Polymyositis, Dermatomyositis
Conditions
Keywords
Inflammatory muscle disease, Muscle weakness, Myositis, inflammatory myopathy, inclusion body myositis, skin rash, autoimmune, difficulty swallowing, dysphagia
Brief summary
This study determined the efficacy, safety, tolerability and the PK profile of BAF312, a novel immunomodulator, in polymyositis and dermatomyositis patients who were not responsive to traditional immunosuppressive and/or corticosteroid therapy. The study consisted of a 12 week, randomized, placebo controlled period, followed by another 12 weeks where all subjects received BAF312 treatment.
Interventions
DRUGBAF312
DRUGPlacebo
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
* Patients with disease at least 3 months before study * Muscle weakness * Received corticosteroids with or with out disease modifying antirheumatic drugs at least 3 months before study however not responding to this therapy
Exclusion criteria
* Other idiopathic inflammatory myopathies * Myopathy other than polymyositis and dermatomyositis * Patients with late stages of disease
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Who Responded to BAF312 | 12 weeks | Preliminary clinical efficacy of BAF312 in patients with Polymyositis and dermatomyositis (PM/DM) using the International Myositis Assessment and Clinical Studies Group (IMACS) core set measures (including manual muscle testing, Physician's Global Activity Assessment (on a horizontal 10 cm visual analogue scale), Patient Global Activity Assessment (on a horizontal 10 cm visual analogue scale), Physical Function (Health Assessment Questionnaire), Muscle-associated Enzymes (CK, LDH, AST, ALT, aldolase) and Extra-Muscular Activity Assessment (Extra-muscular portion of Myositis Disease Activity Assessment Tool). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Mean Plasma Concentrations of BAF312 | baseline to end of trial (day 196) | — |
| Summary of CRP Levels | 12 weeks | Biomarkers reflecting efficacy in reducing systemic inflammatory components of the disease using serum markers such as C-reactive protein (CRP) |
| Efficacy in Modifying Health-related Quality of Life Measured by SF-36 | 12 weeks | Short Form (36) Health Survey. The SF-36 consists of eight scaled scores, which are the weighted sums of the questions in their section. Each scale is directly transformed into a 0-100 scale on the assumption that each question carries equal weight. The lower the score the more disability. The higher the score the less disability i.e., a score of zero is equivalent to maximum disability. |
| Myositis Disease (MD) Activity Scores | Week 12 | Myositis Disease Activity Scores. This is a combined tool that captures the physician's assessment of disease activity of various organ systems via the MYOSITIS INTENTION TO TREAT ACTIVITY INDEX (MITAX) and via the MYOSITIS DISEASE ACTIVITY ASSESSMENT VISUAL ANALOGUE SCALES (MYOACT) It rates the physician's overall assessment of the ongoing current disease activity for various systems by drawing a vertical mark on the 10-cm line for each system according to the following scale: 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. |
| Number of Participants With a Change in Steroids Use After BAF312 Administration -Period 2 | 12 weeks | — |
| Patient Global Activity Assessment | Baseline, Week 12 | Patient's overall assessment on a single 0-10 cm scale, where the higher score indicates higher disease activity. |
| Manual Muscle Testing (MMT) - 8 Score | Baseline, Week 12 | Manual Muscle Testing - 8 (MMT-8): Assessment of designated muscles manually by scoring each muscle from 0 to 10 where 0 is no strength and 10 is maximum strength. MMT- 8 includes 7 bilateral muscles (potential score 0-70 x 2) and one unilateral (axial) muscle (0-10 x1) so the total score ranges from 0 to 150 (maximum) where higher score indicates more strength. |
| Health Assessment Questionnaire | Baseline, Week 12 | Health Assessment Questionnaire (HAQ): This questionnaire is a patient reported outcome (PRO) which is self-administered by the patient. It is used to assess disability and comprises various categories related to usual daily activities. The patients report the amount of difficulty they have in performing some of these activities. Each question asks on a scale ranging from 0 to 3 if the categories can be performed without any difficulty (scale 0) up to cannot be done at all (scale 3). The total score is derived from these sub-scores and ranges from 0 to 3 where higher HAQ indicates more disability. |
| Serum Levels of Muscle Enzymes | Baseline, Week 12 | — |
| Physician Global Activity Assessment | Baseline, Week 12 | Physician's overall assessment on a single 0-10 cm scale, where the higher score indicates higher disease activity. |
Countries
Czechia, Hungary, Sweden, United Kingdom, United States
Participant flow
Recruitment details
The study was terminated after 18 patients had been enrolled, of which 14 were eligible for the primary efficacy analysis.
