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Cyclophosphamide and Azathioprine vs Tacrolimus in Antisynthetase Syndrome-related Interstitial Lung Disease

Study Purpose

"Antisynthetase syndrome (ASS) is one of the most severe inflammatory myopathy (IM), due to pulmonary involvement (interstitial lung disease, ILD). Until now, the most commonly used immunosuppresive therapy in Europe is Cyclophosphamide followed by different immunosuppressive drugs as maintenance therapy, including Azathioprine (and so called " European Strategy "). In the USA however, the first-line immunosuppressive treatment is Tacrolimus (so called " American Strategy "). None of these two different strategies has ever been studied prospectively, and there is no clear comparison of short and long-term treatment efficacy and tolerance. Thus, there are yet no evidences helping the clinicians in the therapeutic management of patients with ASS-related ILD. The aim of this study is therefore to compare both strategies as first line treatments or in relapsing patients : CATR.PAT study is a 52 weeks, randomized, comparative, controlled, open-labeled, phase III, therapeutic clinical trial, comparing two treatment strategies."

Recruitment Criteria

Accepts Healthy Volunteers Healthy volunteers are participants who do not have a disease or condition, or related conditions or symptoms	No
Study Type An interventional clinical study is where participants are assigned to receive one or more interventions (or no intervention) so that researchers can evaluate the effects of the interventions on biomedical or health-related outcomes. An observational clinical study is where participants identified as belonging to study groups are assessed for biomedical or health outcomes. Searching Both is inclusive of interventional and observational studies.	Interventional
Eligible Ages	18 Years and Over
Gender	All

More Inclusion & Exclusion Criteria

Inclusion Criteria:

1. Age ≥ 18. 2. Signed informed consent. 3. Affiliation to the Social security system. 4. Diagnosis of ASS: positive test for any of the 5 anti-tRNA synthetase antibodies routinely tested (ELISA, Luminex or Linear-dot), including anti-Jo-1, anti-PL7, anti-PL12, anti-EJ and anti-OJ. 5. Diagnosis of ILD-related ASS: interstitial lung disease on HRCT. 6. Moderate to severe ILD on PFT : FVC < 80% and or cDLCO < 70% 7. beta-HCG test negative or negative uterine echography (for women of child bearing potential) 8. Women of childbearing potential must have an oral contraception (macroprogestatifs) during all the duration of study treatment and 12 months after the last dose of study treatment. 9. Males who are sexually active with women of childbearing potential must agree to follow instructions for method(s) of contraception for the duration of study treatment and 6 months after the last dose of study treatment.

Exclusion Criteria:

1. Pregnancy and/or breast feeding. 2. Others contraindications to the treatments, including hypersensitivity to the drug (including excipient and active compounds), medical contraception contraindications, severe renal failure, severe hepatic insufficiency and severe psychiatric disorders. Specific contraindications are listed for each experimental medication in Table 6 (according to updated Summary of product characteristics, see Appendix 8) 3. Fever or active bacterial infection (ie. septicemia, pneumopathy, pyelonephritis, acute prostatitis …), or parasitic infection (ie. Anguillulosis …),or fungal infection (ie. Invasive pulmonary aspergillosis …), or viral infection (HIV seropositivity, Active Tuberculosis, active B/C viral hepatitis, CMV, active EBV…) 4. Active neoplasm. 5. Previous inefficacy of Cyclophosphamide, Azathioprine or Tacrolimus, not related to adhesion problems. 6. Previous use of 3 daily IV steroids < 3 months before patient's enrollment. 7. ASS-related ILD worsening or relapse under Prednisone > 0.5 mg/kg/day. 8. Previous use of Cyclophosphamide, Azathioprine or Tacrolimus in the last 6 months. 9. Severe ASS requiring ICU (respiratory disease, myocarditis), plasma exchange or IV-Ig. 10. Positivity of auto-antibodies associated to Systemic Sclerosis (anti-Telomerase, anti-Centromères, anti-Polymerase III). 11. Patients with QTc > 450 msec. 12. Patients with history of long QT syndrome (including familial) or ventricular arrhythmias. 13. Concomitant use of drugs prolonging QT / QTc (list of treatments in annex) 14. Hypokalemia. 15. Patients with pulmonary hypertension detected on echocardiography during the screening/selection visit (systolic pulmonary artery pressure (PAP) was 37-50 mmHg, and/or tricuspid regurgitation velocity 2.8-3.4 ms-1) are excluded.

Trial Details

Trial ID: This trial id was obtained from ClinicalTrials.gov, a service of the U.S. National Institutes of Health, providing information on publicly and privately supported clinical studies of human participants with locations in all 50 States and in 196 countries.	NCT03770663
Phase Phase 1: Studies that emphasize safety and how the drug is metabolized and excreted in humans. Phase 2: Studies that gather preliminary data on effectiveness (whether the drug works in people who have a certain disease or condition) and additional safety data. Phase 3: Studies that gather more information about safety and effectiveness by studying different populations and different dosages and by using the drug in combination with other drugs. Phase 4: Studies occurring after FDA has approved a drug for marketing, efficacy, or optimal use.	Phase 3
Lead Sponsor The sponsor is the organization or person who oversees the clinical study and is responsible for analyzing the study data.	Assistance Publique - Hôpitaux de Paris
Principal Investigator The person who is responsible for the scientific and technical direction of the entire clinical study.	N/A
Principal Investigator Affiliation	N/A
Agency Class Category of organization(s) involved as sponsor (and collaborator) supporting the trial.	Other
Overall Status	Recruiting
Countries	France
Conditions The disease, disorder, syndrome, illness, or injury that is being studied.	Antisynthetase Syndrome (ASS), Interstitial Lung Disease

Additional Details

"During the study period, according to randomization into two groups (n=38 patients, respectively), patients will receive either:

- Group 1 & 2 : 3 IV pulses of Methylprednisolone (7.5 mg/kg/day followed by tapering doses of oral Prednisone, started at 1 mg/kg/day from D4 to M12.

In association with :

- Group 1 : European Standard of care : 6 IV pulses of Cyclophosphamide (1000 mg) followed from M5 to M12 by oral Azathioprine (2 mg/kg/day), with a maximum of 150 mg/d) - Group 2 : American Strategy Tacrolimus is given orally from M0 to M12 (started at the initial dose of 2x2mg/d).

Tacrolimus doses are regularly adapted to its serum concentration to reach 5-15 ng/ml."

Arms & Interventions

Arms

Experimental: European strategy

3 IV pulses of Methylprednisolone (7.5 mg/kg/day followed by tapering doses of oral Prednisone, started at 1 mg/kg/day from D4 to M12 In association with: 6 IV pulses of Cyclophosphamide (1000mg) followed from M5 to M12 by oral Azathioprine (2mg/kg/day), with a maximum of 150mg/day

Experimental: American strategy

3 IV pulses of Methylprednisolone (7.5 mg/kg/day followed by tapering doses of oral Prednisone, started at 1 mg/kg/day from D4 to M12 In association with: Tacrolimus given orally from M0 to M12 (started at the initial dose of 2x2mg/day). Tacrolimus doses are regularly adapted to its serum concentration to reach 5-15ng/mL.

Interventions

Drug: - Cyclophosphamide and azathioprine

European strategy 6 IV pulses of Cyclophosphamide (1000mg) followed from M5 to M12 by oral Azathioprine (2mg/kg/day), with a maximum of 150mg/day

Drug: - Tacrolimus

American strategy Tacrolimus given orally from M0 to M12 (started at the initial dose of 2x2mg/day). Tacrolimus doses are regularly adapted to its serum concentration to reach 5-15ng/mL.

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