Supplementary Appendix

Contents:

S1: Criteria for diagnosis of IPF in subjects enrolled in the COMET trial

S2: Full list of exclusion criteria for the COMET trial

S3: Research bronchoscopy protocol followed by study centers for the COMET trial

S4: Institutional review board committee names and approval numbers for all study centers in the COMET trial

S1: Criteria for diagnosis of IPF in subjects enrolled in the COMET trial

The diagnosis of IPF was based on clinical/radiographic and/or pathologic data (i.e. surgical lung biopsy). Criteria for the diagnosis of IPF without a surgical lungbiopsy included the presence of all major criteria and three of the four minor criterialisted below. Major criteria included 1) exclusion of other known causes of interstitiallung disease such as connective tissue diseases, environmental, and drug exposures, 2)restriction on pulmonary function testing (FVC < 90%) and/or evidence of impaired gasexchange (DLCO < 80%), and 3) HRCT features of definite UIP. Minor criteria included1) age > 50 years, 2) insidious onset of unexplained dyspnea, 3) duration of illness for ≥ 3 months, and 4) bibasilar inspiratory crackles.

S2: Full list of exclusion criteria for the COMET trial

  1. Confirmed diagnosis of idiopathic pulmonary fibrosis (IPF) at the study center more than two years prior to screening
  2. Environmental exposure (occupational, environmental, drug, etc.) felt by the principal investigator (PI) to be the etiology of the interstitial disease
  3. Diagnosis of collagen-vascular conditions
  4. FEV1/FVC ratio < 0.60 at screening (post bronchodilator)
  5. Significant bronchodilator response on screening spirometry, defined as a change in FEV1 ≥ 12% and absolute change > 200 mL or change in FVC ≥ 12% and absolute change > 200 mL
  6. Evidence of active infection at screening
  7. Listed for lung transplantation at time of screening
  8. Unstable or deteriorating cardiac disease at screening
  9. Myocardial infarction, coronary artery bypass, or angioplasty within 6 months of screening
  10. Unstable angina pectoris or congestive heart failure requiring hospitalization within 6 months of screening
  11. Uncontrolled arrhythmia at screening
  12. Severe uncontrolled hypertension at screening
  13. Known HIV or hepatitis C at screening
  14. Known cirrhosis or chronic active hepatitis at screening
  15. Active substance and/or alcohol abuse at screening
  16. Subjects who are pregnant or breastfeeding at screening
  17. Women of childbearing potential who are not using a medically approved means of contraception at screening
  18. Known bleeding abnormality that would preclude the performance of transbronchial lung biopsy
  19. PT, INR ≥ 1.5, PTT ≥ 45 at time of screening
  20. Clinically relevant lab abnormalities at time of screening specified as any of the below:
  21. Creatinine > 2x upper limit of normal (ULN)
  22. White blood cells < 3,500/mm3
  23. Hematocrit < 25% or > 59%
  24. Platelets < 100,000/mm3
  25. Total bilirubin > 2x ULN
  26. Aspartate or alanine aminotransferases
  27. Serum glutamic-oxalacetic transaminase
  28. Serum glutamic pyruvic transaminase > 1.5x ULN
  29. Alkaline phosphatase > 3x ULN
  30. Albumin < 3.0 mg/dL
  31. Any condition other than IPF that, in the opinion of the site PI, is likely to result in the death of the subject within the next year
  32. Any condition that, in the judgment of the site PI, might cause participation in this study to be detrimental to the subject or that the site PI deems makes the subject a poor candidate