Participants by arm
| Arm | Count |
|---|---|
| BAF312/BAF312 2 tablets each of BAF312 5mg for oral administration in period 1 and 2 tablets each of BAF312 5mg in period 2 | 8 |
| Placebo/BAF312 2 tablets of Placebo for oral administration in period 1 and 2 tablets each of BAF312 5mg in period 2 | 10 |
| Total | 18 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 0 | 2 |
| Overall Study | Lack of Efficacy | 0 | 1 |
| Overall Study | Protocol Violation | 1 | 0 |
| Overall Study | Withdrawal by Subject | 0 | 2 |
Baseline characteristics
| Characteristic | BAF312/BAF312 | Placebo/BAF312 | Total |
|---|---|---|---|
| Age, Continuous | 51.4 Years STANDARD_DEVIATION 6.48 | 48.1 Years STANDARD_DEVIATION 15.57 | 49.6 Years STANDARD_DEVIATION 12.18 |
| Sex: Female, Male Female | 4 Participants | 7 Participants | 11 Participants |
| Sex: Female, Male Male | 4 Participants | 3 Participants | 7 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 16 | 0 / 10 |
| other Total, other adverse events | 12 / 16 | 7 / 10 |
| serious Total, serious adverse events | 0 / 16 | 3 / 10 |
Outcome results
Primary
Number of Participants Who Responded to BAF312
Preliminary clinical efficacy of BAF312 in patients with Polymyositis and dermatomyositis (PM/DM) using the International Myositis Assessment and Clinical Studies Group (IMACS) core set measures (including manual muscle testing, Physician's Global Activity Assessment (on a horizontal 10 cm visual analogue scale), Patient Global Activity Assessment (on a horizontal 10 cm visual analogue scale), Physical Function (Health Assessment Questionnaire), Muscle-associated Enzymes (CK, LDH, AST, ALT, aldolase) and Extra-Muscular Activity Assessment (Extra-muscular portion of Myositis Disease Activity Assessment Tool).
Time frame: 12 weeks
Population: All patients with evaluable (or complete) PD measurement and no major protocol deviations which impact on PD data were included in the PD analysis set.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| BAF312/BAF312 | Number of Participants Who Responded to BAF312 | 4 Participants |
| Placebo/BAF312 | Number of Participants Who Responded to BAF312 | 1 Participants |
Secondary
Efficacy in Modifying Health-related Quality of Life Measured by SF-36
Short Form (36) Health Survey. The SF-36 consists of eight scaled scores, which are the weighted sums of the questions in their section. Each scale is directly transformed into a 0-100 scale on the assumption that each question carries equal weight. The lower the score the more disability. The higher the score the less disability i.e., a score of zero is equivalent to maximum disability.
Time frame: 12 weeks
Population: All patients with evaluable (or complete) PD measurement and no major protocol deviations which impact on PD data were included in the PD analysis set.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| BAF312/BAF312 | Efficacy in Modifying Health-related Quality of Life Measured by SF-36 | Physical component score | 36.469 score on a scale | Standard Deviation 7.552 |
| BAF312/BAF312 | Efficacy in Modifying Health-related Quality of Life Measured by SF-36 | Mental component score | 44.449 score on a scale | Standard Deviation 7.2194 |
| Placebo/BAF312 | Efficacy in Modifying Health-related Quality of Life Measured by SF-36 | Physical component score | 30.406 score on a scale | Standard Deviation 14.5402 |
| Placebo/BAF312 | Efficacy in Modifying Health-related Quality of Life Measured by SF-36 | Mental component score | 49.063 score on a scale | Standard Deviation 12.9628 |
Secondary
Health Assessment Questionnaire
Health Assessment Questionnaire (HAQ): This questionnaire is a patient reported outcome (PRO) which is self-administered by the patient. It is used to assess disability and comprises various categories related to usual daily activities. The patients report the amount of difficulty they have in performing some of these activities. Each question asks on a scale ranging from 0 to 3 if the categories can be performed without any difficulty (scale 0) up to cannot be done at all (scale 3). The total score is derived from these sub-scores and ranges from 0 to 3 where higher HAQ indicates more disability.
