Back to resultsCyclophosphamide and Azathioprine vs Tacrolimus in Antisynthetase Syndrome-related Interstitial Lung Disease (CATR-PAT)
Primary Purpose
Antisynthetase Syndrome (ASS), Interstitial Lung Disease
Status
Recruiting
Phase
Phase 3
Locations
France
Study Type
Interventional
Intervention
Cyclophosphamide and azathioprine
Tacrolimus
Sponsored by
About this trial
This is an interventional treatment trial for Antisynthetase Syndrome (ASS)
Eligibility Criteria
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-Centromères, 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.
Sites / Locations
- Hôpital Universitaire Pitié SalpêtrièreRecruiting
Arms of the Study
Arm 1
Arm 2
Arm Type
Experimental
Experimental
Arm Label
European strategy
American strategy
Arm Description
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
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.
Outcomes
Primary Outcome Measures
Progression free survival
Compare the efficacy of Cyclophosphamide and Azathioprine vs Tacrolimus in patients with ASS related-ILD Time from the initiation of treatment to the first event related to ASS related-ILD (progression free survival)
Secondary Outcome Measures
Variation of the six minute walk tests
Compare Global variation of the M0 and M12-six minute walk tests (distance in meter, differential of saturation in %)
Forced Vital Capacity (FVC)
Compare Global variation of M0 and M12-FVC (both absolute and %)
Diffusing Lung Carbon Monoxyde Capacity (cDLCO)
Compare Global variation of M0 and M12 cDLCO (both absolute and %)
Rate of pulmonary improvement
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 parenchyma evaluated by the extension score and -10% of the coarseness score of fibrosis): see Appendix 3' 3D. and/or improvement of PaO2 > 10 mmHg (FiO2=21%), without hyperventilation at any test
Time to extra-pulmonary improvement
Evaluated as follow :
4A. improvement of the muscle involvement assessed by muscle manual testing (MMT/150, see Appendix 5) at each visit, is defined by an increased score > 20% 4B. 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) 4C. improvement of the joint involvement, assessed by the ACR score at every visit is defined by a decrease > 20% of baseline number of swelling and painful joints.
Rate of extra-pulmonary improvement
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.
Treatments tolerance
6A. any serious adverse event attributable to any experimental medication, which requires hospitalization, is recorded at any time 6B. side effects are declared by the patients, recorded and reported by the investigators at every visit 6C. the number of patients switching of experimental treatment is recorded 6D. the cumulative dose (mg/kg) of steroids will be compared at the end of the study
Treatment Efficacy
6A. any serious adverse event attributable to any experimental medication, which requires hospitalization, is recorded at any time 6B. side effects are declared by the patients, recorded and reported by the investigators at every visit 6C. the number of patients switching of experimental treatment is recorded 6D. the cumulative dose (mg/kg) of steroids will be compared at the end of the study
Quality of Life with SF-36 scale
Full Information
NCT ID
NCT03770663
First Posted
December 7, 2018
Last Updated
February 6, 2021
Sponsor
Assistance Publique - Hôpitaux de Paris
1. Study Identification
Unique Protocol Identification Number
NCT03770663
Brief Title
Cyclophosphamide and Azathioprine vs Tacrolimus in Antisynthetase Syndrome-related Interstitial Lung Disease
Acronym
CATR-PAT
Official Title
Cyclophosphamide and Azathioprine vs Tacrolimus in Antisynthetase Syndrome-related Interstitial Lung Disease : Multicentric Randomized Phase III Trial
Study Type
Interventional
2. Study Status
Record Verification Date
February 2021
Overall Recruitment Status
Recruiting
Study Start Date
February 5, 2021 (Actual)
Primary Completion Date
January 2, 2024 (Anticipated)
Study Completion Date
January 2, 2024 (Anticipated)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Assistance Publique - Hôpitaux de Paris
4. Oversight
Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes
5. Study Description
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."
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Antisynthetase Syndrome (ASS), Interstitial Lung Disease
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
76 (Anticipated)
8. Arms, Groups, and Interventions
Arm Title
European strategy
Arm Type
Experimental
Arm Description
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
Arm Title
American strategy
Arm Type
Experimental
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
Cyclophosphamide and azathioprine
Intervention Description
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
Intervention Name(s)
Tacrolimus
Intervention Description
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.
Primary Outcome Measure Information:
Title
Progression free survival
Description
Compare the efficacy of Cyclophosphamide and Azathioprine vs Tacrolimus in patients with ASS related-ILD Time from the initiation of treatment to the first event related to ASS related-ILD (progression free survival)
Time Frame
From baseline to 12 months
Secondary Outcome Measure Information:
Title
Variation of the six minute walk tests
Description
Compare Global variation of the M0 and M12-six minute walk tests (distance in meter, differential of saturation in %)
Time Frame
at baseline, 3 months, 6 months, 9 months and 12 months
Title
Forced Vital Capacity (FVC)
Description
Compare Global variation of M0 and M12-FVC (both absolute and %)
Time Frame
at baseline, 3 months, 6 months, 9 months and 12 months
Title
Diffusing Lung Carbon Monoxyde Capacity (cDLCO)
Description
Compare Global variation of M0 and M12 cDLCO (both absolute and %)
Time Frame
at baseline, 3 months, 6 months, 9 months and 12 months
Title
Rate of pulmonary improvement
Description
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 parenchyma evaluated by the extension score and -10% of the coarseness score of fibrosis): see Appendix 3' 3D. and/or improvement of PaO2 > 10 mmHg (FiO2=21%), without hyperventilation at any test
Time Frame
at baseline, 3 months, 6 months, 9 months and 12 months
Title
Time to extra-pulmonary improvement
Description
Evaluated as follow :
4A. improvement of the muscle involvement assessed by muscle manual testing (MMT/150, see Appendix 5) at each visit, is defined by an increased score > 20% 4B. 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) 4C. improvement of the joint involvement, assessed by the ACR score at every visit is defined by a decrease > 20% of baseline number of swelling and painful joints.
Time Frame
at each visits
Title
Rate of extra-pulmonary improvement
Description
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.
Time Frame
at baseline and 12 months
Title
Treatments tolerance
Description
6A. any serious adverse event attributable to any experimental medication, which requires hospitalization, is recorded at any time 6B. side effects are declared by the patients, recorded and reported by the investigators at every visit 6C. the number of patients switching of experimental treatment is recorded 6D. the cumulative dose (mg/kg) of steroids will be compared at the end of the study
Time Frame
At every visit
Title
Treatment Efficacy
Description
6A. any serious adverse event attributable to any experimental medication, which requires hospitalization, is recorded at any time 6B. side effects are declared by the patients, recorded and reported by the investigators at every visit 6C. the number of patients switching of experimental treatment is recorded 6D. the cumulative dose (mg/kg) of steroids will be compared at the end of the study
Time Frame
at every visit
Title
Quality of Life with SF-36 scale
Time Frame
Baseline, 6 months, 12 months
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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-Centromères, 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.
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Olivier BENVENISTE, MD
Phone
+33 (0)1 42 16 10 88
Email
olivier.benveniste@aphp.fr
First Name & Middle Initial & Last Name or Official Title & Degree
HERVIER Baptiste, MD
Phone
+33 (0)1 49 42 55
Email
baptiste.hervier@aphp.fr
Facility Information:
Facility Name
Hôpital Universitaire Pitié Salpêtrière
City
Paris
ZIP/Postal Code
75013
Country
France
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Olivier BENVENISTE, MD
Email
olivier.benveniste@aphp.fr
12. IPD Sharing Statement
Learn more about this trial
Cyclophosphamide and Azathioprine vs Tacrolimus in Antisynthetase Syndrome-related Interstitial Lung Disease
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