Table 1 PRECIS-2 Domains and the CleanUP-IPF Design

1. Eligibility—To what extent are the participants in the trial similar to those who would receive this intervention if it was part of usual care?

Median Investigator Score* – 5 Very Pragmatic

All patients who would receive the treatment if the drugs in CleanUP-IPF are found to be effective have been enrolled. No additional procedures have been required of patients to enroll in the study. The design allows physicians to identify and diagnosis patients according to their usual practice. The PTC has attempted to identify a group of clinics that are more generalizable than prior IPF studies which relied primarily on large academic medical centers. The exclusions are tightly aligned with the subset of patients who are unlikely to receive the treatment if the trial is positive (e.g. those with contra-indications).

2. Recruitment—How much extra effort is made to recruit participants over and above what would be used in the usual care setting to engage with patients?

Median Investigator Score – 5 Very Pragmatic

Patients in CleanUP-IPF are primarily identified from routine clinic visits and little effort is made to identify patients using electronic health records or mailings. The NIH and PTC have invested very limited amounts to support the enrolling sites. Payments to enrolling sites are strictly tied to enrollment and data collection (i.e. there are no infrastructure payments). Patients enrolled in CleanUP-IPF receive a study drug voucher which serves to partially cover the cost of study medications. Additionally patients enrolled at certain sites receive reimbursement for certain study related activities such as parking and gas mileage.

3. Setting—How different are the settings of the trial from the usual care setting?

Median Investigator Score – 4.5 Rather Pragmatic

CleanUP-IPF is being conducted in a single country; however, the expectation would be that the treatment(s) are applied regardless of the country of residence for the patient.

The PTC is making an effort to identify a representative set of sites to enroll patients. The total number of enrolling sites is expected to reach approximately 30–40. The majority of sites are tied to major academic medical centers. This set of sites reasonably matches the sites that are expected to treat this fairly rare and difficult to diagnose disease. The PTC is working to ensure that the sex, racial, and ethnicity characteristics of enrolled populations closely match the broader population with the disease. Most of the study sites identify and enroll patients at the clinics where these patients are seen in usual practice.

4. Organization—How different are the resources, provider expertise, and the organization of care delivery in the intervention arm of the trial from those available in usual care?

Median Investigator Score – 4 Rather Pragmatic

The CleanUP-IPF study has attempted to structure the study to closely mimic the ultimate delivery of the treatment, if and when, it is moved to usual care. Certain design features including the use of a voucher system to reimburse care do not match the intended delivery. The study investigators and coordinators have received ample training from the PTC but that training was mostly designed to improve the proper execution of the clinical research. The study investigators did not require any additional study training or years of experience to be recruited into the PTC site list. The ultimate delivery of the antimicrobial therapy would not require additional health care resources or staff.

5. Flexibility (delivery)—How different is the flexibility in how the intervention is delivered and the flexibility anticipated in usual care?

Median Investigator Score – 4 Rather Pragmatic

The CleanUP-IPF study does employ a highly protocol driven assessment of safety for patients randomized to the antimicrobial treatment strategy. However, there are no programs in place to improve compliance with of the enrolling physicians. The timing of the intervention is not tightly defined and can be applied at any point during the chronic phase of the disease. There are no restrictions placed on other potential therapies used to treat IPF. Restrictions and monitoring of other therapies are driven by safety concerns.

6. Flexibility (adherence)—How different is the flexibility in how participants are monitored and encouraged to adhere to the intervention from the flexibility anticipated in usual care?

Median Investigator Score – 4 Rather Pragmatic

The eligibility criteria did not place any restrictions on the ability of participants to be complaint during the trial. The study does not withdraw any patients from the trial for the lack of compliance to study procedures. The study team does not explicitly meet with enrolling sites to discuss issues related to adherence to study drug. The flexibility for patients enrolled is very high with allowances to switch to a different study drug if there are issues with the assigned therapy.

7. Follow-up—How different is the intensity of measurement and follow-up of participants in the trial from the typical follow-up in usual care?

Median Investigator Score – 4.5 Rather Pragmatic

The CleanUP-IPF follow-up schedule was closely tied to the follow-up for IPF patients in usual care. There are addition assessments at the 12 and 24 months that are included to provide the key data for secondary endpoints. The intervention arm has a few additional follow-up telephone calls and blood draws to assess the patient for any potential safety issues. Sites are encouraged to use data from the electronic health record to use for assessments related to lung function when possible. There are no follow-up visits that are triggered based on potential endpoint events. Most participants enrolled in the study are also contributing data to several ancillary studies which require additional blood and stool samples.

8. Primary outcome—To what extent is the trial’s primary outcome directly relevant to participants?

Median Investigator Score – 5 Very Pragmatic

The key question that CleanUP-IPF is attempted to address is whether the use of antimicrobial therapy reduces mortality and respiratory related hospitalizations. All-cause mortality has been identified as the most important endpoint for patients with IPF. Similarly, the need for acute care in the form of hospitalizations is an outcome that patients would prefer to avoid. Traditional phase II and III trials in IPF have used biomarkers related to lung function or functional assessments such as 6-min walk distance as the primary endpoint [30]. The rationale for this decision is usually tied to feasibility concerns related to time-to-event studies with clinical endpoints. It is our understanding that CleanUP-IPF will be one of the first IPF trials to use a clinical endpoint as the primary outcome. Similarly, the sample size is believed to be the largest IPF trial conducted only in the US. A slight weakness of the primary outcome is the inclusion of the non-fatal respiratory hospitalization component [31]. The trial will use a central adjudication process for the mortality and hospitalization events which lowers the pragmatism. The time horizon for CleanUP-IPF with a maximum follow-up of 3 years is highly pragmatic.

9. Primary analysis—To what extent are all data included in the analysis of the primary outcome?

Median Investigator Score – 5 Very Pragmatic

CleanUP-IPF uses a superiority design and the primary analysis population is based on all randomized patients. There are no special allowances for redefining the population for issues related to imperfect adherence or changes in the eligibility criteria that are identified after randomization. The use of all-cause mortality in the primary endpoint means that individuals with deaths that are unrelated to the disease or treatment are still included in the analysis. Similarly, the use of the respiratory hospitalization component means that patients with lung transplantation are included in the primary analysis. The primary analysis will use a covariate adjusted model but those covariates are expected to be obtained in 100% of patients prior to randomization. It is expected that the primary outcome will have nearly complete data at the time of the final study visits.