CleanUP IPF for the Pulmonary Trials Cooperative (CleanUp-IPF)

Study of Clinical Efficacy of Antimicrobial Therapy Strategy Using Pragmatic Design in Idiopathic Pulmonary Fibrosis

The purpose of this study is to compare the effect of standard care, versus standard of care plus antimicrobial therapy (co-trimoxazole or doxycycline), on clinical outcomes in patients diagnosed with idiopathic pulmonary fibrosis (IPF).

Study Overview

• Status: Terminated
• Conditions: Idiopathic Pulmonary Fibrosis
• Intervention / Treatment: Drug: Antimicrobial therapy: Co-trimoxazole or Doxycycline; Other: No Intervention: Standard of Care

Detailed Description

This is a randomized, un-blinded, phase III, multi-center clinical trial of an antimicrobial therapy strategy in idiopathic pulmonary fibrosis patients. Our overall hypothesis is that reducing harmful microbial impact with antimicrobial therapy will reduce the risk of non-elective, respiratory hospitalization or death in patients with Idiopathic Pulmonary Fibrosis (IPF).

Subjects will be randomized 1:1 to either receive a prescription drug voucher for oral antimicrobial therapy in the form of one double strength 160 milligrams (mg) trimethoprim/800mg sulfamethoxazole (double strength co-trimoxazole) twice daily plus folic acid 5 mg daily OR doxycycline 100mg once daily if weight < 50 kilograms (kg) or 100mg twice daily if weight > 50 kg. Patients randomized to receive antimicrobial therapy will be given co-trimoxazole unless they have an allergy, contraindication to co-trimoxazole, renal insufficiency (glomerular filtration rate (GFR) < 30 milliliters (ml)), are hyperkalemic (potassium > 5 milliequivalents(mEq)/liter(L)), or are concomitantly taking an angiotensin converting enzyme inhibitor (ACEI), angiotensin receptor blocker (ARB), or potassium sparing diuretic in which case they will receive doxycycline.

Participation in this study will be between 12 months and 36 months depending on time of enrollment.

• Study Type: Interventional
• Enrollment (Actual): 513
• Phase: Phase 3

Contacts and Locations

Study Locations

• United States
  • Alabama
    • Birmingham, Alabama, United States, 35294
      • University of Alabama at Birmingham
  • Arizona
    • Tucson, Arizona, United States, 85724
      • University of Arizona
  • California
    • Sacramento, California, United States, 95817
      • University of California Davis Medical Center
    • Stanford, California, United States, 94305
      • Stanford
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Northwestern University
    • Chicago, Illinois, United States, 60637
      • University of Chicago
    • Chicago, Illinois, United States, 60153
      • Loyola University Chicago
  • Kansas
    • Kansas City, Kansas, United States, 66160
      • University of Kansas
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Beth Israel Deaconess Medical Center
    • Boston, Massachusetts, United States, 02115
      • Brigham and Women's Hospital
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • University of Michigan
    • Grand Rapids, Michigan, United States, 49503
      • Spectrum Health
  • Minnesota
    • Minneapolis, Minnesota, United States, 55455
      • University of Minnesota
  • New Hampshire
    • Lebanon, New Hampshire, United States, 03756
      • Dartmouth-Hitchcock Medical Center
  • New York
    • Albany, New York, United States, 12208
      • Albany Medical College
    • New York, New York, United States, 10032
      • Columbia University
    • New York, New York, United States, 10065
      • Weill Cornell Medicine
    • Rochester, New York, United States, 14642
      • University of Rochester
    • Rochester, New York, United States, 55905
      • Mayo Clinic
  • Ohio
    • Cincinnati, Ohio, United States, 45267
      • University of Cincinnati
    • Cleveland, Ohio, United States, 44195
      • Cleveland Clinic
    • Columbus, Ohio, United States, 43221
      • Ohio State
  • Pennsylvania
    • Hershey, Pennsylvania, United States, 17033
      • Pennsylvania State University
    • Philadelphia, Pennsylvania, United States, 19122
      • Temple University
  • Tennessee
    • Nashville, Tennessee, United States, 37232
      • Vanderbilt
  • Texas
    • San Antonio, Texas, United States, 78229
      • University of Texas at San Antonio
  • Utah
    • Salt Lake City, Utah, United States, 84108
      • University of Utah
  • Virginia
    • Charlottesville, Virginia, United States, 22908
      • University of Virginia
    • Falls Church, Virginia, United States, 22042
      • Inova
  • Washington
    • Seattle, Washington, United States, 98195
      • Washington University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 40 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. ≥ 40 years of age
2. Diagnosed with idiopathic pulmonary fibrosis (IPF) by enrolling investigator
3. Signed informed consent

