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S T U D Y P R O T O C O L Open Access
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
Kevin J. Anstrom
1*
, Imre Noth
2
, Kevin R. Flaherty
3
, Rex H. Edwards
4
, Joan Albright
1
, Amanda Baucom
5
,
Maria Brooks
5
, Allan B. Clark
6
, Emily S. Clausen
7
, Michael T. Durheim
1,8
, Dong-Yun Kim
9
, Jerry Kirchner
1
,
Justin M. Oldham
10
, Laurie D. Snyder
1
, Andrew M. Wilson
6
, Stephen R. Wisniewski
5
, Eric Yow
1
,
Fernando J. Martinez
11
and For the CleanUP-IPF Study Team
Abstract
Compelling data have linked disease progression in patients with idiopathic pulmonary fibrosis (IPF) with lung
dysbiosis and the resulting dysregulated local and systemic immune response. Moreover, prior therapeutic trials have
suggested improved outcomes in these patients treated with either sulfamethoxazole/ trimethoprim or doxycycline.
These trials have been limited by methodological concerns. This trial addresses the primary hypothesis that long-term
treatment with antimicrobial therapy increases the time-to-event endpoint of respiratory hospitalization or all-cause
mortality compared to usual care treatment in patients with IPF. We invoke numerous innovative features to achieve
this goal, including: 1) utilizing a pragmatic randomized trial design; 2) collecting targeted biological samples to allow
future exploration of ‘personalized’therapy; and 3) developing a strong partnership between the NHLBI, a broad range
of investigators, industry, and philanthropic organizations. The trial will randomize approximately 500 individuals in a 1:
1 ratio to either antimicrobial therapy or usual care. The site principal investigator will declare their preferred initial
antimicrobial treatment strategy (trimethoprim 160 mg/ sulfamethoxazole 800 mg twice a day plus folic acid 5 mg daily
or doxycycline 100 mg once daily if body weight is < 50 kg or 100 mg twice daily if ≥50 kg) for the participant prior to
randomization. Participants randomized to antimicrobial therapy will receive a voucher to help cover the additional
(Continued on next page)
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* Correspondence: kevin.anstrom@duke.edu
1
Duke Clinical Research Institute, Duke University, Durham, North Carolina,
USA
Full list of author information is available at the end of the article
Anstrom et al. Respiratory Research (2020) 21:68
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(Continued from previous page)
prescription drug costs. Additionally, those participants will have 4–5 scheduled blood draws over the initial 24 months
of therapy for safety monitoring. Blood sampling for DNA sequencing and genome wide transcriptomics will be
collected before therapy. Blood sampling for transcriptomics and oral and fecal swabs for determination of the
microbiome communities will be collected before and after study completion. As a pragmatic study, participants in
both treatment arms will have limited in-person visits with the enrolling clinical center. Visits are limited to assessments
of lung function and other clinical parameters at time points prior to randomization and at months 12, 24, and 36. All
participants will be followed until the study completion for the assessment of clinical endpoints related to
hospitalization and mortality events.
Trial Registration: ClinicalTrials.gov identifier NCT02759120.
Keywords: Idiopathic pulmonary fibrosis, Pragmatic clinical trial, Doxycycline, Co-trimoxazole,
Background
IPF is a chronic, fibrotic, and progressive interstitial lung
disease characterized by the histopathologic pattern of
usual interstitial pneumonia in the absence of an identi-
fiable cause or association. Disease progression is highly
heterogeneous with a median survival of approximately
3–5 years following diagnosis. Furthermore, the increas-
ing rate of mortality and hospitalization related to the
disease suggests that the prevalence is increasing [1].
Studies of pirfenidone and nintedanib have shown con-
sistent beneficial effects in forced vital capacity and led
to approval of both agents by the U.S. Food and Drug
Administration [1–3]. However, both agents demon-
strated inconsistent benefits on clinical endpoints, may
be difficult to tolerate, and are expensive. As a result,
there remains an unmet clinical need for effective and
low cost treatment strategies to improve the quality-of-
life and clinical outcomes in patients with IPF.
Here we describe the design and rationale for
CleanUP-IPF clinical trial. In particular, the pragmatic
nature of the study represents the first IPF study that
may demonstrate a significant treatment effect for a clin-
ical endpoint and offers a model to identify effective
treatment strategies for rare diseases.
Methods
What is the rationale for the antimicrobial therapies?
Compelling data have linked disease progression with
lung dysbiosis and the resulting local and systemic im-
mune response in IPF patients [4–8]. Murine data sup-
port the impact of lung microbes on increased fibrotic
response [9,10]. In other chronic disorders, antimicro-
bial therapy has been suggested to favorably alter the
lung microbial community [11]. This trial utilizes a prag-
matic approach with antimicrobial agents that have been
suggested to have a similar effect in IPF patients. The
use of two potentially effective therapies minimizes po-
tential risk while increasing the number of patients that
can be treated with such innovative therapy.
What is the rationale for using co-trimoxazole? An ini-
tial randomized trial of 20 patients with advanced fi-
brotic lung disease showed favorable improved exercise
capacity and symptom scores in the participants
assigned to co-trimoxazole [12]. Following these results,
a UK National Institute for Health Research funded
study called TIPAC randomized 180 patients with inter-
stitial lung disease to co-trimoxazole or placebo [13].
