Polymyositis
Conditions
Keywords
Polymyositis, Myositis, PM, chronic muscle inflammation, inflammatory myopathy, inclusion body myositis
Brief summary
This study assessed the efficacy, safety and tolerability of BAF312 administered orally in patients with clinically active polymyositis and also in patients with polymyositis who had shown inadequate response to corticosteroids and or DMARDs (disease modifying antirheumatic drugs).
Detailed description
This study was stopped prematurely due to overall slow recruitment and no evidence for efficacy in a parallel study in dermatomyositis with an assumed similar pathophysiology. With very small sample sizes per group the overall results for this study including primary and all other efficacy and PD data are inconclusive
Interventions
DRUGPlacebo
Matching placebo tablet for oral administration
DRUGBAF312
BAF312 in 4 dosage strengths in tablet form: 0.25 mg, 0.5 mg, 1 mg, 2 mg for oral administration
Sponsors
Novartis Pharmaceuticals
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
* definite or probable for polymyositis at least three months before Baseline * active disease as defined by elevated CK levels, or other enzymes, or MRI/biopsy if enzymes are normal, and persisting muscle weakness * stable dose of corticosteroid for at least 2 weeks prior to Baseline and should not have received a medium or high dose in the last 8 weeks prior to study entry. * patients treated with methotrexate must have been on a stable dose for at least 6 weeks prior to Baseline.
Exclusion criteria
* Patients with overlap polymyositis, late-stage polymyositis, or other types of myositis. * Preexisting severe cardiac or pulmonary involvement, malignancy of any organ system or significant eye diseases. * Uncontrolled diabetes mellitus or diabetes complicated with organ involvement. * Pregnant or nursing (lactating) women
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline at Week 12 for BAF312 2 mg, 10 mg or Placebo (Once Daily) for Combined Efficacy Endpoint: Manual Muscle Testing in 24 Muscles (MMT24) | Baseline, at 12 weeks | Manual Muscle Testing Scoring Sheet: Neck flexors, neck extensors and other designated muscles bilaterally (Biceps brachii, Deltoid middle, Quadriceps, Gluteus maximus, Gluteus medius, Trapezius, Iliopsoas, Hamstrings, Wrist extensors, Wrist Flexors, Ankle plantar flexors and Ankle dorsiflexors) were tested on a 0-10 scale by the Investigator. Posterior credibility interval from Bayesian analysis displayed as confidence interval. The scores range was 0 to 260. Higher scores indicate better outcome. |
| Percent Change From Baseline at Week 12 for BAF312 2 mg, 10 mg or Placebo (Once Daily) Serum Creatine Kinase (CK) Levels | Baseline, at 12 weeks | Serum creatine kinase (CK) were analyzed as part of the blood chemistry panel. Posterior credibility interval from Bayesian analysis displayed as confidence interval. The variable CK was log-transformed for statistical analysis and after estimation was converted to percent change from baseline divided by the mean baseline |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Six-minute Walking Distance (6MWD) at Week 12 | Baseline, 12 weeks | This test assessed the distance a patient could walk in 6 minutes (Rutkove et al 2002). If the patient was not able to walk for 6 minutes then a 2 minute walking test was conducted |
| Six-minute Walking Distance (6MWD) at Week 24 | Baseline, 24 weeks | This test assessed the distance a patient could walk in 6 minutes (Rutkove et al 2002). If the patient was not able to walk for 6 minutes then a 2 minute walking test was conducted |