Exclusion Criteria:

1. Received antimicrobial therapy in the past 30 days

2. Contraindicated for antibiotic therapy, including but not exclusive to:

   1. Allergy or intolerance to both tetracyclines AND trimethoprim, sulfonamides or their combination

   2. Allergy or intolerance to tetracyclines AND known potassium level > 5 mEq/L in the past 90 days.

      • If the enrolling physician feels the potassium level has normalized, documentation to that effect must be provided.
   3. Allergy or intolerance to tetracyclines AND concomitant use of angiotensin converting enzyme inhibitor (ACEI), angiotensin receptor blocker (ARB), potassium sparing diuretic, dofetilide, methotrexate, azathioprine, mycophenolate mofetil, cyclophosphamide
   4. Allergy or intolerance to tetracyclines AND known glucose-6-phosphate dehydrogenase deficiency
   5. Allergy or intolerance to tetracyclines AND untreated folate or B12 deficiency

   6. Allergy or intolerance to tetracyclines AND known renal insufficiency (defined as a glomerular filtration rate (GFR) < 30 ml within the previous 90 days)

      • If the enrolling physician feels the renal dysfunction has resolved, documentation to that effect must be provided.
3. Pregnant or anticipate becoming pregnant
4. Use of an investigational study agent for IPF therapy within the past 30 days, or an IV infusion with a half-life of four (4) weeks.
5. Concomitant immunosuppression with azathioprine, mycophenolate, cyclophosphamide, or cyclosporine.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Antimicrobial therapy; Co-trimoxazole OR doxycycline	Drug: Antimicrobial therapy: Co-trimoxazole or Doxycycline; 160mg trimethoprim/800mg sulfamethoxazole (double strength co-trimoxazole) twice daily plus folic acid 5 mg daily OR doxycycline 100mg once daily if weight < 50 kilograms or 100mg twice daily if weight > 50 kilograms for up to 36 months
Other: Standard of care; Standard of care for patients with IPF for comparison	Other: No Intervention: Standard of Care; Standard of care

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Number of Participants With First Non-elective, Respiratory Hospitalization or All-cause Mortality	Randomization to up to 35 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Death From Any Cause		Randomization to up to 35 months
Number of Participants With First Non-elective, Respiratory Hospitalization		Randomization to up to 35 months
Number of Participants With First Non-elective, All-cause Hospitalization		Randomization to up to 35 months
Total Number of Non-elective Respiratory Hospitalizations		Randomization to up to 35 months
Total Number of Non-elective All-cause Hospitalizations		Randomization to up to 35 months
Percent Change in Forced Vital Capacity (FVC)		Randomization to 12 months
Percent Change in Diffusion Capacity of Lungs for Carbon Monoxide (DLCO)		Randomization to 12 months
Total Number of Respiratory Infections		Randomization to up to 35 months
Change in UCSD-Shortness of Breath Questionnaire	Change in University of California San Diego (UCSD) Shortness of Breath Questionnaire (0 - 120 range). A lower score indicates a better health score. The UCSD-Shortness of Breath Questionnaire assesses the severity of shortness of breath during specific activities of daily living.	Randomization to 12 months
Change in Fatigue Severity Scale Score	Fatigue Severity Scale score (1 - 7 range). A lower score indicates a better health score. The Fatigue Severity Scale measures the severity of fatigue and its effect on a person's activities and lifestyle.	Randomization to 12 months
Change in Leicester Cough Questionnaire Score	Leicester Cough Questionnaire score (3 - 21 range). A higher score indicates a better health score. The Leicester Cough Questionnaire measures quality of life in people with a chronic cough.	Randomization to 12 months
Change in EuroQol Index (EQ-5D) Score	European Quality of Life-5 dimensions (EQ-5D) score (0 - 1 range). A higher score indicates a better health score. The EQ-5D measures quality of life across 5 dimensions (1. Mobility, 2. Self-care, 3. Usual activities, 4. Pain/discomfort, 5. Anxiety/depression.	Randomization to 12 months
Change in ICEpop CAPability Measure for Older People (ICECAP-O) Score	Change in ICEpop (Investigating Choice Experiments for the Preferences of Older People) CAPability measure for Older people (ICECAP-O) score (0 - 1 range). A lower score indicates a better health score. The ICEpop CAPability measure for Older people (ICECAP-O) is intended for use in economic evaluations of care services for older people.	Randomization to 12 months
Change in Short Form-12 Health Survey (SF-12) 6D Score	Change in Short Form-12 health survey (SF-12) 6D score (0.29 - 1.00 range). A higher indicates a better health score. The SF-12 6D score provides and economic evaluation.	Randomization to 12 months
Change in Short Form-12 Health Survey (SF-12) Physical Score	Change in short form-12 health survey (SF-12) physical component summary (PSC) score (0 - 100 range). A higher score indicates a better health score. The short form-12 health survey physical score assesses limitations in physical activities because of health problems.	Randomization to 12 months
Change in SF-12 Health Survey (SF-12) Mental Score	Change in short form-12 health survey (SF-12) mental component summary (MCS) score (0 - 100 range). A higher score indicates a better health score. The short form-12 health survey (SF-12) mental component summary (MCS) assesses general mental health.	Randomization to 12 months