The primary endpoint was forced vital capacity. An as-
treated analysis suggested favorable results for quality-
of-life and all-cause mortality. Based on these findings,
the investigators hypothesized that a larger study with
better treatment adherence could prove that co-
trimoxazole is a cheap and effective therapy for IPF. A
limitation of the TIPAC study was the lack of significant
findings using the intention-to-treat analyses. A further
clinical trial, EME-TIPAC, is underway to replicate this
study in a larger study population [14].
What is the rationale for using doxycycline? Aprior
single-center study examined 6 patients with IPF treated
with long-term doxycycline [15]. Patients were treated for
a mean of 303 days with assessments of body mass index,
6-min walk test, St. George Respiratory Questionnaire,
FVC, and several biomarkers. Patients were included if
they signed informed consent documents, had an IPF
diagnosis from a pulmonologist and radiologist (major
and minor criteria according to the ATS-ERS guidelines
of 2001) age 30–70 years, and FVC percent predicted >
40%. Briefly, patients were excluded if they had a contra-
indication to doxycycline or a recent exacerbation of IPF
among other reasons. Patients received 100 mg of doxy-
cycline once daily if body weight was < 50 kg and 100 mg
of doxycycline twice daily if body weight was > 50 kg. A
key study endpoint was inhibition of MMP activity in BAL
fluid after at least 6 months of therapy. The study results
include large but not statistically significant changes in 6-
min walk distance (141 ft, p= 0.110) and FVC percent pre-
dicted (6.3%, p= 0.311). [Appendix Table 3]Additionally,
the study found large and statistically significant changes
in St. George Respiratory Questionnaire, MMP9 activity,
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MMP3 activity, MMP9 expression, TIMP-1 expression,
and VEGF expression. In spite of these consistent differ-
ences, this study has a number of limitations. A separate
open label study in a small number of patients treated
with a mean of 531 days of doxycycline experienced im-
provement clinically, physiologically and radiologically
[16]. These small, single center studies did not have a
proper control group and had a relatively unstructured
protocol. Nevertheless, these case series suggest that doxy-
cycline has the potential to be an effective treatment for
IPF given the high responsiveness of the anti-MMPs
activity.
Pulmonary Trials Cooperative
In 2014, the National Institutes of Health (NIH) issued a
pair of funding opportunity announcements for applica-
tions to create the Pulmonary Trials Cooperative (PTC).
https://grants.nih.gov/grants/guide/rfa-files/RFA-HL-15-
015.html and https://grants.nih.gov/grants/guide/rfa-files/
RFA-HL-15-016.html. One announcement called for U01
applications to serve as the Protocol Leadership Group
(PLG) and the other announcement called for a Network
Management Core (NEMO) to serve as the clinical coord-
inating body for the PTC. The PTC was designed to con-
duct multiple simple, pragmatic Phase II and III studies to
evaluate the potential benefits of new and existing treat-
ment strategies. The primary responsibility of the NEMO,
which is coordinated by investigators at the University of
Pittsburgh, is to facilitate the trials conducted by the PTC.
The primary responsibility of the PLGs is to develop a
protocol and provide the necessary resources to support
the conduct and data analyses for that project. The
NEMO recruits and activates a number of clinical sites to
identify and enroll patients depending on the study proto-
col. In general, the role of the clinical sites is to enroll par-
ticipants, deliver the study intervention, complete study
visits (in-person and phone calls), conduct procedures as
defined in the study protocol, aid in data interpretation
and participate in manuscript generation. Currently, the
PTC is conducting four randomized controlled trials –
three in patients with chronic obstructive pulmonary dis-
ease [INSIGHT-COPD (NCT02634268), LEEP
(NCT02696564), and RETHINC (NCT02867761)] and one
in patients with IPF, CleanUP-IPF (http://www.pulmonary-
trials.org/). The CleanUP-IPF PLG is led by investigators
from Weill Cornell Medicine, University of Virginia, and
the Duke Clinical Research Institute.
CleanUP-IPF study overview
Participants will be randomized to one of two strategies
–usual care or usual care plus anti-microbial therapy in
a 1:1 allocation ratio. Prior to randomization, eligible
participants and their physician will declare a preference
for the co-trimoxazole or the doxycycline stratum. It is
expected that the majority of participants will be in the
co-trimoxazole stratum. Once participants are random-
ized to usual care or usual care plus anti-microbial ther-
apy, their follow-up schedule will vary based on their
assigned therapy (i.e. usual care, co-trimoxazole, or
doxycycline). Participants in the anti-microbial strategy
will receive a voucher to help cover the costs associated
with the study medications. Compared with standard
clinical trials in patients with IPF, the in-person follow-
up visits will be infrequent (e.g. similar to usual care at
most US clinical centers). A robust protocol has been
implemented to track the participants for potential
safety issues. Suspected clinical events of interest, specif-
ically hospitalizations and acute worsening, will be
reviewed by an independent adjudication committee.
The study will be reviewed by an independent NIH-
appointed Data and Safety Monitoring Board (DSMB). It
is expected that all patients will be followed until a com-
mon end date based on the study progress.
Key design elements
As described earlier, the FOA requested proposals for
simple, pragmatic Phase II and III clinical trials. There is
considerable variability in the definitions and interpreta-
tions of pragmatic clinical trials. Often, pragmatic trials
are designed to capitalize on previously captured data (e.g.
electronic health records), information collected from par-
ticipants during their usual activities (e.g. patient reported
outcomes), and a patient-centric design [17,18]. For many
researchers, the ADAPTABLE clinical trial assessing the
benefits and effectiveness of two different aspirin dosing
strategies is considered a highly pragmatic study [19,20].