| BAF312 Trough Plasma Concentrations (PK Set) | -7 Baseline, day 28, 56, 84 | All blood samples were taken by either direct venipuncture or an indwelling cannula inserted in a forearm vein. For each sample, approximately 2 mL of blood was drawn. BAF312 was determined in ethylenediaminetetraacetic acid (EDTA) plasma using a validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) bioanalytical method for the quantification. The anticipated lower limit of quantification (LLOQ) was 0.02 ng/mL using 0.1 mL of plasma |
Countries
Canada, Czechia, Hungary, Poland, Taiwan, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| BAF312 2mg/BAF312 2mg Patients in Period 1 continue on same 2 mg dose of BAF312 in Period 2 | 7 |
| BAF312 10 mg/BAF312 10 mg Patients in Period 1 continue on same 10 mg dose of BAF312 in Period 2 | 2 |
| Placebo/BAF312 2 mg Patients on placebo in Period 1 switch to active 2 mg BAF312 in Period 2 | 4 |
| Placebo/BAF312 10 mg Patients on placebo in Period 1 switch to active 10 mg BAF312 in Period 2 | 1 |
| Total | 14 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Period 1 - Randomized | Adverse Event | 1 | 0 | 1 | 0 |
Baseline characteristics
| Characteristic | BAF312 10 mg/BAF312 10 mg | Placebo/BAF312 2 mg | BAF312 2mg/BAF312 2mg | Placebo/BAF312 10 mg | Total |
|---|---|---|---|---|---|
| Age, Continuous | 47.0 years STANDARD_DEVIATION 21.21 | 48.0 years STANDARD_DEVIATION 8.83 | 50.3 years STANDARD_DEVIATION 14.78 | 53.0 years STANDARD_DEVIATION 0 | 49.4 years STANDARD_DEVIATION 12.51 |
| Baseline MMT24 Score | 184.0 scores on a scale STANDARD_DEVIATION 19.8 | 189.5 scores on a scale STANDARD_DEVIATION 45.65 | 202.6 scores on a scale STANDARD_DEVIATION 41.74 | 166.0 scores on a scale STANDARD_DEVIATION 0 | 193.6 scores on a scale STANDARD_DEVIATION 37.9 |
| Disease duration | 5.4 years STANDARD_DEVIATION 2.74 | 2.7 years STANDARD_DEVIATION 1.67 | 5.6 years STANDARD_DEVIATION 4.46 | 16.9 years STANDARD_DEVIATION 0 | 5.6 years STANDARD_DEVIATION 4.77 |
| Race/Ethnicity, Customized Asian | 1 participants | 1 participants | 0 participants | 0 participants | 2 participants |
| Race/Ethnicity, Customized Black | 0 participants | 0 participants | 0 participants | 1 participants | 1 participants |
| Race/Ethnicity, Customized Caucasian | 1 participants | 3 participants | 7 participants | 0 participants | 11 participants |
| Sex: Female, Male Female | 2 Participants | 2 Participants | 5 Participants | 1 Participants | 10 Participants |
| Sex: Female, Male Male | 0 Participants | 2 Participants | 2 Participants | 0 Participants | 4 Participants |
| Taking DMARD at baseline | 2 participants | 4 participants | 7 participants | 1 participants | 14 participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 6 / 7 | 2 / 2 | 4 / 5 | 4 / 6 | 2 / 3 |
| serious Total, serious adverse events | 1 / 7 | 0 / 2 | 0 / 5 | 0 / 6 | 0 / 3 |
Outcome results
Primary
Change From Baseline at Week 12 for BAF312 2 mg, 10 mg or Placebo (Once Daily) for Combined Efficacy Endpoint: Manual Muscle Testing in 24 Muscles (MMT24)
Manual Muscle Testing Scoring Sheet: Neck flexors, neck extensors and other designated muscles bilaterally (Biceps brachii, Deltoid middle, Quadriceps, Gluteus maximus, Gluteus medius, Trapezius, Iliopsoas, Hamstrings, Wrist extensors, Wrist Flexors, Ankle plantar flexors and Ankle dorsiflexors) were tested on a 0-10 scale by the Investigator. Posterior credibility interval from Bayesian analysis displayed as confidence interval. The scores range was 0 to 260. Higher scores indicate better outcome.
