Abatacept for the Treatment of Myositis-associated Interstitial Lung Disease

Interstitial Lung Disease Clinical Trial

— ATtackMy-ILD  

Official title:

A Randomized, Controlled Pilot Trial to Evaluate the Efficacy and Safety of Subcutaneous Abatacept in Treating Interstitial Lung Disease Associated With the Anti-synthetase Syndrome

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT03215927
• Other study ID #: BMS: IM101-657
• Status: Active, not recruiting
• Phase: Phase 2
• Start date: June 1, 2017
• Est. completion date: July 30, 2023

Study information

• Verified date: May 2023
• Source: University of Pittsburgh
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

A randomized, controlled pilot trial to evaluate the efficacy and safety of subcutaneous Abatacept in treating interstitial lung disease associated with the anti-synthetase syndrome.

Description:

This is a proof of concept study to evaluate the efficacy, safety and tolerability of abatacept in Syn-ILD in a multi-center randomized, placebo-controlled 6-month (24-week) pilot study.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 20
• Est. completion date: July 30, 2023
• Est. primary completion date: May 30, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

1. Age = 18 years.

2. Anti-synthetase syndrome defined as the patient possessing 1 antisynthetase autoantibody (Jo-1, PL-12, PL-7, KS, OJ, EJ, Zo) in the presence of autoimmune ILD.

3. ILD defined by radiographic (HRCT chest) findings of reticulation, honeycombing or ground glass opacities (GGO) without another plausible explanation. HRCT chest defining ILD for inclusion criteria, should be within last 1 year done as SOC.

4. Active ILD (see Section 4.2).

5. Baseline FVC a) % <80% b) FVC 80-100% with > = 10% decline in FVC in last 12 months as minimal threshold of ILD severity (PFT done within last 3 months is acceptable for inclusion criteria determination)

6. SOC immunosuppressive therapy (IS) therapy:

1. Steroids (prednisone or other forms of steroid in equivalent doses) OR one of the other immunosuppressive agent (either Mycophenolate (MMF) or Azathioprine (AZA) OR a combination of steroid and an immunosuppressive agent. MMF (maximum of 3 gm/day) or azathioprine (maximum of 200 mg/day).Goal is to start the trial drug (or placebo) soon after starting SOC (MMF/AZA/Steroids) and their doses are stable. Note that patients on steroids alone as well as not on steroids can be enrolled in the trial as well.

2. Desired dose of the SOC therapy should be reached 4 weeks prior to first study visit (Visit 1). No dose changes are allowed 4 weeks prior to first study visit.

3. Dose of concomitant therapy (SOC) cannot be changed during the 24 weeks of the trial unless safety/toxicity issues supervene.

4. If on steroid, the steroid dose must be stable for 2 weeks prior to Visit 1.

7. No other concomitant IS medications including methotrexate, cyclosporine, intravenous immunoglobulin (IVIG), tacrolimus, cyclophosphamide or tofacitinib.

8. No concomitant biologic agents (i.e. rituximab, anti-tumor necrosis factor (TNF) agents, tocilizumab).

9. Additional IS therapy: Patient cannot begin any new IS therapy or new steroid taper for the 24-week study period, except if severe clinical worsening (flare up) of the disease requiring rescue therapy occurs (i.e. documentation of worsening of PFT/HRCT and patient and physician determination of worsening). See section of rescue medication below for details.

10. If the enrolling physician is planning to discontinue current IS agent or steroid before clinical trial, then following washout period is required prior to Visit 1.

Medication Washout Period methotrexate 4 weeks Other IS agent (e.g. azathioprine, cyclosporine, tacrolimus, leflunomide, mycophenolate mofetil) 4 weeks IVIg or cyclophosphamide 3 months rituximab 6 months infliximab or adalimumab 8 weeks glucocorticoids 2 weeks etanercept 2 weeks anakinra 1 week pirfenidone 4 weeks

11. Men and women of reproductive potential must agree to use an acceptable method of birth control during the trial period.

