Study Evaluating Efficacy and Safety of Octagam 10% in Patients With Dermatomyositis (Idiopathic Inflammatory Myopathy)

Study Overview
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Brief Summary
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Prospective, Double-blind, Randomized, Placebo-Controlled Phase III Study Evaluating Efficacy and Safety of Octagam 10% in Patients With Dermatomyositis (ProDERM study)

Official Title
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Prospective, Double-blind, Randomized, Placebo-Controlled Phase III Study Evaluating Efficacy and Safety of Octagam 10% in Patients With Dermatomyositis (ProDERM Study)

Conditions
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Dermatomyositis

Intervention / Treatment
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* Drug: Octagam 10%
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects with diagnosis of definite or probable DM according to the Bohan and Peter criteria. Subjects under treatment with corticosteroids and/or maximally 2 immune-suppressants and being on stable therapy for at least 4 weeks (see Section 4.2.1) OR Subjects with previous failure of response or previous intolerance to corticosteroid and at least 1 additional immunosuppressive drug, and with steroid/immunosuppressive drugs washed out as per Section 4.2.1 (Table 2). Subjects with active disease, assessed and agreed upon by an independent adjudication committee. Manual Muscle Testing-8 (MMT-8) score <142, with at least 2 other abnormal Core Set Measures (CSM) (Visual Analogue Scale [VAS] of patient global activity ≥2 cm, physician's global disease activity ≥2 cm, extra-muscular activity ≥2 cm; at least one muscle enzyme >1.5 times upper limit of normal, Health Assessment Questionnaire ≥0.25). Males or females ≥ 18 to < 80 years of age. Voluntarily given, fully informed written consent obtained from subject before any study-related procedures are conducted. Subject must be capable to understand and comply with the relevant aspects of the study protocol. Exclusion Criteria: Cancer-associated myositis, defined as the diagnosis of myositis within 2 years of the diagnosis of cancer (except basal or squamous cell skin cancer or carcinoma in situ of the cervix that has been excised and cured and at least 1 or 5 years, respectively, have passed since excision). Evidence of active malignant disease or malignancies diagnosed within the previous 5 years (including hematological malignancies and solid tumors) or breast cancer diagnosed within the previous 10 years. Subjects with overlap myositis (except for overlap with Sjögren's syndrome), connective tissue disease associated DM, inclusion body myositis, polymyositis, juvenile dermatomyositis or drug-induced myopathy. Subjects with immune-mediated necrotizing myopathy with absence of typical DM rash. Subjects with generalized, severe musculoskeletal conditions other than DM that prevent a sufficient assessment of the subject by the physician. Subjects who have received IgG treatment within the last 6 months before enrolment. Subjects who received blood or plasma-derived products (other than IgG) or plasma exchange within the last 3 months before enrolment. Subjects starting or planning to start a physical therapy-directed exercise regimen during the trial. Cardiac insufficiency (New York Heart Association III/IV), cardiomyopathy, significant cardiac dysrhythmia requiring treatment, unstable or advanced ischemic heart disease. Severe liver disease, with signs of ascites and hepatic encephalopathy. Severe kidney disease (as defined by estimated glomerular filtration rate (eGFR) < 30 mL/min/1.73 m2). Known hepatitis B, hepatitis C or HIV infection. Subjects with a history of TEE such as deep vein thrombosis, pulmonary embolism, myocardial infarction, ischemic stroke, transient ischemic attack, peripheral artery disease (Fontaine IV) ever. Body mass index ≥40 kg/m2. Medical conditions whose symptoms and effects could alter protein catabolism and/or IgG utilization (e.g. protein-losing enteropathies, nephrotic syndrome). Known IgA deficiency with antibodies to IgA. History of hypersensitivity, anaphylaxis or severe systemic response to immuno-globulin, blood or plasma derived products or any component of Octagam 10%. Known blood hyperviscosity, or other hypercoagulable states. Subjects with a history of drug abuse within the past 5 years prior to study enrollment. Subjects unable or unwilling to understand or comply with the study protocol. Participating in another interventional clinical study with investigational treatment within 3 months prior to study enrollment. Women who are breast feeding, pregnant, or planning to become pregnant, or are unwilling to apply an effective birth control method (such as implants, injectables, combined oral contraceptives, some intrauterine devices [IUDs], sexual abstinence or vasectomized partner) up to four weeks after the last IMP infusion. Subjects who are accommodated in an institution or care facility based on an official directive or court order. Subjects who are in any way dependent on the Sponsor, Investigator or Study Site. Subjects who received forbidden medication within the washout period as defined in Section 4.2.2 (Table 3).

