Cyclophosphamide Systemic Sclerosis Associated Interstitial Lung Disease (SCLEROCYC)

Intravenous Cyclophosphamide for the Treatment of Systemic Sclerosis Associated Interstitial Lung Disease

By including in this study patients with significant worsening of their lung volumes and / or their DLCO (carbon monoxide diffusing capacity) in the previous year, on the basis of an open retrospective study we recently conducted, we hope to demonstrate that a strategy combining prednisone and intravenous cyclophosphamide therapy is accompanied by an increase in the frequency stabilization / improvement of lung volumes and / or DLCO of patients at 12 months of 15% in the placebo and prednisone cyclophosphamide 50% in cyclophosphamide and prednisone.We also hope to demonstrate significant decrease in the number of patients excluded for failure in the CYC arm as compared to the placebo arm.

Study Overview

• Status: Completed
• Conditions: Systemic Sclerosis; Interstitial Lung Disease; Scleroderma; Lung Fibrosis
• Intervention / Treatment: Drug: Cyclophosphamide; Drug: Placebo

Detailed Description

This is a randomized prospective multicenter study evaluating the efficacy against placebo of cyclophosphamide in combination with prednisone in the treatment of systemic sclerosis related interstitial lung disease. Patients will be allocated, after randomization into two groups receiving both corticosteroids: a group of patients receiving placebo of cyclophosphamide and a group of patients treated with cyclophosphamide. Cyclophosphamide will be administered IV at a dose of 0.7 g / m (maximum 1200 mg) every 4 weeks. In patients over 65 or if the creatinine clearance below 30 ml / min the dose should be reduced to 0.6 g / m². The duration of treatment with cyclophosphamide will be 12 months.

• Study Type: Interventional
• Enrollment (Actual): 40
• Phase: Phase 3

Contacts and Locations

Study Locations

• France
  • Paris, France, 75014
    • Cochin Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Age ≥ 18 years old
• Signed informed consent
• Patient with systemic sclerosis fulfilling the ACR -American college of rheumatology - (Masi et al. 1980) and/or Leroy and Medsger (LeRoy and Medsger 2001) diagnostics criteria with worsening ILD (interstitial lung disease) identified on a high resolution chest CT scan and by worsening of forced vital capacity (FVC) and/or total lung capacity (TLC) ≥10% and/or worsening of DLCO ≥ 15% as compared to values obtained within the 3 to 18 months preceding inclusion (for DLCO, in the absence of pulmonary arterial hypertension upon echocardiography)
• Smokers may be included (DLCO must be performed at least 72h after stopping tobacco intake).
• Patients with pulmonary hypertension (mean pulmonary arterial pressure <35 mmHg upon right heart catheterisation) secondary to hypoxia due to pulmonary fibrosis will also be included into the study.

• Physical examination prior to inclusion into the study (results must be given to the patient).

  -: Contraception considered effective by the investigator (abstinence and / or oral contraception or mechanical) for women of childbearing age (negative pregnancy test at baseline)

• Affiliation with a mode of social security (profit or being entitled)

Exclusion Criteria:

• Prednisone prescribed a dose greater than 15 mg/d during the last 3 months.
• Scleroderma renal crisis or acute or critical limb ischemia within the last year preceding inclusion,
• Left ventricular ejection fraction below 40% evaluated by echocardiography.
• Out of proportion pulmonary hypertension (mean pulmonary artery pressure above 35 mmHg upon right heart catheterization).
• CYC treatment during the last 12 months.
• Allergy, hypersensitivity or documented adverse events or contra-indications to the drugs used in the study (cyclophosphamide, Uromitexan, corticosteroids, domperidone ...)
• Patients with a past history of cancer within four years before inclusion and/or a history of chemotherapy for cancer within four years before inclusion (in remission or without disease activity for more than four years). Inclusion is authorized for patients with a basal cell carcinoma in the last 5 years.
• Severe infection: sepsis, cellulitis, gangrene in the last three months
• Past history of cystitis related to cyclophosphamide treatment
• Association to another connective disease : systemic lupus erythematosus, syndrome of Gougerot-Sjögren with anti-SSA/SSB, mixed connective tissue disease
• Patient breastfeeding
• Failure to sign the informed consent or unable to consent
• Patient participating in another clinical trial
• Injection of Rituximab within 6 months preceding inclusion
• Methotrexate or Cellcept treatment at inclusion

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: QUADRUPLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Cyclophosphamide; Prednisone 15 mg/d + monthly pulse cyclophosphamide 700 mg/m ² diminished to 600 mg/m ² in patients over 65 years or having a creatinine clearance lower than 30 ml/min for 12 months.	Drug: Cyclophosphamide; Prednisone 15 mg/d + monthly pulse cyclophosphamide 700 mg/m ² diminished to 600 mg/m ² in patients over 65 years or having a creatinine clearance lower than 30 ml/min for 12 months.
PLACEBO_COMPARATOR: Placebo; Prednisone 15 mg/d + monthly pulse of placebo of cyclophosphamide. The posology and the methods of administration of the placebo of cyclophosphamide (NaCl) will be the same as those used for cyclophosphamide	Drug: Placebo; Prednisone 15 mg/d + monthly pulse of placebo of cyclophosphamide. The posology and the methods of administration of the placebo of cyclophosphamide (NaCl) will be the same as those used for cyclophosphamide

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Forced vital capacity	Forced vital capacity at 12 months	at 12 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mortality		at 12 months
Progression free survival	Progression free survival	at 12 months
Carbon monoxide diffusing capacity (DLCO)		at 12 months
Treatment failure	Failure of cyclophosphamide or placebo	at 12 months
Walk test distance	Six minutes walk test distance, O2 desaturation and gradient between maximal and minimal SAO2 during the test	at 12 months
Dyspnea	NYHA (Classification de la New York Heart Association), BDI (Beck Depression Inventory) and Borg index	at 12 months
Health Assessment Questionnaire		at 12 months
Quality of life	Saint-Georges; SF-36	at 12 months
Chest CT (computed tomography) scan	CT (computed tomography) scan abnormalities	at 12 months

Collaborators and Investigators

• Sponsor: Assistance Publique - Hôpitaux de Paris
• Collaborators: Hôpital Claude-Huriez

Study record dates

Study Major Dates

• Study Start (ACTUAL): January 14, 2013
• Primary Completion (ACTUAL): February 22, 2018
• Study Completion (ACTUAL): February 22, 2018

Study Registration Dates

• First Submitted: April 2, 2012
• First Submitted That Met QC Criteria: April 2, 2012
• First Posted (ESTIMATE): April 4, 2012

Study Record Updates

• Last Update Posted (ACTUAL): November 18, 2019
• Last Update Submitted That Met QC Criteria: November 15, 2019
• Last Verified: November 1, 2019

More Information

Terms related to this study

• Keywords: Cyclophosphamide; Intravenous; Interstitial lung disease; Systemic sclerosis; Worsening
• Additional Relevant MeSH Terms: Pathologic Processes; Skin Diseases; Respiratory Tract Diseases; Connective Tissue Diseases; Sclerosis; Lung Diseases; Scleroderma, Systemic; Scleroderma, Diffuse; Pulmonary Fibrosis; Lung Diseases, Interstitial; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antirheumatic Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Cyclophosphamide
• Other Study ID Numbers: P081241; 2011-004709-26 (EUDRACT_NUMBER)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO