Clinical trial NCT00112385: A Pilot Study of Etanercept in Dermatomyositis
Official title: A Pilot Study of Etanercept in Dermatomyositis
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Dermatomyositis
Keywords: dermatomyositis
etanercept
tumor necrosis factor alpha
Lead sponsor: Brigham and Women's Hospital
Sponsor class: OTHER
Collaborators: name: Amgen
First posted: 2005-06-03
Enrollment: 16
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: Inclusion Criteria:

Study subjects must meet the following criteria:

1. Meet the diagnostic criteria for DM (a-c; a,b,d; or a,c,d)

   1. Subjects must have symmetric proximal greater than distal weakness
   2. Characteristic DM rash consisting of any or all of the following: heliotrope, shawl sign, V-sign, Gottron's sign, Gottron's papules, periungual telangiectasias
   3. 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.
   4. 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
2. Newly diagnosed subjects should be able to walk independently 30 feet (cane, walkers, orthoses allowed). However, subjects with refractory dermatomyositis may be non-ambulatory.
3. Age \> 18 years
4. Patients must not use topical skin ointments for treatment of the dermatological manifestations as it will interfere with skin assessment.
5. Men and women of childbearing age must be willing to use a method of birth control.
6. Able to give informed consent
7. 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:

1. 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
2. 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
3. Forced Vital Capacity \< 50% of predicted
4. History of non-compliance with other therapies
5. Any prior or concurrent cyclophosphamide, or current use of any immunosuppressive agent besides methotrexate (e.g., azathioprine, mycophenolate, or cyclosporine)
6. Coexistence of other neuromuscular disease that may complicate interpretation of the results of the study
7. Drug or alcohol abuse within last 3 months
8. Pregnancy or breast feeding
9. Juvenile DM
10. Subjects who have known hypersensitivity to Enbrel or any of its components or who is known to have antibodies to etanercept
11. Use of a live vaccine 90 days prior to, or during this study.
12. 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.
13. Concurrent sulfasalazine therapy

