1. What institution is the lead site for the Phase 2 IRB? (Updated May 2019)

The University of Illinois at Chicago is the Prime awardee and the lead site for the Phase 2 IRB. Johns Hopkins University is the data coordinating center for RELIANCE.

2. What institution is the data coordinating center for RELIANCE? (Updated May 2019)

Johns Hopkins University is the data coordinating center for Phase 2 of RELIANCE.

3. Where can I find my site's landing page and landing page password? (Updated Aug 2024)

An email with your site's landing page and password was sent to your site PI. If you need your information resent please contact Nina Bracken (ngrude@uic.edu), Jill Meinert (jmeiner1@jhu.edu), Data coordinating center (jhsph.reliance@jhu.edu)

4. Someone new joined our team, how do I make sure they receive RELIANCE trial meeting invites and emails? (Updated Dec 2020)

The Lead Coordinator for each site is tasked with maintaining their site's directory. This can be edited on the DCC Investigator Page http://reliancetrial.org/secure/reliance/default.htm

Username: reliance
Password: Pragmatic1!

If you would like to confirm a new coordinator should be added to Coordinator Call and Office Hour calendar invitations, please email jhsph.reliance@jhu.edu

5. What if my patient is already enrolled in the AIRWISE COPD study? (Updated May 2019)

RELIANCE allows concurrent enrollment in other clinical trials. If your patient is participating in the AIRWISE study, they can still be enrolled in RELIANCE. We recommend you confirm concurrent enrollment with study administrators for the AIRWISE study.

See PDF for a comparison of the RELIANCE and AIRWISE COPD study.

6. What role is the FDA playing in the trial? (Updated June 2019)

The Sentinel System is the FDA’s active safety surveillance system and uses routine querying tools and pre-existing electronic healthcare data to monitor safety of medical products. The Sentinel Operations Center (SOC) at Harvard Pilgrim Health Care Institute (HPHCI) works closely with FDA and other collaborators to coordinate and/or lead Sentinel System activities. The FDA’s SOC will work with the RELIANCE data coordinating center to link patients aged 65 and older enrolled in the PCORI RELIANCE trial to traditional fee-for-service Medicare data. Linkage of the RELIANCE trial to Medicare data will provide additional information on the primary outcome, all-cause rehospitalization or death, select secondary outcomes such as all-cause healthcare utilization and medication adherence; and will also provide an opportunity to test distributed regression methods with vertically partitioned data. This activity will support FDA’s assessment of the use of real world evidence to help support the approval of new indications for approved drugs which is mandated by the 21st Century Cures Act, as well as build and test infrastructure and methods to conduct pragmatic clinical trials.

7. Where are the package inserts for azithromycin and roflumilast located? (Updated May 2019)

Package inserts (i.e., FDA prescribing information) can be found on the All Sites Overview. A link to this page is also accessible from your site's Administrative page. If you need the link to your Administrative page resent, please contact reliance@uic.edu.

8. Has anyone done a Medicare prior authorization before? (Updated Nov, 2019)

Based on conversation during the January 8, 2020 Coordinator Call, some site Coordinators have been involved in the process of requesting prior authorization from a patient’s insurance company. Coordinators who were involved were Research Nurses who were also clinical Nurses and had completed for clinical purposes. A few Coordinators noted they had asked a clinic Nurse if they could shadow the process so they were aware of what went into the request. Coordinators are not expected to complete the prior authorization, unless this is their role outside of the RELIANCE study. This should be completed by clinic personnel, or as it normally would occur in practice.

9. Is there a preferred guideline for reference for Azithromycin/Roflumilast? (Updated Nov, 2019)

Recommendations about the use of chronic azithromycin or roflumilast are available in several recent publications, including the 2015 ACCP/CTS guidelines (1), 2017 ERS/ATS guidelines (2), and the 2020 GOLD strategy report (3).

The 2017 ERS/ATS guidelines identified several research needs, including “head-to-head studies comparing the benefits and adverse effects of oral medications that reduce the risk of COPD exacerbations (e.g. long-term azithromycin versus roflumilast or N-acetylcysteine)... [and]... defining subgroups of patients who are more or less likely to benefit from macrolide therapy (e.g. by smoking status) is necessary.” The RELIANCE study is one effort to address these evidence gaps.

(1) Criner GJ, et al. Prevention of acute exacerbations of COPD: American College of Chest Physicians and Canadian Thoracic Society Guideline. Chest. 2015 Apr;147(4):894-942.
(2) Wedzicha JA, et al. Prevention of COPD exacerbations: a European Respiratory Society/American Thoracic Society guideline. Eur Respir J. 2017 Sep 9;50(3):1602265.
(3) 2020 GOLD strategy report.

10. How do I add a new coordinator at my site? (Updated Sep, 2021)

https://docs.google.com/document/d/1029-tgQgGBcokzIouaAE5sb96v6xx99E9ZCq48hrbO8/edit

11. How might I respond to a patient's or caregiver's question regarding azithromycin use and risk of developing antibiotic resistance? (Updated Aug, 2024)

Simple response for patient

Many patients with COPD across the U.S. use chronic azithromycin therapy. Pulmonary doctors have not reported that this leads to illnesses with resistant organisms so continue to prescribe azithromycin. But doctors don’t know if using azithromycin is better or not as good as roflumilast. That’s why pulmonary doctors across the country are part of the RELIANCE study – so that we can study both medications head-to-head.

Explanation for coordinators

The MACRO study (Albert, NEJM, 2011) reported an increase in cultures with Az-resistant organisms (azithromycin vs. placebo group, 81 vs. 41% placebo, p <.0001), data-preserve-html-node="true" but we've not seen an increase in clinical infections with Az-resistant organisms. In the BACE trial (Vermeersch, AJRCCM, 2019), there were no significant differences for positive sputum cultures with newly acquired pathogens, nor for macrolide-resistant bacteria during follow-up. We're doing the RELIANCE study to understand better the relative harms and benefits of initiating chronic Azithromycin vs. Roflumilast.

1. Does my site need to submit a separate IRB application for our University and Hospital? (Updated May 2019)

Many institutions in the RELIANCE network are affiliated with both a University and a Hospital. Most institution’s hospitals and affiliated clinics are covered by the academic institution’s IRB. If you are unsure, please check with your institution’s IRB.

