Immune Mediated Necrotizing Myopathy
Conditions
Brief summary
The purpose of the study is to evaluate the safety and efficacy of zilucoplan in patients with Immune-Mediated Necrotizing Myopathy (IMNM). Subjects will be randomized in a 1:1 ratio to receive daily SC doses of 0.3 mg/kg zilucoplan or matching placebo for 8 weeks.
Interventions
DRUGzilucoplan
Daily subcutaneous (SC) inection
OTHERPlacebo
Daily subcutaneous (SC) inection
Sponsors
Ra 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
* Clinical diagnosis of IMNM (Immune-Mediated Necrotizing Myopathy) * Positive serology for anti-3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMGCR) or anti-signal recognition particle (SRP) autoantibodies * Clinical evidence of weakness (≤ grade 4 out of 5) on manual muscle testing in at least one proximal limb muscle group * Creatine kinase (CK) of \>1000 U/L at Screening * No change in corticosteroid dose for at least 30 days prior to Baseline or anticipated to occur during the first 8-weeks on study * No changes in immunosuppressive therapy, including dose, for at least 30 days prior to Baseline or anticipated to occur during the first 8-weeks on study
Exclusion criteria
* History of meningococcal disease * Current or recent systemic infection within 2 weeks prior to Screening or infection requiring intravenous (IV) antibiotics within 4 weeks prior to Screening * Recent initiation of intravenous immunoglobulin (IVIG) (i.e., first cycle administered less than 90 days prior to Baseline) * Rituximab use within 90 days prior to Baseline or anticipated to occur during study * Statin use within 30 days prior to Baseline or anticipated to occur during study * Plasma exchange within 4 weeks prior to Baseline or expected to occur during the 8-week Treatment Period
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage Change From Baseline to Week 8 in Serum Creatine Kinase (CK) Levels | Baseline (Day 1) and end of Main Portion (Week 8) | All laboratory samples were obtained prior to administration of study drug at applicable visits. CK levels were measured by a central laboratory. |
| Number of Participants Who Experienced a Treatment-Emergent Adverse Event (TEAE) | Baseline (Day 1) to end of Main Portion (Week 8) | A TEAE was defined as: * An adverse event (AE) that occurred after study treatment start that was not present at the time of treatment start. * An AE that increased in severity after treatment start if the event was present at the time of treatment start. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline to Week 8 in Proximal Manual Muscle Testing (MMT) Score | Baseline (Day 1) and end of Main Portion (Week 8) | The proximal MMT assessed muscle strength using manual muscle testing in 7 muscle groups (left and right sides assessed separately). The total MMT score for this study, inclusive of both sides, could range from 0-140, where 0 means no strength in any muscles and 140 means full strength in all the muscles examined. A negative change from Baseline indicated a worse outcome. |
| Change From Baseline to Week 8 in Physician Global Activity Visual Analogue Scale (VAS) Score | Baseline (Day 1) and end of Main Portion (Week 8) | The Physician Global Activity VAS Score measured the treating physician's global evaluation of the participant's overall disease activity using a 10 cm VAS labelled with no activity at the left end and maximum activity at the right end. The Physician Global Activity VAS Score ranged from 0 (absent extramuscular disease activity) to 10 (maximum extramuscular disease activity). A negative change from Baseline indicated a better outcome. |
| Change From Baseline to Week 8 in Patient Global Activity VAS Score | Baseline (Day 1) and end of Main Portion (Week 8) | The Patient Global Activity VAS Score measured the treating participant's global evaluation of their overall disease activity using a 10 cm VAS labelled with no activity at the left end and maximum activity at the right end. The Patient Global Activity VAS score ranged from 0 (absent extramuscular disease activity) to 10 (maximum extramuscular disease activity). A negative change from Baseline indicated a better outcome. |
| Number of Participants Who Achieve at Least Minimal Response Based on the American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) Response Criteria Scale | Baseline (Day 1) and end of Main Portion (Week 8) | The ACR/EULAR scale utilized a conjoint analysis-based continuous model using absolute percent change from Baseline in core set measures (physician, patient, and Myositis Disease Activity Assessment Tool (MDAAT); muscle strength; Health Assessment Questionnaire (HAQ); and muscle enzyme levels). A total improvement score (range 0-100) was determined by summing scores for each core set measure and comparing improvement in each respective core set measure. The threshold for minimal improvement was ≥20 in the total improvement score with higher scores indicating a better outcome. |
| Change From Baseline to Week 8 in MDAAT Extramuscular Disease Activity VAS Score | Baseline (Day 1) and end of Main Portion (Week 8) | The MDAAT extramuscular disease activity VAS score measured the degree of disease activity of extramuscular organ systems and muscle. The scoring was performed by the physician and ranged from 0 (absent extramuscular disease activity) to 10 (maximum extramuscular disease activity). A negative change from Baseline indicated a better outcome. |