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 79 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>Subjects randomized to placebo will receive 4 infusions of placebo every 4 weeks during the blinded First Period (16 weeks). If confirmed deterioration (deterioration at 2 consecutive visits) during the First Period, subjects will be switched to Octagam 10%. After response assessment at Week 16, all subjects with no confirmed deterioration and subjects switched to Octagam 10% due to confirmed deterioration but without further confirmed deterioration during the First Period will continue to receive 2.0 g/kg of Octagam 10% every 4 weeks during the subsequent 6-months open-label Extension Period. At Week 28, subjects who are stable on 2.0 g/kg Octagam 10% can be switched to 1.0 g/kg Octagam 10%, at the discretion of the investigator. Subjects randomized to placebo and switched to Octagam 10% due to confirmed deterioration, who deteriorate also during Octagam 10% treatment at 2 consecutive visits will drop-out after response assessment at Week 16 and will not enter the Extension Period. | Other: Placebo<br>* Patients to be treated with a Placebo<br>|
| Experimental: Octagam10%<br>Subjects randomized to Octagam will receive 4 infusions of 2.0 g/kg Octagam 10% every 4 weeks during the blinded First Period (16 weeks). If confirmed deterioration (deterioration at 2 consecutive visits) during the First Period, subjects will be switched to the alternate treatment. After response assessment at Week 16, all subjects with no confirmed deterioration during the First Period will continue receiving 2.0 g/kg of Octagam 10% every 4 weeks during the subsequent 6-months open-label Extension Period. At Week 28, subjects who are stable on 2.0 g/kg Octagam 10% can be switched to 1.0 g/kg Octagam 10%, at the discretion of the investigator. Subjects randomized to Octagam and switched to the alternate treatment due to confirmed deterioration will drop-out after response assessment at Week 16 and will not enter the Extension Period. | Drug: Octagam 10%<br>* Patients to be treated with Octagam 10%<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Measure the Number of Patients Who Had an Increase of ≥20 Points on the Total Improvement Score (TIS) | Proportion of responders in the 2.0 g/kg Octagam 10% and placebo arms at Week 16 relative to baseline (Week 0). A responder being defined as a patient with an increase of ≥20 points on the Total Improvement Score (TIS, a scale from 0 to 100; 20-39 points being minimal improvement, 40-59 points being moderate improvement, and ≥60 points being major improvement | At week 16 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of TIS Responders by Improvement Category at Week 16 | The TIS (Total Improvement Score) is a scale from 0 to 100 that allows for the discrimination between minimal, moderate and major responders depending on their improvement in the combined 6 CSM: ≥20 to 39 points being minimal improvement, ≥40 to 59 points being moderate improvement, and ≥60 points being major improvement. Primary: Total number of all patients who had at least minimal, moderate, or major response. At Least Moderate: Number of patients who had moderate or major response. At Least Major: Number of patients who had a major response. | 16 weeks | 
| Proportion of TIS Responders by Improvement Category at Week 40 | The TIS (Total Improvement Score) is a scale from 0 to 100 that allows for the discrimination between minimal, moderate and major responders depending on their improvement in the combined 6 CSM: ≥20 to 39 points being minimal improvement, ≥40 to 59 points being moderate improvement, and ≥60 points being major improvement. At Least Minimal: Total number of all patients who had minimal, moderate, or major response. At Least Moderate: Number of patients who had moderate or major response. At Least Major: Number of patients who had a major response. | 40 weeks | 