2. Should the Phase 2 protocol be submitted as a separate application from Phase 1? (Updated May 2019)

Yes. Please see the Phase 2 IRB Registration Instructions document on your study page under Phase 2 IRB Materials.

3. Do I need to complete a continuing review application for the Phase 1 protocol? (Updated June 2019)

The University of Illinois at Chicago (Prime) and Johns Hopkins University (DCC) will be keeping the Phase 1 protocol open for continued data analysis and potential publications. We recommend that you check the date of your local expiration and contact your local IRB to ensure you are following your institutions IRB policies when it comes to closing the Phase 1 protocol at your site.

1. What institution is the lead site for the Phase 2 IRB? (Updated May 2019)

The University of Illinois at Chicago is the Prime awardee and the lead site for the Phase 2 IRB. Johns Hopkins University is the data coordinating center for RELIANCE.

2. Can we use our local IRB for Phase 2 of RELIANCE? (Updated May 2019)

Use of SMART IRB is preferred by both the funder, PCORI, and the RELIANCE Executive Committee. If your institution or your PI feel your site should use your local IRB, you may proceed after communicating this to the RELIANCE team by sending an email to reliance.team@reliance-study.org with a cc to your PI.

3. Does my site need to submit a separate IRB application for our University and Hospital? (Updated May 2019)

Many institutions in the RELIANCE network are affiliated with both a University and a Hospital. Most institution’s hospitals and affiliated clinics are covered by the academic institution’s IRB. If you are unsure, please check with your institution’s IRB.

4. What is the electronic data capture (EDC) system that will be used in Phase 2? (Updated May 2019)

DatStat is developing data entry portals for patients, investigators, and call center personnel to be used in Phase 2. The Data Coordinating Center will use a locally developed HIPAA-compliant EDC. For more information please see additional data security information here.

5. How long will RELIANCE keep personal identifiers? (Updated May 2019)

Please see additional data security information here.

6. Will participants be able to opt out of providing their social security number (SSN)
          and health insurance information? (Updated May 2019)

No, this is required for participation.

7. Will there be additional compensation for sites for changes to the Phase 2 protocol since
          charges may be incurred locally for revision? (Updated May 2019)

There are no plans to provide additional compensation for amendments.

8. Who at the site will be provided a CHAIRb portal account? (Updated May 2019)

Individuals who are listed in your site's contact database as PI, Co-I, and Coordinator will be automatically provided accounts. You can request additional accounts for personnel at your site by emailing reliance.team@reliance-study.org and cc'ing your site PI.

9. Will the study be activated under the current protocol (2.2) or will there be amendments? (Updated Oct 2019)

Protocol v3.1 was approved by CHAIRb in August 2019. This protocol amendment should be registered with your local IRB.

10. Is the eligibility at baseline form required? Will it be uploaded to the study portal or is it a tool for coordinators? (Updated Oct 2019)

Yes, the eligibility at baseline form is required prior to randomization. Sites will be provided with a separate screening form that will be helpful to use while identifying patients based on review of electronic health records.

11. If a site is using CHAIRb and CHAIRb approves e-consent, can a site use e-consent even if e-consent is not typically approved by a site's local IRB? (Updated Oct 2019)

We recommend each site review this with their local IRB representative.

12. Can a site use it's own e-consent? (Updated Oct 2019)

If a site has ceded review to the central IRB, CHAIRb, an e-consent would need to be reviewed and approved by CHAIRb.

13. Will there be in-person monitoring visits? (Updated Nov, 2019)

No in-person monitoring visits are currently planned. However, visits to specific sites may be requested by the independent data safety monitoring board (DSMB), central IRB (CHAIRb), or the study funder (Patient Centered Outcomes Research Institute [PCORI]).

14. Participant protection with giving out SSN? (Updated Nov, 2019)

Social security numbers and health insurance claims numbers are routinely used by hospitals, clinics, and payers (health insurance companies) to identify patients as part of usual healthcare operations. Participant social security numbers are considered protected health information and are thus subject to the full protection of the HIPAA act. We are undertaking measures to protect confidentiality and privacy as required by regulatory boards, the independent data safety monitoring board, the study funder, and the U.S. Food and Drug Administration.

15. Do I call the Call Center to report an event? (Updated Nov, 2019)

Adverse events should be reported through the on-line Investigator Portal (see RELIANCE MOP).

16. If a participant refuses to provide their social security number (SSN), are they excluded? (Updated Nov, 2019)

Yes, the individual is not eligible if they do not provide the SSN. The study team needs the social security number and health insurance claims number to link each participant to claims data, which will be used to assess healthcare utilization outcomes. If a participant refuses to provide their social security number (SSN), they are not eligible since we will not be able to use claims data to assess health care utilization outcomes (see RELIANCE MOP).

17. Can you download the consent form? (Updated Nov, 2019)

Yes, study staff can download the consent form. If sites are relying on the central IRB (CHAIRb), both study staff and patients can download the consent form from the central IRB (CHAIRb) portal located here. If you need help with your login or password, contact 'chairb@uic.edu'. If you need help navigating the CHAIRb portal, we have posted navigation slides on your Administrative page under the Protocol and other study documents tab.

18. Is there a copy of the baseline form? (Updated Nov, 2019)

Yes, study staff will be able to download the enrollment/baseline forms from the DCC-hosted RELIANCE Investigator Site here, beginning 02/29/2020. The study staff will also be able to view the baseline form through the Investigator Portal, beginning 02/10/2020.

19. Do you need to complete the registration form before eligibility form? (Updated Nov, 2019)

No. Eligibility Form should be completed first to assess a participant’s fit for the trial. We strongly recommend but do not require registration be completed prior to randomization. Follow-up is a vital part of the RELIANCE study, and we will need to obtain participant contact information to complete appropriate follow-up.

20. Is pharmacy information collected for the Call Center to know? (Updated Nov, 2019)

No, pharmacy information is not collected. The Call Center will refer the participant to their prescribing physician if there is an issue with the prescription pick up.

21. Do prescribing clinicians need to be listed as IRB-approved personnel? Some clinicians may not have gone through Human Subjects Protection training. (Updated Nov, 2019)

To answer this question, we need to first briefly explain RELIANCE clinician responsibilities. To optimize the opportunity to assess the real-world effects of roflumilast or azithromycin in clinical populations, the RELIANCE study is embedded in clinical practice. As an embedded clinical trial, a patient may interact with 1, 2, or all 3 types of clinicians below. It is also possible that a particular clinician serves in 1, 2, or all 3 roles.