| Change From Baseline to Week 8 in Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue Scale Score | Baseline (Day 1) and end of Main Portion (Week 8) | The FACIT-Fatigue Scale is a 13-item tool which measured an individual's level of fatigue during their usual daily activities over the past week. The level of fatigue was measured on a 4-point Likert scale. The total FACIT-Fatigue Scale score for this study could range from 0-52, where 0 means the participants were very much fatigued during their usual daily activities and 52 means the participants were not at all fatigued during their usual daily activities. A negative change from Baseline indicated a worse outcome. |
| Change From Baseline to Week 8 in HAQ Score | Baseline (Day 1) and end of Main Portion (Week 8) | The HAQ had 8 sections: dressing, arising, eating, walking, hygiene, reach, grip, and activities with 2 to 3 questions for each section. Scoring within each section ranged from 0 (without any difficulty) to 3 (unable to do). The total HAQ score was then calculated by summing the scores and dividing by the number of categories answered. The total HAQ score for this study could range from 0-3, where 0 means no functional impairment and 3 means complete functional impairment. A negative change from Baseline indicated a better outcome. |
| Change From Baseline to Week 8 in Triple Timed Up and Go Test (3TUG) Time | Baseline (Day 1) and end of Main Portion (Week 8) | The 3TUG test involved the ambulatory participant getting up from a seated position in a chair, walking at their normal pace for 3 meters, turning around, walking back to the chair, and sitting down. This sequence was repeated 3 times without rest, and the 3TUG test time is the average of the 3 lap times. A negative change from baseline indicated a better outcome. |
Countries
France, Netherlands, United Kingdom, United States
Participant flow
Recruitment details
This study was performed in 4 countries (France, the Netherlands, the United Kingdom, and the United States of America) between 07 November 2019 and 14 June 2021.
Pre-assignment details
Of the 37 participants who were screened, 10 participants were deemed ineligible and were screen failures. 27 participants with immune-mediated necrotizing myopathy were randomized in a 1:1 ratio to receive zilucoplan 0.3 mg/kg or a matching placebo for the 8-week Treatment Period in the Main Portion of the study. All eligible participants were given the option to receive daily subcutaneous (SC) zilucoplan 0.3 mg/kg in the Extension Portion of the study.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Participants were randomized to receive daily SC doses of matching placebo during the 8-week Main Portion of the study. All eligible participants were given the option to receive daily SC zilucoplan 0.3 mg/kg in the Extension Portion of the study. | 15 |
| Zilucoplan 0.3 mg/kg Participants were randomized to receive daily SC doses of zilucoplan 0.3 mg/kg during the 8-week Main Portion of the study. All eligible participants were given the option to receive daily SC zilucoplan 0.3 mg/kg in the Extension Portion of the study. | 12 |
| Total | 27 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 1 | 1 |
| Overall Study | Physician Decision | 3 | 1 |
| Overall Study | Study Terminated by Sponsor | 10 | 9 |
| Overall Study | Withdrawal by Subject | 1 | 1 |
Baseline characteristics
| Characteristic | Placebo | Total | Zilucoplan 0.3 mg/kg |
|---|---|---|---|
| Age, Continuous | 52.8 years STANDARD_DEVIATION 13.6 | 54.6 years STANDARD_DEVIATION 11.8 | 56.9 years STANDARD_DEVIATION 9 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 4 Participants | 9 Participants | 5 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 8 Participants | 13 Participants | 5 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 3 Participants | 5 Participants | 2 Participants |
| Race/Ethnicity, Customized American Indian/Alaska native | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Asian | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Black or African American | 1 Participants | 4 Participants | 3 Participants |
| Race/Ethnicity, Customized Missing | 3 Participants | 5 Participants | 2 Participants |
| Race/Ethnicity, Customized Native Hawaiian or other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Other/Mixed | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Unknown or Not Reported | 1 Participants | 1 Participants | 0 Participants |
| Race/Ethnicity, Customized White | 10 Participants | 17 Participants | 7 Participants |
| Sex: Female, Male Female | 7 Participants | 13 Participants | 6 Participants |
| Sex: Female, Male Male | 8 Participants | 14 Participants | 6 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 15 | 0 / 12 | 1 / 25 |
| other Total, other adverse events | 13 / 15 | 9 / 12 | 15 / 25 |
| serious Total, serious adverse events | 3 / 15 | 0 / 12 | 8 / 25 |
Outcome results
Primary
Number of Participants Who Experienced a Treatment-Emergent Adverse Event (TEAE)
A TEAE was defined as: * An adverse event (AE) that occurred after study treatment start that was not present at the time of treatment start. * An AE that increased in severity after treatment start if the event was present at the time of treatment start.
