Tocilizumab in the Treatment of Refractory Polymyositis and Dermatomyositis

NCT02043548 | Completed Phase 2 Results DMC

• 1 other identifier: ML28681
• Study Type: interventional
• Target: 36
• Locations: 1 country
• Sites: 7

Brief Summary

The purpose of this multi-center pilot study is to determine if the drug tocilizumab (Actemra) is effective in the treatment of patients with refractory adult polymyositis (PM) and dermatomyositis (DM).

Conditions

Dermatomyositis; Polymyositis

Keywords

dermatomyositis; polymyositis; tocilizumab; Actemra

Outcome Measures

Primary Outcomes (1)

• Compare the Average Total Improvement Scores at Visits 2 Through 7 During the 6-month Treatment Period Between the Treatment and Placebo Arms

  The total improvement score was calculated by adding the improvement scores of all six core set measures based on 2016 American College of Rheumatology (ACR)/European League Against Rheumatism(EULAR) myositis response criteria. The minimum and maximum values of the average Total Improvement Scores are 0 and 100; The minimum and maximum values of the average Total Improvement Scores of our included patients are 5.0 and 67.1; The higher scores mean a better outcome.

  Week 4, 8, 12, 16, 20, and 24

Secondary Outcomes (5)

• Comparison of the Time to First Definition of Improvement (DOI) Between the 2 Arms

  Week 4, 8, 12, 16, 20, and 24

• Count of the Adverse Events Between the Treatment and Placebo Arms.

  Week 4, 8, 12, 16, 20, and 24

• Comparison of the Steroid-sparing Effect (Calculated Using Prednisone Dose Equivalents) Between the Treatment and Placebo Arms

  Week 4, 8, 12, 16, 20, and 24

• Comparison of Individual Average Core Set Measure in Subjects Over Time Between the 2 Arms (Repeated Measures Analysis)

  Week 4, 8, 12, 16, 20, and 24

• Magnitude of the Effect Size Between the Both Treatment Arms

  Week 4, 8, 12, 16, 20, and 24

Study Arms (2)

Group A: Tocilizumab

ACTIVE COMPARATOR

Tocilizumab will be given at a dose of 8mg/kg by IV infusion every 4 weeks at 6 time points (Visits 1, 2, 3, 4, 5 and 6).

Drug: tocilizumab

Group B: Placebo

PLACEBO COMPARATOR

Placebo arm - no active drug

Drug: placebo

Interventions

tocilizumab DRUG

given at a dose of 8mg/kg by IV infusion every 4 weeks at 6 time points (Visits 1, 2, 3, 4, 5 and 6).

Also known as: Actemra

Group A: Tocilizumab

placebo DRUG

given by IV infusion every 4 weeks at 6 time points (Visits 1, 2, 3, 4, 5 and 6).