Time frame: Baseline, at 12 weeks
Population: Pharmacodynamic (PD) included patients with PD data and no major protocol deviations
| Arm | Measure | Value (MEAN) |
|---|---|---|
| BAF312 2mg | Change From Baseline at Week 12 for BAF312 2 mg, 10 mg or Placebo (Once Daily) for Combined Efficacy Endpoint: Manual Muscle Testing in 24 Muscles (MMT24) | 11.2 scores on a scale |
| BAF312 10 mg | Change From Baseline at Week 12 for BAF312 2 mg, 10 mg or Placebo (Once Daily) for Combined Efficacy Endpoint: Manual Muscle Testing in 24 Muscles (MMT24) | 39.0 scores on a scale |
| Placebo | Change From Baseline at Week 12 for BAF312 2 mg, 10 mg or Placebo (Once Daily) for Combined Efficacy Endpoint: Manual Muscle Testing in 24 Muscles (MMT24) | 9.1 scores on a scale |
Comparison: It was a Bayesian analysis with non-informative prior for co-primary endpoints, MMT-24 and CK, with dual criteria for statistical significance: ≥ 90% posterior probability (PP) of achieving an increase from baseline in MMT24 and decrease in CK and clinical relevance: ≥ 50% PP achieving an increase of 15 points in MMT24 and a decrease of 30% in CK vs. placebo. For this table the value is the posterior probability of achieving an increase in MMT24 and a decrease in CK in 2mg group vs. placebo
Comparison: It was a Bayesian analysis with non-informative prior for co-primary endpoints, MMT-24 and CK, with dual criteria for statistical significance: ≥ 90% posterior probability (PP) of achieving an increase from baseline in MMT24 and decrease in CK and clinical relevance: ≥ 50% PP achieving an increase of 15 points in MMT24 and a decrease of 30% in CK vs. placebo. . For this table the value is the PP of achieving an increase of 15 points in MMT24 and a decrease of 30% in CK in 2mg group vs. placebo
Comparison: It was a Bayesian analysis with non-informative prior for co-primary endpoints, MMT-24 and CK, with dual criteria for statistical significance: ≥ 90% posterior probability (PP) of achieving an increase from baseline in MMT24 and decrease in CK and clinical relevance: ≥ 50% PP achieving an increase of 15 points in MMT24 and a decrease of 30% in CK vs. placebo. For this table the value is the posterior probability of achieving an increase in MMT24 and a decrease in CK in 10mg group vs. placebo
Comparison: It was a Bayesian analysis with non-informative prior for co-primary endpoints, MMT-24 and CK, with dual criteria for statistical significance: ≥ 90% posterior probability (PP) of achieving an increase from baseline in MMT24 and decrease in CK and clinical relevance: ≥ 50% PP achieving an increase of 15 points in MMT24 and a decrease of 30% in CK vs. placebo. . For this table the value is the PP of achieving an increase of 15 points in MMT24 and a decrease of 30% in CK in 10mg group vs. placebo
Primary
Percent Change From Baseline at Week 12 for BAF312 2 mg, 10 mg or Placebo (Once Daily) Serum Creatine Kinase (CK) Levels
Serum creatine kinase (CK) were analyzed as part of the blood chemistry panel. Posterior credibility interval from Bayesian analysis displayed as confidence interval. The variable CK was log-transformed for statistical analysis and after estimation was converted to percent change from baseline divided by the mean baseline
Time frame: Baseline, at 12 weeks
Population: Pharmacodynamic (PD) included patients with PD data and no major protocol deviations
| Arm | Measure | Value (MEAN) |
|---|---|---|
| BAF312 2mg | Percent Change From Baseline at Week 12 for BAF312 2 mg, 10 mg or Placebo (Once Daily) Serum Creatine Kinase (CK) Levels | -19.7 U/L |
| BAF312 10 mg | Percent Change From Baseline at Week 12 for BAF312 2 mg, 10 mg or Placebo (Once Daily) Serum Creatine Kinase (CK) Levels | -55.6 U/L |
