Study Evaluating Efficacy and Safety of Octanorm in Patients With Dermatomyositis

Study Overview
=================
Brief Summary
-----------------
DOUBLE-BLIND, RANDOMIZED, PLACEBO-CONTROLLED PHASE III STUDY EVALUATING EFFICACY AND SAFETY OF SUBCUTANEOUS HUMAN IMMUNOGLOBULIN (OCTANORM) IN PATIENTS WITH DERMATOMYOSITIS

Official Title
-----------------
Double-blind, Randomized, Placebo-Controlled Phase III Study Evaluating Efficacy and Safety of Subcutaneous Human Immunoglobulin (Octanorm) in Patients With Dermatomyositis (SCGAM-02)

Conditions
-----------------
Dermatomyositis

Intervention / Treatment
-----------------
* Drug: Octanorm
* Other: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Subjects with diagnosis of definite or probable DM according to the Bohan and Peter criteria. Subjects who have responded to IGIV treatment as assessed by the treating physician and being on a stable dose for at least 3 months on 2 g/kg bodyweight (+/- 10%). For subjects being on other medication(s) for the treatment of DM (immunosuppressants, corticosteroids): a) subject was on such medication(s) at the start of IGIV treatment in the first place, and b) received such medication(s) for at least 3 months prior to study enrolment and at a stable dose for at least 4 weeks prior to study enrolment at the maximally allowed conditions as per Table 2 (see section 4.2.1). MMT-8 score ≥144, with at least 3 other CSM to be normal or near normal as per the following criteria: Visual Analogue Scale [VAS] of patient global disease activity ≤2 cm, physician's global disease activity ≤2 cm, extra-muscular disease activity ≤2 cm; no muscle enzyme >4 times upper limit of normal due to myositis, Health Assessment Questionnaire [HAQ] ≤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 and willing 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 >5 years (>10 years for breast cancer) of cancer diagnosis who have been treated and are in remission are allowed. Subjects with overlap myositis (except for overlap with Sjögren's syndrome), connective tissue disease associated DM, inclusion body myositis, polymyositis 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 received blood or plasma-derived products (other than IGIV) or plasma exchange within the last 3 months before enrolment. Subjects with administration of permitted concomitant medications exceeding the maximally allowed conditions as per section 4.2.1. Subjects with administration of forbidden concomitant medications within the washout periods as defined in Table 3: see section 4.2.2. Subjects starting or planning to start a physical therapy-directed exercise regimen during the trial. Subjects on stable physical therapy for >4 weeks are allowed but the regimen should remain the same throughout 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 deep vein thrombosis within the last year prior to study enrolment or pulmonary embolism ever. Body mass index >40 kg/m2 and/or body weight >120 kg. 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 immunoglobulin, blood or plasma derived products or any component of octanorm 16.5% such as polysorbate 80 or to sodium chloride. Known blood hyperviscosity, or other hypercoagulable states. Subjects with a history of drug abuse within the past 5 years prior to study enrolment. Participating in another interventional clinical study with investigational treatment within 3 months prior to study enrolment. Subjects who participated in the Octagam 10% Dermatomyositis Study (GAM10-08) can be included. Women who are breast feeding, pregnant, or planning to become pregnant, or are unwilling to apply an effective birth control method (as per protocol section 7.3.9 b) up to four weeks after the last IMP infusion received.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Octanorm<br>0.5g/kg/week octanorm 16.5% | Drug: Octanorm<br>* Octanorm 0.5g/kg/week<br>|
| Placebo Comparator: Placebo<br>Placebo | Other: Placebo<br>* Placebo<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| MMT-8 | MMT-8; a set of 8 designated muscles tested bilaterally [potential score 0 - 150] | 32 weeks | 
| CDASI | The CDASI is a clinician-scored single page instrument that separately measures activity and damage in the skin of DM patients for use in clinical practice or clinical/therapeutic studies. | 32 weeks | 
| Physician's Global Disease Activity VAS Worsening | 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). | 32 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Extra-Muscular Disease Activity | Extra-muscular activity (part of MDAAT; a combined tool that captures the physician's assessment of disease activity of various organ systems using a scale from 0 = Not present in the last 4 weeks to 4 = New - in the last 4 weeks [compared to the previous 4 weeks] and a VAS). | 32 weeks | 
| Muscle Enzymes - Aldolase | Measurement of aldolase in blood | 32 weeks | 
| Muscle Enzymes - Creatine Kinase | Measurement of creatine kinase in blood | 32 weeks | 
| Muscle Enzymes - Alanine Aminotransferase | Measurement of alanine aminotransferase in blood | 32 weeks | 
| Muscle Enzymes - Aspartate Aminotransferase | Measurement of aspartate aminotransferase in blood | 32 weeks | 
| Muscle Enzymes - Lactate Dehydrogenase | Measurement of lactate dehydrogenase in blood | 32 weeks | 
| 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). | 32 weeks | 
| 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. | 32 weeks | 
| Mean Change in TIS | Total Improvement Score | 32 weeks | 
| Time to Clinically Important Deterioration | Time to clinically important deterioration | 32 weeks | 
| Adverse Events | Occurrence of all adverse events | 32 weeks | 
| TEEs | Monitoring safety with occurrence of all thromboembolic events (TEEs) | 32 weeks | 
| HTRs | Monitoring safety with occurrence of all hemolytic transfusion reactions (HTRs) | 32 weeks | 
| Injection Site Reactions | Monitoring safety by assessing local injection site reactions | 32 weeks | 
| Blood Pressure | Monitoring safety through blood pressure values | 32 weeks | 
| Heart Rate | Monitoring safety through heart rate values | 32 weeks | 
| Body Temperature | Monitoring safety through body temperature values | 32 weeks | 
| Respiratory Rate | Monitoring safety through respiratory rate values | 32 weeks | 
| Physical Examination | The physical examination outcome will be analyzed based on changes from baseline as adverse events. | 32 Weeks | 
| Sodium | Monitoring safety through lab sodium levels | 32 weeks | 
| Potassium | Monitoring safety through lab potassium levels | 32 weeks | 
| Glucose | Monitoring safety through lab glucose levels | 32 weeks | 
| ALAT | Monitoring safety through lab ALAT levels | 32 weeks | 
| ASAT | Monitoring safety through lab ASAT levels | 32 weeks | 
| LDH | Monitoring safety through lab LDH levels | 32 weeks | 
| Total Bilirubin | Monitoring safety through lab total bilirubin levels | 32 weeks | 
| Blood Urea Nitrogen | Monitoring safety through lab blood urea nitrogen levels | 32 weeks | 
| Urea | Monitoring safety through lab urea levels | 32 weeks | 
| Creatinine | Monitoring safety through lab creatinine levels | 32 weeks | 
| Albumin | Monitoring safety through lab albumin levels | 32 weeks | 
| Hematocrit | Monitoring safety through lab hematocrit levels | 32 weeks | 
| Hemoglobin | Monitoring safety through lab hemoglobin levels | 32 weeks | 
| Red Blood Cell Count | Monitoring safety through lab red blood cell count levels | 32 weeks | 
| White Blood Cell Count | Monitoring safety through lab white blood cell count levels | 32 weeks | 
| Platelets | Monitoring safety through lab platelet levels | 32 weeks | 
| Serum Haptoglobin | Monitoring safety through lab serum haptoglobin levels | 32 weeks | 
| Plasma-Free Hemoglobin | Monitoring safety through lab plasma-free hemoglobin | 32 weeks | 
| Direct Coombs' Test | Monitoring safety through Direct Coombs' test | 32 weeks | 
| D-dimers | Monitoring safety through D-dimers test | 32 weeks | 
| Serum IgG | Monitoring safety through lab IgG levels | 32 weeks | 
| Aldolase | Monitoring safety through lab aldolase levels | 32 weeks | 
| Creatine Kinase | Monitoring safety through lab creatine kinase levels | 32 weeks | 
| Pregnancy Test | Monitoring safety through pregnancy test | 32 weeks | 
| Urine Protein | Monitoring safety through lab urine protein levels | 32 weeks | 
| Urine Glucose | Monitoring safety through lab urine glucose levels | 32 weeks | 
| Urine pH | Monitoring safety through lab urine pH levels | 32 weeks | 
| Urine Nitrite | Monitoring safety through lab urine nitrite levels | 32 weeks | 
| Urine Ketones | Monitoring safety through lab urine ketone levels | 32 weeks | 
| Urine Leukocytes | Monitoring safety through lab urine leukocyte levels | 32 weeks | 
| Urine Hemoglobin | Monitoring safety through lab urine hemoglobin levels | 32 weeks | 
| Urine Bilirubin | Monitoring safety through lab urine bilirubin levels | 32 weeks | 
| Urine Urobilinogen | Monitoring safety through lab urine urobilinogen levels | 32 weeks | 
| Urine Hemosiderin | Monitoring safety through lab urine hemosiderin levels | 32 weeks | 
| HIV | Monitoring safety through HIV testing | 32 weeks | 
| Hepatitis B | Monitoring safety through hepatitis B testing | 32 weeks | 
| Hepatitis C | Monitoring safety through hepatitis C testing | 32 weeks |