Myositis
Conditions
Keywords
Inflammatory Myositis, Dermatomyositis, Polymyositis, Muscle Pain, Myositis, Refractory myositis
Brief summary
The goal of the trial is to evaluate the efficacy and safety of belimumab as a maintenance therapy in adults with refractory Idiopathic inflammatory myositis (IIM) as compared with standard of care. This is a multicentre double-blind, placebo-controlled trial.
Detailed description
Adults with refractory IIM will be enrolled. IIM is defined as Dermatomyositis (DM) or Polymyositis (PM), meeting the Bohan & Peter (1975) diagnostic criteria for definite or probable DM or PM. Refractory IIM is defined as chronic active IIM with a history of inadequate response or intolerance to three months of glucocorticoids and/or at least a history of inadequate response or intolerance to three months of one other immunosuppressive agent (IS) (azathioprine, methotrexate, mycophenolate mofetil, leflunomide, tacrolimus, cyclosporine, cyclophosphamide, Rituximab or intravenous gamma globulin \[IVIG\]).
Interventions
DRUGBelimumab
Randomized phase: Week 0 - Week 40
DRUGPlacebo
Randomized phase: Week 0 - Week 40
Sponsors
GlaxoSmithKline
Northwell Health
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Subjects enrolled in the study must meet the following inclusion criteria: 1. Adults \>18 years of age 2. Have a diagnosis of: 1. definite or probable dermatomyositis (DM) or 2. Definite or probable diagnosis of polymyositis (PM) with presence of one of myositis specific antibodies. In the absence of myositis specific auto-antibodies, the diagnosis of PM will require review of the muscle biopsy and adjudication by the predetermined committee of experts. 3. Presence of positive autoantibody (ANA \>1:80 or RNP or SSA/SSB or any of the myositis specific autoantibody: antisynthetase autoantibodies (anti-Jo-1, PL-7, PL-12, EJ, OJ, KS), anti-SRP, anti-Mi-2, anti-p140). 4. Have refractory IIM as defined by inadequate response or intolerance to at least 3 months of glucocorticoids and/or at least one other immunosuppressive agent, such as azathioprine, methotrexate, IVIG, mycophenolate mofetil, leflunomide, tacrolimus, cyclosporine cyclophosphamide, and Rituximab. 5. Have active IIM at screening. This requires at least 3 criteria from the CSM 6. Dermatomyositis patients that do not meet the MMT criteria, must have: 1. a cutaneous VAS score of \>3 cm on a 10 cm VAS scale (MDAAT) will be required: 2. elevation of at least one muscle enzyme (creatine kinase \[CK\]; aldolase; lactate dehydrogenase \[LDH\]; alanine aminotransferase \[ALT\]; or aspartate aminotransferase \[AST\]) to a minimum level of 1.3 times the upper limit of normal, 3. and 1 additional core set measure 7. For patients with ≥ 7 years of IIM, muscle biopsy or muscle MRI within 4 months prior to enrollment will be required to document active myositis to avoid enrolling patients with significant index of damage/ muscle atrophy. This is not applicable to DM patients with a cutaneous VAS score of \>3 cm on a 10 cm VAS scale (MDAAT). 8. Have a stable background glucocorticoid therapy for at least 2 weeks prior to screening (Prednisone (or equivalent) dose \< 15 mg daily) 9. Have a stable immunosuppressive therapy (IS) (azathioprine, mycophenolate mofetil, tacrolimus, cyclosporine for \> 2 months prior to screening. Patients on intravenous gamma globulin (IVIG) have to be on a stable dose and frequency regimen for ≥ 3 months. 10. Have the ability to understand the requirements of the study and provide written informed consent (including consent for the use and disclosure of research-related health information) and comply with the study protocol procedures (including required study visits) 11. Female subjects of childbearing potential must have a negative urine pregnancy test at screening and agree to 1 of the following: 1. Complete abstinence from intercourse from 2 weeks prior to administration of the 1st dose of study agent until 16 weeks after the last dose of study agent (Sexual inactivity by abstinence must be consistent with the preferred and usual lifestyle of the subject. Periodic abstinence (e.g. calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception); or 2. Consistent and correct use of 2 of acceptable methods of birth control for 1 month prior to the start of the study agent, during the study, and 16 weeks after the last dose of study agent
Exclusion criteria
Subjects meeting any of the following criteria will be excluded from the study: 1. Have severe muscle damage as defined by a Muscle Damage Index (MDI) \> 5.0 cm using a visual analogue scale (VAS) 10.0 cm in length or evidence of severe muscle atrophy on muscle MRI. 2. History of malignant neoplasm within the last 5 years, except for adequately treated cancers of the skin (basal or squamous cell). 3. Have a history of a primary immunodeficiency 4. Have a significant IgG deficiency (IgG level \< 400 mg/dl) Have an IgA deficiency (IgA level \< 10 mg/dL) 5. Discontinuation IS agent \< 3 months prior to Screening. Including: azathioprine, methotrexate, mycophenolate mofetil, leflunomide, tacrolimus, cyclosporine, or intravenous gamma globulin \[IVIG\] 6. Have received Rituximab within 365 days prior to Screening. 7. Have received cyclophosphamide within 180 days prior to Screening 8. Have received treatment with: 1. Initiated IVIG 3 months prior to Screening 2. Pulse steroids 2 months prior to Screening 9. Have received treatment with Belimumab at any time prior to Screening 10. Have received a biologic investigational agent within 365 days prior to Screening. 11. Have received a non-biologic investigational agent within 30 days or 5 half-lives of the agent (whichever is longer) prior to Screening. 12. Have a history of an anaphylactic reaction to parenteral administration of contrast agents, human or murine proteins or monoclonal antibodies. 13. Infection history: 1. Currently on any suppressive therapy for a chronic infection (such as tuberculosis - including latent tuberculosis, pneumocystis, cytomegalovirus, herpes simplex virus, herpes zoster and atypical mycobacteria). NOTE: Testing for latent TB is a standard of care for patients on immunosuppressive therapy and results will be obtained from their medical record. If no TB history is found for these patients, a Quantiferon Gold or PPD test will be performed prior to Day 0 as part of standard of care. 2. Hospitalization for treatment of infection within 60 days of Day 0. 3. Use of parenteral (IV or IM) antibiotics (antibacterials, antivirals, anti-fungals, or anti parasitic agents) within 60 days of Day 0. 14. Have a historically positive HIV test or test positive at screening for HIV. 15. Have a history of autoimmune hepatitis 16. Hepatitis status will be obtained from patients' medical records. If unavailable, testing will be done as part of standard of care. Patients are excluded if there is evidence of infection with: a. Hepatitis B: i. Positive hepatitis B surface antigen (HBsAg) or positive hepatitis B core antibody (HBcAb) or b. Hepatitis C: i. Positive hepatitis C antibody with confirmatory hepatitis C viral load by PCR. 17. Clinically significant elevation of GGT (\>1.5xULN), bilirubin (\>1.25xULN, direct 35%), or INR (\>1.2, excluding patients on anti-coagulant therapies) or other clinically significant abnormal laboratory value in the opinion of the investigator. 18. Have current drug or alcohol abuse or dependence, or a history of drug or alcohol abuse or dependence within 364 days prior to Day 0. 