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Abatacept in Juvenile Dermatomyositis (AID)

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ClinicalTrials.gov Identifier: NCT02594735
Recruitment Status : Recruiting
First Posted : November 3, 2015
Last Update Posted : September 6, 2018
Sponsor:
Information provided by (Responsible Party):
Rodolfo Curiel, George Washington University

Brief Summary:
The purpose of this study is to assess the safety and efficacy of subcutaneous abatacept in 10 patients seven years of age and older with refractory JDM.

Condition or disease Intervention/treatment Phase
Dermatomyositis Drug: Abatacept Phase 4

Detailed Description:

JDM is a chronic systemic autoimmune disease with a predominance of muscle and skin inflammation of unknown etiology and varying prognosis. Children with JDM unresponsive to corticosteroids or other immunosuppressive medications face poor clinical and functional outcome and suffer various sequelae of the disease. Abatacept is a fully human soluble recombinant protein consisting of the cytotoxic T cell Lymphocyte Antigen-4 (CTLA4) fused with Fc region of human IgG1 that has been modified to prevent complement fixation and antibody-dependent cellular cytotoxicity. Abatacept binds specifically to the CD80 (B7-1) and CD86 (B7-2) molecules, those expressed on antigen-presenting cells (APCs). Upon engagement of CTLA4 to CD80 or CD86, the resultant inhibition of signal transduction inhibits T cell activation.. The rationale for use of Abatacept in the therapy of JDM includes the expression of CTLA4, CD28, CD86, and CD40 on inflammatory cells of muscle biopsies of patients with DM, as well as CTLA4 and CD28 on muscle cells.

A patient's participation in this study will last approximately 24 weeks with possible extension to 48 weeks. At screening, participants will have a physical exam, muscle strength assessment, blood and urine collection, and chest x-ray; they will also be asked to complete several questionnaires. All participants will receive each week subcutaneous injection of Abatacept. Each injection will be given on an outpatient basis.

There will be a total of 6 study visits. All participants will visit the outpatient clinic at selected time points for muscle strength testing, a physical exam, disease activity measurements, blood and urine collection, and muscle MRI; they will also be asked to complete several questionnaires. During the study, participants will be monitored closely for improvement or worsening of their disease and for serious drug related side effects.

Eligibility Ages Eligible for Study: ≥ 7 years and older Genders Eligible for Study: Both Race/Ethnic Backgrounds Eligibility for Study: No restrictions


Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 10 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Abatacept for the Treatment of Refractory Juvenile Dermatomyositis
Study Start Date : November 2015
Estimated Primary Completion Date : December 2018
Estimated Study Completion Date : December 2018


Arm Intervention/treatment
open label
A patient's participation in this study will last approximately 24 weeks ( screening visit and 5 intervention visits) with possible extension to 48 weeks. At screening, participants will have a physical exam, muscle strength assessment, blood and urine collection, and chest x-ray; they will also be asked to complete several questionnaires. All participants will receive each week subcutaneous injection of Abatacept. During intervention phase of the trial, muscle strength testing, physical exam, disease activity measurements, blood and urine collection, and muscle MRI will be performed. Participants will also be asked to complete several questionnaires. Participants will be also monitored closely for for serious drug related side effects.
Drug: Abatacept
Study participation will consist of a screening visit and 5 protocol visits over six months (week 0, week 6, week 12, week 18, and week 24) for each subject, and phone follow-up (week 2, week 4, week 8, week 10, week 14, week 16, week 20, and week 22). At Visit 1, which will be treatment initiation, eligible subjects will be instructed on the use and side effects of subcutaneous abatacept and will be started on the study drug (abatacept 125 mg SQ weekly for subjects with body weight ≥ 50 KG or abatacept 87.5mg SQ for subjects with body weight < 50 KG).
Other Name: Orencia




Primary Outcome Measures :
  1. Number of patients meeting the definition of improvement (DOI) at week 24: at least 3 of 6 Core Set Measures (CSM) improved by ≥ 20% with no more than 2 CSM worsening by ≥ 25% (not including the manual muscle testing). [ Time Frame: week 0 to week 24 ]
    Improvement in myositis disease activity will be assessed using the IMACS myositis definition of improvement (DOI): at least 3 of 6 Core Set Measures (CSM) improved by ≥ 20% with no more than 2 CSM worsening by ≥ 25% (a worsening measure cannot be the manual muscle testing (MMT).