Similarly, there is considerable debate about the nature
and utility of large simple trials [21]. Some argue that
there should be many more clinical trials that enroll large
number of participants and result in minimal burden for
patients and enrolling sites. Others note that such trials fit
a niche; however, they generally will fail to serve a purpose
given regulatory and logistical constraints [22].
In an attempt to answer a clinically important question,
the study investigators designed a very streamlined clinical
trial with an existing therapy in a highly generalizable
population. This approach was in response to the increas-
ingly complicated and burdensome clinical trial environ-
ment [23,24]. After funding was awarded, the study team
added several refinements to the study protocol that made
the study more flexible and safer. The PRECIS-2 tool is a
commonly used tool to assess pragmatism of clinical re-
search studies [25–29]. The tool was developed from the
input of dozens of clinical trialists and measures 9 differ-
ent aspects of the clinical trial –eligibility criteria, recruit-
ment, setting, study organization, flexibility of delivery,
flexibility of adherence, follow-up, primary outcome, and
primary analysis. Each domain is scored from 1 (very
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explanatory) to 5 (very pragmatic). Table 1shows the
PRECIS-2 domains and the CleanUP-IPF investigator’s
opinions on the pragmatism for each of them. In the opin-
ion of the investigators, all of the 9 domains scored be-
tween moderately pragmatic and very pragmatic.
Protocol specifics
Study objective
The primary objective of the study is to compare usual
care vs. usual care plus antimicrobial therapy (co-trimoxa-
zole or doxycycline) on clinical outcomes in patients diag-
nosed with IPF. The hypothesis is that reducing harmful
microbial impact with antimicrobial therapy will reduce
the risk of non-elective, respiratory hospitalization or
death in patients with IPF. A total of 30–40 U.S. clinical
centers are expected to enroll a total of 500 participants.
Eligibility
The detailed inclusion and exclusion criteria are enu-
merated in Table 2. There are a total of three inclusion
criteria, only one of which requires any clinical informa-
tion. Another ongoing clinical trial, EME-TIPAC, study-
ing a similar hypothesis at approximately 40 U.K. sites
used a more explanatory approach including the use of a
placebo-controlled design [14]. The studies are very
similar in terms of the inclusion criteria but clearly differ
when examining the exclusion criteria. For CleanUP-
IPF, the exclusions only prohibit those with contraindi-
cations to the study interventions.
Interventions
Participants randomized to antimicrobial therapy will be
treated with trimethoprim 160 mg/sulfamethoxazole 800
mg (double strength co-trimoxazole) twice a day plus folic
acid 5 mg daily unless there is a contraindication to this
therapy. The addition of folate administration was employed
to minimize the risk of leukopenia associated with inhib-
ition of folic acid metabolism by trimethoprim [32]; folic
acid replacement has been used successfully with chronic
use of this antimicrobial agent in HIV patients and patients
with interstitial lung disease [13,33]. If the participant de-
velops an intolerance to co-trimoxazole, the dosage can be
decreased to trimethoprim 160 mg/sulfamethoxazole 800
mg (one double strength co-trimoxazole) three times
weekly plus folic acid 5 mg daily. If intolerance continues
with co-trimoxazole, then the antimicrobial agent can be
changed to doxycycline (without folic acid). See Fig. 1for
the flow diagram for participants randomized to antimicro-
bial therapy. Participants in the doxycycline cohort who are
randomized to usual care plus antimicrobial therapy will be
treated with doxycycline (without folic acid) with a weight-
based dosing (100 mg once daily if body weight is < 50 kg
and 100 mg twice daily if ≥50 kg).
Pre-randomization evaluations
Prior to randomization, the study coordinator will col-
lect the following information:
Patient characteristics (sex, race, ethnicity, age,
height, weight)
Information on how IPF diagnosis was made
Co-morbidities and details on patient history of
gastroesophageal reflux disease (GERD)
Physical exam findings
Current concomitant medications
Urine dipstick pregnancy test
Evaluation of renal function
Evaluation of potassium level
Evaluation of leukocyte count and platelet count in
recipients randomized to co-trimoxazole
In addition, the following procedures will be per-
formed prior to randomization unless recent clinically
indicated tests are available:
Spirometry and DLCO
Quality of life questionnaires
Buccal and fecal sample collection
Blood draw for genotype and gene expression
Chemistry panel and liver function tests
Complete Blood Count
Duration of intervention
After randomization, participants assigned to the anti-
microbial arm will be given a prescription drug voucher
from Trialcard to help defray the cost of study drug.
Participants will have minimal in-person visits over the
course of the 36-month study but those visits depend on
the assigned study arm. Participants assigned to the
usual care arm have scheduled in-clinic visits at 12 and
24 months. Participants in the antimicrobial arm have
additional visits at 1 week, 3 months, and 6 months to
monitor safety related to the study drugs.
Diagnosis
The diagnosis of participants will be highly pragmatic.
The diagnosis of IPF within the trial will match the pro-
cesses used to diagnose the disease based on international
guidelines [34,35]. The study will collect information on
how IPF diagnosis was made using an IPF Diagnosis
Checklist.