Time frame: Baseline, Week 12
Population: PD set in all disease types
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| BAF312/BAF312 | Health Assessment Questionnaire | Baseline | 1.2969 Score on a scale | Standard Deviation 0.53426 |
| BAF312/BAF312 | Health Assessment Questionnaire | Week 12 | 1.2143 Score on a scale | Standard Deviation 0.41278 |
| Placebo/BAF312 | Health Assessment Questionnaire | Baseline | 1.2031 Score on a scale | Standard Deviation 0.90863 |
| Placebo/BAF312 | Health Assessment Questionnaire | Week 12 | 1.3929 Score on a scale | Standard Deviation 0.86129 |
Secondary
Manual Muscle Testing (MMT) - 8 Score
Manual Muscle Testing - 8 (MMT-8): Assessment of designated muscles manually by scoring each muscle from 0 to 10 where 0 is no strength and 10 is maximum strength. MMT- 8 includes 7 bilateral muscles (potential score 0-70 x 2) and one unilateral (axial) muscle (0-10 x1) so the total score ranges from 0 to 150 (maximum) where higher score indicates more strength.
Time frame: Baseline, Week 12
Population: PD set in all disease types
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| BAF312/BAF312 | Manual Muscle Testing (MMT) - 8 Score | Baseline | 106.8 scores on a scale | Standard Deviation 12.56 |
| BAF312/BAF312 | Manual Muscle Testing (MMT) - 8 Score | Week 12 | 115.0 scores on a scale | Standard Deviation 10.31 |
| Placebo/BAF312 | Manual Muscle Testing (MMT) - 8 Score | Baseline | 106.6 scores on a scale | Standard Deviation 19.7 |
| Placebo/BAF312 | Manual Muscle Testing (MMT) - 8 Score | Week 12 | 100.7 scores on a scale | Standard Deviation 23.75 |
Secondary
Mean Plasma Concentrations of BAF312
Time frame: baseline to end of trial (day 196)
Population: PK Analysis set in all disease types
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| BAF312/BAF312 | Mean Plasma Concentrations of BAF312 | baseline | 0 ng/ml | Standard Deviation 0 |
| BAF312/BAF312 | Mean Plasma Concentrations of BAF312 | Day 8 | 29.6 ng/ml | Standard Deviation 25.7 |
| BAF312/BAF312 | Mean Plasma Concentrations of BAF312 | Day 28 | 121 ng/ml | Standard Deviation 73.1 |
| BAF312/BAF312 | Mean Plasma Concentrations of BAF312 | Day 56 | 160 ng/ml | Standard Deviation 62.3 |
| BAF312/BAF312 | Mean Plasma Concentrations of BAF312 | Day 84 | 163 ng/ml | Standard Deviation 77.3 |
| BAF312/BAF312 | Mean Plasma Concentrations of BAF312 | Day 92 | 80.0 ng/ml | Standard Deviation 83.3 |
| BAF312/BAF312 | Mean Plasma Concentrations of BAF312 | Day 112 | 120 ng/ml | Standard Deviation 49 |
| BAF312/BAF312 | Mean Plasma Concentrations of BAF312 | Day 140 | 129 ng/ml | Standard Deviation 65.5 |
| BAF312/BAF312 | Mean Plasma Concentrations of BAF312 | Day 168 | 125 ng/ml | Standard Deviation 61.9 |
| BAF312/BAF312 | Mean Plasma Concentrations of BAF312 | Day 196 | 27.9 ng/ml | Standard Deviation 79.2 |
Secondary
Myositis Disease (MD) Activity Scores
Myositis Disease Activity Scores. This is a combined tool that captures the physician's assessment of disease activity of various organ systems via the MYOSITIS INTENTION TO TREAT ACTIVITY INDEX (MITAX) and via the MYOSITIS DISEASE ACTIVITY ASSESSMENT VISUAL ANALOGUE SCALES (MYOACT) It rates the physician's overall assessment of the ongoing current disease activity for various systems by drawing a vertical mark on the 10-cm line for each system according to the following scale: 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.
