Active Dermatomyositis
Conditions
Keywords
Dermatomyositis
Brief summary
This study investigated the dose response relationship for the efficacy and safety of BAF312 compared to placebo in active DM patients over a treatment period of 6+6 months and to determine the minimum dose required for a maximal clinical effect. The study was composed of 2 periods: a double-blind period 1 with BAF312 administered at different daily doses (0.5, 2, 10 mg and placebo) and a fixed-dose Period 2 in which BAF312 was administered at the dose of 2 mg daily .
Detailed description
The study was prematurely terminated based on the results of an interim analysis where BAF312 did not demonstrate superior efficacy over placebo and a dose-response relationship was not observed. There were no safety concerns. Approximately 56 participants were planned to be randomized. A total of 17 participants were enrolled and randomized by the time the study was terminated.
Interventions
DRUGBAF312
BAF312 was provided as film-coated tablets in strengths of 0.25, 0,5, 1 and 2 mg for oral administration.
DRUGPlacebo
Matching placebo to BAF312 as tablets for oral administration.
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: Written informed consent must be obtained before any assessment is performed. * Patients who have been defined as definite or probable based on the criteria of Bohan and Peter (Bohan and Peter 1975) for dermatomyositis at least 3 months before screening * Patients must have active disease as defined by muscle weakness * Patients may be on a stable dose of corticosteroid (up/equal to 20 mg once daily prednisone equivalent) * Patients currently treated with oral or subcutaneous MTX must have been a stable dose of no more/equal to than 25 mg per week * Patients currently treated with Azathioprine must have been a stable maintenance dose of no more/equal to 3 mg/kg/day * Negative cancer screening conducted in the 12 months prior to screening visit Key
Exclusion criteria
* Dermatomyositis patients having overlap myositis or any other type of myositis including paraneoplastic myositis, drug-induced myopathy, necrotizing myositis * Preexisting severe cardiac or pulmonary conditions, 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 in Manual Muscle Testing - 24 Muscles (MMT-24) Score | Baseline, 6 months | Each muscles tested was evaluated on a 0 - 10 scale where 0 indicated the weakest muscle score and 10 indicated the strongest muscle score. The total MMT24 score ranged from 0 - 240, where an increasing trend in the values indicates improvement. A positive change from baseline indicates improvement. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| BAF312 Plasma Concentration | 6 months | — |
| Peripheral Blood Lymphocyte Counts | baseline, 6 months | Absolute lymphocyte counts |
| Change From Baseline in Manual Muscle Testing - 24 Muscles (MMT-24) Score | baseline, 3 months | Each muscles tested was evaluated on a 0-10 scale where 0 indicated the weakest muscle score and 10 indicated the strongest muscle score. the total MMT24 score ranged from 0-240, where an increasing trend in the values indicates improvement. A positive change from baseline indicates improvement. |
| Change From Baseline in 6 Minutes Walking Distance (6-MWD) Test | baseline, 6 months | — |
Countries
Czechia, Japan, United States
Participant flow
Recruitment details
The study was composed of 2 periods: a double-blind period 1 with BAF312 administered at different daily doses (0.5, 2, 10 mg and placebo) and a fixed-dose Period 2 in which BAF312 was administered to all randomized at the dose of 2 mg daily .
Pre-assignment details
Participants were randomized to each treatment group in a1:1:1:1 ratio.
Participants by arm
| Arm | Count |
|---|---|
| BAF312 0.5mg During period 1, participants were uptitrated daily from BAF312 0.25 mg to 0.5 mg over a 10 day period. After, participants continued on 0.5 mg daily for up to 24 weeks. During period 2, participants were uptitrated daily from BAF312 0.25 mg to 2.0 mg over a 10 day period. After, participants continued on 2.0 mg daily for up to 24 weeks. | 5 |
| BAF312 2mg During period 1, participants were uptitrated daily from BAF312 0.25 mg to 2.0 mg over a 10 day period. After, participants continued on 2.0 mg daily for up to 24 weeks. During period 2, participants were uptitrated daily from BAF312 0.25 mg to 2.0 mg over a 10 day period. After, participants continued on 2.0 mg daily for up to 24 weeks. | 4 |
| BAF312 10 mg During period 1, participants were uptitrated daily from BAF312 0.25 mg to 10.0 mg over a 10 day period. After, participants continued on 10.0 mg daily for up to 24 weeks. During period 2, participants were uptitrated daily from BAF312 0.25 mg to 2.0 mg over a 10 day period. After, participants continued on 2.0 mg daily for up to 24 weeks. | 4 |
| Placebo During period 1, participants received matching placebo daily for up to 24 weeks. During period 2, participants were uptitrated daily from BAF312 0.25 mg to 2.0 mg over a 10 day period. After, participants continued on 2.0 mg daily for up to 24 weeks. | 4 |
| Total | 17 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 1 | 0 | 2 | 2 |
Baseline characteristics
| Characteristic | BAF312 0.5mg | BAF312 2mg | BAF312 10 mg | Placebo | Total |
|---|---|---|---|---|---|
| Age, Continuous | 51.8 Years STANDARD_DEVIATION 16.72 | 44.0 Years STANDARD_DEVIATION 6.98 | 51.8 Years STANDARD_DEVIATION 4.79 | 48.0 Years STANDARD_DEVIATION 10.61 | 49.1 Years STANDARD_DEVIATION 10.74 |
| Sex: Female, Male Female | 4 Participants | 2 Participants | 4 Participants | 3 Participants | 13 Participants |
| Sex: Female, Male Male | 1 Participants | 2 Participants | 0 Participants | 1 Participants | 4 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 | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk |
|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 1 / 5 | 1 / 4 | 4 / 4 | 4 / 4 | 2 / 5 | 1 / 4 | 4 / 4 | 2 / 4 |
| serious Total, serious adverse events | 1 / 5 | 0 / 4 | 0 / 4 | 1 / 4 | 0 / 5 | 0 / 4 | 1 / 4 | 1 / 4 |
Outcome results
Primary
Change From Baseline in Manual Muscle Testing - 24 Muscles (MMT-24) Score
Each muscles tested was evaluated on a 0 - 10 scale where 0 indicated the weakest muscle score and 10 indicated the strongest muscle score. The total MMT24 score ranged from 0 - 240, where an increasing trend in the values indicates improvement. A positive change from baseline indicates improvement.