Safety related concerns & safety reviews
The safety testing in this study is based on prior experi-
ence with these antimicrobial agents in other settings [33,
36–45]. Participants are encouraged to follow the assigned
treatment strategy for the study duration; however, in all
cases the participant’s safety based on the clinical
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Table 1 PRECIS-2 Domains and the CleanUP-IPF Design
PRECIS-2 Domains [Loudon BMJ 2015] PRECIS-2 Score for CleanUP-IPF
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 prac-
tice. The PTC has attempted to identify a group of clinics that are more
generalizable than prior IPF studies which relied primarily on large aca-
demic 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 sup-
port the enrolling sites. Payments to enrolling sites are strictly tied to en-
rollment 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 pa-
tients enrolled at certain sites receive reimbursement for certain study re-
lated 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 investi-
gators 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 add-
itional 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 de-
fined 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
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judgment of the treating physician will take priority over
the specific treatment assignment. There is the potential
of adverse cardiovascular events secondary to co-
trimoxazole therapy; this is felt to possibly reflect a tri-
methoprim drug interaction resulting in hyperkalemia [38,
41]. Review of prior literature suggests that the major risk
factors for trimethoprim related hyperkalemia include
higher trimethoprim dose, arenal insufficiency with
hypoaldosteronism, potassium altering medications, and
age [40]. Our inclusion/exclusion criteria should mitigate
this risk as well as monitoring for hyperkalemia early after
the introduction of co-trimoxazole therapy [40].
Primary Endpoints & Endpoint Adjudication
The primary endpoint of this study will be the time to first
non-elective, respiratory hospitalization or all-cause mortal-
ity. The significance of respiratory hospitalization as a po-
tential trial endpoint in IPF has been demonstrated in
several studies [46]. In pooled data from the IPF Clinical
Research Network (IPFnet) clinical trials, both non-elective
hospitalization and disease progression as defined by a 10%
decrease in FVC occurred frequently across strata of base-
line physiologic impairment. Both of these events were as-
sociated with subsequent time to death from any cause.
After adjustment for gender, age, and baseline lung func-
tion, the risk of all-cause mortality during trial follow-up
was nearly six-fold higher among patients who had a non-
elective hospitalization of respiratory cause early during the
trial, compared with those who had not (hazard ratio [HR]
5.97, 95% confidence interval [CI] 1.81, 19.74). By contrast,
non-respiratory hospitalizations were not associated with
subsequent risk of mortality. These findings build upon
earlier observations both in clinical trials and in clinical
practice [47,48]. As such, non-elective respiratory
hospitalization appears to be the optimal clinical intermedi-
ate marker for long-term mortality in IPF. This evidence
has been incorporated in CleanUP-IPF, including the use of
an adjudication group based on IPFnet experience [49].
The CleanUP-IPF event adjudicationprocessisdesignedto
be both efficient and accurate, incorporating the
Table 1 PRECIS-2 Domains and the CleanUP-IPF Design (Continued)
PRECIS-2 Domains [Loudon BMJ 2015] PRECIS-2 Score for CleanUP-IPF
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 sev-
eral 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 hos-
pitalizations. 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 end-
points. 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 sam-
ple 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 ad-
judication process for the mortality and hospitalization events which
lowers the pragmatism. The time horizon for CleanUP-IPF with a max-
imum 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 individ-
uals with deaths that are unrelated to the disease or treatment are still in-
cluded 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 pa-
tients prior to randomization. It is expected that the primary outcome will
have nearly complete data at the time of the final study visits.
*Scores are based on survey responses from 14 CleanUP-IPF clinical sites
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assessments of both the local site investigator and an inde-
pendent central adjudication to confirm the clinical cause
of a hospitalization or mortality event.
Secondary endpoints
A number of clinical events, quality-of-life, and lung
function measures have been identified as secondary
endpoints. These include:
Time to death from any cause
Time to first non-elective, respiratory hospitalization
Time to first non-elective, all-cause hospitalization
Total number of non-elective respiratory
hospitalizations
Total number of non-elective all-cause
hospitalizations
Change in FVC from randomization to 12 months
Change in DLCO from randomization to 12 months
Table 2 Comparison of CleanUP-IPF with EME-TIPAC eligibility criteria
Inclusion Criteria
CleanUP-IPF
(NCT 02759120)
EME-TIPAC
(ISRCTN 17464641)
1. ≥40 years of age
2. Diagnosed with IPF by enrolling investigator
3. Signed informed consent
1. Age greater than or equal to 40 years
2. A diagnosis of IPF based on multi-disciplinary consensus according to
the latest international guidelines.
3. Patients may receive oral prednisolone up to a dose of 10 mg per day,
anti-oxidant therapy, pirfenidone or other licensed medication for IPF e.g.
nintedanib. Patients should be on a stable treatment regimen for at least 4
weeks to ensure baseline values are representative.
4. MRC dyspnea score of greater than 1.
5. Able to provide informed consent
Exclusion Criteria Exclusion Criteria (as of January 7, 2019)*
1. Received antimicrobial therapy in the past 30 days for treatment
purposes (antibiotic prophylaxis for procedures do not meet criteria, nor
do antivirals)
2. Contraindicated for antibiotic therapy
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.
1. FVC > 75% predicted.
2. A recognized significant co-existing respiratory disease, defined as a re-
spiratory condition that exhibits a greater clinical effect on respiratory
symptoms and disease progression than IPF as determined by the principal
investigator.
3. Patients with airways disease defined as forced expiratory volume in 1 s
(FEV1)/FVC < 60%
4. A self-reported respiratory tract infection within 4 weeks of screening de-
fined as two or more of cough, sputum or breathlessness and requiring
antimicrobial therapy.
5. Significant medical, surgical or psychiatric disease that in the opinion of
the patient’s attending physician would affect subject safety or influence
the study outcome including liver (Serum transaminase > 3 x upper limit of
normal (ULN), Bilirubin > 2 x ULN) and renal failure (creatinine clearance <
30 ml/min).