12. Subject has provided written informed consent.

Exclusion Criteria:

A patient will be excluded if any of the following Exclusion Criteria are met:

1. Severe end stage lung disease:

1. FVC =30% or Forced expiratory volume (FEV1) = 30% or

2. Requirement of high O2 requirement = 6 L/min at rest for >1 month before the study enrollment or

3. Listed for lung transplantation or

4. PI feels that ILD is severe and end stage fibrosis is such that there is low potential for improvement with any disease modifying intervention.

2. Subjects under the age of 18.

3. 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).

4. Any major episode of infection requiring hospitalization or treatment with IV antibiotics within 4 weeks of screening.

5. Active tuberculosis (TB) requiring treatment within the previous 3 years. Patients should be screened for latent TB using purified protein derivative (PPD)/or quantiferon gold within last 1 year and, if positive, treated following local practice guidelines prior to initiating abatacept (ABT). Patients treated for active tuberculosis with no recurrence in 3 years are permitted.

6. Primary or secondary immunodeficiency (history of or currently active) unless related to primary disease under investigation.

7. Pregnant women or nursing (breast feeding) mothers.

8. 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.

9. Major surgery (including joint surgery) within 8 weeks prior to screening or planned major surgery within 6 months following randomization.

10. Treatment with any other investigational agent within 4 weeks (or 5 half-lives of the investigational drug, whichever is longer) of screening.

11. Previous treatment with the following cell-depleting therapies, including investigational agents or approved therapies: CAMPATH, anti-CD4, anti-CD5, and anti-CD3.

12. Previous treatment with ABT.

13. History of severe allergic or anaphylactic reactions to monoclonal antibodies.

14. Evidence of serious uncontrolled concomitant cardiovascular, nervous system, renal, hepatic, endocrine (include uncontrolled diabetes mellitus) or gastrointestinal disease (including complicated diverticulitis, ulcerative colitis, or Crohn's disease.)

15. Evidence of concomitant lung disease which PI feels may interfere with clinical assessment of ILD for example severe active chronic obstructive pulmonary disease (COPD), asthma, occupational lung disease, pulmonary sarcoidosis, etc.

16. Prisoners or subjects who are compulsory detained

Related Conditions & MeSH terms

• Interstitial Lung Disease
• Lung Diseases
• Lung Diseases, Interstitial
• Myositis

Intervention

Drug:
• Abatacept
Abatacept 125mg subcutaneous weekly

Other:
• Placebo
Placebo

Locations

Country	Name	City	State
United States	John Hopkins Medical Center	Baltimore	Maryland
United States	Cedars-Sinai Medical Center	Beverly Hills	California
United States	Brigham & Women's Hospital	Boston	Massachusetts
United States	University of Colorado Anschutz Medical Campus	Denver	Colorado
United States	University of Pittsburgh	Pittsburgh	Pennsylvania

Sponsors (2)

Lead Sponsor	Collaborator
Rohit Aggarwal, MD	Bristol-Myers Squibb

Country where clinical trial is conducted

United States, 

References & Publications (21)

Ando M, Miyazaki E, Yamasue M, Sadamura Y, Ishii T, Takenaka R, Ito T, Nureki S, Kumamoto T. Successful treatment with tacrolimus of progressive interstitial pneumonia associated with amyopathic dermatomyositis refractory to cyclosporine. Clin Rheumatol. 2010 Apr;29(4):443-5. doi: 10.1007/s10067-009-1358-x. Epub 2010 Feb 4. — View Citation

Arabshahi B, Silverman RA, Jones OY, Rider LG. Abatacept and sodium thiosulfate for treatment of recalcitrant juvenile dermatomyositis complicated by ulceration and calcinosis. J Pediatr. 2012 Mar;160(3):520-2. doi: 10.1016/j.jpeds.2011.11.057. Epub 2012 Jan 13. — View Citation

