A Pilot Study of Etanercept in Dermatomyositis

Study Overview
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Brief Summary
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The purpose of the study is to obtain preliminary data regarding the safety and tolerability of etanercept in DM. In addition, we will use the study to assess the variability, reliability, and responsiveness of the core set of outcome measures recommended by IMACS. The study will be performed under the aegis of the Muscle Study Group (MSG), consisting of experienced investigators with an avid interest in myopathies. The ultimate goal of this pilot study will be to obtain necessary, prerequisite information important in designing future therapeutic trials of etanercept and other agents in patients with DM. The specific aims of the study are: Aim 1: To preliminarily assess the safety and tolerability of etanercept in patients with DM. Aim 2: To assess the safety and tolerability of prednisone in the dosing schedule we propose to use. Aim 3: To evaluate outcome measures recommended by IMACS and assess their variability, reliability, and responsiveness in order to facilitate the design of future therapeutic trials in the inflammatory myopathies.

Detailed Description
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Dermatomyositis (DM) is one of the major subtypes of idiopathic inflammatory myopathy. Prednisone is the initial treatment of choice in most patients with DM. However, because of the high rate of patients with disabling weakness despite treatment with prednisone, the long-term side effects of prednisone, and the many side effects associated with other second-line immunosuppressive agents (e.g., methotrexate, azathioprine), better treatment options are needed. There is evidence that tumor necrosis factor-a (TNF-a) plays a role in the pathogenesis of DM. Thus, etanercept, which blocks TNF-a, is a logical drug to assess in DM. Etanercept has been associated with a number of side effects including an increased risk of infection, inducing other autoimmune diseases, and perhaps cancer. These risks may be further enhanced in DM in which the frequency of other autoimmune disorders (e.g., connective tissue disease) and malignancy are already increased. The goal of this pilot study will be to assess the safety and tolerability of etanercept in DM.We will perform a double-blind, placebo-controlled pilot study of etanercept in 40 patients with DM randomized in a 3:1 ratio to receive etanercept or placebo. All newly diagnosed and untreated patients will be started on a standard dose of prednisone and tapering schedule. Refractory patients who have been or are currently being treated with prednisone, IVIG, or methotrexate can also participate. Subjects will be followed for 1 year and we will assess various outcome variables recommended by the The International Myositis Assessment Clinical Study Group (IMACS). The primary aim of the study is to preliminarily assess the safety and tolerability of etanercept in patients with DM. We hypothesize that etanercept will be safe and well tolerated in this population. The second aim is to assess the safety and tolerability of prednisone in the dosing schedule we propose to use. We hypothesize that most patients will be able to tolerate the reduction of the prednisone dosage but most will not be able to be completely weaned off the medication. We believe we will find a relationship between prednisone dosage and its related side effects. The third aim of the study is to assess the variability, reliability, and responsiveness of the outcome measures recommended by IMACS using this pilot study of etanercept as the vehicle. The information gained from this study is necessary in order to design larger therapeutic trials of etanercept and other drugs in dermatomyositis.