1. Study clinician: the site principal investigator or co-investigator(s), who have administrative and regulatory responsibilities to ensure the study is implemented per the IRB-approved study protocol. Study clinicians should be listed as IRB-approved personnel.

2. Prescribing clinician: the clinicians who write the prescription for roflumilast or azithromycin as per the study protocol. The prescribing clinician does not need to be listed as IRB-approved personnel if this clinician would be prescribing roflumilast or azithromycin as part of their clinical practice (e.g., the prescribing clinician is also the patient’s treating clinician; or, the treating clinician is aware of the medication [roflumilast or azithromycin] that will be prescribed and has requested the prescribing clinician to write the prescription for roflumilast or azithromycin as per the study protocol). Otherwise, the prescribing clinician should be listed as IRB-approved personnel.

3. Treating clinicians: the clinician who is providing routine clinical care for individuals with COPD, including study participants. The treating clinician does not need to be listed as IRB-approved personnel.

22. When picking up a prescription, prior authorization may be needed, or the prescription could be too expensive, how does this affect 1-week follow-up call? (Updated Nov, 2019)

One of the objectives of the 1-week follow-up call is to determine if the participant has picked up the prescription for roflumilast or azithromycin. Some of the follow up questions on the 1 week call ask about prior authorization and barriers to filling the prescription.

23. What if the initial prescription isn’t filled? (Updated Nov, 2019)

In routine clinical practice, some patients do not fill the initial prescription or the follow-up prescriptions. Once the participant is randomized in the RELIANCE study, they will be followed as per the study protocol, even if they don’t fill the initial prescription. The call center will ask questions about whether the participant filled the initial prescription on the first follow-up call.

24. How is RELIANCE addressing the cost differential between the two medicines? (Updated Nov, 2019)

We will collect data about participant-reported out-of-pocket costs for roflumilast and azithromycin and can use this information to estimate how differences in out-of-pocket costs of these medicines are associated with participants’ use of these medicines and health outcomes.

The study will be providing information on defraying medication costs that is available to individuals whether or not they are enrolled in the RELIANCE study. By design, the RELIANCE study does not seek to reduce the price differential between the two medicines.

The goal of the RELIANCE study is to compare the harms and benefits of two medications that are both guideline-recommended to reduce the risk of COPD exacerbations in routine healthcare conditions. In the case of RELIANCE, only one of the two medicines (azithromycin) can be purchased as a low-cost generic medicine. However, azithromycin can lead to bacterial resistance, which may affect treatment options for COPD exacerbations, pneumonia, or other infections. Also, there is a small increase in risk of cardiac dysrhythmias or hearing abnormalities with azithromycin. Unlike azithromycin, Roflumilast is FDA-approved to reduce the risk of COPD exacerbations, but also can cause side effects (see Drug comparison for physicians poster). In routine healthcare, if the patient or a clinician has a preference for one medication over the other (e.g., due to pill size, potential side effects, cost), then it will determine which medicine is prescribed. In routine healthcare, the patient or treating clinician may also stop the medication because the patient can no longer afford it or has side effects; in such cases, the treating clinician may opt to switch the patient to the other medication (e.g., azithromycin to roflumilast or vice versa).

The RELIANCE study seeks to enroll participants when neither the patient nor the treating clinician has a preference for starting one medication over the other due to pill size, potential side effects, out-of-pocket cost, or other factors. Depending on local practices the RELIANCE study is ok if as part of the screening process the study coordinator or investigators obtain prior-authorization so that an informed consent can occur that includes out-of-pocket costs in assessing equipoise. Once the patient is randomized, then the participant will be analyzed according to the intention-to-treat principle, even if they later discontinue the medication that was originally prescribed or switched to the alternate medication. Because participants with COPD may be using many medications, not only roflumilast or azithromycin, we are providing participants some tips about how to reduce medication costs; see Physician Materials found here: https://reliance-uic.squarespace.com/recruitment-materials.

25. Is there compensation for the 1-week follow-up call? (Updated Nov, 2019)

Participants are compensated following randomization. They are not compensated for the First-week follow-up call.

Participants are compensated for completing subsequent follow-up calls. Participants will receive a $15 gift card of choice via mail, or an Amazon e-code immediately after the completion of each of the follow-up calls: 3-month, 6-month, 12-month, 18-month, 24-month, 30-month, 36-month

26. Will sites receive the annual continuing review report submitted to the central IRB? (Updated Nov, 2019)

Yes, the annual continuing review report submitted to CHAIRb will be shared with sites.

27. What if the prescribed medication (Azithromycin or Roflumilast) is discontinued later, maybe after a couple of months, by another physician? (Updated Nov, 2019)

Medication discontinuation will be captured as an outcome as part of RELIANCE follow-up.

In routine healthcare, the patient or treating clinician may stop the medication because the patient can no longer afford it or has side effects; in such cases, the treating clinician may opt to switch the patient to the other medication (e.g., azithromycin to roflumilast or vice versa).

The goal of the RELIANCE study is to compare the harms and benefits of two medications that are both guideline-recommended to reduce the risk of COPD exacerbations in routine healthcare conditions. The RELIANCE study therefore does not prohibit stopping medications or switching to the other medicine for any reason. The RELIANCE study will compare the proportion of participants in each group who discontinue the medications they were originally randomized to, as well as the proportion of participants in each group who are crossed-over by the treating clinician to the alternate medication. Once the patient is randomized, then the participant will be analyzed according to the intention-to-treat principle, even if they later discontinue the medication that was originally prescribed or switched to the alternate medication.