Buch MH, Boyle DL, Rosengren S, Saleem B, Reece RJ, Rhodes LA, Radjenovic A, English A, Tang H, Vratsanos G, O'Connor P, Firestein GS, Emery P. Mode of action of abatacept in rheumatoid arthritis patients having failed tumour necrosis factor blockade: a histological, gene expression and dynamic magnetic resonance imaging pilot study. Ann Rheum Dis. 2009 Jul;68(7):1220-7. doi: 10.1136/ard.2008.091876. Epub 2008 Sep 4. Erratum In: Ann Rheum Dis. 2011 Aug;70(8):1519. — View Citation

Cutolo M, Soldano S, Montagna P, Sulli A, Seriolo B, Villaggio B, Triolo P, Clerico P, Felli L, Brizzolara R. CTLA4-Ig interacts with cultured synovial macrophages from rheumatoid arthritis patients and downregulates cytokine production. Arthritis Res Ther. 2009;11(6):R176. doi: 10.1186/ar2865. Epub 2009 Nov 23. — View Citation

Elhai M, Meunier M, Matucci-Cerinic M, Maurer B, Riemekasten G, Leturcq T, Pellerito R, Von Muhlen CA, Vacca A, Airo P, Bartoli F, Fiori G, Bokarewa M, Riccieri V, Becker M, Avouac J, Muller-Ladner U, Distler O, Allanore Y; EUSTAR (EULAR Scleroderma Trials and Research group). Outcomes of patients with systemic sclerosis-associated polyarthritis and myopathy treated with tocilizumab or abatacept: a EUSTAR observational study. Ann Rheum Dis. 2013 Jul;72(7):1217-20. doi: 10.1136/annrheumdis-2012-202657. Epub 2012 Dec 19. — View Citation

Guglielmo S, Bertinaria M, Rolando B, Crosetti M, Fruttero R, Yardley V, Croft SL, Gasco A. A new series of amodiaquine analogues modified in the basic side chain with in vitro antileishmanial and antiplasmodial activity. Eur J Med Chem. 2009 Dec;44(12):5071-9. doi: 10.1016/j.ejmech.2009.09.012. Epub 2009 Sep 15. — View Citation

Israel-Assayag E, Fournier M, Cormier Y. Blockade of T cell costimulation by CTLA4-Ig inhibits lung inflammation in murine hypersensitivity pneumonitis. J Immunol. 1999 Dec 15;163(12):6794-9. — View Citation

Jimenez-Alvarez L, Arreola JL, Ramirez-Martinez G, Ortiz-Quintero B, Gaxiola M, Reynoso-Robles R, Avila-Moreno F, Urrea F, Pardo A, Selman M, Zuniga J. The effect of CTLA-4Ig, a CD28/B7 antagonist, on the lung inflammation and T cell subset profile during murine hypersensitivity pneumonitis. Exp Mol Pathol. 2011 Dec;91(3):718-22. doi: 10.1016/j.yexmp.2011.09.010. Epub 2011 Sep 14. — View Citation

Kerola AM, Nieminen TV, Kauppi MJ, Kautiainen H, Puolakka K, Virta LJ, Kerola T. Increased risk of levothyroxine-treated hypothyroidism preceding the diagnosis of rheumatoid arthritis: a nationwide registry study. Clin Exp Rheumatol. 2014 Jul-Aug;32(4):455-9. Epub 2014 Jun 6. — View Citation

Khanna D, Mittoo S, Aggarwal R, Proudman SM, Dalbeth N, Matteson EL, Brown K, Flaherty K, Wells AU, Seibold JR, Strand V. Connective Tissue Disease-associated Interstitial Lung Diseases (CTD-ILD) - Report from OMERACT CTD-ILD Working Group. J Rheumatol. 2015 Nov;42(11):2168-71. doi: 10.3899/jrheum.141182. Epub 2015 Mar 1. — View Citation

Kurasawa K, Nawata Y, Takabayashi K, Kumano K, Kita Y, Takiguchi Y, Kuriyama T, Sueishi M, Saito Y, Iwamoto I. Activation of pulmonary T cells in corticosteroid-resistant and -sensitive interstitial pneumonitis in dermatomyositis/polymyositis. Clin Exp Immunol. 2002 Sep;129(3):541-8. doi: 10.1046/j.1365-2249.2002.01933.x. — View Citation