19. Have evidence of serious suicide risk including any history of suicidal behaviour in the last 6 months and/or any suicidal ideation in the last 2 months or who in the investigator's judgment, pose a significant suicide risk. 20. Have any concurrent significant medical or psychiatric illness that the investigator considers would make the candidate unsuitable for the study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Response Rate During Randomized Phase | 40 weeks | Definition of Improvement (DOI) is ≥ 20% of improvement in any 3 of the core set measures (CSM) - Manual Muscle Testing, Patient Global , Physician Global, Muscle Enzyme change , HAQ and Extra- muscular activity and no more than 2 CSM worsening by ≥ 25% (excluding MMT). Total Improvement Score ( TIS) is a sum of weighted scores of absolute change of core set measures ( MMT, Patient Global , Physician Global, Muscle Enzyme change , HAQ and Extra-muscluar activity ). The scores range from 0 to 100, with higher scores indicating greater improvement. TIS ≥ 40 indicates a moderate response and ≥ 60 TIS indicates a major response. |
| Mean Total Improvement Score (TIS) During Randomized Phase | 40 Week | It is a composite measure calculated as a sum of weighted scores assigned to absolute changes for each measure (MMT , Patient Global, Physician Global, Muscle enzymes, Extramuscluar activity and HAQ) . Total score could range from 0 to 100. TIS ≥ 20 indicates minimal improvement, TIS ≥ 40 indicates moderate response and TIS ≥ 60 indicates a major response. 2016 ACR/EULAR Criteria for Minimal, Moderate, and Major Clinical Response in Adult Dermatomyositis and Polymyositis and Juvenile Dermatomyositis (Aggarwal R et al 2016) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Response Rate After Open Label Phase | 64 weeks | It is a composite measure calculated as a sum of weighted scores assigned to absolute changes for each measure (MMT , Patient Global, Physician Global, Muscle enzymes, Extramuscluar activity and HAQ) . Total score could range from 0 to 100. TIS ≥ 20 indicates minimal improvement, TIS ≥ 40 indicates moderate response and TIS ≥ 60 indicates a major response. 2016 ACR/EULAR Criteria for Minimal, Moderate, and Major Clinical Response in Adult Dermatomyositis and Polymyositis and Juvenile Dermatomyositis (Aggarwal R et al 2016) |
| Mean Total Improvement Score (TIS) After Open Label Phase | 64 Week | Definition of Improvement (DOI) is ≥ 20% of improvement in any 3 of the core set measures (CSM) - Manual Muscle Testing, Patient Global , Physician Global, Muscle Enzyme change , HAQ and Extra- muscular activity and no more than 2 CSM worsening by ≥ 25% (excluding MMT). Total Improvement Score ( TIS) is a sum of weighted scores of absolute change of core set measures ( MMT, Patient Global , Physician Global, Muscle Enzyme change , HAQ and Extra-muscluar activity ). The scores range from 0 to 100, with higher scores indicating greater improvement. TIS ≥ 40 indicates a moderate response and ≥ 60 TIS indicates a major response. Minimal, Moderate, and Major Clinical Response in Adult Dermatomyositis and Polymyositis and Juvenile Dermatomyositis (Aggarwal R et al 2016) |
Countries
United States
Participant flow
Recruitment details
19 Patients signed consent forms, but two withdrew consent forms before randomization, and were not included in the baseline characteristics analysis, 17 patients were randomized. Two patients out of 17 received less than five doses of Study Drug and as per protocol were excluded from the final efficacy analysis but not safety analysis.
Participants by arm
| Arm | Count |
|---|---|
| Arm 1 (Belimumab + SoC (Randomized Phase and Open Label Phase) Patients in this arm will be given belimumab with a background of standard of care therapy during the randomized controlled treatment period.
Belimumab: Randomized phase: Week 0 - Week 40
Patients in this arm will continue to receive belimumab during the open label phase of the study (week 40 - week 64) | 10 |
| Arm 2 (Placebo + SoC (Randomized Phase) Followed by Belimumab + SoC (Open Label Phase) Patients in this arm will be given a placebo with a background of standard of care therapy during the randomized controlled treatment period.