28. I have discussed the “ site planning checklist” with the investigator – I am not sure what do we need to do in order to “activate” (Updated Dec, 2019)

Great work! Sites should confirm their status during Coordinator Calls scheduled weekly on Wednesdays 10-11am CT during the start-up phase (Dec 2019 - Feb 2020). In order to activate, the following must be complete for your site:

1. Executed Phase 2 subcontract amendment
2. IRB approval for Protocol, site-level consent, and recruitment materials
3. KAT completion by PI, Co-I, and Lead Coordinator
4. Receipt of enrollment + recruitment materials kit
5. Receipt of enrollment gift cards (5)

29. I found out that at least one pharmacy does not have Roflumilast in stock – How would knowing that or “flagging” it to MD/patients make a difference? (Updated Dec, 2019)

Some medications may have limited availability depending on your region. Coordinators can be prepared for this by calling local pharmacies to ask whether or not they stock roflumilast (please reference the Site Planning Checklist available on your site’s Administrative page under Site Activation Materials for additional planning measures). By knowing this ahead of time, the prescription could be routed to another pharmacy in the area to be filled.

30. From talking to clinic nurses, it seems that most rx. for Roflumilast requires pre-authorization, and since there might be a supply issue as above, wouldn’t it greatly affect the 1st call responses? (Updated Dec, 2019)

Yes, we expect there to be delays for some participants. This will not impact the Call Center’s ability to complete the First Follow-up with the participant. Although we hope the participant is able to fill their prescription for their wellbeing, the Call Center is prepared to complete the remainder of the information collected during the First Follow-up Survey with the participant regardless of whether or not the prescription has been filled.

1. Can patients be on therapies in addition to those mentioned on the eligibility requirements? Eligibility requirement is worded: Current medications include inhaled LAMA, LABA/LAMA, or ICS/LABA. (Updated Oct 2019)

We expect patients with COPD to be prescribed other COPD and non-COPD medicines. The treating clinician should determine if any of the concomitant medications affect the balance of risks and benefits when considering treatment intensification options.

2. How long do patients need to be on triple therapy? (Updated Oct 2019)

We are comparing treatment options as they would be used in practice. A patient’s current medications must include LAMA, LABA/LAMA, or ICS/LABA. The protocol does not specify a minimum duration of use of inhaled medications before considering treatment intensification.

3. If a patient has been on short-term Azithromycin in the past 30 days are they ineligible for the study? (Updated Oct 2019)

If the participant has been using azithromycin for 2 or more days per week over the past 30 days they are ineligible for the study. This individual could be eligible for the RELIANCE study if: 1) the patient and the treating clinician elect to discontinue azithromycin therapy for at least 30 days as part of routine clinical practice; AND 2) on day 31 or later meets all the eligibility criteria at the time of re-assessment. Please see the information below for more details.

Eligibility depends on the consecutive number of days of azithromycin therapy. Given the pragmatic clinical trial design in which the study is embedded in clinical practice, we recommend using the information from patient self-report to the treating clinician as it most closely mimics clinical practice. Chronic medication use in the real-world may include use that is less than prescribed. Published chronic azithromycin dosing regimens in COPD include once per day (1), three times per week (2), and every other day (3). Azithromycin has a long half-life (68 hours) (4), so daily use may not necessarily offer greater benefits; head-to-head comparisons of different long-term regimens of azithromycin in COPD to reduce COPD exacerbations have not been published. The median plasma half-lives of roflumilast and its N-oxide metabolite are approximately 17 and 30 hours, respectively (5). In vitro data indicate that roflumilast is more potent than roflumilast N-oxide at inhibiting the PDE4 enzyme; however, analyses of area-under-the-curve (AUC) concentrations of roflumilast N-oxide are approximately 10 times greater than that of roflumilast in pharmacokinetic trials, suggesting that most of its pharmacological effects (possibly up to 90%) can be attributed to its N-oxide metabolite.

Patients are ineligible if they report to their treating clinician that they have been using azithromycin therapy for 2 or more days per week over the past 30 consecutive days. The patient is eligible if 1) the patient reports using azithromycin therapy for an average of fewer than 2 days per week over the past 30 consecutive days; and 2) the patient meets all other eligibility criteria.

A patient who is determined to be ineligible because they report to their treating clinician that they have been using azithromycin therapy for 2 or more days per week over the past 30 consecutive days could be eligible for the RELIANCE study if the patient and the treating clinician would be willing to discontinue azithromycin therapy for at least 30 days AND meets all other eligibility criteria at the time of re-assessment.

We recognize that roflumilast has a shorter half life than azithromycin, but to simplify the assessment of eligibility, we are using the same number of days per week for both medicines to define “prior use for 30 days or more”.

(1) Albert RK, Connett J, Bailey WC, Casaburi R, Cooper JA Jr, Criner GJ, Curtis JL, Dransfield MT, Han MK, Lazarus SC, Make B, Marchetti N, Martinez FJ, Madinger NE, McEvoy C, Niewoehner DE, Porsasz J, Price CS, Reilly J, Scanlon PD, Sciurba FC, Scharf SM, Washko GR, Woodruff PG, Anthonisen NR; COPD Clinical Research Network. Azithromycin for prevention of exacerbations of COPD. N Engl J Med. 2011 Aug 25;365(8):689-98. doi: 10.1056/NEJMoa1104623. Erratum in: N Engl J Med. 2012 Apr 5;366(14):1356. PMID: 21864166; PMCID: PMC3220999.

(2) Uzun S, Djamin RS, Kluytmans JAJW, et al. Azithromycin maintenance treatment in patients with frequent exacerbations of chronic obstructive pulmonary disease (COLUMBUS): a randomised, double-blind, placebo-controlled trial. Lancet Respir Med 2014; 2: 361–368.

(3) Vermeersch K, Gabrovska M, Aumann J, Demedts IK, Corhay JL, Marchand E, Slabbynck H, Haenebalcke C, Haerens M, Hanon S, Jordens P, Peché R, Fremault A, Lauwerier T, Delporte A, Vandenberk B, Willems R, Everaerts S, Belmans A, Bogaerts K, Verleden GM, Troosters T, Ninane V, Brusselle GG, Janssens W. Azithromycin during Acute Chronic Obstructive Pulmonary Disease Exacerbations Requiring Hospitalization (BACE). A Multicenter, Randomized, Double-Blind, Placebo-controlled Trial. Am J Respir Crit Care Med. 2019 Oct 1;200(7):857-868.

(4) https://www.accessdata.fda.gov/drugsatfda_docs/label/2009/050693s014,050730s021lbl.pdf

(5) Baye J. Roflumilast (daliresp): a novel phosphodiesterase-4 inhibitor for the treatment of severe chronic obstructive pulmonary disease. P T. 2012 Mar;37(3):149-61.