Official Title
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A Pilot Study of Etanercept in Dermatomyositis

Conditions
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Dermatomyositis

Intervention / Treatment
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* Drug: Etanercept
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Study subjects must meet the following criteria: Meet the diagnostic criteria for DM (a-c; a,b,d; or a,c,d) Subjects must have symmetric proximal greater than distal weakness Characteristic DM rash consisting of any or all of the following: heliotrope, shawl sign, V-sign, Gottron's sign, Gottron's papules, periungual telangiectasias Laboratory evidence of myopathy with at least one of the following: an elevated serum CK or aldolase level, myositis-specific antibody, electromyography (EMG) demonstrating myopathic features (e.g., muscle membrane instability, myopathic units, or early recruitment), or an abnormal skeletal muscle MRI showing diffuse or patchy edema within the muscles. A muscle biopsy will be optional if the patient fulfills criteria a-c. The subject must demonstrate symmetric proximal weakness (criteria a) for entry into the study. If the subject does not have a definite rash (criteria b) or laboratory evidence of a myopathy (criteria c), a muscle biopsy will be required. The muscle biopsy must demonstrate one of the following: perifascicular atrophy, expression of MHC 1 on perifascicular muscle fibers, MAC deposition on small blood vessels, tubuloreticular inclusions in endothelial cells on EM, or MXA expression on muscle fibers of blood vessels Newly diagnosed subjects should be able to walk independently 30 feet (cane, walkers, orthoses allowed). However, subjects with refractory dermatomyositis may be non-ambulatory. Age > 18 years Patients must not use topical skin ointments for treatment of the dermatological manifestations as it will interfere with skin assessment. Men and women of childbearing age must be willing to use a method of birth control. Able to give informed consent Subject or designee must have the ability to self-inject investigational product or have a care giver at home who can administer subcutaneous injections Exclusion Criteria The presence of any of the following excludes subject participation in the study: Presence of any one of the following medical conditions: active infection, uncontrolled diabetes mellitus, MI, CVA or TIA within 3 months of screening visit, symptomatic cardiomyopathy (congestive heart failure), symptomatic coronary artery disease, uncontrolled hypertension (sitting systolic BP <80 mm Hg or > 160 or diastolic BP > 100 mm Hg), oxygen-dependent severe pulmonary disease, systemic lupus erythematosus (SLE), cancer (other than basal cell skin cancer) less than 5 years previously, HIV or other immunosuppressing disease, positive PPD test or any history of mycobacterial disease, chronic hepatitis B or hepatitis C, history of multiple sclerosis, transverse myelitis, optic neuritis, chronic inflammatory demyelinating neuropathy, epilepsy, or other chronic serious medical illnesses Presence of any of the following on routine blood screening: WBC<3000, Platelets < 100,000, hematocrit < 30%, BUN > 30 mg %, symptomatic liver disease with serum albumin < 3 G/DL, PT or PTT > upper range of control values Forced Vital Capacity < 50% of predicted History of non-compliance with other therapies Any prior or concurrent cyclophosphamide, or current use of any immunosuppressive agent besides methotrexate (e.g., azathioprine, mycophenolate, or cyclosporine) Coexistence of other neuromuscular disease that may complicate interpretation of the results of the study Drug or alcohol abuse within last 3 months Pregnancy or breast feeding Juvenile DM Subjects who have known hypersensitivity to Enbrel or any of its components or who is known to have antibodies to etanercept Use of a live vaccine 90 days prior to, or during this study. Subject is currently enrolled in another investigational device or drug trial(s), or subject has received other investigational agent(s) within 28 days of baseline visit. Concurrent sulfasalazine therapy

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 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: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Etanercept<br>Subjects randomized to Etanercept will be provided with syringes contain 50 mg and will be injected subcutaneously once a week for 52 weeks. | Drug: Etanercept<br>* Etanercept 50 mg will be injected subcutaneously once per week for 52 weeks<br>|