Time frame: Week 12
Population: PD set in all disease types
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| BAF312/BAF312 | Myositis Disease (MD) Activity Scores | Extramuscular global assessment | 1.51 cm | Standard Deviation 1.171 |
| BAF312/BAF312 | Myositis Disease (MD) Activity Scores | Cutaneous disease activity | 1.11 cm | Standard Deviation 0.997 |
| Placebo/BAF312 | Myositis Disease (MD) Activity Scores | Extramuscular global assessment | 2.27 cm | Standard Deviation 1.607 |
| Placebo/BAF312 | Myositis Disease (MD) Activity Scores | Cutaneous disease activity | 1.31 cm | Standard Deviation 1.999 |
Secondary
Number of Participants With a Change in Steroids Use After BAF312 Administration -Period 2
Time frame: 12 weeks
Population: The Safety set included all patients who received at least one dose of study medication.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| BAF312/BAF312 | Number of Participants With a Change in Steroids Use After BAF312 Administration -Period 2 | Steroid reduction | 3 Participants |
| BAF312/BAF312 | Number of Participants With a Change in Steroids Use After BAF312 Administration -Period 2 | Steroid increase1 | 1 Participants |
| BAF312/BAF312 | Number of Participants With a Change in Steroids Use After BAF312 Administration -Period 2 | Steroid stable | 3 Participants |
| Placebo/BAF312 | Number of Participants With a Change in Steroids Use After BAF312 Administration -Period 2 | Steroid increase1 | 2 Participants |
| Placebo/BAF312 | Number of Participants With a Change in Steroids Use After BAF312 Administration -Period 2 | Steroid reduction | 2 Participants |
| Placebo/BAF312 | Number of Participants With a Change in Steroids Use After BAF312 Administration -Period 2 | Steroid stable | 4 Participants |
Secondary
Patient Global Activity Assessment
Patient's overall assessment on a single 0-10 cm scale, where the higher score indicates higher disease activity.
Time frame: Baseline, Week 12
Population: PD set in all disease types
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| BAF312/BAF312 | Patient Global Activity Assessment | Baseline | 4.36 cm | Standard Deviation 1.986 |
| BAF312/BAF312 | Patient Global Activity Assessment | Week 12 | 4.50 cm | Standard Deviation 1.557 |
| Placebo/BAF312 | Patient Global Activity Assessment | Baseline | 4.75 cm | Standard Deviation 2.435 |
| Placebo/BAF312 | Patient Global Activity Assessment | Week 12 | 5.44 cm | Standard Deviation 2.421 |
Secondary
Physician Global Activity Assessment
Physician's overall assessment on a single 0-10 cm scale, where the higher score indicates higher disease activity.
Time frame: Baseline, Week 12
Population: PD set in all disease types
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| BAF312/BAF312 | Physician Global Activity Assessment | Baseline | 4.88 cm | Standard Deviation 0.947 |
| BAF312/BAF312 | Physician Global Activity Assessment | Week 12 | 3.04 cm | Standard Deviation 1.816 |
| Placebo/BAF312 | Physician Global Activity Assessment | Baseline | 3.93 cm | Standard Deviation 1.557 |
| Placebo/BAF312 | Physician Global Activity Assessment | Week 12 | 4.91 cm | Standard Deviation 2.601 |
Secondary
Serum Levels of Muscle Enzymes
Time frame: Baseline, Week 12
Population: PD set in all disease types
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| BAF312/BAF312 | Serum Levels of Muscle Enzymes | Creatine Kinase - Baseline | 204.0 U/L | Standard Deviation 237.37 |
| BAF312/BAF312 | Serum Levels of Muscle Enzymes | Creatine Kinase - Week 12 | 153.7 U/L | Standard Deviation 128.62 |
| Placebo/BAF312 | Serum Levels of Muscle Enzymes | Creatine Kinase - Baseline | 872.5 U/L | Standard Deviation 1256.6 |
| Placebo/BAF312 | Serum Levels of Muscle Enzymes | Creatine Kinase - Week 12 | 858.1 U/L | Standard Deviation 1499.12 |
Secondary
Summary of CRP Levels
Biomarkers reflecting efficacy in reducing systemic inflammatory components of the disease using serum markers such as C-reactive protein (CRP)
Time frame: 12 weeks
Population: The Safety set included all patients who received at least one dose of study medication.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| BAF312/BAF312 | Summary of CRP Levels | 4.14 mg/L | Standard Deviation 3.87 |
| Placebo/BAF312 | Summary of CRP Levels | 6.38 mg/L | Standard Deviation 8.999 |