  2. Incidence of treatment-emergent adverse events. [ Time Frame: week 0 to week 24 ]
    Safety will be assessed by review of adverse events using NCI Common Terminology criteria version 4.0 June 2010. Particular attention to serious adverse events and infections will be given. An adverse event diary will be maintained throughout the study. Patient evaluations will include: vital sign measurement, physical examination, and laboratory parameters for hematology and routine chemistries


Secondary Outcome Measures :
  1. Number of patients improving in Physician and Patient/Parent global activity measurement from baseline [ Time Frame: week 0 to week 24 ]
    Physician and Patient/Parent global activity will be measured using a visual analogue scale (VAS) from 1 to centimeters

  2. Number of patients with steroid-sparing benefit from baseline [ Time Frame: week 0 to week 24 ]

    Patients who have achieved Definition of Improvement (DOI) at week 6 (visit 2) or at any point thereafter and is rated by their study physician as at least minimally improved, then tapering of corticosteroids may commence using a precise dose reduction schedule as follows:

    For patients taking 40 to 60 mg daily, prednisone will be tapered by 10 mg ,For patients taking 20 to 35 mg daily, prednisone will be tapered by 5 mg. For patients taking 7.5 to 15 mg daily, prednisone will be tapered by 2.5 mg. For patients taking 1 to 5 mg daily, prednisone will be tapered by 1 mg For patients receiving intravenous pulse methylprednisolone therapy, they may alternatively reduce the dose of IV therapy, instead of oral by a decrease of 25%


  3. Number of patient with improvement in Muscle strength [ Time Frame: week 0 to week 24 ]
    Muscle strength will be measured using the Manual Muscle Testing (MMT). MMT is a quantitative testing of eight proximal, distal and axial muscle groups tested unilaterally (using a 0-10 point scale)

  4. Number of patient with improvement in cutaneous activity disease from baseline [ Time Frame: week 0 to week 24 ]
    Cutaneous activity will be measured using the Cutaneous Dermatomyositis Disease Area and Severity Index (CDASI) It measures activity and damage in the skin. It has 3 activity scales (erythema, scale, erosion/ulceration) and 2 damage measures (poikiloderma and calcinosis). In addition, Gottron's papules on the hands are evaluated in terms of activity (erythema/ulceration) and damage (dyspigmentation or scarring). Activity in terms of periungal changes and alopecia is also measured. Each of the 3 activity scales and 2 damage measures is assessed over 15 body areas; the worst level of activity is scored, whereas the damage measures is scored for their presence or absence

  5. Number of patient with improvement in muscle inflammation from baseline [ Time Frame: week 0 to week 24 ]
    Muscle inflammation will be measured by examining a thigh/pelvis STIR MRI at baseline and 6 month follow-up. MRI readings will be blinded to the clinical assessment

  6. Number of patient developing HAHA (human anti-human) antibodies [ Time Frame: week 0 to week 24 ]
    The ELISA (enzyme-linked immunosorbent assay) technique will be used to detect HAHA

  7. Number of patients with improvement in physical function from baseline [ Time Frame: week 0 to 24 ]
    Physical function will be measured by using the Stanford HAQ/CHAQ: Health Assessment Questionnaire: The Stanford HAQ is a brief self-report questionnaire assessing physical function pertaining to activities of daily living in a variety of domains. The C-HAQ was adapted directly from the HAQ and it has also been successfully applied to patient with juvenile myositis.

  8. Number of patients with improvement in extra-muscular activity from baseline [ Time Frame: week 0 to 24 ]
    The extra-muscular activity will be measured by using the Myositis Disease Activity Assessment Tool (MDAAT) .MDAAT is a combined tool that captures the physician's assessment of disease activity of various organ systems using a 0 to 4 scale (0 = Not present in the last 4 weeks; 4 = New - in the last 4 weeks (compared to the previous 4 weeks)) and a visual analog scale (VAS) to capture the ongoing disease activity over the past 4 weeks for each organ system on the 0-10cm VAS scale

  9. Number of patients with improvement is muscle enzymes from baseline [ Time Frame: week 0 to 24 ]
    The muscle enzymes includes creatine kinase (CK), aldolase, lactate dehydrogenase (LDH), alanine aminotransferase (ALT) and aspartate aminotransferase (AST). If more than one muscle enzyme is identified as being elevated (a minimum level of 1.3 x the upper limit of normal), then the most abnormal will be selected and this enzyme will be the target enzyme followed to evaluate disease improvement or worsening.