4. Is an exacerbation defined as a hospital visit or are in-clinic visits, outpatient/urgent care are also acceptable? (Updated Oct 2019)

To be eligible, the individual is required to have a hospitalization with a physician-diagnosed COPD exacerbation in the previous 12 months. Exacerbations treated in clinic, in urgent care, or in the emergency department do not meet the “Hospitalized for a COPD exacerbation in the past 12 months” criterion.

We are using this definition of hospitalization for COPD exacerbation so that the RELIANCE study could be used to support hospital-level efforts to reduce readmissions and reduce CMS penalties.

5. If patients have both COPD and asthma, can they join the study? (Updated Oct 2019)

Yes. We expect some patients to carry a diagnosis of both asthma and COPD. They are eligible as long as they have a diagnosis of COPD associated with chronic bronchitis.

6. Are patients who are taking Azithromycin three days per week (e.g., Monday, Wednesday, Friday) eligible? (Updated Nov, 2019)

See response to #3 above. Eligibility depends on the consecutive number of days of azithromycin therapy. If the patient has been using azithromycin 3 days per week for the past 2 weeks (14 days), they are eligible as long as they meet all other eligibility criteria.

7. If a participant falls and goes to the hospital, does that count as a hospitalization? Elective surgery, etc. (Updated Nov, 2019)

Yes. The primary outcome for the RELIANCE study is the combined endpoint of death or first all-cause hospitalization. All-cause hospitalization refers to hospitalization for any reason. We selected all-cause hospitalization, rather than COPD-related hospitalization for the primary endpoint because it can be difficult to differentiate COPD-related vs. unrelated causes of hospitalization. We will, however, attempt to identify COPD-related hospitalizations as a secondary outcome.

8. What if the participant signs a consent form and is registered and then found to be ineligible? What if they're eligible months later? Do they get a new ppt ID? (Updated Nov, 2019)

It is possible that the patient is found to be ineligible after they sign a consent form. They cannot be randomized at that point, but they may be re-screened for eligibility at a later date. They will receive a new participant ID each time they are re-screened for eligibility.

The patient MUST be eligible at the time of randomization.

9. Are we using GOLD guidelines to define severe COPD? Are we looking at spirometry to confirm diagnosis? (Updated Nov, 2019)

The treating clinician makes the decision on participant eligibility, including the presence of “severe COPD.” While we encourage treating clinicians to use treatment guidelines when making a diagnosis and making treatment decisions, we do not require spirometry to diagnose COPD or to define severe COPD.

In real-world clinical practice, there is variable use of spirometry to diagnose COPD or to define severe COPD. The RELIANCE study is designed to be embedded in real-world practice. Thus, the RELIANCE study does not require tests outside of what occurs in real-world clinical practice.

10. For the RELIANCE study, we have found that clinicians may not use the words “chronic bronchitis” in the clinical documentation. What defines “chronic bronchitis” for the study? (Updated Feb 2020)

Given the pragmatic clinical trial design in which the study is embedded in clinical practice, we recommend using a definition consistent with clinical practice. We defer to the study clinicians as to the definition most appropriate for your site. Based on discussions with clinicians, “daily phlegm or daily sputum even when the patient is not having a COPD exacerbation” may be a practical definition. We do not specify the minimum duration of these symptoms as it may be difficult to determine in clinical practice and it may not be clinically appropriate to wait 1 or 2 years to determine if a patient has daily cough with sputum for 2 consecutive years.

11. If a patient was hospitalized with a COPD exacerbation associated with COVID-19 do they meet the hospitalized with a diagnosis of COPD exacerbation eligibility criterion? (Updated Apr 2020)

Often people hospitalized with a COPD exacerbation also have other associated conditions and diagnoses, for example, a patient may be hospitalized with COVID-19 and may be treated for a COPD exacerbation. Such patients are eligible for the trial.

12. I have a provider that sees a large population of COPD patients and he states he does not prescribe azithromycin to anyone if they are a current smoker as the literature does not support that it will decrease exacerbations. I will have to say when reading the NEJM article Azithromycin for Prevention of Exacerbation of COPD, Richard K Albert, et. al., and specifically the supplemental data along with the citation in the ERS/ATS Guidelines based on the additional analysis in the Blue Journal, it is difficult to argue with him. With that said, is there any other published evidence that I can use to help persuade this provider to consider smokers for the Reliance study? This provider is a great referral source and I would like to keep him engaged. (Updated Oct, 2020)

Your Pulmonologist is correct, there are post-hoc studies that did not find benefit from using azithromycin in current smokers. Dr. Richard Albert emphasized that definitive statements should not be based on a post-hoc analysis, especially one that included a relatively small number of patients (246 - half of whom received azithromycin). Dr. Albert also noted that the confidence intervals around the effect of azithromycin in smokers were the widest of any subgroup tested (mostly as a function of the small number of patients studied).

There is a large body of literature pointing out that post-hoc analyses are hypothesis generating and findings need to be confirmed in prospective studies, which is exactly what RELIANCE is designed to do. RELIANCE was designed to fill several gaps in evidence, one of which was in response to the 2015 American Thoracic Society/European Respiratory Society research statement for COPD which called for trials that compare outcomes among current smokers with former smokers. The RELIANCE study is designed to test the pre-specified hypothesis that azithromycin is inferior to roflumilast among current smokers. Confirmation of inferiority of azithromycin (vs. roflumilast) among current smokers will support efforts designed to promote personalized health decisions on the basis of smoking, as well as efforts to reduce the use of antibiotics in circumstances without clear benefit. RELIANCE will also be the first head-to-head study of long-term roflumilast vs. azithromycin in high-risk patients with COPD with sufficient precision to examine the potential for heterogeneity of treatment effects among current vs. past smokers. If RELIANCE confirms what these post hoc analyses suggest, as a pragmatic study it is designed to be simple to implement within health systems.

13. Is a patient eligible if they were seen and treated for COPD exacerbation in the observation unit or ED but not "admitted" to the hospital? (Updated Sept, 2022)

Yes. The Executive Committee reviewed and confirmed that a patient is eligible for enrollment if they had observation status for at least 24 hours and meet all other eligibility, despite not being admitted to the hospital.