Placebo: Randomized phase: Week 0 - Week 40
Patients in this arm will receive belimumab during the open label phase of the study (week 40 - week 64). | 7 |
| Total | 17 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Week 0 - Week 40 (Randomized Phase) | Lost to Follow-up | 2 | 1 |
| Week 40 - Week 64 (Open Lable Phase) | Lost to Follow-up | 1 | 1 |
Baseline characteristics
| Characteristic | Arm 2 (Placebo + SoC (Randomized Phase) Followed by Belimumab + SoC (Open Label Phase) | Arm 1 (Belimumab + SoC (Randomized Phase and Open Label Phase) | Total |
|---|---|---|---|
| Age, Continuous | 52 years | 46 years | 46 years |
| Concurrent prednisone (Mean dose (mg)(SD)) | 4.3 mg STANDARD_DEVIATION 4.5 | 7.63 mg STANDARD_DEVIATION 7.23 | 6.25 mg STANDARD_DEVIATION 6.13 |
| Disease Characteristics Mean (SD) Extra-Muscle activity score Visual Analogue Score (0 - absence of activity -10 max activity) | 1.39 Score on a scale STANDARD_DEVIATION 1.36 | 0.96 Score on a scale STANDARD_DEVIATION 1.61 | 1.10 Score on a scale STANDARD_DEVIATION 1.45 |
| Disease Characteristics Mean (SD) Health Assessment Questionnaire (HAQ) disability scale(0 - no disability -3 max disability) | 1.2 Score on a scale STANDARD_DEVIATION 0.51 | 1.39 Score on a scale STANDARD_DEVIATION 0.68 | 1.33 Score on a scale STANDARD_DEVIATION 0.6 |
| Disease Characteristics Mean (SD) Manual Muscle Testing (MMT)- measure of muscle strength (0 -150 max muscle strength ) | 115.0 Score on a scale STANDARD_DEVIATION 8.25 | 115.2 Score on a scale STANDARD_DEVIATION 6.37 | 115.12 Score on a scale STANDARD_DEVIATION 10.5 |
| Disease Characteristics Mean (SD) Muscle activity score on Visual Analogue Score (0 absence of activity -10 max activity) | 5.1 Score on a scale STANDARD_DEVIATION 0.94 | 4.54 Score on a scale STANDARD_DEVIATION 1.8 | 4.91 Score on a scale STANDARD_DEVIATION 1.58 |
| Disease Characteristics Mean (SD) Myositis Damage Index (MDI) (0 - no damage -10 highest level of damage) | 1.7 Score on a scale STANDARD_DEVIATION 2.11 | 0.95 Score on a scale STANDARD_DEVIATION 1.52 | 1.46 Score on a scale STANDARD_DEVIATION 1.94 |
| Disease Duration | 4.3 years STANDARD_DEVIATION 4.35 | 3.5 years STANDARD_DEVIATION 3.92 | 3.82 years STANDARD_DEVIATION 3.99 |
| Percentage of participants on concurrent immunosuppressive agents % of participants on IVIG | 6 Participants | 1 Participants | 7 Participants |
| Percentage of participants on concurrent immunosuppressive agents % of participants on Methotrexate or MMF or AZA | 5 Participants | 8 Participants | 13 Participants |
| Percentage of participants on concurrent immunosuppressive agents % of participants on Methotrexate or MMF or AZA and IVIG | 4 Participants | 4 Participants | 8 Participants |
| Percent of participants with concurrent prednisone therapy | 3 Participants | 8 Participants | 11 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 2 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 6 Participants | 6 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) White | 4 Participants | 4 Participants | 8 Participants |
| Sex: Female, Male Female | 5 Participants | 7 Participants | 12 Participants |
| Sex: Female, Male Male | 2 Participants | 3 Participants | 5 Participants |
| Subtype of Idiopathic Inflammatory Myositis (IIM) Dermatomyositis (DM) | 3 Participants | 3 Participants | 6 Participants |
| Subtype of Idiopathic Inflammatory Myositis (IIM) Polymyositis (PM) | 4 Participants | 7 Participants | 11 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 6 / 10 | 6 / 7 | 6 / 14 |
| other Total, other adverse events | 5 / 10 | 6 / 7 | 6 / 14 |