Primary outcomes:
measure: Occurrence of at Least One Adverse Event
timeFrame: at each visit during the 12 month study
measure: Tolerability
timeFrame: At any point between Baseline (week 0) and the end of the study (Week 52)
measure: Average Change in Oral Temperature From Baseline to Week 52
timeFrame: At Baseline (Week 0) and Week 52
measure: Average Change in Respiration Rate From Baseline to Week 52
timeFrame: At Baseline (Week0) and Week 52
measure: Average Change in Systolic Blood Pressure From Baseline to Week 52
timeFrame: At Baseline (Week0) and Week 52
measure: Average Change in Diastolic Blood Pressure Comparing Baseline to Week 52.
timeFrame: At Baseline (Week0) and Week 52
measure: Average Change in Pulse Comparing Baseline to Week 52
timeFrame: At Baseline (Week0) and Week 52
measure: Average Change in Body Weight in Kilograms (kg) Comparing Baseline to Week 52.
timeFrame: At Baseline (Week0) and Week 52
measure: Frequency of Subjects With Treatment Emergent, Clinically Significant, Abnormal Creatine Kinase (CK) Laboratory Values From Baseline to Week 52
timeFrame: At Screening, Baseline (Week0), Week 4, 8, 12, 16, 20, 24, 32, 40, and 52
measure: Frequency of Subjects With Treatment Emergent, Clinically Significant, Abnormal Alanine Aminotransferase (ALT) Laboratory Values From Baseline to Week 52
timeFrame: At Screening, Baseline (Week0), Week 4, 8, 12, 16, 20, 24, 32, 40, and 52
measure: Frequency of Subjects With Treatment Emergent, Clinically Significant, Abnormal Gamma-glutamyl Transpeptidase (GGT) Laboratory Values From Baseline to Week 52
timeFrame: Screening, Baseline (Week0), Week 4, 8, 12, 16, 20, 24, 32, 40, and 52
measure: Frequency of Subjects With Treatment Emergent, Clinically Significant, Abnormal Aldolase Laboratory Values From Baseline to Week 52
timeFrame: Screening, Baseline (Week0), Week 4, 8,12, 16, 20, 24, 32, 40, and 52
measure: Frequency of Subjects With Treatment Emergent, Clinically Significant, Abnormal Glucose Laboratory Values From Baseline to Week 52
timeFrame: At Screening, Baseline (Week0), Week 4, 8, 12, 16, 20, 24, 32, 40, and 52
measure: Frequency of Subjects With Treatment Emergent, Clinically Significant, Abnormal Potassium Laboratory Values From Baseline to Week 52
timeFrame: Screening, Baseline (Week0), Week 4, 8, 12, 16, 20, 24, 32, 40, and 52
measure: Frequency of Subjects With Treatment Emergent, Clinically Significant, Abnormal White Blood Cell Count (WBC) Values From Baseline to Week 52
timeFrame: Screening, Baseline (Week0), Week 4, 8, 12, 16, 20, 24, 32, 40, and 52
measure: Frequency of Subjects With Treatment Emergent, Clinically Significant, Abnormal Hemoglobin Laboratory Values From Baseline to Week 52
timeFrame: At Screening, Baseline (Week0), Week 4, 8, 12, 16, 20, 24, 32, 40, and 52
measure: Frequency of Subjects With Treatment Emergent, Clinically Significant, Abnormal Hematocrit Laboratory Values From Baseline to Week 52
timeFrame: At Screening, Baseline (Week0), Week 4, 8, 12, 16, 20, 24, 32, 40, and 52
measure: Frequency of Subjects With Treatment Emergent, Clinically Significant, Abnormal Platelet Counts From Baseline to Week 52
timeFrame: At Screening, Baseline (Week0), Week 4, 8, 12, 16, 20, 24, 32, 40, and 52
measure: Frequency of Subjects With Treatment Emergent, Clinically Significant, Abnormal Urine Leukocyte Values From Baseline to Week 52
timeFrame: At Screening, Baseline (Week0), Week 4, 8, 12, 16, 20, 24, 32, 40, and 52
measure: Frequency of Subjects With Treatment Emergent, Clinically Significant, Abnormal Urine Protein Laboratory Values From Baseline to Week 52
timeFrame: At Screening, Baseline (Week0), Week 4, 8, 12, 16, 20, 24, 32, 40, and 52
measure: Frequency of Subjects With Treatment Emergent, Clinically Significant, Abnormal Urine Glucose Laboratory Values From Baseline to Week 52
timeFrame: At Screening, Baseline (Week0), Week 4, 8, 12, 16, 20, 24, 32, 40, and 52
measure: Frequency of Subjects With Treatment Emergent, Clinically Significant, Abnormal Urine Ketone Laboratory Values From Baseline to Week 52
timeFrame: At Screening, Baseline (Week0), Week 4, 8, 12, 16, 20, 24, 32, 40, and 52
measure: 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
timeFrame: Screening visit and Week 52
measure: Frequency of Subjects With Treatment Emergent, Clinically Significant, Abnormal Antinuclear Antibody Test (ANA) Values From the Screening Visit to Week 52
timeFrame: At Screening, Week 12, 24, 40, and 52
measure: Frequency of Subjects With Treatment Emergent, Clinically Significant, Abnormal Monoclonal Protein Detection by Serum Protein Electrophoresis (SPEP) From the Screening Visit to Week 52
timeFrame: Screening visit, Week 12, 24, 40, and 52
measure: Average Cumulative Dosage of Prednisone Over the One Year Study Period
timeFrame: Baseline until week 52
Secondary outcomes:
measure: Average Prednisone Dosage After Week 24
timeFrame: from week 24 to 52
measure: Average Daily Dose of Prednisone From Baseline to Week 52
timeFrame: Baseline through Week 52
Other outcomes:
measure: The Number of Participants Who Were Classified as Treatment Failures
timeFrame: At any point during the 52 week study
measure: Change in the Average Manual Muscle Testing (MMT) Score From Baseline to Week 52
timeFrame: At Baseline (Week 0) and Week 52
measure: Average Change in Time to Rise From a Chair From Baseline to Week 52
timeFrame: At Baseline (Week0) and Week 52
measure: Average Change in Time (Seconds) to Walk 30 Feet Comparing Performance at Baseline to Week 52
timeFrame: At Baseline (Week0) and Week 52
measure: Average Change in Z-score for Dual-emission X-ray Absorptiometry (DEXA) of the Femur From the Screening Visit to Week 52
timeFrame: Screening and Week 52
measure: Average Change in Z-score for Dual-emission X-ray Absorptiometry (DEXA) of the Lumbar Spine From the Screening Visit to Week 52
timeFrame: Screening visit and Week 52.
measure: Average Change in Physician Global Activity Assessment From Baseline to Week 52
timeFrame: At Baseline (Week0) and Week 52
measure: Average Change in Patient Global Activity Assessment Score From Baseline to Week 52
timeFrame: At Baseline (Week0) and Week 52
measure: Average Change in Cutaneous Disease Activity and Severity Index (CDASI) Score From Week 52 to Baseline
timeFrame: At Baseline (Week0) and Week 52
measure: Change in Pruritis Rating From Baseline to Week 52
timeFrame: At Baseline (Week0), and Week 52
measure: Change in Health Assessment Questionnaire (HAQ) Score From Baseline to Week 52
timeFrame: At Baseline (Week0) and Week 52
measure: Forced Vital Capacity (FVC) Average Change in Percent Predicted From Screening to Week 52.
timeFrame: Screening Visit and Week 52.
measure: Average Change in Percent Predicted Forced Expiratory Volume in 1 Second (FEV1) From the Screening Visit to Week 52
timeFrame: Screening Visit and Week 52
measure: Average Change in Percent Predicted Diffusion Capacity (DLCO)From the Screening Visit to Week 52
timeFrame: Screening visit and Week 52
Locations:
city: Boston
country: United States
facility: Brigham and Women's Hospital
state: Massachusetts
Study officials:
affiliation: Brigham and Women's Hospital
name: Anthony A Amato, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Muscle Study Group. A randomized, pilot trial of etanercept in dermatomyositis. Ann Neurol. 2011 Sep;70(3):427-36. doi: 10.1002/ana.22477. Epub 2011 Jun 17.