6. Patients receiving recognized immunosuppressant medication (except
prednisolone above) including azathioprine and mycophenolate mofetil.
7. Female subjects must be of non-childbearing potential, defined as fol-
lows: postmenopausal females who have had at least 12 months of spon-
taneous amenorrhea or 6 months of spontaneous amenorrhea with serum
FSH > 40mIU/ml or females who have had a hysterectomy or bilateral oo-
phorectomy at least 6 weeks prior to enrollment.
8. Allergy or intolerance to trimethoprim or sulphonamides or their
combination.
9. Untreated folate or B12 deficiency.
10. Known glucose-6-phosphate dehydrogenase (G6PD) deficiency or G6PD
deficiency measured at screening in males of African, Asian or Mediterra-
nean descent.
11. Receipt of an investigational drug or biological agent within the 4
weeks prior to study entry or 5 times the half-life if longer.
12. Receipt of short course antibiotic therapy for respiratory and other
infections within 4 weeks of screening.
13. Patients receiving long term (defined as > 1 month of therapy)
prophylactic antibiotic treatment will not be eligible as this may have an
impact on lung microbiota. Such patients may enroll in the EME-TIPAC trial,
if this is supported by their clinician, after a ‘wash-out period’of 3 months.
14. Serum Potassium greater than 5.0 mmol/l due to the potentially
increased risk of hyperkalemia in patients taking co-trimoxazole in combin-
ation with potassium sparing diuretics (including angiotensin converting
enzyme inhibitors or angiotensin receptor blockers)
*The study eligibility criteria are taken verbatim from the official trial registration (http://www.isrctn.com/ISRCTN17464641)
Anstrom et al. Respiratory Research (2020) 21:68 Page 7 of 13
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
Total number of respiratory infections
UCSD-Shortness of Breath Questionnaire at 12
months
Fatigue Severity Scale score at 12 months [50]
Leicester Cough Questionnaire score at 12 months
[51]
EQ-5D score and SF-12 score at 12 months
ICEpop CAPability measure for Older people score
at 12 months [52,53]
Safety endpoints
The electronic data collection forms will collect a tar-
geted set adverse events of special interest such as
arrhythmia, diarrhea, hyperkalemia, rash, and vomiting.
General statistical considerations
In this unblinded trial, all participants will be random-
ized to treatment in a 1:1 allocation ratio using a simple
randomization scheme within the electronic data collec-
tion system. It was the belief of the investigators that
blinding would add substantial additional complexity
without commensurate incremental benefit related to
testing the primary hypothesis of a treatment strategy
trial. Means, standard deviations, medians, 25th and
75th percentiles will be presented for continuous vari-
ables; the number and frequency of patients in each
category will be presented for nominal variables. Statis-
tical tests with a two-sided pvalue < 0.05 will be consid-
ered statistically significant, unless otherwise stated.
Analyses will be performed using SAS software (SAS In-
stitute, Inc., Cary, NC).
Analysis of the primary endpoint
Detailed description of the plan for statistical analysis of
each endpoint will be produced in a separate Statistical
Analysis Plan. The primary analysis will be based on
intention to treat. Crossovers (e.g. drop-in and drop-out)
will be tracked and an alternate analysis cohort will be de-
veloped based on these data. Participants receiving lung
transplantation during the course of follow-up will be cen-
sored for all endpoints at the time of transplantation.
The statistical comparison of the two randomized arms
with respect to the primary endpoint will be a time-to-
event analysis, and therefore will be based on the time
from randomization to first non-elective, respiratory
hospitalization or death from any cause. The Cox propor-
tional hazards regression model will be the primary tool
to analyze and assess outcome differences between the
two treatment arms. The Cox model will include an indi-
cator variable for treatment group, age, sex, baseline
DLCO, baseline FVC, use of N-Acetylcysteine at enroll-
ment, indicator variables for the use of nintedanib or
Fig. 1 Flow diagram for participants randomized to antimicrobial therapy
Anstrom et al. Respiratory Research (2020) 21:68 Page 8 of 13
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
pirfenidone at enrollment, and choice of antimicrobial
agent prior to randomization. Hazard ratios and 95% con-
fidence intervals will summarize the differences between
treatment arms. Kaplan-Meier estimates will be used to
display event rates by treatment group.
For the primary analysis, participants who are event-
free (i.e. subjects without any respiratory hospitalization
or death event at the time of analysis) will be censored
at their last visit or lung transplantation. The censoring
mechanism is assumed to be non-informative. Support-
ive analyses will be performed to assess the impact of a
potential informative censoring.
Sample size and power calculations
Based on IPFnet data, it is anticipated that the event rate
in the placebo arm will be highly dependent on the pro-
portion of patients enrolled at the different gender, age,
and lung physiology (GAP) index scores [31,54]. Given
the availability of two U.S. Food and Drug Administra-
tion (FDA)-approved drugs for IPF, it is our belief that
the study population will be heavily weighted toward
GAP index scores of 3. In Appendix Table 4, the statis-
tical power is determined for designs enrolling 500 par-
ticipants with usual care group events rates varying from
24 to 36% and (12-month) treatment effects varying
from 30 to 35%. In general, the proposed design pro-
vides adequate power except when the 12-month
standard-of-care group event rate is below 24% and the
reduction in events is less than 30%. We plan to enroll
500 patients window with a minimum of 12 months of
follow-up on all patients. Appendix Table 5shows the
required number of endpoint events to have adequate
power across varying hazard ratios.