Lumsden JM, Roberts JM, Harris NL, Peach RJ, Ronchese F. Differential requirement for CD80 and CD80/CD86-dependent costimulation in the lung immune response to an influenza virus infection. J Immunol. 2000 Jan 1;164(1):79-85. doi: 10.4049/jimmunol.164.1.79. — View Citation

Maeshima K, Kiyonaga Y, Imada C, Iwakura M, Hamasaki H, Haranaka M, Ishii K. Successful treatment of refractory anti-signal recognition particle myopathy using abatacept. Rheumatology (Oxford). 2014 Feb;53(2):379-80. doi: 10.1093/rheumatology/ket251. Epub 2013 Aug 6. No abstract available. — View Citation

Mera-Varela A, Perez-Pampin E. Abatacept therapy in rheumatoid arthritis with interstitial lung disease. J Clin Rheumatol. 2014 Dec;20(8):445-6. doi: 10.1097/RHU.0000000000000084. No abstract available. — View Citation

Mitsui T, Kuroda Y, Ueno S, Kaji R. The effects of FK506 on refractory inflammatory myopathies. Acta Neurol Belg. 2011 Sep;111(3):188-94. — View Citation

Murata K, Dalakas MC. Expression of the costimulatory molecule BB-1, the ligands CTLA-4 and CD28, and their mRNA in inflammatory myopathies. Am J Pathol. 1999 Aug;155(2):453-60. doi: 10.1016/s0002-9440(10)65141-3. — View Citation

Nagaraju K, Raben N, Villalba ML, Danning C, Loeffler LA, Lee E, Tresser N, Abati A, Fetsch P, Plotz PH. Costimulatory markers in muscle of patients with idiopathic inflammatory myopathies and in cultured muscle cells. Clin Immunol. 1999 Aug;92(2):161-9. doi: 10.1006/clim.1999.4743. — View Citation

Ochi S, Nanki T, Takada K, Suzuki F, Komano Y, Kubota T, Miyasaka N. Favorable outcomes with tacrolimus in two patients with refractory interstitial lung disease associated with polymyositis/dermatomyositis. Clin Exp Rheumatol. 2005 Sep-Oct;23(5):707-10. — View Citation

Platt AM, Gibson VB, Patakas A, Benson RA, Nadler SG, Brewer JM, McInnes IB, Garside P. Abatacept limits breach of self-tolerance in a murine model of arthritis via effects on the generation of T follicular helper cells. J Immunol. 2010 Aug 1;185(3):1558-67. doi: 10.4049/jimmunol.1001311. Epub 2010 Jul 2. — View Citation

Takada K, Nagasaka K, Miyasaka N. Polymyositis/dermatomyositis and interstitial lung disease: a new therapeutic approach with T-cell-specific immunosuppressants. Autoimmunity. 2005 Aug;38(5):383-92. doi: 10.1080/08916930500124023. — View Citation

Wilkes MR, Sereika SM, Fertig N, Lucas MR, Oddis CV. Treatment of antisynthetase-associated interstitial lung disease with tacrolimus. Arthritis Rheum. 2005 Aug;52(8):2439-46. doi: 10.1002/art.21240. — View Citation

* Note: There are 21 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Forced Vital Capacity (FVC)% Change	The primary outcome criteria for efficacy will be the FVC% change from the baseline visit to week 24 between the 2 treatment arms (SOC/placebo vs. SOC/Abatacept).	24 Weeks
Secondary	Time to progression free survival where progression	The first occurrence of any of the following: death or lung transplant or FVC =10% decline or FVC =5% decline with diffuse capacity of lung for carbon dioxide (DLCO) =15% decline.	24 weeks
Secondary	Comparison of change in patient reported dyspnea scores	measured by University of California San Diego Shortness of Breath Questionnaire (UCSD SOBQ) (range 0-120, higher score is worsening dyspnea).	24 weeks
Secondary	Time to improvement in FVC% by =10	Comparison of FVC% results from pulmonary function tests from baseline, 3 and 6 months. Improvement is defined as an FVC% change =10.	24 weeks