The hospitalization criterion for COPD is met if any of the following are true in the past 12 months:

(1)Orders for inpatient admission for COPD exacerbation were written but the patient did not get to an inpatient unit due to bed availability; OR

(2)Admitted to an observation unit for COPD exacerbation with a total ED plus observation unit stay for >24 hours; or

(3)Admitted to a CMS recognized acute hospital-at-home program for COPD exacerbation.

14. Is a patient who is prescribed any of the following medicines on a scheduled basis (e.g., every 6 hours (or QID)) eligible for the RELIANCE study? (Updated Nov, 2020)

1) a short acting beta agonist (SABA), or
2) a short acting muscarinic antagonist (SAMA), or
3) a combination SABA/SAMA

Yes. The Executive Committee determined that since these patients are receiving functional controller therapy from a clinical standpoint, they meet the eligibility requirement for RELIANCE.

**1. Can an APN also conduct the routine visit and prescribe the medication if that is part of routine care? ** (Updated Oct 2019)

Yes, as long as it is part of routine care.

**2. Could an RN introduce the study to patients and then let the study coordinator know the patient is interested? ** (Updated Oct 2019)

Yes, as long as they have been trained by site Investigator or designee to introduce the study and are familiar with materials, as appropriate. We will provide communication support that can be used by a clinic nurse.

**3. When during enrollment should study coordinators address the issue of medication costs? ** (Updated Oct 2019)

We would like to follow usual care as it relates to discussion of treatments, side effects, and cost of care. We recommend the treating clinician discuss the potential for differences in out-of-pocket costs when discussing roflumilast and azithromycin as treatment options, before written informed consent is obtained.
Please review the study enrollment pathways in which the coordinator is involved.

**4. Is there a step in enrollment for verifying patient insurance for the medications? ** (Updated Oct 2019)

We are comparing treatment options as they would be used in practice. Insurance verification, and documentation of prior authorization is not an eligibility criterion. If patients or clinicians need assistance with prior authorization forms, coordinators can work with the clinic nurse to assist in the process. We do not intend for the coordinator to complete prior authorization forms, unless this is part of their typical role outside of the study. For example, we understand some coordinator roles are being filled by a research or clinic nurse who typically assists with patient care in the clinic.

**5. What is the time frame for data entry after enrollment? **(Updated Oct 2019)

All data entry should be completed within 72 hours.

**6. Will there be a site activation visit? ** (Updated Oct 2019)

There will be a coordinator protocol exam, site activation activities, and in-person coordinator training but there will not be an in-person site activation visit.

**7. Is there a budget for mailing postcards or letters to patients for recruitments? ** (Updated Oct 2019)

Clinical Centers are reimbursed $1,000 per participant enrolled. Clinical Centers may use part of these funds to provide postcards to increase recruitment potential.

**8. Where can I find my site’s recruitment goals for RELIANCE? ** (Updated Oct 2019)

RELIANCE will employ competitive enrollment across sites; each site may enroll as many participants as are eligible and willing to participate. The Data Coordinating Center will be keeping a close eye on enrollment efforts network-wide, and by Clinical Center. Internal enrollment targets should be discussed with your site PI and Co-I.

**9. If a patient is recruited at bedside, when does the 24 hour period for randomization begin? ** (Updated Oct 2019)

We recognize that enrollment could occur in a single visit, or unfold over multiple days. In some cases additional information is needed before eligibility is confirmed, for example a patient may go home before they are able to complete all forms to be randomized. When we say ‘enrolled’ we define this as having signed a consent form. On pathway, please note section citing a 7 day period. Coordinators should also note that the maximum time between enrollment and randomization may be up to 7 days.

10. When should sites plan to randomize their first participant? (Updated Nov, 2019)

The sites have been asked to initiate recruitment activities by December 1, 2019; Site Planning checklists for coordinators and investigators have been distributed (and are available at https://reliance-uic.squarespace.com/site-activation-materials). Site planning checklists are due January 31, 2020. The clinical trial data infrastructure is expected to be ready to randomize the first participant on February 10, 2020.

We have decided to stage the opening of RELIANCE in order to ensure an orderly start-up. The data system is complex and we want to ensure that it is working as designed before the trial is launched across all sites. We have done extensive testing but crucial pieces cannot be tested until the data system is released. Up to 7 sites will open on February 10, 2020, and if all goes well, all other sites will be opened on March 2, 2020. The vanguard sites are Johns Hopkins, Kaiser Permanente Northwest, University of Arizona, University of Illinois at Chicago, University of Kansas, University of North Carolina, and University of Vermont.

11. What should sites be doing in preparation to randomize their first participant? (Updated Nov, 2019)

Please consult Site Planning checklists for instructions on preparation. Checklists for coordinators and investigators have been distributed and are available at https://reliance-uic.squarespace.com/site-activation-materials. The sites have been asked to initiate recruitment activities by December 1, 2019.

12. Can participants enroll in other studies while in RELIANCE? (Updated Nov, 2019)

Yes, depending on the eligibility criteria of the other studies in question.

In routine clinical practice, patients using long-term roflumilast or azithromycin may enroll in studies. In keeping with evaluating the real-world effects of roflumilast or azithromycin, the RELIANCE study does not preclude participants from enrolling in other studies while a participant in the RELIANCE study. We suggest reviewing the eligibility criteria of other studies when considering co-enrolling a RELIANCE participant in other studies.

13. If a patient is on azithromycin for 30 days or more, can they be re-randomized? (Updated Nov, 2019)

No, once a participant has been randomized in the RELIANCE study, they cannot be randomized again.

In the real-world clinical practice, patients may be prescribed one medication and then later elect to cross-over to an alternate medicine. However, once the patient is randomized to roflumilast or azithromycin in the RELIANCE study, they are not eligible to be re-randomized. The study participant (along with their treating clinician) is permitted to prematurely discontinue the medication or cross-over to the alternate medicine without additional randomizations. The study will collect information about medication discontinuations and crossovers.

14. If all enrollment activities happen on the same day, is the 7-day period for eligibility at baseline still applicable? (Updated Nov, 2019)

The 7-day period of eligibility is not relevant if all enrollment activities (i.e., Consent, Eligibility, Registration, Randomization, Prescription, and Baseline EHR) happen on the same day.