  10. Number of patients with changes in biomarkers of disease activity [ Time Frame: week 0 to 24 ]
    The following biomarker of disease activity will be measured (blinded to the clinical assessment information and drug dose): i. Immunophenotyping for CD4, CXCR3, IFNγ (TH1), CD4, CCR4, CRTH2, IL4 (TH2), CD4, CCR6, IL17a (TH17), CD4, CD25, Foxp3 (T regulatory cells), B cell markers and macrophage markers along with B71, B72, CTLA4, CT28 on fresh lymphocytes ii. Isolation of T cells, B cells, dendritic cells, monocyte and macrophages, and freeze the isolated cells for subsequent molecular and functional analysis, including gene expression profiling iii. Cytokine 30-plex panel on serum samples iv. Peripheral blood mononuclear cells for RNA gene expression using a gene bead chip panel.



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Ages Eligible for Study:   7 Years and older   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Adults with definite or probable JDM and pediatric patients 7 years of age and older with definite or probable JDM.
  2. Body weight of at least 25 kg (or at least 55 lbs) and age ≥ 7 years of age.
  3. Patients must reside within the United States.
  4. Refractory myositis, as defined by the intolerance to or an inadequate response to corticosteroids plus an adequate regimen of at least one other immunosuppressive agent, including azathioprine, methotrexate, IVIG, mycophenolate mofetil, cyclophosphamide, tacrolimus or cyclosporine A, or a biologic therapy. The definition of intolerance is: side effects that require discontinuation of the medication or an underlying condition that precludes the further use of the medication.
  5. At least moderately active disease as documented by:

    • MD global VAS with a minimum value of 2.5 cm on a 10 cm scale AND
    • At least 2 other abnormal core set measures listed below:
  6. Therapy with prednisone or another glucocorticoid is required, unless there is documented intolerance in the medical record or a medical condition that contraindicates further use of prednisone. The prednisone dose must be stable for at least 4 weeks prior to the screening visit.
  7. Background therapy with at least 1 non-corticosteroid immunosuppressive agent is required at a stable dose for at least 6 weeks prior to the screening visit unless there is documentation that the patient is intolerant, which is defined as side effects that require discontinuation of the medication(s) or an underlying condition that precludes the further use of the IS medication.
  8. If an immunosuppressive agent was discontinued prior to the screening visit then there must be a:

    • 4 week washout for prednisone or methotrexate
    • 8 week washout for any other IS agent
    • For discontinuation of biologic therapies, a washout of 5 terminal half lives
  9. If on hydroxychloroquine or colchicine, the dose should be stable for 6 weeks prior to Visit 1.
  10. If on statin or fibric acid derivative agents, the dose should be stable for 6 weeks prior to Visit 1.
  11. Ability of patient or parent to complete self-report questionnaires.
  12. Men and women of reproductive potential must agree to use a reliable method of birth control during the 24 week duration of the trial described in the reproductive risks section of this protocol (section 4.3). They must also agree to use a reliable method of birth control for 100 days after the last dose of study drug is administered.
  13. Patients must agree to forgo immunization with a live vaccine during the course of the study or within 3 months after discontinuation.
  14. Patients must have a letter from the referring rheumatologist or specialist supervising the care of the JDM, agreeing to the patient's participation in the study and to continuing to provide care for the patient, including emergency care during the trial.

Core Set Measures:

  • An MMT-8 score that is no greater than 125/150
  • Patient/Parent Global VAS with a minimum value of 2.0 cm on a 10cm scale
  • CHAQ/HAQ disability index with a minimum value of 0.25
  • Elevation of at least one of the muscle enzymes [which includes creatine kinase (CK), aldolase, lactate dehydrogenase (LDH), alanine aminotransferase (ALT) and aspartate aminotransferase (AST)] at a minimum level of 1.3 x the upper limit of normal.
  • Global extra-muscular disease activity score with a minimum value of 2.0 cm on a 10 cm VAS scale

Exclusion Criteria:

  1. Drug-induced myositis (myositis in patients taking medications known to induce myositis-like syndromes, including, but not limited to, statin agents, fibric acid derivatives, and colchicine).
  2. Juvenile polymyositis; inclusion body myositis; 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 if at least 5 years since excision
  3. Myositis in overlap with another connective tissue disease (CTD) that precludes the accurate assessment of a treatment response (for example, difficulty in assessing muscle strength in a scleroderma patient with associated myositis)
  4. History of receiving a live vaccine 4 weeks prior to initiation of study treatment
  5. Joint disease, severe calcinosis, or other musculoskeletal condition, which precludes the ability to quantitate muscle strength.
  6. Wheelchair bound patients.
  7. Known hypersensitivity to abatacept or prior receipt of abatacept
  8. Concomitant illness that would prevent adequate patient assessment or in the investigators opinion pose an added risk for study participants:
  9. Recurrent or chronic infections, including HIV, tuberculosis, hepatitis B and C, or TB infection, including contact with a household contact with active tuberculosis (TB) and who did not receive appropriate and documented prophylaxis for TB. (a documented negative Hepatitis B surface antigen and Hepatitis C antibody completed at the screening visit or within 6 weeks prior to screening visit is required)
  10. Have had symptomatic herpes zoster or herpes simplex infection (not including simple oral HSV lesions) within 12 weeks prior to entry or during screening period
  11. Have a history of disseminated/complicated herpes zoster (for example, multi-dermatomal involvement, ophthalmic zoster, central nervous system (CNS) involvement, post-herpetic neuralgia)
  12. Known liver disease (i.e. cirrhosis or other conditions compromising the synthetic function of the liver)
  13. Disorders that would preclude accurate assessment of neuromuscular function
  14. Cardiomyopathy or arrhythmias that in the investigators opinion poses an additional risk for study participants
  15. New York Heart Association Classification III or IV for congestive heart failure
  16. Psychiatric illness that precludes compliance or neuromuscular assessment
  17. Serum creatinine > 2.0mg/dl
  18. Pregnant females or nursing mothers
  19. Life threatening illness that would interfere with the patient's ability to complete the study.
  20. Known or suspected history of drug or alcohol abuse within the past 6 months as determined by the medical record or patient interview
  21. Anticipated poor compliance
  22. Participation in another clinical experimental therapeutic study within 30 days of screening visit.
  23. Any history or evidence of severe illness or any other condition that would make the patient, in the opinion of the investigator unsuitable for the study.
  24. Low total WBC <2.000, platelets < 100,000/mm3; hemoglobin <10 gm/dl
  25. History of recurrent infection including active skin infections with calcinosis
  26. Subjects with a history of cancer in the last 5 years
  27. Subjects who have at any time received treatment with any investigational drug within 28 days (or less than 5 terminal half-lives of elimination) of the day 1 dose of study drug, including waiting until CD19 returns to a detectable level and IgG level is within normal limits (normal serum levels of IgG per reference lab: 7-9 years ≥572 mg/dl, 10-11 yrs ≥698 mg/dl, 12-13 yrs ≥759 mg/dl, 14-15 yrs ≥716 mg/dl,16-19 yrs ≥549 mg/dl, >19 yrs ≥700 mg/dl) for those patients who have received rituximab
  28. Concomitant treatment with anti-TNF therapies, rituximab or anakinra or other biologic therapies.
  29. Initiation of colchicine and hydroxychloroquine as new drugs during study participation is not allowed.
  30. Initiation of statins or fibric acid derivatives during study participation is not allowed.
  31. Initiation of an exercise program within 4 weeks of the screening visit. Only a stretching program may be initiated during the study (See section 5.4 Other Restrictions)
  32. Prisoners or subjects who are involuntarily incarcerated.
  33. Subjects who are compulsorily detained for treatment of either a psychiatric or physical (e.g., infectious disease) illness.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02594735


Contacts
Contact: Rodolfo V Curiel, MD (202)750-0377 rcuriel@mfa.gwu.edu
Contact: Hassan Awal 202-741-2389 hawal@mfa.gwu.edu

Locations
United States, District of Columbia
2300 M Street, 9th floor. Medical Faculty Associates, The George Washington University. Recruiting
Washington, District of Columbia, United States, 20037
Contact: Rodolfo V Curiel, MD    202-750-0377    rcuriel@mfa.gwu.edu   
Contact: Hassan Awal    202-741-2389    hawal@mfa.gwu.edu   
Sponsors and Collaborators
George Washington University
Investigators
Principal Investigator: Rodolfo V Curiel, MD The George Washington University

Publications:

Responsible Party: Rodolfo Curiel, Dr. Rodolfo V. Curiel, MD, Associate Professor of Medicine, Division of Rheumatology; Director, Myositis Center, George Washington University
ClinicalTrials.gov Identifier: NCT02594735     History of Changes
Other Study ID Numbers: IRB 111418
First Posted: November 3, 2015    Key Record Dates
Last Update Posted: September 6, 2018
Last Verified: September 2018

Keywords provided by Rodolfo Curiel, George Washington University:
Juvenile dermatomyositis
inflammatory myopathies
Orencia
Abatacept

Additional relevant MeSH terms:
Myositis
Dermatomyositis
Polymyositis
Muscular Diseases
Musculoskeletal Diseases
Neuromuscular Diseases
Nervous System Diseases
Connective Tissue Diseases
Skin Diseases
Abatacept
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents