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Evaluating Safety & Efficacy of Apremilast in the Treatment of Cutaneous Disease in Patients With Recalcitrant Dermatomyositis

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ClinicalTrials.gov Identifier: NCT03529955
Recruitment Status : Recruiting
First Posted : May 21, 2018
Last Update Posted : April 18, 2019
Sponsor:
Information provided by (Responsible Party):
Tulane University

Brief Summary:

With limited treatment options available for dermatomyositis, the investigators hypothesize that apremilast, a phosphodiesterase-4 (PDE-4) inhibitor, is a safe and efficacious add-on treatment in patients with refractory cutaneous dermatomyositis.

The study will investigate the efficacy, safety and toxicity of apremilast given at 30 mg twice daily to patients with refractory cutaneous dermatomyositis. Clinical response will be assessed at 1 and 3 months. Patients will also be evaluated for durability of their response for up to 6 months.

Treatment will be monitored with frequent clinical visits (0, 1, 3 and 6 months) and blood tests (CBC, CMP, creatine kinase, aldolase). Treatment will be discontinued at disease progression or unacceptable adverse events. Disease progression is defined as 4 points increase in the cutaneous dermatomyositis disease area and severity index (CDASI) score, worsening of muscle disease by manual muscle testing (MMT-8) score and 5 points increase in dermatomyositis life quality index (DLQI).

5 mm skin biopsies from lesional skin will be performed before treatment with apremilast and after 3 months of treatment for gene expression profiling and confirmatory immunohistochemical stains.


Condition or disease Intervention/treatment Phase
Dermatomyositis, Adult Type Drug: Apremilast 30mg Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 10 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 2, Open Label Single Arm Study for Evaluating Safety & Efficacy of Apremilast in the Treatment of Cutaneous Disease in Patients With Recalcitrant Dermatomyositis
Actual Study Start Date : June 12, 2018
Estimated Primary Completion Date : January 2020
Estimated Study Completion Date : April 2020


Arm Intervention/treatment
Experimental: Dermatomyositis patients with refractory cutaneous disease
Patients with dermatomyositis and refractory skin disease on steroids and one steroid-sparing agent.
Drug: Apremilast 30mg
Patients with refractory cutaneous dermatomyositis will be started on apremilast 30 mg twice a day in addition to a stable dose of their treatment regimen (including steroids and steroid sparing agents).




Primary Outcome Measures :
  1. The primary endpoint analysis would be overall response rate measured by the number of participants experiencing at least 4 points decrease in CDASI activity score at 3 months. [ Time Frame: Data collected at 3 months after baseline visit ]

    Cutaneous dermatomyositis disease area and severity index (CDASI) activity score is a validated tool to measure skin disease activity in dermatomyositis. The overall response rate (ORR) includes partial and complete responses. Complete response is defined by a CDASI activity score of zero. Partial response is defined by a decrease of CDASI activity score of at least 4 points. Calculation is performed as the CDASI activity score at 3 month(s) minus the score at baseline. Missing data will be handled using the last observation carried forward approach (LOCF).

    CDASI activity score: Units on a scale from 0-100. Higher scores represent worse outcome.



Secondary Outcome Measures :
  1. 2. The secondary endpoint analysis would be safety as measured by the number of participants experiencing adverse events and serious adverse events occurring during 6 months of therapy and 1 month follow up. [ Time Frame: 7 months ]
    The proportion of participants experiencing adverse events and serious adverse events will be measured over 7 months period (6 months during the study and 1 month follow up).

  2. 3. An additional secondary endpoint analysis would be durability of response measured by the number of participants with maintenance of their CDASI activity score or change in their CDASI activity score by at least 4 points compared to 3 months. [ Time Frame: Data collected at 6 months compared to data collected at 3 months ]

    The durability of response will be measured using the CDASI activity score at 6 months minus CDASI activity score at 3 months. Complete response durability is defined as zero or minus difference between CDASI activity score at 6 months and CDASI activity score at 3 months. Partial response durability is defined as >4 points difference between CDASI activity score at 6 months and CDASI activity score at 3 months. Missing data will be handled using the last observation carried forward approach (LOCF).

    CDASI activity score: Units on a scale from 0-100. Higher scores represent worse outcome.


  3. 4. An additional secondary endpoint analysis would be delayed response measured by the number of participants experiencing at least 4 points decrease in CDASI activity score at 6 months compared to baseline. [ Time Frame: Data collected at 6 months after baseline visit ]

    Complete delayed response is defined by a CDASI activity score of zero at 6 months. Partial delayed response is defined by a decrease of CDASI activity score of at least 4 points at 6 months compared to baseline. Calculation is performed as the CDASI activity score at 6 months minus the score at baseline. Missing data will be handled using the last observation carried forward approach (LOCF).

