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

NCT ID: NCT03770663

Last Updated: 2021-02-09

Basic Information

• Recruitment Status: UNKNOWN
• Clinical Phase: PHASE3
• Total Enrollment: 76 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2021-02-05
• Study Completion Date: 2024-01-02

Brief 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."

Detailed 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."

Conditions

Antisynthetase Syndrome (ASS); Interstitial Lung Disease

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

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

Group Type: EXPERIMENTAL

Cyclophosphamide and azathioprine

Intervention Type: DRUG

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

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.

Group Type: EXPERIMENTAL

Tacrolimus

Intervention Type: DRUG

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.

Interventions

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

Intervention Type: 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.

Intervention Type: DRUG

Eligibility 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.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Assistance Publique - Hôpitaux de Paris

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Locations

Hôpital Universitaire Pitié Salpêtrière

Paris, , France

Site Status: RECRUITING

Countries

France

Central Contacts

Olivier BENVENISTE, MD

Role: CONTACT

olivier.benveniste@aphp.fr

+33 (0)1 42 16 10 88

HERVIER Baptiste, MD

Role: CONTACT

baptiste.hervier@aphp.fr

+33 (0)1 49 42 55

Facility Contacts

Olivier BENVENISTE, MD

Role: primary

olivier.benveniste@aphp.fr

Other Identifiers

2016-002921-12

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

P140217

Identifier Type: -

Identifier Source: org_study_id