**15. For multi day enrollment, do you have to wait until they come back or is it ok to schedule a return non-clinical appointment to complete enrollment activities? ** (Updated Nov, 2019)

If a patient’s enrollment activities are consistent with the multi-day enrollment pathway, it is acceptable to schedule a non-clinical appointment to complete enrollment activities.

16. Can most of the enrollment be done on the telephone? (Updated Nov, 2019)

Yes. If a participant has time constraints and/or there is limited space in the clinic during their visit, most of the enrollment can be done by telephone. Currently, the Participant must sign the consent form while at an in-person visit. The study team is working on remote / telephone based consent options with the IRB and will update sites when this is available. Other enrollment activities and forms may be completed by phone. See Enrollment Pathway #4 for reference: https://reliance-uic.squarespace.com/recruitment-materials

17. What is the process for non-PI clinicians to enroll participants? Are special documents needed? Is sign-off needed? (Updated Nov, 2019)

If non-PI clinicians are completing all enrollment activities, including the consent process and data entry, they must be listed as study personnel and complete the Knowledge Assessment Test (KAT) found on the DCC-hosted Investigator Site: http://www.reliancetrial.org/secure/reliance

Non-PI clinicians can refer patients, confirm a patient’s eligibility based on their clinical status, or serve as the prescribing clinician (i.e., write a prescription for the medication) without study-specific training or being listed as IRB-approved study personnel.

**18. Are there time parameters for writing the prescription to when the participant is randomized? ** (Updated Nov, 2019)

There should be no more than 24 hours between the randomization and writing a prescription. If more than 24 hours elapses, then it is considered a protocol deviation and the site coordinator should complete an Unusual Event form located on the Investigator Portal.

**19. If a patient was randomized to Azithromycin and finds out it is not covered by their insurance and the doctor switches them to Roflumilast, can they still be in the study? ** (Updated Nov, 2019)

Yes, this outcome will be tracked as part of RELIANCE. In the real world clinical practice, we expect that some patients are unable to fill a prescription as prescribed and may switch to an alternate study medication. RELIANCE seeks to understand the harms and benefits of initiating long-term therapy with roflumilast and azithromycin as they would be used in real-world practice.

If a patient was randomized to azithromycin and finds out it is not covered by their insurance and the doctor switches them to roflumilast, they remain a RELIANCE study participant and will be included in the study analysis (this is part of the “intention-to-treat principle”).

**20. How does the multi-day enrollment process work with the 1-week follow-up call? ** (Updated Nov, 2019)

The First-week follow-up call timeframe is based on the date of randomization. If the participant signs the consent and completes the eligibility form, but does not complete the registration or other enrollment documents and is not randomized until 2 days later, the First-week follow-up call timeframe is based on this date.

**21. When/how do we order recruiting materials? ** (Updated Dec, 2019)

Sites can order printed enrollment and recruitment materials by completing an order form on their site’s administrative page. If you need your site’s administrative page url or password resent, please email reliance@uic.edu. Click the orange Order gift cards and materials tab to complete the form. Please allow 10 days for processing and shipping. Please keep an up to date inventory of all your study materials to be sure you are prepared.

**22. I have a “real world” question pertaining to a patient that I am seeing in clinic today. I have her on azithromycin 250 3xweek but she is still having COPD exacerbations and had a recent hospitalization on that Rx. I am thinking that my choices are either to switch her over to roflumilast or increase her azithromycin dose. I am in total equipoise about what to do. Could I approach her to randomize her for RELIANCE? ** (Updated Dec, 2019)

RELIANCE is intended to answer “real world” questions like this one. In the “real world”, it is possible that clinicians stop medications they don’t think are helping or are no longer needed. Clinicians may also want to switch to other treatment options, if they don’t think the current medication is working. In this case, the clinician and patient would benefit from guidance about whether to use a higher dose of azithromycin or switch to roflumilast. To be eligible for the RELIANCE study, the clinician would need to stop azithromycin for at least 30 days. We suggest using the 30-day period for the patient to learn about the RELIANCE study, including reviewing IRB-approved study information. After at least 30 days have elapsed, the patient is eligible for the RELIANCE study as long as they still meet all the eligibility criteria. If the patient is randomized to azithromycin, the clinician and patient may choose to use a higher dose of azithromycin then they were using before (e.g., 250 mg/day or 500 mg three times per week). If the patient is randomized to roflumilast, the clinician and patient can choose among various dosing options. We recommend starting roflumilast 250 mcg/day X 4 weeks, then 500 mcg/day; this dose escalation has been shown to be easier for patients to avoid treatment-related side effects. However, the clinician and patient may select an alternate dosing regimen.

23. Can participants randomized to roflumilast receive samples while waiting for prior authorization approval? (Updated Jan, 2020)

In most instances, a prior authorization is required for this medication, thereby delaying the start of treatment. This would allow the participant to start treatment right away instead of having to wait for approval to get their prescription filled. If providing sample medication to patients who are prescribed roflumilast is standard practice at the study site, then it is okay to provide sample roflumilast to RELIANCE participants. However, it would not be appropriate to provide sample roflumilast just because they are in the RELIANCE study. Usual care should not differ from patients receiving roflumilast to those participating in RELIANCE.

If roflumilast sample is provided, the coordinator will record that in the Prescription Form on item #20 in the text box under “Comments”. The coordinator will also record the dose and the duration of the sample provided.

24. During e-consent, what do I do if my participant is logged out or closes the webpage after activating their account but before logging into the Participant Portal to start e-consent? (Updated Feb, 2021)

If your participant is logged out or loses track of the webpage, ask them to type in reliance-study.org. In the upper right corner, there is a link for the Participant Portal. They should click this and then use their email address and the password they just created to login. The direct link for the Participant Portal is: https://reliance.datstat.com/portal/login

25. Do you have an example of how to refer a patient to the RELIANCE call center? (Updated Jan, 2025)

Yes, please refer to the link: https://www.reliance-study.org/dr-jedlovszky

26. I have a patient I want to refer for central enrollment into RELIANCE, but they have a scheduled surgery for which they will be hospitalized for more than 24 hours.  Should I wait to refer them to the study? (Updated Jan, 2025)

Yes, if your patient has a scheduled surgery for which they will be hospitalized for more than 24 hours, please refer them after the surgery is complete and they are discharged from the hospital.