Time frame: Baseline, 6 months
Population: The pharmacodynamic (PD) analysis set, which included all randomized participants, was considered for the analysis. Participants with valid baseline MMT24 score and at least one valid post baseline MMT24 score were included in the analysis.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| BAF312 0.5mg | Change From Baseline in Manual Muscle Testing - 24 Muscles (MMT-24) Score | 28.286 score on a scale | Standard Error 8.1539 |
| BAF312 2mg | Change From Baseline in Manual Muscle Testing - 24 Muscles (MMT-24) Score | 12.367 score on a scale | Standard Error 7.0967 |
| BAF312 10 mg | Change From Baseline in Manual Muscle Testing - 24 Muscles (MMT-24) Score | 14.026 score on a scale | Standard Error 8.1541 |
| Placebo | Change From Baseline in Manual Muscle Testing - 24 Muscles (MMT-24) Score | 27.735 score on a scale | Standard Error 8.2175 |
p-value: 0.962195% CI: [-22.447, 23.549]Repeated measures analysis
p-value: 0.163795% CI: [-37.128, 6.391]Repeated measures analysis
p-value: 0.240995% CI: [-36.806, 9.388]Repeated measures
Secondary
BAF312 Plasma Concentration
Time frame: 6 months
Population: Pharmacokinetics (PK) analysis set: The PK analysis set included all patients with available PK data and no protocol deviations with relevant impact on PK data.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| BAF312 0.5mg | BAF312 Plasma Concentration | 5.13 ng/ml |
| BAF312 2mg | BAF312 Plasma Concentration | 25.9 ng/ml |
| BAF312 10 mg | BAF312 Plasma Concentration | 54.5 ng/ml |
Secondary
Change From Baseline in 6 Minutes Walking Distance (6-MWD) Test
Time frame: baseline, 6 months
Population: PD analysis set
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| BAF312 0.5mg | Change From Baseline in 6 Minutes Walking Distance (6-MWD) Test | 26.8 meters | Standard Deviation 104.15 |
| BAF312 2mg | Change From Baseline in 6 Minutes Walking Distance (6-MWD) Test | 22.2 meters | Standard Deviation 81.62 |
| BAF312 10 mg | Change From Baseline in 6 Minutes Walking Distance (6-MWD) Test | 7.7 meters | Standard Deviation 66.73 |
| Placebo | Change From Baseline in 6 Minutes Walking Distance (6-MWD) Test | 4.1 meters | Standard Deviation 72.18 |
Secondary
Change From Baseline in Manual Muscle Testing - 24 Muscles (MMT-24) Score
Each muscles tested was evaluated on a 0-10 scale where 0 indicated the weakest muscle score and 10 indicated the strongest muscle score. the total MMT24 score ranged from 0-240, where an increasing trend in the values indicates improvement. A positive change from baseline indicates improvement.
Time frame: baseline, 3 months
Population: PD analysis set
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| BAF312 0.5mg | Change From Baseline in Manual Muscle Testing - 24 Muscles (MMT-24) Score | 26.087 score on a scale | Standard Error 7.0583 |
| BAF312 2mg | Change From Baseline in Manual Muscle Testing - 24 Muscles (MMT-24) Score | 21.867 score on a scale | Standard Error 7.0967 |
| BAF312 10 mg | Change From Baseline in Manual Muscle Testing - 24 Muscles (MMT-24) Score | 3.988 score on a scale | Standard Error 7.0607 |
| Placebo | Change From Baseline in Manual Muscle Testing - 24 Muscles (MMT-24) Score | 32.325 score on a scale | Standard Error 7.1026 |
Secondary
Peripheral Blood Lymphocyte Counts
Absolute lymphocyte counts
Time frame: baseline, 6 months
Population: Safety analysis set: the safety analysis set included all patients that received any study drug.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| BAF312 0.5mg | Peripheral Blood Lymphocyte Counts | Baseline | 0.898 10^9 cells/Liter | Standard Deviation 0.3807 |
| BAF312 0.5mg | Peripheral Blood Lymphocyte Counts | 6 months | 0.730 10^9 cells/Liter | Standard Deviation 0.477 |
| BAF312 2mg | Peripheral Blood Lymphocyte Counts | 6 months | 0.358 10^9 cells/Liter | Standard Deviation 0.0699 |
| BAF312 2mg | Peripheral Blood Lymphocyte Counts | Baseline | 1.410 10^9 cells/Liter | Standard Deviation 0.7057 |
| BAF312 10 mg | Peripheral Blood Lymphocyte Counts | Baseline | 1.255 10^9 cells/Liter | Standard Deviation 0.6178 |
| BAF312 10 mg | Peripheral Blood Lymphocyte Counts | 6 months | 0.203 10^9 cells/Liter | Standard Deviation 0.0666 |
| Placebo | Peripheral Blood Lymphocyte Counts | Baseline | 1.080 10^9 cells/Liter | Standard Deviation 0.0689 |
| Placebo | Peripheral Blood Lymphocyte Counts | 6 months | 1.040 10^9 cells/Liter | Standard Deviation 0.19 |