| serious Total, serious adverse events | 1 / 10 | 0 / 7 | 0 / 14 |
Outcome results
Primary
Mean Total Improvement Score (TIS) During Randomized Phase
It is a composite measure calculated as a sum of weighted scores assigned to absolute changes for each measure (MMT , Patient Global, Physician Global, Muscle enzymes, Extramuscluar activity and HAQ) . Total score could range from 0 to 100. TIS ≥ 20 indicates minimal improvement, TIS ≥ 40 indicates moderate response and TIS ≥ 60 indicates a major response. 2016 ACR/EULAR Criteria for Minimal, Moderate, and Major Clinical Response in Adult Dermatomyositis and Polymyositis and Juvenile Dermatomyositis (Aggarwal R et al 2016)
Time frame: 40 Week
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Arm 1 (Belimumab + SoC (Randomized Phase and Open Label Phase) | Mean Total Improvement Score (TIS) During Randomized Phase | 38.8 score on a scale | Standard Deviation 24.9 |
| Arm 2 (Placebo + SoC (Randomized Phase) Followed by Belimumab + SoC (Open Label Phase) | Mean Total Improvement Score (TIS) During Randomized Phase | 37.9 score on a scale | Standard Deviation 5.8 |
Comparison: Mean Total Improvement Score (TIS) during Randomized Phase at Week 40p-value: 0.92ANOVA
Primary
Response Rate During Randomized Phase
Definition of Improvement (DOI) is ≥ 20% of improvement in any 3 of the core set measures (CSM) - Manual Muscle Testing, Patient Global , Physician Global, Muscle Enzyme change , HAQ and Extra- muscular activity and no more than 2 CSM worsening by ≥ 25% (excluding MMT). Total Improvement Score ( TIS) is a sum of weighted scores of absolute change of core set measures ( MMT, Patient Global , Physician Global, Muscle Enzyme change , HAQ and Extra-muscluar activity ). The scores range from 0 to 100, with higher scores indicating greater improvement. TIS ≥ 40 indicates a moderate response and ≥ 60 TIS indicates a major response.
Time frame: 40 weeks
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Arm 1 (Belimumab + SoC (Randomized Phase and Open Label Phase) | Response Rate During Randomized Phase | Week 40 : Percent patients reaching Total improvement score of ≥40 | 5 Participants |
| Arm 1 (Belimumab + SoC (Randomized Phase and Open Label Phase) | Response Rate During Randomized Phase | Week 40 : Percent of patient with major improvement TIS ≥60 | 2 Participants |
| Arm 1 (Belimumab + SoC (Randomized Phase and Open Label Phase) | Response Rate During Randomized Phase | Week 40 : Definition of Improvement (DOI) | 3 Participants |
| Arm 2 (Placebo + SoC (Randomized Phase) Followed by Belimumab + SoC (Open Label Phase) | Response Rate During Randomized Phase | Week 40 : Definition of Improvement (DOI) | 1 Participants |
| Arm 2 (Placebo + SoC (Randomized Phase) Followed by Belimumab + SoC (Open Label Phase) | Response Rate During Randomized Phase | Week 40 : Percent patients reaching Total improvement score of ≥40 | 2 Participants |
| Arm 2 (Placebo + SoC (Randomized Phase) Followed by Belimumab + SoC (Open Label Phase) | Response Rate During Randomized Phase | Week 40 : Percent of patient with major improvement TIS ≥60 | 0 Participants |
Comparison: Definition of Improvement (DOI) at week 40p-value: 0.695% CI: [0.08, 2.65]ANOVA
Comparison: Percent patients reaching Total improvement score of ≥40 at Week 40p-value: 0.6195% CI: [0.16, 1.82]ANOVA
Comparison: Percent of patient with major improvement TIS ≥60 at Week 40p-value: 0.2395% CI: [0, 1.47]ANOVA
Secondary
Mean Total Improvement Score (TIS) After Open Label Phase