1. How will participants know it is the RELIANCE Call Center calling? (Updated Nov, 2019)

The Call Center toll-free number 1-833-687-2673 (1-833-Our-COPD) is programmed to appear as “RELIANCE Study” on Caller-ID so participants know it is the RELIANCE study team calling. This service may vary by telephone service provider.

When participants are enrolled, Coordinators are also encouraged to suggest that participants save the Call Center number in their cell phone as a contact. Study follow-up materials provided to participants following enrollment will also include the Call Center phone number.

Based on the participant’s preference, they may also receive a text message or email reminders of their follow-up every 3-6 months.

2. How will the Call Center know who to call when? (Updated Nov, 2019)

The Call Center Portal automates the Call Center Agent’s participant call list based on data entry (enrollment forms) and auto-calculated visit windows. Call Center Agents will begin calling participants who opted for follow-up through the Call Center 7 days before their next follow-up is “due”.

3. How long does the Call Center keep calling people? (Updated Nov, 2019)

A participant will be followed for a minimum of 6 months and a maximum of 36 months, depending on when they were enrolled in the study. If a participant passes away or is hospitalized, the Call Center will no longer follow the participant.

4. Is there a maximum number of call attempts the Call Center makes? (Updated Nov, 2019)

Each follow-up call’s window extends until the next follow-up call opens. For example, the 3-month follow-up call may be completed until 1-week before the 6-month follow-up call is due. After the first two weeks of call attempts, if the follow-up is not completed, the Call Center will space call attempts to occur once per week, until the follow-up is completed, or the call window closes.

5. Under what conditions would the Call Center contact the coordinator or site? (Updated Nov, 2019)

The Call Center may contact the site coordinator if they have a question about a form completed during enrollment, or if they are unable to contact a participant for follow-up.

6. Are we calling participants at times the participant wants to be called? (Updated Nov, 2019)

Yes, the Call Center will contact the participant at their preferred time shared during enrollment (see Registration Form), if the preferred call time changes the Call Center will update this field in the participant’s record and it will be applied moving forward.

7. What if the participant says “I really don’t want you to call me anymore”? (Updated Nov, 2019)

The Call Center agent will ask if the participant is willing to share the reason for no longer wishing to be contacted, and will also offer the option of completing follow-up surveys through the Participant Portal instead. If the participant indicates they no longer wish to complete follow-up, they will be removed from the Call Center call list and will be listed as ‘passive follow-up only’. The Coordinator will complete a Close-out form for this participant at the end of the study.

If a participant wishes to submit a written notice withdrawing from the study, they will be instructed to write to the site PI and will be provided the address (obtained from the signed consent form, accessible to the Call Center Agent through the Portal). The Call Center will complete an Exit Form indicating the participant wishes to withdraw which will trigger a notification to the Site Coordinator to complete a Close-out form and the participant will be removed from all further contact lists.

8. Are participants informed that calls will be recorded? (Updated Nov, 2019)

Yes, study participants will be informed at the beginning of each call that calls are recorded for quality assurance and training purposes.

9. What if participant reports on a follow up survey/interview that a symptom does not prevent him/her from doing their daily activities but sought medical care? Ex. Skin rash (Updated July, 2020)

Note, Serious Symptom (Sx) report will be triggered because participant sought medical care. Complete the Sx report form indicating the option that includes “or sought medical care” and note in the comments section of the Sx report that the participant reported that their symptom was moderate, i.e. did not prevent participant from doing their daily activities.

1. What is the process for AE and suicidality? Will coordinators be involved? (Updated Oct 2019)

Coordinators will not be directly involved in the assessment of suicidality and adverse events. The Call Center and/or Data Coordinating Center may reach out to obtain additional information if needed from a Coordinators and/or Investigator. Please refer to the MOP.

2. Is there a definitive study termination process? (Updated Nov, 2019)

Yes. If a participant meets a primary outcome (death or hospitalization) the Call Center will be prompted to complete an Exit Form, which will prompt the Site Coordinator to complete a Close-out Form in the Investigator Portal. Sites should review and adhere to any local regulatory policies regarding the removal of a participant from local procedures related to study participation.

3. Will email notifications to sites such as Adverse Events or new symptoms be sent with an ‘Important’ notification? (Updated Nov, 2019)

Email notifications to Clinical Center personnel will be sent with a subject line describing the event, for example, “RELIANCE: New or worse, moderate or severe symptom”. Email notifications will not automatically be sent with an important (!) notification, as in our humble opinion, these are overused.

4. Is there any local site documentation that needs to be done differently for Serious Adverse Events? (Updated Nov, 2019)

Sites should review and adhere to any local regulatory policies regarding site-level documentation of Adverse Events while relying on a central IRB.
If a Serious Symptom or Unusual Event form is completed by either the Site Coordinator or the Call Center and requires additional information from the Site Investigator or Coordinator, the DCC will contact the site to obtain this information.

The local Site Investigator will be notified if an event that qualifies as a serious adverse event occurs involving a participant enrolled at their site.

1. Can the study portal be used on a phone? (Updated Oct 2019)

Yes, the study portal is optimized for mobile use.

2. In the study portal, is it possible to download a PDF of consent? Site needs to attach in the patient chart. (Updated Oct 2019)

The patient will sign a paper copy of the consent form. The Coordinator will then scan and upload the signed PDF to the study portal. From here, the signed copy can be downloaded to accommodate site-level institutional policies. The network is also working on establishing e-consent as an option for participating centers in the future.

3. When patients receive a link to verify email, how long until the link expires? (Updated Oct 2019)

The patient portal link expires after 24 hours. A new link will be sent if clicked after expiration.

4. Will study coordinators need to upload documents to the study portal? (Updated Oct 2019)

Yes. The signed consent form should be uploaded to the study portal.

5. Will web links/resources be accessible from one source? (Updated Nov, 2019)

Yes. All study resources will be available through links found within the DCC-hosted Investigator Site: http://www.reliancetrial.org/secure/reliance.

6. Will you be providing the eligibility form or do we create our own? If the eligibility form comes from Reliance – when can we expect to receive it? (Updated Dec, 2019)

The Eligibility Form can be found on the DCC-hosted Investigator site under Documents -> Forms Site: http://www.reliancetrial.org/secure/reliance Username: reliance Password: Pragmatic1!