Evolution of Lung 18FDG Uptake in Patients With Idiopathic Pulmonary Fibrosis and Receiving Pirfenidone

Idiopathic pulmonary fibrosis (IPF) is a rare and fatal lung disease characterized by unpredictable changes with variable kinetics of progression. Changes in pulmonary function (FVC, DLCO) assessed at the time of diagnosis, or decline in pulmonary function within 12 months after diagnosis, are the best predictors of survival, but poorly predicted disease activity and evolution. 18FDG positron emission tomography (18FDG PETscan) provides the ability to quantify cell metabolism in vivo and non-invasively using a labeled non-metabolizable substrate. Several parameters can be measured in an automated and reproducible way, such as the mean fixation intensity (SUV mean), the maximum fixation intensity (SUV max), the hyperfixing volume measurement (MLV) or the glycolytic activity measurement tissue or TLG (total lesions glycolysis). Several studies have demonstrated an increase of glycolytic activity in lung fibroblast from IPF patient. In a recent study, the investigators demonstrated a strong correlation between the lung uptake parameters and the lung function tests results (LFTs) and prognostic score GAP. In addition, MLV and TLG were factors prognostic and independently associated with progression-free survival at 12 months. In a preliminary study, the investigators studied the change of these parameters in twelve patients treated with pirfenidone for IPF who performed an 18FDG PETscan before the initiation of treatment and about twelve weeks later. A mean decrease of 30% in TLG value between the two evaluations was observed. These preliminary data suggest that pirfenidone influences lung metabolism in patients with IPF. The investigators aim to conduct a prospective study to confirm and refine the preliminary data.

Idiopathic pulmonary fibrosis (IPF) is a rare and fatal lung disease characterized by an unpredictable evolution with variable kinetics of progression and burdened by the occurrence of exacerbation. The evaluation of the prognosis in a given patient remains difficult. Impaired lung function assessed by the value of forced vital capacity (FVC) and diffusion of lung carbon monoxide (DLCO) at the time of diagnosis, or decline in lung function within 6 or 12 months after the diagnosis, are the best predictive markers of survival but fail to assess or to predict lung function decline. Until recently, lung transplantation was the only IPF treatment and remains associated with high morbidity and mortality. Pirfenidone and nintedanib - anti-fibrotic treatments - are now validated therapies in the management of mild-to-moderate IPF defined by FVC ≥ 50% of predictive value and by DLCO ≥ 30 % of predicted value. Several international clinical trials demonstrated that pirfenidone and nintedanib significantly reduce the lung function decline and the exacerbations incidence and significantly improve survival. The emergence of these innovative but costly therapies - which are associated with a non-negligible rate of adverse effects - requires the development of tools to evaluate their effectiveness and monitor anti-fibrotic activity. The 18-fluorodesoxyglucose (18FDG) lung uptake may be the first tool to predict early therapeutic response. PET offers the possibility to quantify in vivo and non-invasively the cell metabolism, using a non-metabolizable substrate labeled as 18FDG. Several parameters can be measured in an automated and reproducible manner such as the mean uptake intensity (SUV mean), the maximum uptake intensity (SUV max), the metabolic lung volume measurement (MLV) or finally the measurement of tissue glycolytic activity or TLG (total lesion glycolysis). 18FDG PET scanner plays a key role in the diagnosis and monitoring of neoplasia and inflammatory diseases such as sarcoidosis. Recent studies reported a change of the metabolic activity of pulmonary fibroblasts issued from IPF, showing increase of glycolytic activity. In a recent study, the investigators demonstrated a strong correlation between the lung uptake parameters and the lung function tests results and prognostic score GAP. In addition, MLV and TLG were prognostic and independently associated with progression-free survival at 12 months. Preliminary data suggest that the intensity of lung 18FDG uptake may be a prognostic marker but also a predictive marker of response to anti-fibrotic treatments. A prospective study must be conducted to confirm or refute these observations.

Primary objective: The main objective of this study is to describe the changes of 18FDG lung uptake assessed by TLG variation in patients with IPF, 12 weeks after the initiation of pirfenidone.

Secondary objectives: Secondary objectives include the following : 1. To describe the changes of 18FDG lung uptake assessed by other 18FDG indices (SUVmean, SUVmax and MLV) in patients with IPF, 12 weeks after the initiation of pirfenidone ; 2. To study the relationship between the variation of 18FDG lung uptake 12 weeks after the initiation of pirfenidone therapy (as assessed by the changes of TLG, SUVmean, SUVmax and MLV) and the decline of FVC 12, 24, 36 and 48 weeks after the initiation of pirfenidone therapy ; 3. To estimate the predictive performance of the variation of 18FDG lung uptake 12 weeks after the beginning of pirfenidone therapy for therapeutic efficacy at 24 weeks.

Experimental plan: This is an interventional, prospective, multicenter, proof of concept study. 18FDG PET-scanner will be performed at baseline and 12 weeks after the beginning of pirfenidone treatment in each patient. Lung Function Tests will be also performed before and 12 weeks after initiation of pirfenidone treatment and will be repeated every 12 weeks until 48 weeks after pirfenidone initiation. A clinical examination and liver enzymes will be assessed every 12 weeks. The occurrence of any adverse event will be collected throughout the trial. LFTs will be interpreted blindly from the results of 18FDG uptake.

Eligibility Criteria:
Inclusion Criteria:

1. IPF, diagnosed accordingly to ATS/ERS/JRS/ALAT international guidelines
2. FVC≥50% and DLCO≥30%
3. Decision to initiate a treatment with pirfenidone
4. Affiliation to the French social security system

Exclusion Criteria:

Will be non-eligible in this study any patient:

1. with an age lower than 18 years
2. with a life expectancy lower than 12 months as assessed by the investigator
3. taking an anti-fibrotic treatment (pirfenidone, nintedanib or any experimental molecule) in the previous three months
4. treated by corticosteroid therapy (daily dose \> 10 mg, prednisone equivalent)
5. with neoplasia localized in thorax
6. with contraindication to pirfenidone according to the French Summary of Product Characteristics : hypersensitivity to the active substance or to any of the excipients, past history of angioedema with pirfenidone, concomitant treatment with fluvoxamine, severe or terminal hepatic insufficiency, severe renal insufficiency (CrCl \<30ml / min) or end-stage requiring dialysis
7. with a positive pregnancy test or currently breastfeeding
8. with contraindication to performing a 18FDG PETscan, ie 18FDG hypersensitivity
9. with emphysema extension \>15% on HRCT according to Cottin et al (16).