Data and safety monitoring board
The NIH-appointed DSMB includes individuals with
pertinent expertise in IPF, clinical trials, ethics and bio-
statistics. The DSMB will advise the PLG and the NIH
regarding the continuing safety of current participants
and those yet to be recruited. The DSMB will meet ap-
proximately 2 times per year to review safety and overall
study progress until the end of the study.
DSMB monitoring plan
Prior to each meeting, the data coordinating center at
Duke Clinical Research Institute will conduct any re-
quested statistical analyses and prepare a summary re-
port along with the following information: patient
enrollment reports, rates of compliance with the
assigned testing strategy, frequency of protocol viola-
tions, and description of serious adverse events. There
will be one planned interim review for efficacy. The effi-
cacy review will focus on the composite endpoint of re-
spiratory hospitalization or all-cause death and should
occur once 300 enrolled subjects have been followed for
12 months. The Lan-DeMets alpha spending function
with O’Brien-Fleming type boundaries will be used for
the interim analysis.
Discussion
Endpoint issues in IPF studies
There has been considerable debate in the IPF clinical
research world about the appropriate endpoint for
Phase III clinical trials [30,31,55–58]. To date, both
FDA-approved drugs (nintedanib and pirfenidone),
have used FVC as the primary endpoint. As a result,
the majority of Phase II and III clinical trials in IPF
have used the measure of lung function as the pri-
mary endpoint. Recently, there has been considerable
work on quality of life and symptoms (including
cough and reflux) [59]. Furthermore, several groups
have pooled clinical trial databases to examine treat-
ment effects of drugs on clinical endpoints including
mortality and respiratory hospitalizations [60,61].
The CleanUP-IPF trial has been designed to have a
composite clinical primary endpoint as part of the
Prospective Open Label Blinded Endpoint (PROBE)
design [62].
Public-private partnership
The parent structure for the trial utilizes the NHLBI
sponsored PTC. A large network of clinical centers
ranging from community-based centers to tertiary in-
stitutions is conducting the study.Financial support
for this study includes contributions from three add-
itional organizations: Three Lakes Partners, IPF Foun-
dation, and Veracyte, Inc. Three Lakes Partners is a
venture philanthropy whose mission is to accelerate
the development of promising technologies for IPF
(https://threelakespartners.org/). The mission of the
IPF Foundation is to advocate and fundraise for the
most promising research to accelerate IPF cures
(https://ipffoundation.org). Veracyte, Inc. is a pioneer
in genomic diagnostics (https://www.veracyte.com)
that has developed a genomic classifier that facilitates
the diagnosis of usual interstitial pneumonia and po-
tentially IPF [63].
In summary, the CleanUP-IPF study has several po-
tentially transformative elements. The pragmatic de-
sign is reducing the participant burden and allowing
for a large enough sample size to evaluate clinical
endpoints. Additionally, the highly flexible design will
allow for mechanistic studies, collection of biological
samples, and pooling of the study database with the
EME-TIPAC study. Finally, the study leverages a
comprehensive private-public partnership including
the NIH, a broad range of investigative institutions,
philanthropic organizations, and industry.
Anstrom et al. Respiratory Research (2020) 21:68 Page 9 of 13
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
Appendix 1
Table 3 Doxycycline study - comparisons of enrollment and follow-up assessments*
Endpoint N Enrollment
Mean (SD)
Follow-up
Mean (SD)
Paired T-test
p-value
Body Mass Index (kg/m
2
) 6 25.41 (4.41) 26.07 (4.45) 0.080
6 Minute Walk Test (feet) 5 1142 (159) 1283 (194) 0.110
St. George’s Respiratory Questionnaire –total score 6 50.90 (8.38) 18.40 (6.39) 0.002
FVC percent predicted (%) 6 61.38 (10.65) 67.67 (14.39) 0.311
MMP9 activity 6 6.19 (2.04) 2.59 (0.66) 0.006
MMP3 activity 6 9.03 (2.02) 4.83 (3.54) 0.041
MMP9 expression 6 3.39 (1.06) 1.45 (0.41) 0.004
TIMP-1 expression 6 5.28 (1.56) 2.72 (0.67) 0.018
VEGF expression 6 9.03 (2.02) 4.83 (3.54) 0.041
*Data are taken from [15]. Activities levels are determined from Western Blot. See [15] for more details
Appendix 2
Table 4 Statistical Power Assuming a Sample Size of 500 Randomized Patients
Standard-of-care event rate* Antimicrobial therapy strategy event rate* One-year Event Rate Reduction Power
24% 16.8% 30% 78%
30% 21.0% 30% 87%
36% 25.2% 30% 93%
24% 16.0% 33.3% 86%
30% 20.0% 33.3% 93%
36% 24.0% 33.3% 97%
24% 15.6% 35% 89%
30% 19.5% 35% 95%
36% 23.4% 35% 98%
*12-month event rates. Calculations assume a 2-sided Type-I error rate of 0.05. The minimum follow-up is planned to be 12 months and the maximum follow-up is
42 months. Drop-out rates are assumed to be approximately 2% per year. Power calculations were based on a log-rank test with assumed event rates were expo-
nentially distributed. Calculations were computing using nQuery 7.0 software
Appendix 3
Table 5 Required number of primary endpoint events
HR = 0.50 HR = 0.55 HR = 0.60 HR = 0.65 HR = 0.70 HR = 0.75
80% power 65 88 120 169 247 379
85% power 75 100 138 194 282 434
90% power 87 118 161 226 330 508
Calculations performed using nQuery 7.0 and assume a 0.05 type I error rate (two-sided) with 1:1 randomization
Anstrom et al. Respiratory Research (2020) 21:68 Page 10 of 13
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
Abbreviations
CI: Confidence interval; DLCO: Diffusing capacity for carbon monoxide;
DSMB: Data and safety monitoring board; FDA: U. S. food and drug
administration; FVC: Forced vital capacity; GAP: Gender, age, and lung
physiology; HR: Hazard ratio; IPF: Idiopathic pulmonary fibrosis; IPFnet: IPF
clinical research network; NEMO: Network management core; NIH: National
institutes of health; PLG: Protocol leadership group; PRECIS-2: PRagmatic
explanatory continuum indicator summary-2; PROBE: Prospective open label
blinded endpoint; PTC: Pulmonary Trials Cooperative
Acknowledgements
We acknowledge Dr. Antonello Punturieri, the NHLBI program officer for the
Pulmonary Trial Cooperative, for his support during the design and conduct
of this trial.
NHLBI –Julie Barndad, Katie Kavounis, Dong-Yun Kim, Antonello Punturieri,
Lora Reineck, Lisa Viviano, Gail Weinmann.
Network Management Core –NEMO –University of Pittsburgh –Steve
Barton, Amanda Baucom, Maria Brooks, Heather Eng, Mike Kania, Yulia
Kushner, Jeffrey Martin, Jeffrey O’Donnell, Vicky Palombizio, Jo Anne Phillips,
Frank C. Sciurba, Jennifer Stevenson, Mary Tranchine, Fallon Wainwright,
Alexander Washy, Stephen R. Wisniewski, Patty Zogran.
CleanUP-IPF Coordinating Center –Duke University –Joan Albright, Kevin J.
Anstrom, Emily S. Clausen, Joanna Cole, Dahlia Cowhig, Coleen Crespo,
Michael Durheim, Jerry Kirchner, Heather Kuehn, Jay Rao, Laurie D. Snyder,
Qinghong Yang, Eric Yow.
Clinical Events Committee –Michael T. Durheim, Brett Ley, Justin M. Oldham.
Albany Medical Center –Scott Beegle, Marc Judson, Rachel Vancavage.
Beth Israel Deaconess Medical Center –Robert Hallowell, Shaelah
Huntington, Joe Zibrak.
Brigham and Women’s–Maura Alvarez, Sarah Chu, Tracy Doyle, Souheil El-
Chemaly, Hilary Goldberg, Swati Gulati, Juan Vicente Rodriguez, Ivan Rosas.
Cleveland Clinic –Daniel Culver, Jessica Glennie, Aman Pande, Andrea Rice,
Richard Rice, Brian Southern, Leslie Tolle, Ron Wehrmann.
Columbia University –Rifat Ahmed, Michaela Anderson, Atif Choudhury,
John Kim, Onumaraekwu Opara, Nina Patel, Anna Podolanczuk.
Cornell University –Sergio Alvarez-Mulett, Robert Kaner, Daniel Libby, Mat-
thew Marcelino, Fernando J. Martinez, Alicia Morris, Elizabeth Peters, Xiaoping
Wu.
Dartmouth-Hitchcock Medical Center –Kathy Dickie, Rick Enelow, Alex
Gifford.
Geisinger Medical Center –Penny Gingrich, Michelle Kopfinger, Yalin Mehta,
Ashley Peters, Jaya Prakash Sugunaraj.
INOVA –Kareem Ahmad, Martha Alemayehu, Shambhu Aryal, Edwinia Battle,
Anne Brown, Ashley Collins, Vijaya Dandamudi, Priscila Dauphin, Christopher
King, Merte Lemma, Steven Nathan, Jennifer Pluhacek, Oksana Shlobin, Drew
Venuto, Serina Zorrilla.
Johns Hopkins University –Wally Arabelis.
Louisiana State University –Matthew Lammi, David Smith, Richard Tejedor.
Loyola University –Chicago –Ken Baker, Bradford Bemiss, Josefina Corral,
Dan Dilling, Patricia Duran, Mary Rose Evans, Katelynn Prodoehl, Sana
Quddus, Kelly Shaffer, Filip Wilk.
Massachusetts General Hospital –Kelsey Brait, Leo Ginns, David Kanarek,
Mamary Kone, Sydney Montesi, Layla Rahimi.
Mayo Clinic –Boleyn Andrist, Misbah Baqir, Shannon Daley, Alana English,
Laura Hammel, Samantha Hughes, Teng Moua.
Medical College of Georgia –Kit Guinan, Linda Tanner-Jones, Varsha Taskar,
Mount Sinai –Stacey-Ann Brown, Chelsea Chung, Michele Cohen, Nicole
Lewis, Aditi Mathur, Linda Rogers.
National Jewish Health –Flavia Hoyte, Barry Make.
Northwestern University –Abbas Arastu, Sangeeta Bhorade, Jane Dematte,
Khalilah Gates, Paul Reyfman, Lewis Smith.
NYU Winthrop –Priya Agarwala.
Ohio State –Nitin Bhatt, Karen Martin, Taylor Wong.
Penn State –Rebecca Bascom, Anne Dimmock, Donna Griffiths, Christie
Schaeffer, Max Whitehead-Zimmers.
Piedmont –Stacy Beasley, Aja Bowser, Amy Case, Michelle Clark, James
Waldron, Liz Wilkins.