Group B: Placebo

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Patients will be included in the trial based on the following criteria:
• Subjects must either have the classic rash(es) of DM (heliotrope, Gottron sign or Gottron papules), possess one of the myositis-associated autoantibodies (e.g. anti-synthetase, anti-signal recognition particle (anti-SRP), anti-Mi-2, anti-PM-Scl, transcription intermediary factor 1-γ (anti TIF1-γ etc.), or have the diagnosis of PM agreed upon by a 3-member Adjudication Committee consisting of a rheumatologist, neurologist and neuromuscular pathologist.
• Refractory myositis patients are defined (see Section 3.1.1) as having failed (or considered intolerant to) an adequate course of glucocorticoids or having failed glucocorticoids and at least one other immunosuppressive (IS) or immunomodulatory agent (e.g. methotrexate, azathioprine, cyclosporine, tacrolimus, mycophenolate mofetil, cyclophosphamide, Intravenous immunoglobulin (IVIg), anti-tumor necrosis factor (anti-TNF) agents, and rituximab).
• Subjects with an Manual muscle score (MMT-8) score ≤ 66 (see Appendix B) must also have at least 2 other core set measures meeting the criteria listed below.
• Subjects with an MMT-8 score \> 66 must have at least 3 other core set measures meeting the criteria listed below and a global extramuscular visual analog score (VAS) score on the Myositis Disease Activity Assessment Tool ( MDAAT) ≥ 5cm on a 10cm scale.
• Criteria for core set measures for study entry:
• Patient global VAS with a minimum value of 2.0cm on a 10cm scale.
• MD global VAS with a minimum value of 2.0cm on a 10cm scale.
• Health Assessment Questionnaire (HAQ) disability index with a minimum value of 0.25
• Elevation of at least one of the muscle enzymes (Creatine kinase (CK), aspartate aminotransferase (AST), alanine transaminase (ALT), aldolase, Lactate dehydrogenase (LDH) at a minimum level of 1.3x the upper limit of normal (ULN).
• Global extramuscular disease activity score with a minimum value of 1.0cm on a 10cm VAS scale on the Myositis Disease Activity Assessment Tool (MDAAT).
• If on prednisone, the dose must be stable for 4 weeks prior to the screening visit. Tapering of the prednisone dose will only be allowed after the subject meets the Definition of Improvement (DOI) or if safety/toxicity issues supervene.
• Prednisone Tapering: Prednisone should be held constant without tapering or escalation (unless there is a serious adverse event or disease flare) until the subject has achieved the DOI. Then, tapering of prednisone may commence using a schedule approximating a 20-25% taper of the existing dose every 4 weeks based on the clinical judgment of the clinical site investigator. Prednisone tapering using the aforementioned guidelines can be commenced at any time if: (a) the patient achieves the DOI or (b) there are complications or circumstances that, in the clinical site investigator's opinion, necessitate the tapering of corticosteroids.
• Prednisone at Entry: It is also recommended that patients be on less than 1mg/kg/day of prednisone at study entry.
• Prednisone Dosing During Flare: If in the clinical site investigator's opinion there are complications or worsening of disease that necessitate an increase in the prednisone dose then the smallest reasonable increase should be considered.

You may not qualify if:

• A patient will be excluded if any of the following criteria are met:
• Subjects under the age of 18.
• Severe muscle damage defined as a global muscle damage score \>5 on a 10cm VAS scale on the Muscle Damage Index (MDI).
• Evidence of active malignant disease, malignancies diagnosed within the previous 5 years (including hematological malignancies and solid tumors, except basal and squamous cell carcinoma of the skin or carcinoma in situ of the cervix uteri that has been excised and cured), or breast cancer diagnosed within the previous 10 years unless related to primary disease under investigation.
• Known active current or history of recurrent bacterial, viral, fungal, mycobacterial or other infections (including but not limited to tuberculosis and atypical mycobacterial disease, Hepatitis B and C, and herpes zoster, but excluding fungal infections of nail beds).
• Any major episode of infection requiring hospitalization or treatment with IV antibiotics within 4 weeks of screening or oral antibiotics within 2 weeks prior to screening.
• Active tuberculosis (TB) requiring treatment within the previous 3 years. Patients should be screened for latent TB and, if positive, treated following local practice guidelines prior to initiating TCZ. Patients treated for tuberculosis with no recurrence in 3 years are permitted.
• Primary or secondary immunodeficiency (history of or currently active) unless related to primary disease under investigation.
• Pregnant women or nursing (breast feeding) mothers.
• Patients with reproductive potential not willing to use an effective method of contraception.
• History of alcohol, drug or chemical abuse within 1 year prior to screening or any medical condition or physical or psychological state that the PI feels would not allow the subject to safely complete the study.
• Initiation of an exercise program for muscle strengthening within 4 weeks of the screening visit or initiation of a muscle strengthening exercise program during the study.
• Major surgery (including joint surgery) within 8 weeks prior to screening or planned major surgery within 6 months following randomization.
• Treatment with any investigational agent within 4 weeks (or 5 half-lives of the investigational drug, whichever is longer) of screening.
• Previous treatment with the following cell-depleting therapies, including investigational agents or approved therapies: CAMPATH, cluster of differentiation 4 (anti-CD4), cluster of differentiation antigen 5 (anti-CD5), and anti¬CD3.