Definition of Improvement (DOI) is ≥ 20% of improvement in any 3 of the core set measures (CSM) - Manual Muscle Testing, Patient Global , Physician Global, Muscle Enzyme change , HAQ and Extra- muscular activity and no more than 2 CSM worsening by ≥ 25% (excluding MMT). Total Improvement Score ( TIS) is a sum of weighted scores of absolute change of core set measures ( MMT, Patient Global , Physician Global, Muscle Enzyme change , HAQ and Extra-muscluar activity ). The scores range from 0 to 100, with higher scores indicating greater improvement. TIS ≥ 40 indicates a moderate response and ≥ 60 TIS indicates a major response. Minimal, Moderate, and Major Clinical Response in Adult Dermatomyositis and Polymyositis and Juvenile Dermatomyositis (Aggarwal R et al 2016)
Time frame: 64 Week
Population: In originally assigned Belimumab group 9 patients completed week 16, 8 completed week 40, 7 completed week 64 In originally assigned placebo group 6 patients completed week 16, 6 completed week 40, 5 completed week 64 The response scores at week 40 and 64 were calculated based on number of patients that completed 16 weeks of study
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Arm 1 (Belimumab + SoC (Randomized Phase and Open Label Phase) | Mean Total Improvement Score (TIS) After Open Label Phase | 41.1 score on a scale | Standard Deviation 25.3 |
| Arm 2 (Placebo + SoC (Randomized Phase) Followed by Belimumab + SoC (Open Label Phase) | Mean Total Improvement Score (TIS) After Open Label Phase | 36 score on a scale | Standard Deviation 13.1 |
Comparison: Mean Total Improvement Score (TIS) after Open Label Phase at 64 Weekp-value: 0.62ANOVA
Secondary
Response Rate After Open Label Phase
It is a composite measure calculated as a sum of weighted scores assigned to absolute changes for each measure (MMT , Patient Global, Physician Global, Muscle enzymes, Extramuscluar activity and HAQ) . Total score could range from 0 to 100. TIS ≥ 20 indicates minimal improvement, TIS ≥ 40 indicates moderate response and TIS ≥ 60 indicates a major response. 2016 ACR/EULAR Criteria for Minimal, Moderate, and Major Clinical Response in Adult Dermatomyositis and Polymyositis and Juvenile Dermatomyositis (Aggarwal R et al 2016)
Time frame: 64 weeks
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Arm 1 (Belimumab + SoC (Randomized Phase and Open Label Phase) | Response Rate After Open Label Phase | Week 64 : Definition of Improvement (DOI) | 3 Participants |
| Arm 1 (Belimumab + SoC (Randomized Phase and Open Label Phase) | Response Rate After Open Label Phase | Week 64 : Percent patients reaching Total improvement score of ≥40 | 4 Participants |
| Arm 1 (Belimumab + SoC (Randomized Phase and Open Label Phase) | Response Rate After Open Label Phase | Week 64 : Percent of patient with major improvement TIS ≥60 | 2 Participants |
| Arm 2 (Placebo + SoC (Randomized Phase) Followed by Belimumab + SoC (Open Label Phase) | Response Rate After Open Label Phase | Week 64 : Definition of Improvement (DOI) | 0 Participants |
| Arm 2 (Placebo + SoC (Randomized Phase) Followed by Belimumab + SoC (Open Label Phase) | Response Rate After Open Label Phase | Week 64 : Percent patients reaching Total improvement score of ≥40 | 2 Participants |
| Arm 2 (Placebo + SoC (Randomized Phase) Followed by Belimumab + SoC (Open Label Phase) | Response Rate After Open Label Phase | Week 64 : Percent of patient with major improvement TIS ≥60 | 0 Participants |
Comparison: Definition of Improvement (DOI) at Week 64p-value: 0.2395% CI: [0, 1.47]ANOVA
Comparison: Percent patients reaching Total improvement score of ≥40 at Week 64p-value: 0.9995% CI: [0.19, 2.51]ANOVA
Comparison: Percent of patient with major improvement TIS ≥60 at Week 64p-value: 0.2395% CI: [0, 1.47]ANOVA