Spectrum Health –Jason Biehl, Melissa Boerman, Jennifer Cannestra, Shelley
Schmidt, Mona Wojtas.
St. Louis University –Ghassan Kamel.
St. Vincent ALA –Airway Clinical Research Center –Michael Busk.
Stanford University –Susan Jacobs, Joshua Mooney, Karen Morris, Rishi Raj.
Temple University –Joanna Beros, Gerard Criner, Puja Dubal, Sheril George,
Carla Grabianowski, Rohit Gupta, Joseph Lambert, Nathaniel Marchetti,
Francine McGonagle, Lauren Miller, Jenna Murray, Erin Narewski, Shubhra
Srivastava-Malhotra, Karen Clark, Matt Kottmann, David Nagel.
University of Kansas –Luigi Boccardi, Kristina Delaney, Stephanie Greer, Mark
Hamblin, Kimberly Lovell, Lindsey Schoon.
University of Alabama at Birmingham –Maria del Pilar Acosta Lara, Swati
Gulati, Leslie Jackson, Thyrza Johnson, Tejaswini Kulkami, Tracy Luckhardt,
Kamesha Mangadi, Emirl Matsuda, Tonja Meadows.
University of Arizona –Valerie Bloss, Sachin Chaudhary, Heidi Erickson,
Bhupinder Natt, Afshin Sam.
University of California –Davis Medical Center –Timothy Albertson, Elena
Foster, Richard Harper, Maya Juarez, Justin Oldham, Chelsea Thompson.
University of California –San Diego –Xavier Soler.
University of Chicago –Ayodeji Adegunsoye, Janine Grohar, Spring Maleckar,
Mary Strek, Rekha Vij.
University of Cincinnati –Amber Crowther, Nishant Gupta, Rebecca Ingledue,
Tammy Roads.
University of Florida –Jacksonville –Vandana Seeram.
University of Illinois at Chicago –Kyle Potter.
University of Miami –Mayilyn Glassberg, Jennifer Parra, Jesenia Portieles,
Emmanuelle Simonet.
University of Michigan –Beth Belloli, Linda Briggs, Candace Flaherty, Kevin R.
Flaherty, MeiLan Han, Cheryl Majors, Margaret Salisbury, Eric White.
University of Minnesota –Maneesh Bhargava, Rebecca Cote, Mandi DeGrote,
Tommy Goodwin, Craig Henke, Hyun Kim, David Perlman.
University of Pittsburgh –Jessica Bon, Chad Karoleski, Frank Sciurba, Elizabeth
Stempkowski, Victor Washy, Robert Wilson.
University of Texas at San Antonio –Maria Castro, Anna Hernandez, Karl
McCloskey, Anoop Nambiar.
University of Utah –Sean Callahan, Cassie Larsen, Joseph Martinez, Mary
Beth Scholand, Scott Sweeten, Martin Villegas, Lindsey Waddoups, Lisa
Weaver.
University of Virginia –Theresa Altherr, Cameron Brown, Imre Noth, Connie
Pace, Tessy Paul.
University of Washington –Bridget Collins, Chessa Goss, Lawrence Ho, Mory
Mehrtash, Ganesh Raghu.
VA Puget Sound –Emily Gleason, Amber Lane.
Vanderbilt University - Jim Del Greco, Rosemarie Dudenhofer, Lisa Lancaster,
Jim Loyd, Susan Martin, Wendi Mason, Eric Smith.
Western Connecticut –Guillermo Ballarino, Thomas Botta, John Chronakos,
Loren Inigo-Santiago, Sakshi Sethi.
Data and Safety Monitoring Board –Deborah Barnbaum, Gordon Bernard,
Joao deAndrade, Daren Knoell, Andrew Limper, Peter Lindenauer, Irina
Petrache, Andre Rogatko, Marinella Temprosa,
Authors’contributions
Drs. Martinez, Noth, and Anstrom drafted the manuscript. All authors
provided critical review and approved the final version.
Funding
NIH funding from grant 5 U01-HL12896 4 supported this project.
Availability of data and materials
Not applicable.
Ethics approval and consent to participate
The protocol was reviewed and approved by an independent DSMB. Each
enrolling site obtained institutional review board (IRB) approval prior to
enrolling any patients. All participants agreed to participate in the clinical
trial.
Consent for publication
The authors consent to publish.
Competing interests
None.
Anstrom et al. Respiratory Research (2020) 21:68 Page 11 of 13
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
Author details
1
Duke Clinical Research Institute, Duke University, Durham, North Carolina,
USA.
2
Division of Pulmonary Medicine, University of Virginia, Charlottesville,
Virginia, USA.
3
Division of Pulmonary & Critical Care Medicine, University of
Michigan Health System, Ann Arbor, MI, USA.
4
Pulmonary Fibrosis
Foundation, Chicago, IL, USA.
5
Graduate School of Public Health, University
of Pittsburgh, Pittsburgh, PA, USA.
6
Norwich Medical School, University of
East Anglia, Norwich, UK.
7
Division of Pulmonary and Critical Care Medicine,
University of Pennsylvania, Philadelphia, PA, USA.
8
Department of Respiratory
Medicine, Oslo University Hospital –Rikshospitalet, Oslo, Norway.
9
National
Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD,
USA.
10
UC Davis, Pulmonary, Critical Care, and Sleep Medicine, Davis,
California, USA.
11
Division of Pulmonary Medicine, Weill-Cornell Medical
Center, Cornell University, New York, NY, USA.
Received: 23 August 2019 Accepted: 19 February 2020
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