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Trial record 77 of 215 for:    Inflammatory Myopathies

Cyclophosphamide and Azathioprine vs Tacrolimus in Antisynthetase Syndrome-related Interstitial Lung Disease (CATR-PAT)

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ClinicalTrials.gov Identifier: NCT03770663
Recruitment Status : Not yet recruiting
First Posted : December 10, 2018
Last Update Posted : December 21, 2018
Sponsor:
Information provided by (Responsible Party):
Assistance Publique - Hôpitaux de Paris

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."


Condition or disease Intervention/treatment Phase
Antisynthetase Syndrome (ASS) Interstitial Lung Disease Drug: Cyclophosphamide and azathioprine Drug: Tacrolimus Phase 3

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."

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 76 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Cyclophosphamide and Azathioprine vs Tacrolimus in Antisynthetase Syndrome-related Interstitial Lung Disease : Multicentric Randomized Phase III Trial
Estimated Study Start Date : January 2, 2019
Estimated Primary Completion Date : January 2, 2021
Estimated Study Completion Date : January 2, 2021


Arm Intervention/treatment
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

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

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.

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.




Primary Outcome Measures :
  1. Progression free survival [ Time Frame: From baseline to 12 months ]
    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 :
  1. Variation of the six minute walk tests [ Time Frame: at baseline, 3 months, 6 months, 9 months and 12 months ]
    Compare Global variation of the M0 and M12-six minute walk tests (distance in meter, differential of saturation in %)

  2. Forced Vital Capacity (FVC) [ Time Frame: at baseline, 3 months, 6 months, 9 months and 12 months ]
    Compare Global variation of M0 and M12-FVC (both absolute and %)

  3. Diffusing Lung Carbon Monoxyde Capacity (cDLCO) [ Time Frame: at baseline, 3 months, 6 months, 9 months and 12 months ]
    Compare Global variation of M0 and M12 cDLCO (both absolute and %)

  4. Rate of pulmonary improvement [ Time Frame: at baseline, 3 months, 6 months, 9 months and 12 months ]

    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


  5. Time to extra-pulmonary improvement [ Time Frame: at each visits ]

    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.


  6. Rate of extra-pulmonary improvement [ Time Frame: at baseline and 12 months ]

    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.


  7. Treatments tolerance [ Time Frame: At every visit ]
    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

  8. Treatment Efficacy [ Time Frame: at every visit ]
    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

  9. Quality of Life with SF-36 scale [ Time Frame: Baseline, 6 months, 12 months ]


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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

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Responsible Party: Assistance Publique - Hôpitaux de Paris
ClinicalTrials.gov Identifier: NCT03770663     History of Changes
Other Study ID Numbers: P140217
2016-002921-12 ( EudraCT Number )
First Posted: December 10, 2018    Key Record Dates
Last Update Posted: December 21, 2018
Last Verified: December 2018

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:
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Myositis
Muscular Diseases
Anti-Inflammatory Agents
Syndrome
Lung Diseases
Lung Diseases, Interstitial
Disease
Pathologic Processes
Respiratory Tract Diseases
Musculoskeletal Diseases
Neuromuscular Diseases
Nervous System Diseases
Cyclophosphamide
Tacrolimus
Azathioprine
Methylprednisolone
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Myeloablative Agonists
Calcineurin Inhibitors
Enzyme Inhibitors
Antiemetics
Autonomic Agents
Peripheral Nervous System Agents