TABLE 1.

Entry criteria

Inclusion criteria

Multidisciplinary consensus diagnosis of FHP

Age 18 to 80 years at randomisation

Diagnosis of FHP, defined from the first instance in which a patient was informed of having FHP, for at least 3–6 months

HRCT according to pre-specified criteria:   Typical FHP#: evidence of lung fibrosis (reticular abnormality and/or traction bronchiectasis and/or architectural distortion and/or honeycombing) with either of the following:

• Profuse poorly defined centrilobular nodules of ground-glass opacity affecting all lung zones

• Inspiratory mosaic attenuation with three-density sign

AND

• Lack of features suggesting an alternative diagnosis

Compatible FHP¶: evidence of lung fibrosis (as above) with any of the following:

• Patchy or diffuse ground-glass opacity

• Patchy, non-profuse centrilobular nodules of ground-glass attenuation

• Mosaic attenuation and lobular air-trapping that do not meet criteria for typical FHP

AND

• Lack of features suggesting an alternative diagnosis.

Indeterminate FHP+: CT signs of fibrosis without other features suggestive of HP and lack of features suggesting an alternative diagnosis

FHP disease severity and progression

FVC ≥40% pred, DLCO ≥30% pred based on historical pulmonary function tests obtained within the 60 days prior to day 1

Presence of fibrotic abnormalities involving ≥5% of the lung parenchyma, with or without traction bronchiectasis or honeycombing, on HRCT scan

Evidence of disease progression: worsening respiratory symptoms and increased extent of fibrosis on HRCT or relative decline in the FVC of at least 5% over 24 months

Able to walk ≥100 m during the 6-min walk test at screening

Informed consent and protocol adherence

Able to understand and sign a written informed consent form

Able to understand the importance of adherence to study treatment and the study protocol and willing to follow all study requirements, including the concomitant medication restrictions, throughout the study

Exclusion criteria

Disease-related exclusions

Not a suitable candidate for enrolment or unlikely to comply with the requirements of this study, in the opinion of the investigator

Cigarette smoking at screening or unwilling to avoid tobacco products throughout the study

Known explanation for the interstitial lung disease, including but not limited to radiation, drug toxicity, sarcoidosis, pneumoconiosis

Clinical diagnosis of any connective tissue disease, including but not limited to scleroderma, polymyositis/dermatomyositis, and rheumatoid arthritis

Expected to receive a lung transplant within 6–12 months from randomisation or on a lung transplant waiting list at randomisation

The Investigator judges that there has been sustained improvement in the severity of FHP during the 6–12 months prior to screening visit 1, based on changes in FVC, DLCO, and/or HRCT scans of the chest

Medical exclusions

Any condition other than FHP that, in the opinion of the investigator, is likely to result in the death of the patient within 6–12 months

Any condition that, in the opinion of the investigator, might be significantly exacerbated by the known side-effects associated with the administration of pirfenidone

Pregnancy or lactation   Women of childbearing capacity are required to have a negative serum pregnancy test before treatment and must agree to maintain highly effective contraception by practicing abstinence or by using at least two methods of birth control from the date of consent through the end of the study; if abstinence is not practiced, one of the two methods of birth control should be an oral contraceptive (e.g. oral contraceptive and a spermicide)

History of ongoing alcohol or substance abuse

History of severe hepatic impairment or end-stage liver disease

History of end-stage renal disease requiring dialysis

Clinical evidence of active infection including, but not limited to, bronchitis, pneumonia, sinusitis, or urinary tract infection

Unstable or deteriorating cardiac disease, including but not limited to the following:

• Unstable angina pectoris or myocardial infarction

• Congestive heart failure requiring hospitalisation

• Uncontrolled clinically significant arrhythmias

Laboratory exclusions

Any of the following liver function test criteria above specified limits: total bilirubin >2.0 mg·dL−1, excluding patients with Gilbert's syndrome; aspartate or alanine aminotransferase (AST/SGOT or ALT/SGPT) >3× ULN; alkaline phosphatase >2.5× ULN within past 30 days

Creatinine clearance <30 mL·min−1, calculated using the Cockcroft–Gault formula within past 30 days

Electrocardiogram with a QTc interval >500 ms at screening

Medication exclusions

Prior use of pirfenidone, nintadinib or known hypersensitivity to any of the components of study treatment

Introduction, increase or escalation of immunosuppressive pharmacological therapy within 1 month (e.g. prednisone, azathioprine, mycophenolic acid and mycophenolate mofetil)§

Use of any of the following therapies within 28 days before screening: bosentan, ambrisentan, cyclophosphamide, cyclosporine, etanercept, iloprost, infliximab, methotrexate, tacrolimus, tetrathiomolybdate, TNF-α inhibitors, imatinib mesylate, interferon γ-1b, and tyrosine kinase inhibitors, fluvoxamine, Sildenafil (daily use)

FHP: fibrotic hypersensitivity pneumonitis; HRCT: high-resolution computed tomography; FVC: forced vital capacity; D_LCO: diffusing capacity of the lung for carbon monoxide; ULN: upper limit of normal; TNF: tumour necrosis factor. In all subjects with biopsy specimens, data on the overall histological pattern and individual features will be determined and scored by an expert chest pathologist using a standardised data collection form. In the absence of surgical lung histology, a high-confidence provisional diagnosis based on the above computed tomography (CT) confidence pattern and multidisciplinary consensus required. ^#: these patients are required to have an identifiable antigen exposure, or indeterminate or unidentifiable antigen exposure and bronchoalveolar lavage (BAL) lymphocytosis (≥20%) or transbronchial biopsies demonstrating non-necrotising granuloma(s) or lymphocytosis, or surgical lung histology consistent with HP. ^¶: these patients are required to have an identifiable or indeterminate antigen exposure and BAL lymphocytosis (≥20%) or transbronchial biopsies demonstrating non-necrotising granuloma(s) or lymphocytosis, or surgical lung histology consistent with HP. Otherwise, surgical lung histology consistent with HP. ⁺: these patients are required to have a known antigen exposure and BAL lymphocytosis (≥20%) or transbronchial biopsies demonstrating non-necrotising granuloma(s) or lymphocytosis, or surgical lung histology consistent with HP. ^§: decreasing or tapering off oral corticosteroids is allowed.