Merck KGaA, Darmstadt, Germany
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Continuous | 53 Years STANDARD_DEVIATION 11.5 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 10 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 18 Participants |
| Sex: Female, Male Female | 15 Participants |
| Sex: Female, Male Male | 2 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 9 | 0 / 11 | 0 / 11 |
| other Total, other adverse events | 7 / 9 | 7 / 11 | 8 / 11 |
| serious Total, serious adverse events | 0 / 9 | 2 / 11 | 0 / 11 |
Outcome results
None listed