Cyclophosphamide and Azathioprine vs Tacrolimus in antisynthetase syndrome-related interstitial lung disease: multicentric randomized phase III trial

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Assistance Publique Hopitaux De Paris

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Respiratory Tract Diseases [C08]

Trial duration

5 Feb 2021 → ongoing

Decision date (initial)

2024-09-17

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Funding sources

Organisation name Direction Générale de l’Offre des Soins du Ministère de la santé et de la prévent

External identifiers

EU CT number

2024-511868-83-00

EudraCT number

2016-002921-12

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Therapy

To compare the efficacy of Cyclophosphamide and Azathioprine vs Tacrolimus in patients with ASS related-ILD.

Secondary objectives 7

1. To compare in patients with ASS related-ILD the Global variation of the M0 and M12 six minutes walk tests (six-MWT)
2. To compare in patients with ASS related-ILD the global variation of M0 and M12 Forced Vital Capacity (FVC) and Diffusing Lung Carbon Monoxyde Capacity (cDLCO)
3. To compare in patients with ASS related-ILD the rate of pulmonary improvement
4. To compare in patients with ASS related-ILD the time to extra-pulmonary improvement
5. To compare in patients with ASS related-ILD the rate of extra-pulmonary improvement
6. To compare in patients with ASS related-ILD the treatment tolerance (and efficacy)
7. To compare in patients with ASS related-ILD the patient's quality of life

Conditions and MedDRA coding

Antisynthetase syndrome-related interstitial lung disease

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 9

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, up to 3 months prior to inclusion.
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 effective contraceptive measure (hormonal, intrauterine device, intrauterine hormone-releasing system, sterilization method)) 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 15

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 7)
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, and > 10 days before patient's morphological and functional examination for enrollment (CT-scan and PFT).
7. ASS-related ILD worsening or relapse while considering inclusion under Prednisone > 0.5 mg/kg/day, > 30 days prior to inclusion.
8. Previous use of Cyclophosphamide, Azathioprine or Tacrolimus in the last 6 months.
9. Severe ASS requiring ICU at the time of inclusion (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.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. The composite primary endpoint is the time from the initiation of treatment to the first event related to ASS related ILD (progression free survival)

Secondary endpoints 7

1. Global variation of the M0 and M12-six minute walk tests is compared (distance in meter, differential of saturation in %).
2. Global variation of M0 and M12-FVC and cDLCO is compared (both absolute and %)
3. Lung improvement is defined (in the absence of any other pulmonary disease) by 3A. Improvement of at least 20% of the dyspnea visual scale score (1-10) 3B. and/or improvement of pulmonary function tests: increase of the baseline FVC by 10% (% patient predicted value or absolute value) or of the baseline cDLCO by 15% (% patient predicted value or absolute). 3C. and/or improvement of ILD on HRCT-scan (-5% involvement of the lung parench
4. Extra-pulmonary improvement is evaluated as follow: improvement of the muscle involvement, assessed by muscle manual testing at each visit, is defined by an increased score > 20%/ biological improvement of the muscle involvement, assessed by creatine kinase levels performed at every visit, is defined by a decreased of baseline creatin kinase > 50% (IU/ml)/improvement of the joint involvement, assessed by the ACR score at every visit is defined by a decrease > 20% of baseline
5. Extra-pulmonary improvement (muscle and joint involvements) is evaluated as follows: 5A. improvement of the muscle involvement, assessed by MMT/150 muscle testing at baseline and M12, is defined by an increased score > 20% 5B. improvement of the joint involvement, assessed by the ACR score at each visit is define by a decrease > 20% of baseline number of swelling and painful joints.
6. Treatments tolerance (and efficacy) is recorded and compared as follows: any serious adverse event attributable to any experimental medication, which requires hospitalization, is recorded at any time. Side effects are declared by the patients, recorded and reported by the investigators at every visit. The number of patients switching of experimental treatment is recorded. The percentage of dose reduction of steroids and proportion of patients who require a dose increase at any time
7. The Quality of Life is assessed by the general questionnaire SF-36. Mean V1 (M0), V7 (M6) and V9 (M12) scores are compared.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 5

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Assistance Publique Hopitaux De Paris

Sponsor organisation

Assistance Publique Hopitaux De Paris

Address

Porte 23, 1 Avenue Claude Vellefaux 1 Avenue Claude Vellefaux

City

Paris Cedex 10

Postcode

75475

Country

France

Scientific contact point

Organisation

Assistance Publique Hopitaux De Paris

Contact name

Coordinating Investigator

Public contact point

Organisation

Assistance Publique Hopitaux De Paris

Contact name

Coordinating Investigator

Locations

1 EU/EEA country · 16 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 10 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

4 submissions — initial application plus substantial / non-substantial modifications