<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT03770663</url>
  </required_header>
  <id_info>
    <org_study_id>P140217</org_study_id>
    <secondary_id>2016-002921-12</secondary_id>
    <nct_id>NCT03770663</nct_id>
  </id_info>
  <brief_title>Cyclophosphamide and Azathioprine vs Tacrolimus in Antisynthetase Syndrome-related Interstitial Lung Disease</brief_title>
  <acronym>CATR-PAT</acronym>
  <official_title>Cyclophosphamide and Azathioprine vs Tacrolimus in Antisynthetase Syndrome-related Interstitial Lung Disease : Multicentric Randomized Phase III Trial</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Assistance Publique - Hôpitaux de Paris</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Assistance Publique - Hôpitaux de Paris</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      &quot;Antisynthetase syndrome (ASS) is one of the most severe inflammatory myopathy (IM), due to&#xD;
      pulmonary involvement (interstitial lung disease, ILD). Until now, the most commonly used&#xD;
      immunosuppresive therapy in Europe is Cyclophosphamide followed by different&#xD;
      immunosuppressive drugs as maintenance therapy, including Azathioprine (and so called &quot;&#xD;
      European Strategy &quot;). In the USA however, the first-line immunosuppressive treatment is&#xD;
      Tacrolimus (so called &quot; American Strategy &quot;). None of these two different strategies has ever&#xD;
      been studied prospectively, and there is no clear comparison of short and long-term treatment&#xD;
      efficacy and tolerance. Thus, there are yet no evidences helping the clinicians in the&#xD;
      therapeutic management of patients with ASS-related ILD.&#xD;
&#xD;
      The aim of this study is therefore to compare both strategies as first line treatments or in&#xD;
      relapsing patients : CATR.PAT study is a 52 weeks, randomized, comparative, controlled,&#xD;
      open-labeled, phase III, therapeutic clinical trial, comparing two treatment strategies.&quot;&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      &quot;During the study period, according to randomization into two groups (n=38 patients,&#xD;
      respectively), patients will receive either:&#xD;
&#xD;
      - Group 1 &amp; 2 : 3 IV pulses of Methylprednisolone (7.5 mg/kg/day followed by tapering doses&#xD;
      of oral Prednisone, started at 1 mg/kg/day from D4 to M12&#xD;
&#xD;
      In association with :&#xD;
&#xD;
        -  Group 1 : European Standard of care :&#xD;
&#xD;
           6 IV pulses of Cyclophosphamide (1000 mg) followed from M5 to M12 by oral Azathioprine&#xD;
           (2 mg/kg/day), with a maximum of 150 mg/d)&#xD;
&#xD;
        -  Group 2 : American Strategy Tacrolimus is given orally from M0 to M12 (started at the&#xD;
           initial dose of 2x2mg/d). Tacrolimus doses are regularly adapted to its serum&#xD;
           concentration to reach 5-15 ng/ml.&quot;&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">February 5, 2021</start_date>
  <completion_date type="Anticipated">January 2, 2024</completion_date>
  <primary_completion_date type="Anticipated">January 2, 2024</primary_completion_date>
  <phase>Phase 3</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Progression free survival</measure>
    <time_frame>From baseline to 12 months</time_frame>
    <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)</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Variation of the six minute walk tests</measure>
    <time_frame>at baseline, 3 months, 6 months, 9 months and 12 months</time_frame>
    <description>Compare Global variation of the M0 and M12-six minute walk tests (distance in meter, differential of saturation in %)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Forced Vital Capacity (FVC)</measure>
    <time_frame>at baseline, 3 months, 6 months, 9 months and 12 months</time_frame>
    <description>Compare Global variation of M0 and M12-FVC (both absolute and %)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Diffusing Lung Carbon Monoxyde Capacity (cDLCO)</measure>
    <time_frame>at baseline, 3 months, 6 months, 9 months and 12 months</time_frame>
    <description>Compare Global variation of M0 and M12 cDLCO (both absolute and %)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Rate of pulmonary improvement</measure>
    <time_frame>at baseline, 3 months, 6 months, 9 months and 12 months</time_frame>
    <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).&#xD;
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 &gt; 10 mmHg (FiO2=21%), without hyperventilation at any test</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Time to extra-pulmonary improvement</measure>
    <time_frame>at each visits</time_frame>
    <description>Evaluated as follow :&#xD;
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 &gt; 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 &gt; 50% (IU/ml) 4C. improvement of the joint involvement, assessed by the ACR score at every visit is defined by a decrease &gt; 20% of baseline number of swelling and painful joints.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Rate of extra-pulmonary improvement</measure>
    <time_frame>at baseline and 12 months</time_frame>
    <description>Extra-pulmonary improvement (muscle and joint involvements) is evaluated as follows :&#xD;
5A. improvement of the muscle involvement, assessed by MMT/150 muscle testing at baseline and M12, is defined by an increased score &gt; 20% 5B. improvement of the joint involvement, assessed by the ACR score at each visit is define by a decrease &gt; 20% of baseline number of swelling and painful joints.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Treatments tolerance</measure>
    <time_frame>At every visit</time_frame>
    <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</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Treatment Efficacy</measure>
    <time_frame>at every visit</time_frame>
    <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</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Quality of Life with SF-36 scale</measure>
    <time_frame>Baseline, 6 months, 12 months</time_frame>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">76</enrollment>
  <condition>Antisynthetase Syndrome (ASS)</condition>
  <condition>Interstitial Lung Disease</condition>
  <arm_group>
    <arm_group_label>European strategy</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <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&#xD;
In association with:&#xD;
6 IV pulses of Cyclophosphamide (1000mg) followed from M5 to M12 by oral Azathioprine (2mg/kg/day), with a maximum of 150mg/day</description>
  </arm_group>
  <arm_group>
    <arm_group_label>American strategy</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <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&#xD;
In association with:&#xD;
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.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Cyclophosphamide and azathioprine</intervention_name>
    <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</description>
    <arm_group_label>European strategy</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Tacrolimus</intervention_name>
    <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.</description>
    <arm_group_label>American strategy</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Age ≥ 18&#xD;
&#xD;
          2. Signed informed consent&#xD;
&#xD;
          3. Affiliation to the Social security system&#xD;
&#xD;
          4. Diagnosis of ASS: positive test for any of the 5 anti-tRNA synthetase antibodies&#xD;
             routinely tested (ELISA, Luminex or Linear-dot), including anti-Jo-1, anti-PL7,&#xD;
             anti-PL12, anti-EJ and anti-OJ.&#xD;
&#xD;
          5. Diagnosis of ILD-related ASS: interstitial lung disease on HRCT.&#xD;
&#xD;
          6. Moderate to severe ILD on PFT : FVC &lt; 80% and or cDLCO &lt; 70%&#xD;
&#xD;
          7. beta-HCG test negative or negative uterine echography (for women of child bearing&#xD;
             potential)&#xD;
&#xD;
          8. Women of childbearing potential must have an oral contraception (macroprogestatifs)&#xD;
             during all the duration of study treatment and 12 months after the last dose of study&#xD;
             treatment&#xD;
&#xD;
          9. Males who are sexually active with women of childbearing potential must agree to&#xD;
             follow instructions for method(s) of contraception for the duration of study treatment&#xD;
             and 6 months after the last dose of study treatment&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Pregnancy and/or breast feeding&#xD;
&#xD;
          2. Others contraindications to the treatments, including hypersensitivity to the drug&#xD;
             (including excipient and active compounds), medical contraception contraindications,&#xD;
             severe renal failure, severe hepatic insufficiency and severe psychiatric disorders.&#xD;
             Specific contraindications are listed for each experimental medication in Table 6&#xD;
             (according to updated Summary of product characteristics, see Appendix 8)&#xD;
&#xD;
          3. Fever or active bacterial infection (ie. septicemia, pneumopathy, pyelonephritis,&#xD;
             acute prostatitis …), or parasitic infection (ie. Anguillulosis …),or fungal infection&#xD;
             (ie. Invasive pulmonary aspergillosis …), or viral infection (HIV seropositivity,&#xD;
             Active Tuberculosis, active B/C viral hepatitis, CMV, active EBV…)&#xD;
&#xD;
          4. Active neoplasm&#xD;
&#xD;
          5. Previous inefficacy of Cyclophosphamide, Azathioprine or Tacrolimus, not related to&#xD;
             adhesion problems.&#xD;
&#xD;
          6. Previous use of 3 daily IV steroids &lt; 3 months before patient's enrollment.&#xD;
&#xD;
          7. ASS-related ILD worsening or relapse under Prednisone &gt; 0.5 mg/kg/day&#xD;
&#xD;
          8. Previous use of Cyclophosphamide, Azathioprine or Tacrolimus in the last 6 months.&#xD;
&#xD;
          9. Severe ASS requiring ICU (respiratory disease, myocarditis), plasma exchange or IV-Ig.&#xD;
&#xD;
         10. Positivity of auto-antibodies associated to Systemic Sclerosis (anti-Telomerase,&#xD;
             anti-Centromères, anti-Polymerase III).&#xD;
&#xD;
         11. Patients with QTc &gt; 450 msec&#xD;
&#xD;
         12. Patients with history of long QT syndrome (including familial) or ventricular&#xD;
             arrhythmias&#xD;
&#xD;
         13. Concomitant use of drugs prolonging QT / QTc (list of treatments in annex)&#xD;
&#xD;
         14. Hypokalemia&#xD;
&#xD;
         15. Patients with pulmonary hypertension detected on echocardiography during the&#xD;
             screening/selection visit (systolic pulmonary artery pressure (PAP) was 37-50 mmHg,&#xD;
             and/or tricuspid regurgitation velocity 2.8-3.4 ms-1) are excluded.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_contact>
    <last_name>Olivier BENVENISTE, MD</last_name>
    <phone>+33 (0)1 42 16 10 88</phone>
    <email>olivier.benveniste@aphp.fr</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>HERVIER Baptiste, MD</last_name>
    <phone>+33 (0)1 49 42 55</phone>
    <email>baptiste.hervier@aphp.fr</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>Hôpital Universitaire Pitié Salpêtrière</name>
      <address>
        <city>Paris</city>
        <zip>75013</zip>
        <country>France</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Olivier BENVENISTE, MD</last_name>
      <email>olivier.benveniste@aphp.fr</email>
    </contact>
  </location>
  <location_countries>
    <country>France</country>
  </location_countries>
  <verification_date>February 2021</verification_date>
  <study_first_submitted>December 7, 2018</study_first_submitted>
  <study_first_submitted_qc>December 7, 2018</study_first_submitted_qc>
  <study_first_posted type="Actual">December 10, 2018</study_first_posted>
  <last_update_submitted>February 6, 2021</last_update_submitted>
  <last_update_submitted_qc>February 6, 2021</last_update_submitted_qc>
  <last_update_posted type="Actual">February 9, 2021</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Myositis</mesh_term>
    <mesh_term>Lung Diseases</mesh_term>
    <mesh_term>Lung Diseases, Interstitial</mesh_term>
    <mesh_term>Syndrome</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Cyclophosphamide</mesh_term>
    <mesh_term>Azathioprine</mesh_term>
    <mesh_term>Tacrolimus</mesh_term>
  </intervention_browse>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03770663
org study id: P140217
secondary id: 2016-002921-12
nct id: NCT03770663
lead sponsor: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
"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."
"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."
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Progression free survival
time frame: From baseline to 12 months
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)
measure: Variation of the six minute walk tests
time frame: at baseline, 3 months, 6 months, 9 months and 12 months
description: Compare Global variation of the M0 and M12-six minute walk tests (distance in meter, differential of saturation in %)
measure: Forced Vital Capacity (FVC)
time frame: at baseline, 3 months, 6 months, 9 months and 12 months
description: Compare Global variation of M0 and M12-FVC (both absolute and %)
measure: Diffusing Lung Carbon Monoxyde Capacity (cDLCO)
time frame: at baseline, 3 months, 6 months, 9 months and 12 months
description: Compare Global variation of M0 and M12 cDLCO (both absolute and %)
measure: Rate of pulmonary improvement
time frame: at baseline, 3 months, 6 months, 9 months and 12 months
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
measure: Time to extra-pulmonary improvement
time frame: at each visits
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.
measure: Rate of extra-pulmonary improvement
time frame: at baseline and 12 months
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.
measure: Treatments tolerance
time frame: At every visit
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
measure: Treatment Efficacy
time frame: at every visit
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
measure: Quality of Life with SF-36 scale
time frame: Baseline, 6 months, 12 months
arm group label: European strategy
arm group type: Experimental
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 group label: American strategy
arm group type: Experimental
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: Cyclophosphamide and azathioprine
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
arm group label: European strategy
intervention type: Drug
intervention name: Tacrolimus
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.
arm group label: American strategy
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Olivier BENVENISTE, MD
phone: +33 (0)1 42 16 10 88
email: olivier.benveniste@aphp.fr
last name: HERVIER Baptiste, MD
phone: +33 (0)1 49 42 55
email: baptiste.hervier@aphp.fr
facility: 
status: Recruiting
contact: 
country: France
responsible party type: Sponsor
mesh term: Myositis
mesh term: Lung Diseases
mesh term: Lung Diseases, Interstitial
mesh term: Syndrome
mesh term: Cyclophosphamide
mesh term: Azathioprine
mesh term: Tacrolimus