Collaborators and Investigators

• Sponsor: Weill Medical College of Cornell University
• Collaborators: National Heart, Lung, and Blood Institute (NHLBI); University of Chicago; University of Pittsburgh; University of Washington; Duke Clinical Research Institute
• Investigators: Principal Investigator: Fernando Martinez, MD, MS, Weill Cornell Medical Medicine

Publications and helpful links

General Publications

• Martinez FJ, Yow E, Flaherty KR, Snyder LD, Durheim MT, Wisniewski SR, Sciurba FC, Raghu G, Brooks MM, Kim DY, Dilling DF, Criner GJ, Kim H, Belloli EA, Nambiar AM, Scholand MB, Anstrom KJ, Noth I; CleanUP-IPF Investigators of the Pulmonary Trials Cooperative. Effect of Antimicrobial Therapy on Respiratory Hospitalization or Death in Adults With Idiopathic Pulmonary Fibrosis: The CleanUP-IPF Randomized Clinical Trial. JAMA. 2021 May 11;325(18):1841-1851. doi: 10.1001/jama.2021.4956.
• Anstrom KJ, Noth I, Flaherty KR, Edwards RH, Albright J, Baucom A, Brooks M, Clark AB, Clausen ES, Durheim MT, Kim DY, Kirchner J, Oldham JM, Snyder LD, Wilson AM, Wisniewski SR, Yow E, Martinez FJ; CleanUP-IPF Study Team. Design and rationale of a multi-center, pragmatic, open-label randomized trial of antimicrobial therapy - the study of clinical efficacy of antimicrobial therapy strategy using pragmatic design in Idiopathic Pulmonary Fibrosis (CleanUP-IPF) clinical trial. Respir Res. 2020 Mar 12;21(1):68. doi: 10.1186/s12931-020-1326-1.

Study record dates

Study Major Dates

• Study Start (Actual): March 22, 2017
• Primary Completion (Actual): March 16, 2020
• Study Completion (Actual): March 16, 2020

Study Registration Dates

• First Submitted: April 28, 2016
• First Submitted That Met QC Criteria: April 28, 2016
• First Posted (Estimate): May 3, 2016

Study Record Updates

• Last Update Posted (Actual): April 8, 2021
• Last Update Submitted That Met QC Criteria: March 11, 2021
• Last Verified: March 1, 2021

More Information

Terms related to this study

• Keywords: Idiopathic Pulmonary Fibrosis; IPF; doxycycline; pulmonary fibrosis; antimicrobial therapy; co-trimoxazole
• Additional Relevant MeSH Terms: Pathologic Processes; Respiratory Tract Diseases; Lung Diseases; Fibrosis; Pulmonary Fibrosis; Idiopathic Pulmonary Fibrosis; Antiprotozoal Agents; Antiparasitic Agents; Antimalarials; Anti-Infective Agents, Urinary; Renal Agents; Anti-Bacterial Agents; Doxycycline; Anti-Infective Agents; Trimethoprim, Sulfamethoxazole Drug Combination
• Other Study ID Numbers: 1504016087; U01HL128954 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD Plan Description: All collected IPD will be uploaded in a de-identified manner into BioLINCC with open access for interested investigators
• IPD Sharing Time Frame: Within a year of the primary paper publication and then indefinitely maintained by BioLINCC
• IPD Sharing Access Criteria: The data will be open access for interested investigators
• IPD Sharing Supporting Information Type: Study Protocol; Statistical Analysis Plan (SAP)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No