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

  • STATUS
    Recruiting
  • End date
    Jan 2, 2024
  • participants needed
    76
  • sponsor
    Assistance Publique - Hôpitaux de Paris
Updated on 15 February 2021

Summary

"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."

Description

"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."

Details
Condition Pulmonary Disease, Lung Disease, Pulmonary Fibrosis, Pulmonary Fibrosis, Interstitial lung disease, Lung Disease, interstitial lung diseases, Antisynthetase Syndrome (ASS), Antisynthetase Syndrome (ASS)
Treatment Tacrolimus, Cyclophosphamide and azathioprine
Clinical Study IdentifierNCT03770663
SponsorAssistance Publique - Hôpitaux de Paris
Last Modified on15 February 2021

Eligibility

Yes No Not Sure

Inclusion Criteria

Age 18
Signed informed consent
Affiliation to the Social security system
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
Diagnosis of ILD-related ASS: interstitial lung disease on HRCT
Moderate to severe ILD on PFT : FVC < 80% and or cDLCO < 70%
beta-HCG test negative or negative uterine echography (for women of child bearing potential)
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
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

Pregnancy and/or breast feeding
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)
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)
Active neoplasm
Previous inefficacy of Cyclophosphamide, Azathioprine or Tacrolimus, not related to adhesion problems
Previous use of 3 daily IV steroids < 3 months before patient's enrollment
ASS-related ILD worsening or relapse under Prednisone > 0.5 mg/kg/day
Previous use of Cyclophosphamide, Azathioprine or Tacrolimus in the last 6 months
Severe ASS requiring ICU (respiratory disease, myocarditis), plasma exchange or IV-Ig
Positivity of auto-antibodies associated to Systemic Sclerosis (anti-Telomerase, anti-Centromres, anti-Polymerase III)
Patients with QTc > 450 msec
Patients with history of long QT syndrome (including familial) or ventricular arrhythmias
Concomitant use of drugs prolonging QT / QTc (list of treatments in annex)
Hypokalemia
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
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