S3: Research bronchoscopy protocol followed by study centers for the COMET trial

Bronchoscopy with BAL and TBBx was performed in stable individuals after obtaining informed consent. Medical history, including current medications and allergies was obtained from all patients. Patients that were on anticoagulants and/or antiplatelet agents had these medications discontinued if it was clinically safe to do so. The decision was at the discretion of the local site primary investigator after communicating with the patient’s prescribing physician. The procedure was performed after enough time had passed from discontinuation of the medication(s) such that platelet function/coagulation status returned to normal. An intravenous line was placed for administration of sedating medications and emergency cardiac medications, if needed. Blood pressure was measured at baseline, then every 5 minutes during the procedure, and then at 15-minute intervals after the procedure. Full resuscitation equipment and supplemental oxygen was readily available. Patients were observed for 2 hours following the procedure before being allowed to leave the procedure unit. The procedure was performed by pulmonary faculty or by a pulmonary fellow under their direct supervision. TBBx were done using fluoroscopic guidance, taking precautions to avoid biopsies at pleural margins. The exact procedural technique varied from study center based on the local physician’s practice and protocol. General guidelines followed by each center are listed.

Pre-procedure Checklist

Prior to beginning the bronchoscopy the following assessments were performed to help insure the study subject’s safety:

  • Availability of emergency equipment and medications was confirmed.
  • Confirmation that subjects had not eaten in at least 6 hours.
  • Review of the medication list with particular attention paid to blood thinners and anti-platelet drugs.
  • Review of medication allergies.
  • Physical examination including assessment of airway anatomy and Mallampati airway classification.
  • Confirmation that all subjects met inclusion/exclusion criteria for the study.

Bronchoscopy Procedure

  • An intravenous line was inserted and normal saline connected and set to a keep open rate.
  • The subjects were connected to telemetry and continuous pulse oximetry.
  • Vital signs were recorded at baseline and every 5 minutes as well as for any change in each subject’s clinical status during the procedure.
  • Supplemental oxygen was administered at 2 liters per minute and titrated to maintain a saturation of at least 90% throughout the procedure.
  • Medications such as midazolam and fentanyl were administered to achieve a level of sedation where the subject was sleeping and comfortable during the procedure but arousable to loud voice or touch and able to maintain spontaneous respirations and airway patency.
  • Topical lidocaine was used to anesthetize the nasal passages and airways.
  • The investigator chose the lung that was most involved by review of the HRCT. BAL was performed in either the lingula or right middle lobe. After the bronchoscope was wedged in a subsegment of the lung the suction trap was changed. Four 50 mL aliquots of normal saline were sequentially instilled with all possible return collected and pooled.
  • Following BAL up to 12 TBBx were obtained from multiple segments within the same lung as the lavage. The investigator stopped taking biopsies prior to collection of all specimens if the subject showed signs of instability such as change in vital signs or oxygenation or if significant bleeding occurred. This was at the discretion of the investigating physician.

Post-bronchoscopy Procedure

  • Vital signs were collected every 15 minutes for 45 minutes and then every 30 minutes until discharge.
  • No oral medications were permitted until the subject’s gag reflex returned.
  • The physician was notified for chest pain, shortness of breath, more than 30mL of bloody sputum, unstable vital signs, or persistent mental status changes.
  • Further evaluation occurred if: blood pressure was less than 90/60 mmHg or decreased by 30 mmHg from pre-procedure, if respiratory rate was greater than 28 breaths per minute or complaints of dyspnea, or if the subject’s temperature was greater than 100.6°F.
  • An upright post-procedure posterior to anterior chest x-ray was performed to evaluate for pneumothorax.

S4: Institutional review board committee names and approval numbers for all study centers in the COMET trial

Site / IRB Name / Approval Number
Brown University / Rhode Island Hospital Committee on Protection of Human Subjects / 0047-10
Cleveland Clinic Foundation / Cleveland Clinic Institutional Review Board / 10-191
National Jewish Medical & Research Center / National Jewish Health IRB / HS-2461
Temple University / Temple University Institutional Review Board / 12885
University of California, Los Angeles / UCLA Office of the Human Research Protection Program / 09-12-058-01A
University of California, San Francisco / UCSF Committee on Human Research / H10449-35653-01
University of Chicago / University of Chicago Institutional Review Board / 09-437-A
University of Michigan / University of Michigan Medical School IRB (IRBMED) / HUM00033126
Vanderbilt University / Vanderbilt University IRB / 091480
University of Michigan DCC / University of Michigan Medical School IRB (IRBMED) / HUM00036004