Time frame: Baseline (Day 1) to end of Main Portion (Week 8)
Population: The Safety Population included all participants who have received at least 1 dose of study drug, with participants analyzed based on the actual study treatment received.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo | Number of Participants Who Experienced a Treatment-Emergent Adverse Event (TEAE) | 13 Participants |
| Zilucoplan 0.3 mg/kg | Number of Participants Who Experienced a Treatment-Emergent Adverse Event (TEAE) | 9 Participants |
Primary
Percentage Change From Baseline to Week 8 in Serum Creatine Kinase (CK) Levels
All laboratory samples were obtained prior to administration of study drug at applicable visits. CK levels were measured by a central laboratory.
Time frame: Baseline (Day 1) and end of Main Portion (Week 8)
Population: The ITT Population with no missing observations at Baseline and Week 8.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Percentage Change From Baseline to Week 8 in Serum Creatine Kinase (CK) Levels | -20.72 percentage change | Standard Deviation 31.22 |
| Zilucoplan 0.3 mg/kg | Percentage Change From Baseline to Week 8 in Serum Creatine Kinase (CK) Levels | -9.86 percentage change | Standard Deviation 26.06 |
p-value: 0.46495% CI: [0.19, 1.57]2-sided Van Elteren test
Secondary
Change From Baseline to Week 8 in Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue Scale Score
The FACIT-Fatigue Scale is a 13-item tool which measured an individual's level of fatigue during their usual daily activities over the past week. The level of fatigue was measured on a 4-point Likert scale. The total FACIT-Fatigue Scale score for this study could range from 0-52, where 0 means the participants were very much fatigued during their usual daily activities and 52 means the participants were not at all fatigued during their usual daily activities. A negative change from Baseline indicated a worse outcome.
Time frame: Baseline (Day 1) and end of Main Portion (Week 8)
Population: The ITT Population with no missing observations at Baseline and Week 8.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline to Week 8 in Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue Scale Score | 3.45 score on a scale | Standard Error 3.41 |
| Zilucoplan 0.3 mg/kg | Change From Baseline to Week 8 in Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue Scale Score | 8.98 score on a scale | Standard Error 4.08 |
p-value: 0.26595% CI: [-4.49, 15.55]Linear Mixed Effect Model
Secondary
Change From Baseline to Week 8 in HAQ Score
The HAQ had 8 sections: dressing, arising, eating, walking, hygiene, reach, grip, and activities with 2 to 3 questions for each section. Scoring within each section ranged from 0 (without any difficulty) to 3 (unable to do). The total HAQ score was then calculated by summing the scores and dividing by the number of categories answered. The total HAQ score for this study could range from 0-3, where 0 means no functional impairment and 3 means complete functional impairment. A negative change from Baseline indicated a better outcome.
Time frame: Baseline (Day 1) and end of Main Portion (Week 8)
Population: The ITT Population with no missing observations at Baseline and Week 8.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline to Week 8 in HAQ Score | 0.022 score on a scale | Standard Error 0.151 |
| Zilucoplan 0.3 mg/kg | Change From Baseline to Week 8 in HAQ Score | -0.125 score on a scale | Standard Error 0.183 |
p-value: 0.50895% CI: [-0.601, 0.307]Linear Mixed Effect Model
Secondary
Change From Baseline to Week 8 in MDAAT Extramuscular Disease Activity VAS Score
The MDAAT extramuscular disease activity VAS score measured the degree of disease activity of extramuscular organ systems and muscle. The scoring was performed by the physician and ranged from 0 (absent extramuscular disease activity) to 10 (maximum extramuscular disease activity). A negative change from Baseline indicated a better outcome.
Time frame: Baseline (Day 1) and end of Main Portion (Week 8)
Population: The ITT Population with no missing observations at Baseline and Week 8.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline to Week 8 in MDAAT Extramuscular Disease Activity VAS Score | -0.144 score on a scale | Standard Error 0.336 |
| Zilucoplan 0.3 mg/kg | Change From Baseline to Week 8 in MDAAT Extramuscular Disease Activity VAS Score | -0.287 score on a scale | Standard Error 0.398 |
p-value: 0.76595% CI: [-1.123, 0.837]Linear Mixed Effect Model
Secondary
Change From Baseline to Week 8 in Patient Global Activity VAS Score
The Patient Global Activity VAS Score measured the treating participant's global evaluation of their overall disease activity using a 10 cm VAS labelled with no activity at the left end and maximum activity at the right end. The Patient Global Activity VAS score ranged from 0 (absent extramuscular disease activity) to 10 (maximum extramuscular disease activity). A negative change from Baseline indicated a better outcome.