Sponsors & Collaborators

• Chester Oddis: lead
• Genentech, Inc.: collaborator

Study Sites (7)

Cedars Sinai Medical Center

Los Angeles, California, 90048, United States

Location

University of Kansas Medical Center

Kansas City, Kansas, 66160, United States

Location

Mayo Clinic

Rochester, Minnesota, 55905, United States

Location

North Shore Long Island Jewish Center

Great Neck, New York, 11021, United States

Location

University of Pittsburgh

Pittsburgh, Pennsylvania, 15261, United States

Location

Vanderbilt University

Nashville, Tennessee, 37235, United States

Location

Medical College of Wisconsin

Milwaukee, Wisconsin, 53226, United States

Location

Related Publications (14)

• Oddis CV, Reed AM, Aggarwal R, Rider LG, Ascherman DP, Levesque MC, Barohn RJ, Feldman BM, Harris-Love MO, Koontz DC, Fertig N, Kelley SS, Pryber SL, Miller FW, Rockette HE; RIM Study Group. Rituximab in the treatment of refractory adult and juvenile dermatomyositis and adult polymyositis: a randomized, placebo-phase trial. Arthritis Rheum. 2013 Feb;65(2):314-24. doi: 10.1002/art.37754.

  PMID: 23124935 BACKGROUND

• Rider LG, Giannini EH, Brunner HI, Ruperto N, James-Newton L, Reed AM, Lachenbruch PA, Miller FW; International Myositis Assessment and Clinical Studies Group. International consensus on preliminary definitions of improvement in adult and juvenile myositis. Arthritis Rheum. 2004 Jul;50(7):2281-90. doi: 10.1002/art.20349.

  PMID: 15248228 BACKGROUND

• Kaly L, Rosner I. Tocilizumab - a novel therapy for non-organ-specific autoimmune diseases. Best Pract Res Clin Rheumatol. 2012 Feb;26(1):157-65. doi: 10.1016/j.berh.2012.01.001.

  PMID: 22424201 BACKGROUND

• Schoels MM, van der Heijde D, Breedveld FC, Burmester GR, Dougados M, Emery P, Ferraccioli G, Gabay C, Gibofsky A, Gomez-Reino JJ, Jones G, Kvien TK, Murakami M, Nishimoto N, Smolen JS. Blocking the effects of interleukin-6 in rheumatoid arthritis and other inflammatory rheumatic diseases: systematic literature review and meta-analysis informing a consensus statement. Ann Rheum Dis. 2013 Apr;72(4):583-9. doi: 10.1136/annrheumdis-2012-202470. Epub 2012 Nov 10.

  PMID: 23144446 BACKGROUND

• Smolen JS, Schoels MM, Nishimoto N, Breedveld FC, Burmester GR, Dougados M, Emery P, Ferraccioli G, Gabay C, Gibofsky A, Gomez-Reino JJ, Jones G, Kvien TK, Murakami M, Betteridge N, Bingham CO 3rd, Bykerk V, Choy EH, Combe B, Cutolo M, Graninger W, Lanas A, Martin-Mola E, Montecucco C, Ostergaard M, Pavelka K, Rubbert-Roth A, Sattar N, Scholte-Voshaar M, Tanaka Y, Trauner M, Valentini G, Winthrop KL, de Wit M, van der Heijde D. Consensus statement on blocking the effects of interleukin-6 and in particular by interleukin-6 receptor inhibition in rheumatoid arthritis and other inflammatory conditions. Ann Rheum Dis. 2013 Apr;72(4):482-92. doi: 10.1136/annrheumdis-2012-202469. Epub 2012 Nov 21.

  PMID: 23172750 BACKGROUND

• Muangchan C, Pope JE. Interleukin 6 in systemic sclerosis and potential implications for targeted therapy. J Rheumatol. 2012 Jun;39(6):1120-4. doi: 10.3899/jrheum.111423. Epub 2012 Apr 15.

  PMID: 22505699 BACKGROUND

• Shirota Y, Yarboro C, Fischer R, Pham TH, Lipsky P, Illei GG. Impact of anti-interleukin-6 receptor blockade on circulating T and B cell subsets in patients with systemic lupus erythematosus. Ann Rheum Dis. 2013 Jan;72(1):118-28. doi: 10.1136/annrheumdis-2012-201310. Epub 2012 Aug 2.