| Placebo Comparator: Placebo<br>Subjects will be given syringes containing placebo. Injections will be given subcutaneously, one time per week for 52 weeks. | Drug: Placebo<br>* Placebo, contained in 50mg syringes, will be injected subcutaneously once per week for 52 weeks.<br>* Other names: Saline;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Occurrence of at Least One Adverse Event | Adverse events (AEs) were assessed using the Common Terminology Criteria for Adverse Events version 3.0 (CTCAE). The grade of mild, moderate or severe matches with the descriptions from the CTCAE dictionary. In general, a Mild AE is asymptomatic; clinical or diagnostic observations only; intervention not indicated. A Moderate AE is minimal, local or noninvasive intervention indicated; limiting activities of daily living. A Severe AE is medically significant but not immediately life-threatening; hospitalization or prolonged hospitalization indicated; disabling; | at each visit during the 12 month study | 
| Tolerability | The reported tolerability measure was defined as the number of participants that completed the entire 52 week study on their originally assigned treatment. | At any point between Baseline (week 0) and the end of the study (Week 52) | 
| Average Change in Oral Temperature From Baseline to Week 52 | The subject's oral temperature was measured in degrees Celsius. The average change was determined by subtracting the Baseline Visit (Week 0) results from the Week 52 results (Week 52- Baseline (Week 0)). This measure was also collected as part of the study protocol at the Screening visit and Week 4,8,12,16,20,24,32 and 40. | At Baseline (Week 0) and Week 52 | 
| Average Change in Respiration Rate From Baseline to Week 52 | The subject's respiration rate was measured as number of breaths per minute. The average change was determined by subtracting the Baseline Visit (Week 0) results from the Week 52 results (Week 52- Baseline (Week 0)). This measure was also collected as part of the study protocol at the Screening visit and Week 4,8,12,16,20,24,32 and 40. | At Baseline (Week0) and Week 52 | 
| Average Change in Systolic Blood Pressure From Baseline to Week 52 | The subject's systolic blood pressure was measured in millimeters of mercury (mmHg). The average value was calculated per treatment group for the Baseline and Week 52 visit based on treatment group. The average change was determined by subtracting the average value Baseline Visit (Week 0) results from the Week 52 results (Week 52- Baseline (Week 0)). This measure was also collected as part of the study protocol at the Screening visit and Week 4,8,12,16,20,24,32 and 40. | At Baseline (Week0) and Week 52 | 
| Average Change in Diastolic Blood Pressure Comparing Baseline to Week 52. | The subject's diastolic blood pressure was measured in millimeters of mercury (mm Hg). The average value was calculated for the Baseline and Week 52 visit based on treatment group. The average change was determined by subtracting the average value Baseline Visit (Week 0) results from the Week 52 results (Week 52- Baseline (Week 0)). This measure was also collected as part of the study protocol at the Screening visit and Week 4,8,12,16,20,24,32 and 40. | At Baseline (Week0) and Week 52 | 
| Average Change in Pulse Comparing Baseline to Week 52 | The subject's pulse was measured in beats per minute (BPM). The average value was calculated per treatment group for the Baseline and Week 52 visit. The average change was determined by subtracting the average value Baseline Visit (Week 0) results from the Week 52 results (Week 52- Baseline (Week 0)). This measure was also collected as part of the study protocol at the Screening visit and Week 4, 8, 12, 16, 20, 24, 32 and 40. | At Baseline (Week0) and Week 52 | 
| Average Change in Body Weight in Kilograms (kg) Comparing Baseline to Week 52. | The subject's body weight was measured in kilograms(kg). The average value was calculated for each treatment group for the Baseline and Week 52 visits. The average change was determined by subtracting the average value at the Baseline Visit (Week 0) results from the Week 52 results (Week 52- Baseline (Week 0)). This measure was also collected as part of the study protocol at the Screening visit and Week 4, 8, 12, 16, 20, 24, 32 and 40. | At Baseline (Week0) and Week 52 | 
| Frequency of Subjects With Treatment Emergent, Clinically Significant, Abnormal Creatine Kinase (CK) Laboratory Values From Baseline to Week 52 | The site investigators used the reference ranges provided by the lab that completed the testing of the sample to determine if the value was abnormal. If a value was abnormal, the site investigator would determine if the value was clinically significant or not. A subject was considered to have a treatment emergent, clinically significant creatine kinase (CK) value if during the course of the study, they had at least one clinically significant CK result that was not present at baseline. Subjects had CK labs drawn at Screening, Baseline (Week0), Week 4, 8, 12, 16, 20, 24, 32, 40, and 52. | At Screening, Baseline (Week0), Week 4, 8, 12, 16, 20, 24, 32, 40, and 52 | 
| Frequency of Subjects With Treatment Emergent, Clinically Significant, Abnormal Alanine Aminotransferase (ALT) Laboratory Values From Baseline to Week 52 | The site investigators used the reference ranges provided by the lab that completed the testing of the sample to determine if the value was abnormal. If a value was abnormal, the site investigator would determine if the value was clinically significant or not. A subject was considered to have a treatment emergent, clinically significant ALT value if during the course of the study, they had at least one clinically significant ALT result that was not present at baseline. Subjects had ALT labs drawn at Screening, Baseline (Week0), Week 4, 8, 12, 16, 20, 24, 32, 40, and 52. | At Screening, Baseline (Week0), Week 4, 8, 12, 16, 20, 24, 32, 40, and 52 | 
| Frequency of Subjects With Treatment Emergent, Clinically Significant, Abnormal Gamma-glutamyl Transpeptidase (GGT) Laboratory Values From Baseline to Week 52 | The site investigators used the reference ranges provided by the lab that completed the testing of the sample to determine if the value was abnormal. If a value was abnormal, the site investigator would determine if the value was clinically significant or not. A subject was considered to have a treatment emergent, clinically significant GGT value if during the course of the study, they had at least one clinically significant GGT result that was not present at baseline. Subjects had GGT labs drawn at Screening, Baseline (Week0), Week 4, 8, 12, 16, 20, 24, 32, 40, and 52. | Screening, Baseline (Week0), Week 4, 8, 12, 16, 20, 24, 32, 40, and 52 | 
| Frequency of Subjects With Treatment Emergent, Clinically Significant, Abnormal Aldolase Laboratory Values From Baseline to Week 52 | The site investigators used the reference ranges provided by the lab that completed the testing of the sample to determine if the value was abnormal. If a value was abnormal, the site investigator would determine if the value was clinically significant or not. A subject was considered to have a treatment emergent, clinically significant Aldolase value if during the course of the study, they had at least one clinically significant Aldolase result that was not present at baseline. Subjects had Aldolase labs drawn at Screening, Baseline (Week0), Week 4, 8, 12, 16, 20, 24, 32, 40, and 52. | Screening, Baseline (Week0), Week 4, 8,12, 16, 20, 24, 32, 40, and 52 | 
| Frequency of Subjects With Treatment Emergent, Clinically Significant, Abnormal Glucose Laboratory Values From Baseline to Week 52 | The site investigators used the reference ranges provided by the lab that completed the testing of the sample to determine if the value was abnormal. If a value was abnormal, the site investigator would determine if the value was clinically significant or not. A subject was considered to have a treatment emergent, clinically significant Glucose value if during the course of the study, they had at least one clinically significant Glucose result that was not present at baseline. Subjects had Glucose labs drawn at Screening, Baseline (Week0), Week 4, 8, 12, 16, 20, 24, 32, 40, and 52. | At Screening, Baseline (Week0), Week 4, 8, 12, 16, 20, 24, 32, 40, and 52 | 
| Frequency of Subjects With Treatment Emergent, Clinically Significant, Abnormal Potassium Laboratory Values From Baseline to Week 52 | The site investigators used the reference ranges provided by the lab that completed the testing of the sample to determine if the value was abnormal. If a value was abnormal, the site investigator would determine if the value was clinically significant or not. A subject was considered to have a treatment emergent, clinically significant Potassium value if during the course of the study, they had at least one clinically significant Potassium result that was not present at baseline. Subjects had Potassium labs drawn at Screening, Baseline (Week0), Week 4, 8, 12, 16, 20, 24, 32, 40, and 52. | Screening, Baseline (Week0), Week 4, 8, 12, 16, 20, 24, 32, 40, and 52 | 