Time frame: Baseline (Day 1) and end of Main Portion (Week 8)
Population: The ITT Population with no missing observations at Baseline and Week 8.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline to Week 8 in Patient Global Activity VAS Score | -0.685 score on a scale | Standard Error 0.707 |
| Zilucoplan 0.3 mg/kg | Change From Baseline to Week 8 in Patient Global Activity VAS Score | -1.966 score on a scale | Standard Error 0.854 |
p-value: 0.22195% CI: [-3.39, 0.829]Linear Mixed Effect Model
Secondary
Change From Baseline to Week 8 in Physician Global Activity Visual Analogue Scale (VAS) Score
The Physician Global Activity VAS Score measured the treating physician's global evaluation of the participant's overall disease activity using a 10 cm VAS labelled with no activity at the left end and maximum activity at the right end. The Physician Global Activity VAS Score ranged from 0 (absent extramuscular disease activity) to 10 (maximum extramuscular disease activity). A negative change from Baseline indicated a better outcome.
Time frame: Baseline (Day 1) and end of Main Portion (Week 8)
Population: The ITT Population with no missing observations at Baseline and Week 8.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline to Week 8 in Physician Global Activity Visual Analogue Scale (VAS) Score | -0.626 score on a scale | Standard Error 0.557 |
| Zilucoplan 0.3 mg/kg | Change From Baseline to Week 8 in Physician Global Activity Visual Analogue Scale (VAS) Score | -0.830 score on a scale | Standard Error 0.671 |
p-value: 0.895% CI: [-1.855, 1.448]Linear Mixed Effect Model
Secondary
Change From Baseline to Week 8 in Proximal Manual Muscle Testing (MMT) Score
The proximal MMT assessed muscle strength using manual muscle testing in 7 muscle groups (left and right sides assessed separately). The total MMT score for this study, inclusive of both sides, could range from 0-140, where 0 means no strength in any muscles and 140 means full strength in all the muscles examined. A negative change from Baseline indicated a worse outcome.
Time frame: Baseline (Day 1) and end of Main Portion (Week 8)
Population: The ITT Population with no missing observations at Baseline and Week 8.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline to Week 8 in Proximal Manual Muscle Testing (MMT) Score | -0.18 score on a scale | Standard Error 3.44 |
| Zilucoplan 0.3 mg/kg | Change From Baseline to Week 8 in Proximal Manual Muscle Testing (MMT) Score | 3.71 score on a scale | Standard Error 3.81 |
p-value: 0.43195% CI: [-6.18, 13.95]Linear Mixed Effect Model
Secondary
Change From Baseline to Week 8 in Triple Timed Up and Go Test (3TUG) Time
The 3TUG test involved the ambulatory participant getting up from a seated position in a chair, walking at their normal pace for 3 meters, turning around, walking back to the chair, and sitting down. This sequence was repeated 3 times without rest, and the 3TUG test time is the average of the 3 lap times. A negative change from baseline indicated a better outcome.
Time frame: Baseline (Day 1) and end of Main Portion (Week 8)
Population: The ITT Population with no missing observations at Baseline and Week 8. The test was also only performed in participants who were ambulatory.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline to Week 8 in Triple Timed Up and Go Test (3TUG) Time | -0.712 seconds | Standard Error 0.789 |
| Zilucoplan 0.3 mg/kg | Change From Baseline to Week 8 in Triple Timed Up and Go Test (3TUG) Time | -1.401 seconds | Standard Error 0.788 |
p-value: 0.49695% CI: [-2.781, 1.404]Linear Mixed Effect Model
Secondary
Number of Participants Who Achieve at Least Minimal Response Based on the American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) Response Criteria Scale
The ACR/EULAR scale utilized a conjoint analysis-based continuous model using absolute percent change from Baseline in core set measures (physician, patient, and Myositis Disease Activity Assessment Tool (MDAAT); muscle strength; Health Assessment Questionnaire (HAQ); and muscle enzyme levels). A total improvement score (range 0-100) was determined by summing scores for each core set measure and comparing improvement in each respective core set measure. The threshold for minimal improvement was ≥20 in the total improvement score with higher scores indicating a better outcome.
Time frame: Baseline (Day 1) and end of Main Portion (Week 8)
Population: The ITT Population with no missing observations at Baseline and Week 8.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo | Number of Participants Who Achieve at Least Minimal Response Based on the American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) Response Criteria Scale | 7 Participants |
| Zilucoplan 0.3 mg/kg | Number of Participants Who Achieve at Least Minimal Response Based on the American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) Response Criteria Scale | 6 Participants |
p-value: 0.91995% CI: [0.214, 5.535]Regression, Logistic