    CDASI activity score: Units on a scale from 0-100. Higher scores represent worse outcome.


  4. 5. An additional secondary endpoint analysis would assess quality of life as measured by the number of participants experiencing at least 5 points decrease on DLQI score at 3 and 6 months. [ Time Frame: Data collected at 3 and 6 months after baseline visit ]

    Dermatology Life Quality Index (DLQI) is a validated tool to measure quality of life in patients with skin disease. Complete response is defined by a DLQI of zero at 3, and 6 months. Partial response is defined by a decrease of DLQI of at least 5 points at 3, and 6 months compared to baseline. Calculation is performed as the DLQI at 3, and 6 months minus the score at baseline. Missing data will be handled using the last observation carried forward approach (LOCF).

    Units : Units on a scale from 0-30, higher scores represent worse outcome.



Other Outcome Measures:
  1. 6. An additional endpoint analysis would assess the proportion of change in muscle enzymes (Creatine kinase and aldolase in patients with muscle disease) as measured by mean of change at 3 and 6 months compared to baseline. [ Time Frame: Data collected at 3 and 6 months after baseline visit ]

    Calculate the mean change in muscle enzymes value creatine kinase and aldolase at 3 and 6 month(s) compared to baseline in patients with muscle disease.

    Units: U/L, higher numbers represent worse outcomes


  2. 7. An additional endpoint analysis would assess the proportion of change in the MMT-8 score in patients with muscle disease as measured by mean of change at 3 and 6 months compared to baseline. [ Time Frame: Data collected at 3 and 6 months after baseline visit ]

    MMT-8 (Manual Muscle Testing-8) score is a validated tool to assess muscle strength. Calculate the mean change in MMT-8 score at 3 and 6 month(s) compared to baseline in patients with muscle disease.

    Units: Units on a scale. Scale goes from 0-150. 150 is perfect strength.


  3. 8. An additional endpoint is to assess the gene expression profiling and immunohistochemistry analysis change on skin biopsies at 3 months compared to baseline. [ Time Frame: Data collected at 3 months after baseline visit ]
    Skin biopsies from lesional skin will be performed before treatment with apremilast and after 3 months of treatment to assess changes in gene expression profiling and immunohistochemistry stain. Gene expression profiling will be analyzed using inferential statistics with a False Discovery Rate (FDR) of < 0.05.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 75 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Must understand the risks and the benefits/purpose of the study and provide signed and dated informed consent.
  • Must be 18 years at time of signing the informed consent form.
  • Willing to participate in all required evaluations and procedures in the study including the ability to swallow pills without difficulty.
  • Patients must have a diagnosis of DM based upon the characteristic cutaneous findings proposed by Sontheimer[6] and/or a skin biopsy consistent with DM.
  • Patients must be candidate for systemic therapy for their DM skin disease defined by inadequate response to aggressive sun protection along with the use of potent topical corticosteroids and/or immunomodulators.
  • Patients with a diagnosis of dermatomyositis on steroid-sparing agent and/or systemic steroids (maximum dose of prednisone 1mg/Kg) and still having cutaneous disease activity of at least 5 on the CDASI scale.
  • If on immunosuppressive treatments and/or steroids, patients must be on stable doses for at least 4 weeks (28 days).
  • Patients must undergo age appropriate cancer screening.
  • Females of childbearing potential (FCBP) must have a negative pregnancy test at screening (day 0 of the study and every month throughout the study). While on investigational product and for at least 28 days after taking the last dose of investigational product.

Exclusion Criteria:

  • Increasing or changing dose of topical therapy within 14 days of study day 0 (including but not limited to topical corticosteroids, tacrolimus, pimecrolimus).
  • Increasing or changing systemic steroids dosing within 28 days of study day 0.
  • Increasing or changing dosing for concurrent therapy agents within 28 days or 5 half-lives of the biologic agent, whichever is longer, before study day 0: methotrexate, azathioprine, mycophenolate mofetil, hydroxychloroquine, dapsone, leflunomide, cyclosporine, biologic agents (anti-TNFs), IVIG, rituximab.
  • History of any clinically significant (as determined by the investigators) cardiac, endocrinologic, pulmonary, neurologic, psychiatric, hepatic, renal, hematologic, immunologic, or other major uncontrolled disease.
  • Any condition, including the presence of laboratory abnormalities, which places the patient at unacceptable risk if he/she were to participate in the study or confounds the ability to interpret data from the study.
  • Pregnant or breastfeeding.
  • Untreated Latent Mycobacterium tuberculosis infection or active tuberculosis infection as indicated by a positive Purified Protein Derivative (PPD) skin test or T-spot.
  • Any condition, including the presence of laboratory abnormalities that places the patient at unacceptable risk if he/she were to participate in the study or confounds the ability to interpret data from the study.
  • Patients with acute dermatomyositis onset and rapid progression of muscle disease or significant systemic involvement including pulmonary diseases associated with DM.
  • Prior major surgery or major life-threatening medical illness within 2 weeks.
  • Inflammatory bowel disease, malabsorption or any other gastrointestinal motility disorders that limit the absorption of the study drug.
  • Active hepatitis B or C infection with detectible viral nucleic acid in the blood or known Human Immunodeficiency Virus (HIV) positivity.
  • Prior history of suicide attempt at any time in the patient's lifetime prior to screening or randomization, or major psychiatric illness requiring hospitalization within the last 3 years.
  • Active substance abuse or a history of substance abuse within 6 months prior to screening.
  • Use of any investigational drug within 4 weeks prior to randomization, or 5 pharmacokinetic/pharmacodynamic half-lives, if known (whichever is longer).
  • Prior treatment with apremilast.
  • Any severe systemic illness requiring IV antibiotics within the two weeks prior to initiation of the study drug.
  • Malignancy or history of malignancy within the past four years, except for:

    • treated [ie, cured] basal cell or squamous cell in situ skin carcinomas;
    • treated [ie, cured] cervical intraepithelial neoplasia (CIN) or carcinoma in situ of cervix with no evidence of recurrence within the previous 4 years.

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): NCT03529955


Contacts
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Contact: Carole Bitar, MD 2026428122 cbitar@tulane.edu
Contact: Erin Boh, MD 5048589407 eboh@tulane.edu

Locations
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United States, Louisiana
Tulane University Recruiting
New Orleans, Louisiana, United States, 70112
Contact: Carole Bitar, MD    202-642-8122    cbitar@tulane.edu   
Contact: Erin Boh, MD       eboh@tulane.edu   
Sponsors and Collaborators
Tulane University
Investigators
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Principal Investigator: Carole Bitar, MD Tulane University
Publications of Results:
Rider LG, Werth VP, Huber AM, Alexanderson H, Rao AP, Ruperto N, Herbelin L, Barohn R, Isenberg D, Miller FW. Measures of adult and juvenile dermatomyositis, polymyositis, and inclusion body myositis: Physician and Patient/Parent Global Activity, Manual Muscle Testing (MMT), Health Assessment Questionnaire (HAQ)/Childhood Health Assessment Questionnaire (C-HAQ), Childhood Myositis Assessment Scale (CMAS), Myositis Disease Activity Assessment Tool (MDAAT), Disease Activity Score (DAS), Short Form 36 (SF-36), Child Health Questionnaire (CHQ), physician global damage, Myositis Damage Index (MDI), Quantitative Muscle Testing (QMT), Myositis Functional Index-2 (FI-2), Myositis Activities Profile (MAP), Inclusion Body Myositis Functional Rating Scale (IBMFRS), Cutaneous Dermatomyositis Disease Area and Severity Index (CDASI), Cutaneous Assessment Tool (CAT), Dermatomyositis Skin Severity Index (DSSI), Skindex, and Dermatology Life Quality Index (DLQI). Arthritis Care Res (Hoboken). 2011 Nov;63 Suppl 11:S118-57. doi: 10.1002/acr.20532. Review.

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Responsible Party: Tulane University
ClinicalTrials.gov Identifier: NCT03529955    
Other Study ID Numbers: 2017-978
First Posted: May 21, 2018    Key Record Dates
Last Update Posted: April 18, 2019
Last Verified: April 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: Data and research resources generated by this study will be made available to the research community and to the public at large. This strategy includes, but not limited to, presentations (poster or oral) at local, national, and international meetings; published abstracts, and journal articles (peer reviewed). Contact information will be provided in publications for direct inquiries of researchers. Data generated from sequencing and gene expression profiling will be deposited into the Gene Expression Omnibus (GEO), NCBI, to be accessible by general public. The study protocol will be shared with other researchers on the clinical trial.gov website. No identified personal patient informations will be shared.
Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: Yes
Keywords provided by Tulane University:
dermatomyositis
apremilast
recalcitrant cutaneous disease
Additional relevant MeSH terms:
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Dermatomyositis
Polymyositis
Myositis
Muscular Diseases
Musculoskeletal Diseases
Neuromuscular Diseases
Nervous System Diseases
Connective Tissue Diseases
Skin Diseases
Apremilast
Anti-Inflammatory Agents, Non-Steroidal
Analgesics, Non-Narcotic
Analgesics
Sensory System Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Anti-Inflammatory Agents
Antirheumatic Agents