Cyclophosphamide for Acute Exacerbation of Idiopathic Pulmonary Fibrosis

Study Overview
=================
Brief Summary
-----------------
Acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF) is a major event of IPF with an annual incidence between 5 and 10% and is responsible for the death of one third of IPF patients. When AE-IPF occurs, it is associated with poor survival with an overall mortality at 3 months upper of 50%. To date, no treatment has been proved to be effective in AE-IPF but the efficacy of cyclophosphamide (CYC) on survival has been suggested, mainly by retrospective series and needs to be confirmed. This confirmation is mandatory to improve prognosis of AE-IPF but also to avoid unsuspected deleterious effect as it as been shown with immunosuppressor in stable IPF.

Detailed Description
-----------------
Acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF) is a major event of IPF with an annual incidence between 5 and 10% and is responsible for the death of one third of IPF patients. When AE-IPF occurs, it is associated with poor survival with an overall mortality at 3 months upper of 50%. To date, no treatment has been proved to be effective in AE-IPF but the efficacy of CYC on survival has been suggested, mainly by retrospective series and needs to be confirmed. This confirmation is mandatory to improve prognosis of AE-IPF but also to avoid unsuspected deleterious effect as it as been shown with immunosuppressor in stable IPF.

Official Title
-----------------
Cyclophosphamide Added to Corticosteroid in the Treatment of Acute Exacerbation of Idiopathic Pulmonary Fibrosis: a Placebo-controlled Randomized Trial

Conditions
-----------------
Idiopathic Pulmonary Fibrosis

Intervention / Treatment
-----------------
* Drug: Cyclophosphamide
* Drug: Placebo
* Drug: Corticosteroid (prednisolone)


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria : ≥18 years of age Definite or probable IPF diagnosis defined on 2011 international recommendations Definite or suspicion of AE defined by IPFnet criteria after exclusion of alternative diagnosis of acute worsening. Efficient contraceptive method within 1 month for women and 3 months for men after the last dose of treatment Affiliation to the social security Able to understand and sign a written informed consent form Exclusion Criteria: Identified etiology for acute worsening (i.e. infectious disease) Known hypersensitivity or contra-indication to CYC or to any component of the study treatment Patient on mechanical ventilation Active bacterial, viral, fungal or parasitic infection Active cancer Patient on a lung transplantation waiting list Treatment with CYC in the last 12 months Patient participating to another clinical trial Pregnancy or lactation

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Corticosteroid with placebo<br>Population is IPF patients with an AE who meet the inclusion and exclusion criteria defined below. All patients will receive non experimental medication with high dose of corticosteroid. | Drug: Placebo<br>* Population is IPF patients with an AE who meet the inclusion and exclusion criteria defined below.<br>* Other names: Control group;Drug: Corticosteroid (prednisolone)<br>* All patients will receive non experimental medication with high dose of corticosteroid.<br>* Other names: Both groups;|
| Experimental: Corticosteroid associated with Cyclophosphamide<br>Population is IPF patients with an AE who meet the inclusion and exclusion criteria defined below. All patients will receive non experimental medication with high dose of corticosteroid. Intravenous Cyclophosphamide (CYC), 600 mg/m² (adapted to age and renal function, maximal dose of 1.2 g) at Day 0, Day 15, M1, M2 | Drug: Cyclophosphamide<br>* Population is IPF patients with an AE who meet the inclusion and exclusion criteria defined below. Intravenous Cyclophosphamide (CYC), 600 mg/m² (adapted to age and renal function, maximal dose of 1.2 g) at Day 0, Day 15, M1, M2<br>Drug: Corticosteroid (prednisolone)<br>* All patients will receive non experimental medication with high dose of corticosteroid.<br>* Other names: Both groups;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Early survival | All cause of mortality at 3 months | 3 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival | Overall Survival at M6 and M12 | 6 months and 12 montns | 
| Respiratory disease-specific mortality | Respiratory disease-specific mortality at M3 and M6 | 6 months | 
| Respiratory Morbidity | \Worsening dyspnea (0-100-mm visual analogue (VAS) scale anchored with 0 ''no breathlessness'' and 10 or 100 ''worst imaginable breathlessness. Worsening is defined an absolute decrease of 10 mm) Or Increase need of supplemental oxygen of more than 3l/min to obtained a SaO2 > 90% or decrease of PaO2 of more than 10 mmHg with the same rate of flow supplemental oxygen Or Decrease FVC of more than 10% of predicted value Or Decrease diffuse capacity for carbon monoxide (DLCO) of more than 15% prednisolone | 6 months | 
| Chest HRCT features (HRCT images will be scored at 5 levels) | Chest HRCT features at M3 and M6 compared to inclusion | 6 months | 
| Prognosis factors of AE-IPF | PFTs results before AE-IPF | 3 months | 
| Time to visit after clinical worsening |  | 3 months | 
| Laboratory evaluation (LDH, CRP) at AE diagnosis (composite) |  | 3 months | 
| Prognosis factors of AE-IPF | PaO2 at AE diagnosis | 3 months | 
| Prognosis factors of AE-IPF | Chest HRCT features at AE diagnosis compared to HRCT before AE-IPF (if available) | 3 months | 
| Prognosis factors of AE-IPF | Chest HRCT classification before AE-IPF (definite UIP, probable UIP, indeterminate), if available | 3 months | 
| Time to dispense treatment of AE-IPF |  | 3 months | 
| Hemorrhagic cystitis (occurence of hematuria on urine dipstick and pelvic pain and/or dysuria should lead to cystoscopy) |  | 6 months | 
| Number of Infectious disease |  | 6 months | 
| Diabetes mellitus (capillary blood glucose monitoring and fasting plasma glucose > 1.26 g/l) |  | 6 months | 
| Hypertension (Blood pressure > 160/100 mmHg) |  | 6 months | 
| Clinical laboratory evaluation (blood count, serum creatinin measurement composite) according to Common Terminology Criteria for Adverse Event (CTCAE). |  | 6 months |