| Mean Change From Baseline (Week 0) to End of First Period (Week 16) in the Modified Cutaneous Dermatomyositis Disease Area and Severity Index (CDASI) | The modified CDASI has 3 activity measures (erythema, scale, and erosion/ulceration) and 2 damage measures (poikiloderma and calcinosis) which are assessed over 15 body areas. In addition, Gottron's papules on the hands are evaluated both for activity and damage. Lastly, the activity of periungual changes and alopecia is assessed. Absence of skin lesions as described above is scored with 0 for each of the above described areas. Skin lesion will be scored with at least 1 (present), some lesions will be graded from 1 (less severe) to 2 (severe); others with 1, 2 or 3. For the total activity score as well as for the total damage score the sub-scores will be added up. The score for total activity ranges from 0 to 100, for total damage from 0 to 32 points. Higher scores indicate greater disease activity or greater disease damage respectively. | First 16 weeks | 
| Mean Change From End of First Period (Week 16) to End of Extension Period (Week 40) in the Modified Cutaneous Dermatomyositis Disease Area and Severity Index (CDASI) | The modified CDASI has 3 activity measures (erythema, scale, and erosion/ulceration) and 2 damage measures (poikiloderma and calcinosis) which are assessed over 15 body areas. In addition, Gottron's papules on the hands are evaluated both for activity and damage. Lastly, the activity of periungual changes and alopecia is assessed Absence of skin lesions as described above is scored with 0 for each of the above described areas. Skin lesion will be scored with at least 1 (present), some lesions will be graded from 1 (less severe) to 2 (severe); others with 1, 2 or 3. For the total activity score as well as for the total damage score the sub-scores will be added up. The score for total activity ranges from 0 to 100, for total damage from 0 to 32 points. Higher scores indicate greater disease activity or greater disease damage respectively. | From week 16 to Week 40 | 
| Mean Change From Baseline (Week 0) to End of Extension Period (Week 40) in the Modified Cutaneous Dermatomyositis Disease Area and Severity Index (CDASI) | The modified CDASI has 3 activity measures (erythema, scale, and erosion/ulceration) and 2 damage measures (poikiloderma and calcinosis) which are assessed over 15 body areas. In addition, Gottron's papules on the hands are evaluated both for activity and damage. Lastly, the activity of periungual changes and alopecia is assessed. Absence of skin lesions as described above is scored with 0 for each of the above described areas. Skin lesion will be scored with at least 1 (present), some lesions will be graded from 1 (less severe) to 2 (severe); others with 1, 2 or 3. For the total activity score as well as for the total damage score the sub-scores will be added up. The score for total activity ranges from 0 to 100, for total damage from 0 to 32 points. Higher scores indicate greater disease activity or greater disease damage respectively. | 40 weeks | 
| Mean Change From Baseline (Week 0) to End of First Period (Week 16) and Extension Period (Week 40) in: SF-36v2 Health Survey | The SF-36 is a multi-purpose, short-form health survey with only 36 questions. It yields an 8-scale profile of functional health and well-being scores as well as psychometrically-based physical and mental health summary measures and a preference-based health utility index. SF-36 scores ranging from 0 to 100. 0 represented the lowest possible score (worst health state) and 100 represented the highest possible score (best health state), with scores in between representing the percentages of the total possible score achieved by respondents on a given scale. | From start of the trial till Week 40 | 
| Mean Change From Baseline (Week 0) to End of First Period (Week 16) and Extension Period (Week 40) in Physician's Global Disease Activity | 10 cm VAS assessing global disease activity from No evidence of disease activity to Extremely active or severe disease activity; Disease Activity being defined as potentially reversible pathology or physiology resulting from the myositis). Assessment completed by physician. 0 is lowest score and 10 is highest score. Higher score associated with worse outcome. | From start of the trial till Week 40 | 
| Mean Change From Baseline (Week 0) to End of First Period (Week 16) and Extension Period (Week 40) in: Patient Global Disease Activity | Patient's Global Disease Activity (10cm VAS assessing the overall activity of the patient's disease today from No evidence of disease activity to Extremely active or severe disease activity, Disease Activity being active inflammation in the patient's muscles, skin, joints, intestines, heart, lungs or other parts of the body, which can improve when treated with medicines). 0 is lowest score and 10 is highest score. Higher score associated with worse outcome. | From start of the trial till Week 40 | 
| Mean Change From Baseline (Week 0) to End of First Period (Week 16) and Extension Period (Week 40) in: MMT-8 | Manual Muscle Testing - MMT-8; a set of 8 designated muscles tested bilaterally [potential score 0 - 150]. Higher score associated with better outcome. | From start of the trial till Week 40 | 
| Mean Change From Baseline (Week 0) to End of First Period (Week 16) and Extension Period (Week 40) in: Health Assessment Questionnaire | Health Assessment Questionnaire (HAQ); a generic rather than a disease-specific instrument; comprised of 8 sections: dressing, arising, eating, walking, hygiene, reach, grip, and activities. There are 2 or 3 questions for each section. Scoring within each section is from 0 [without any difficulty] to 3 [unable to do]. For each section the score given to that section is the worst score within the section. The 8 scores of the 8 sections are summed and divided by 8). Assessment completed by patients. Lowest score 0 highest score 24. Higher score associated with worse outcome. | From start of the trial till Week 40 | 
| Mean Change From Baseline (Week 0) to End of First Period (Week 16) and Extension Period (Week 40) in Enzymes (Alanine Aminotransferase) |  | From start of the trial till Week 40 | 
| Mean Change From Baseline (Week 0) to End of First Period (Week 16) and Extension Period (Week 40) in Enzymes (Aspartate Aminotransferase) |  | From start of the trial till Week 40 | 
| Mean Change From Baseline (Week 0) to End of First Period (Week 16) and Extension Period (Week 40) in Enzymes (Lactate Dehydrogenase) |  | From start of the trial till Week 40 | 
| Mean Change From Baseline (Week 0) to End of First Period (Week 16) and Extension Period (Week 40) in Enzymes (Aldolase) |  | From start of the trial till Week 40 | 
| Mean Change From Baseline (Week 0) to End of First Period (Week 16) and Extension Period (Week 40) in Enzymes (Creatine Kinase) |  | From start of the trial till Week 40 | 
| Mean Change From Baseline (Week 0) to End of First Period (Week 16) and Extension Period (Week 40) in: Extra-muscular Activity | 10 cm VAS assessing extra-muscular activity from No evidence of disease activity to Extremely active or severe disease activity. It encompasses an overall evaluation for the disease activity in all the extramuscular organ systems and excludes muscle disease activity. Assessment completed by physician. 0 is lowest score and 10 is highest score. Higher score associated with worse outcome. | From start of the trial until Week 40 | 
| Mean TIS From Baseline (Week 0) to End of First Period (Week 16) and From Baseline (Week 0) to End of Extension Period (Week 40) | The TIS (Total Improvement Score) is a scale from 0 to 100 that allows for the discrimination between minimal, moderate and major responders depending on their improvement in the combined 6 CSM: ≥20 to 39 points being minimal improvement, ≥40 to 59 points being moderate improvement, and ≥60 points being major improvement. | Up to 40 weeks | 
| Time to Minimal, Moderate and Major Improvement in TIS | When interpreting these time to event evaluations, one has to keep in mind that eventually all patients were treated with octagam 10%, so that differences in time to response for the Overall Period reflect this delayed start of treatment rather than the true difference between treatment with octagam 10% and placebo. | Up to 40 weeks | 
| Time to Confirmed Deterioration in the First Period and Overall | Confirmed deterioration is defined as disease worsening on 2 consecutive visits. Worsening criteria are defined as either Physician's Global Disease Activity worsening ≥2cm and Manual Muscle Testing worsening ≥20% or Extra-muscular Activity worsening ≥2cm or any 3 of the following scores worsening by ≥30%: Physician's Global Disease Activity, Manual Muscle Test, Extra-muscular Activity, Patient's Global Disease Activity or Health Assessment Questionnaire. | Up to 40 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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DM