| Placebo | Percent Change From Baseline at Week 12 for BAF312 2 mg, 10 mg or Placebo (Once Daily) Serum Creatine Kinase (CK) Levels | -0.5 U/L |
Secondary
BAF312 Trough Plasma Concentrations (PK Set)
All blood samples were taken by either direct venipuncture or an indwelling cannula inserted in a forearm vein. For each sample, approximately 2 mL of blood was drawn. BAF312 was determined in ethylenediaminetetraacetic acid (EDTA) plasma using a validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) bioanalytical method for the quantification. The anticipated lower limit of quantification (LLOQ) was 0.02 ng/mL using 0.1 mL of plasma
Time frame: -7 Baseline, day 28, 56, 84
Population: P
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| BAF312 2mg | BAF312 Trough Plasma Concentrations (PK Set) | Day - 7 | 0 ng/mL | Standard Deviation 0 |
| BAF312 2mg | BAF312 Trough Plasma Concentrations (PK Set) | Day 28 | 25.3 ng/mL | Standard Deviation 11.2 |
| BAF312 2mg | BAF312 Trough Plasma Concentrations (PK Set) | Day 56 | 25.1 ng/mL | Standard Deviation 12.6 |
| BAF312 2mg | BAF312 Trough Plasma Concentrations (PK Set) | Day 84 | 21.4 ng/mL | Standard Deviation 10.1 |
| BAF312 10 mg | BAF312 Trough Plasma Concentrations (PK Set) | Day 84 | 240 ng/mL | Standard Deviation 0 |
| BAF312 10 mg | BAF312 Trough Plasma Concentrations (PK Set) | Day - 7 | 0 ng/mL | Standard Deviation 0 |
| BAF312 10 mg | BAF312 Trough Plasma Concentrations (PK Set) | Day 56 | 270 ng/mL | Standard Deviation 0 |
| BAF312 10 mg | BAF312 Trough Plasma Concentrations (PK Set) | Day 28 | 182 ng/mL | Standard Deviation 0 |
Secondary
Six-minute Walking Distance (6MWD) at Week 12
This test assessed the distance a patient could walk in 6 minutes (Rutkove et al 2002). If the patient was not able to walk for 6 minutes then a 2 minute walking test was conducted
Time frame: Baseline, 12 weeks
Population: Pharmacodynamic (PD) included patients with PD data and no major protocol deviations
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| BAF312 2mg | Six-minute Walking Distance (6MWD) at Week 12 | Period 1, Week 12 | 362.47 meters | Standard Deviation 52.02 |
| BAF312 2mg | Six-minute Walking Distance (6MWD) at Week 12 | Distance walked,change from BL at Wk 12 | 46.82 meters | Standard Deviation 65.64 |
| BAF312 10 mg | Six-minute Walking Distance (6MWD) at Week 12 | Period 1, Week 12 | 393.00 meters | Standard Deviation 0 |
| BAF312 10 mg | Six-minute Walking Distance (6MWD) at Week 12 | Distance walked,change from BL at Wk 12 | 23.00 meters | Standard Deviation 0 |
| Placebo | Six-minute Walking Distance (6MWD) at Week 12 | Period 1, Week 12 | 303.10 meters | Standard Deviation 112.48 |
| Placebo | Six-minute Walking Distance (6MWD) at Week 12 | Distance walked,change from BL at Wk 12 | -6.40 meters | Standard Deviation 21.981 |
Secondary
Six-minute Walking Distance (6MWD) at Week 24
This test assessed the distance a patient could walk in 6 minutes (Rutkove et al 2002). If the patient was not able to walk for 6 minutes then a 2 minute walking test was conducted
Time frame: Baseline, 24 weeks
Population: Pharmacodynamic (PD) included patients with PD data and no major protocol deviations
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| BAF312 2mg | Six-minute Walking Distance (6MWD) at Week 24 | Period 2, Week 24 | 364.60 meters | Standard Deviation 73.803 |
| BAF312 2mg | Six-minute Walking Distance (6MWD) at Week 24 | Distance walked,change from baseline at Wk 24 | 48.95 meters | Standard Deviation 91.922 |
| BAF312 10 mg | Six-minute Walking Distance (6MWD) at Week 24 | Period 2, Week 24 | 329.33 meters | Standard Deviation 186.551 |
| BAF312 10 mg | Six-minute Walking Distance (6MWD) at Week 24 | Distance walked,change from baseline at Wk 24 | 4.33 meters | Standard Deviation 51.637 |