  PMID: 22858586 BACKGROUND

• Narazaki M, Hagihara K, Shima Y, Ogata A, Kishimoto T, Tanaka T. Therapeutic effect of tocilizumab on two patients with polymyositis. Rheumatology (Oxford). 2011 Jul;50(7):1344-6. doi: 10.1093/rheumatology/ker152. Epub 2011 Apr 22. No abstract available.

  PMID: 21515628 BACKGROUND

• Scuderi F, Mannella F, Marino M, Provenzano C, Bartoccioni E. IL-6-deficient mice show impaired inflammatory response in a model of myosin-induced experimental myositis. J Neuroimmunol. 2006 Jul;176(1-2):9-15. doi: 10.1016/j.jneuroim.2006.03.026. Epub 2006 May 24.

  PMID: 16725212 BACKGROUND

• Bilgic H, Ytterberg SR, Amin S, McNallan KT, Wilson JC, Koeuth T, Ellingson S, Newman B, Bauer JW, Peterson EJ, Baechler EC, Reed AM. Interleukin-6 and type I interferon-regulated genes and chemokines mark disease activity in dermatomyositis. Arthritis Rheum. 2009 Nov;60(11):3436-46. doi: 10.1002/art.24936.

  PMID: 19877033 BACKGROUND

• Sugihara T, Sekine C, Nakae T, Kohyama K, Harigai M, Iwakura Y, Matsumoto Y, Miyasaka N, Kohsaka H. A new murine model to define the critical pathologic and therapeutic mediators of polymyositis. Arthritis Rheum. 2007 Apr;56(4):1304-14. doi: 10.1002/art.22521.

  PMID: 17394136 BACKGROUND

• Okiyama N, Sugihara T, Iwakura Y, Yokozeki H, Miyasaka N, Kohsaka H. Therapeutic effects of interleukin-6 blockade in a murine model of polymyositis that does not require interleukin-17A. Arthritis Rheum. 2009 Aug;60(8):2505-12. doi: 10.1002/art.24689.

  PMID: 19644888 BACKGROUND

• Oddis CV, Rider LG, Reed AM, Ruperto N, Brunner HI, Koneru B, Feldman BM, Giannini EH, Miller FW; International Myositis Assessment and Clinical Studies Group. International consensus guidelines for trials of therapies in the idiopathic inflammatory myopathies. Arthritis Rheum. 2005 Sep;52(9):2607-15. doi: 10.1002/art.21291. No abstract available.

  PMID: 16142757 BACKGROUND

• Sampson HA, Munoz-Furlong A, Campbell RL, Adkinson NF Jr, Bock SA, Branum A, Brown SG, Camargo CA Jr, Cydulka R, Galli SJ, Gidudu J, Gruchalla RS, Harlor AD Jr, Hepner DL, Lewis LM, Lieberman PL, Metcalfe DD, O'Connor R, Muraro A, Rudman A, Schmitt C, Scherrer D, Simons FE, Thomas S, Wood JP, Decker WW. Second symposium on the definition and management of anaphylaxis: summary report--Second National Institute of Allergy and Infectious Disease/Food Allergy and Anaphylaxis Network symposium. J Allergy Clin Immunol. 2006 Feb;117(2):391-7. doi: 10.1016/j.jaci.2005.12.1303.

  PMID: 16461139 BACKGROUND

MeSH Terms

Conditions

Dermatomyositis; Polymyositis

Interventions

tocilizumab

Condition Hierarchy (Ancestors)

Myositis; Muscular Diseases; Musculoskeletal Diseases; Neuromuscular Diseases; Nervous System Diseases; Connective Tissue Diseases; Skin and Connective Tissue Diseases; Skin Diseases

Results Point of Contact

• Title: Chester Oddis, MD
• Organization: University of Pittsburgh

cvo5@pitt.edu

412-383-8861

Study Officials

• Chester V. Oddis, MD

  University of Pittsburgh

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Chester Oddis, MD

Study Record Dates

• First Submitted: January 17, 2014
• First Posted: January 23, 2014
• Study Start: October 1, 2014
• Primary Completion: July 30, 2019
• Study Completion: July 31, 2019
• Last Updated: October 30, 2020
• Results First Posted: October 30, 2020

Record last verified: 2020-10

Data Sharing

• IPD Sharing: Will not share

Locations

US (7)