| Frequency of Subjects With Treatment Emergent, Clinically Significant, Abnormal White Blood Cell Count (WBC) Values From Baseline to Week 52 | The site investigators used the reference ranges provided by the lab that completed the testing of the sample to determine if the value was abnormal. If a value was abnormal, the site investigator would determine if the value was clinically significant or not. A subject was considered to have a treatment emergent, clinically significant White Blood Cell (WBC) value if during the course of the study, they had at least one clinically significant WBC result that was not present at baseline. Subjects had WBC labs drawn at Screening, Baseline (Week0), Week 4, 8, 12, 16, 20, 24, 32, 40, and 52. | Screening, Baseline (Week0), Week 4, 8, 12, 16, 20, 24, 32, 40, and 52 | 
| Frequency of Subjects With Treatment Emergent, Clinically Significant, Abnormal Hemoglobin Laboratory Values From Baseline to Week 52 | The site investigators used the reference ranges provided by the lab that completed the testing of the sample to determine if the value was abnormal. If a value was abnormal, the site investigator would determine if the value was clinically significant or not. A subject was considered to have a treatment emergent, clinically significant Hemoglobin value if during the course of the study, they had at least one clinically significant Hemoglobin result that was not present at baseline. Subjects had hemoglobin labs drawn at Screening, Baseline (Week0), Week 4, 8, 12, 16, 20, 24, 32, 40, and 52. | At Screening, Baseline (Week0), Week 4, 8, 12, 16, 20, 24, 32, 40, and 52 | 
| Frequency of Subjects With Treatment Emergent, Clinically Significant, Abnormal Hematocrit Laboratory Values From Baseline to Week 52 | The site investigators used the reference ranges provided by the lab that completed the testing of the sample to determine if the value was abnormal. If a value was abnormal, the site investigator would determine if the value was clinically significant or not. A subject was considered to have a treatment emergent, clinically significant hematocrit value if during the course of the study, they had at least one clinically significant hematocrit result that was not present at baseline. Subjects had hematocrit labs drawn at Screening, Baseline (Week0), Week 4, 8, 12, 16, 20, 24, 32, 40, and 52. | At Screening, Baseline (Week0), Week 4, 8, 12, 16, 20, 24, 32, 40, and 52 | 
| Frequency of Subjects With Treatment Emergent, Clinically Significant, Abnormal Platelet Counts From Baseline to Week 52 | The site investigators used the reference ranges provided by the lab that completed the testing of the sample to determine if the value was abnormal. If a value was abnormal, the site investigator would determine if the value was clinically significant or not. A subject was considered to have a treatment emergent, clinically significant platelet value if during the course of the study, they had at least one clinically significant platelet result that was not present at baseline. Subjects had platelet labs drawn at Screening, Baseline (Week0), Week 4, 8, 12, 16, 20, 24, 32, 40, and 52. | At Screening, Baseline (Week0), Week 4, 8, 12, 16, 20, 24, 32, 40, and 52 | 
| Frequency of Subjects With Treatment Emergent, Clinically Significant, Abnormal Urine Leukocyte Values From Baseline to Week 52 | The site investigators used the reference ranges provided by the lab that completed the testing of the sample to determine if the value was abnormal. If a value was abnormal, the site investigator would determine if the value was clinically significant or not. A subject was considered to have a treatment emergent, clinically significant value if during the course of the study, they had at least 1 clinically significant urine leukocyte result that was not present at baseline. Subjects had urine leukocyte labs collected at Screening, Baseline (Week0), Week 4, 8, 12, 16, 20, 24, 32, 40, and 52. | At Screening, Baseline (Week0), Week 4, 8, 12, 16, 20, 24, 32, 40, and 52 | 
| Frequency of Subjects With Treatment Emergent, Clinically Significant, Abnormal Urine Protein Laboratory Values From Baseline to Week 52 | The site investigators used the reference ranges provided by the lab that completed the testing of the sample to determine if the value was abnormal. If a value was abnormal, the site investigator would determine if the value was clinically significant or not. A subject was considered to have a treatment emergent, clinically significant value if during the course of the study, they had at least one clinically significant urine protein result that was not present at baseline. Subjects had urine protein labs collected at Screening, Baseline (Week0), Week 4, 8, 12, 16, 20, 24, 32, 40, and 52. | At Screening, Baseline (Week0), Week 4, 8, 12, 16, 20, 24, 32, 40, and 52 | 
| Frequency of Subjects With Treatment Emergent, Clinically Significant, Abnormal Urine Glucose Laboratory Values From Baseline to Week 52 | The site investigators used the reference ranges provided by the lab that completed the testing of the sample to determine if the value was abnormal. If a value was abnormal, the site investigator would determine if the value was clinically significant or not. A subject was considered to have a treatment emergent, clinically significant value if during the course of the study, they had at least one clinically significant urine glucose result that was not present at baseline. Subjects had urine glucose labs collected at Screening, Baseline (Week0), Week 4, 8, 12, 16, 20, 24, 32, 40, and 52. | At Screening, Baseline (Week0), Week 4, 8, 12, 16, 20, 24, 32, 40, and 52 | 
| Frequency of Subjects With Treatment Emergent, Clinically Significant, Abnormal Urine Ketone Laboratory Values From Baseline to Week 52 | The site investigators used the reference ranges provided by the lab that completed the testing of the sample to determine if the value was abnormal. If a value was abnormal, the site investigator would determine if the value was clinically significant or not. A subject was considered to have a treatment emergent, clinically significant value if during the course of the study, they had at least one clinically significant urine ketone result that was not present at baseline. Subjects had urine ketone labs collected at Screening, Baseline (Week0), Week 4, 8, 12, 16, 20, 24, 32, 40, and 52. | At Screening, Baseline (Week0), Week 4, 8, 12, 16, 20, 24, 32, 40, and 52 | 
| Frequency of Subjects With Treatment Emergent, Clinically Significant, Abnormal Serum 25-hydroxyvitamin D (25-OH VitD) Laboratory Values From the Screening Visit to Week 52 | The site investigators used the reference ranges provided by the lab that completed the testing of the sample to determine if the value was abnormal. If a value was abnormal, the site investigator would determine if the value was clinically significant or not. A subject was considered to have a treatment emergent, clinically significant value if during the course of the study, they had at least one clinically significant serum 25-hydroxyvitamin D (25-OH VitD) result that was not present at baseline. Subjects had 25-OH VitD labs collected at Screening and at the Week 52 visit. | Screening visit and Week 52 | 
| Frequency of Subjects With Treatment Emergent, Clinically Significant, Abnormal Antinuclear Antibody Test (ANA) Values From the Screening Visit to Week 52 | The site investigators used the reference ranges provided by the lab that completed the testing of the sample to determine if the value was abnormal. If a value was abnormal, the site investigator would determine if the value was clinically significant or not. A subject was considered to have a treatment emergent, clinically significant value if during the course of the study, they had at least one clinically significant Antinuclear Antibody Test (ANA) result that was not present at baseline. Subjects had ANA labs collected at Screening, Week 12, 24, 40, and 52. | At Screening, Week 12, 24, 40, and 52 | 
| Frequency of Subjects With Treatment Emergent, Clinically Significant, Abnormal Monoclonal Protein Detection by Serum Protein Electrophoresis (SPEP) From the Screening Visit to Week 52 | The site investigators used the reference ranges provided by the lab that completed the testing of the sample to determine if the value was abnormal. If a value was abnormal, the site investigator would determine if the value was clinically significant or not. A subject was considered to have a treatment emergent, clinically significant value if during the course of the study, they had at least one clinically significant monoclonal protein value that was not present at baseline. Subjects had monoclonal protein labs collected at Screening, Week 12, 24, 40, and 52. | Screening visit, Week 12, 24, 40, and 52 | 
| Average Cumulative Dosage of Prednisone Over the One Year Study Period | The average cumulative dosage of prednisone over the one year period of the study was calculated. The results are presented by treatment group. | Baseline until week 52 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Average Prednisone Dosage After Week 24 | We calculated the average dosage of prednisone from the week 24 visit until the end of the study (week 52). | from week 24 to 52 | 
| Average Daily Dose of Prednisone From Baseline to Week 52 | The average daily dose of prednisone from baseline to week 52 was calculated by treatment group. | Baseline through Week 52 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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dermatomyositis, etanercept, tumor necrosis factor alpha