key: cord-0861053-vgu9bcxj
authors: Shah, Tayyab; McCarthy, Marianne; Nasir, Irem; Archer, Herb; Ragheb, Elio; Kluger, Jonathan; Kashyap, Nitu; Paredes, Carlos; Patel, Prashant; Lu, Jing; Kandel, Prakash; Song, Christopher; Khan, Mustafa; Haq, Faheem Ul; Ahmad, Rami; Howes, Christopher; Cambi, Brian; Lancaster, Gilead; Cleman, Michael; De La Cruz, Charles; Parise, Helen; Lansky, Alexandra
title: Design and rationale of the colchicine/statin for the prevention of COVID-19 complications (COLSTAT) trial
date: 2021-08-28
journal: Contemp Clin Trials
DOI: 10.1016/j.cct.2021.106547
sha: 9e46c38c2be2025a1843a9fd672a771029837f29
doc_id: 861053
cord_uid: vgu9bcxj

Background Despite improvement in the standard of care (SOC) for hospitalized COVID-19 patients, rates of morbidity and mortality remain high. There continues to be a need for easily available and cost-effective treatments. Colchicine and rosuvastatin are both safe and well-studied medications with anti-inflammatory and other pleiotropic effects that may provide additional benefits to hospitalized COVID-19 patients. Methods and results The Colchicine/Statin for the Prevention of COVID-19 Complications (COLSTAT) Trial is a pragmatic, open-label, multicenter, randomized trial comparing the combination of colchicine and rosuvastatin in addition to SOC to SOC alone in hospitalized COVID-19 patients. Four centers in the Yale New Haven Health network will enroll a total of 466 patients with 1:1 randomization. The trial will utilize the electronic health record (Epic® Systems, Verona, Wisconsin, USA) at all stages including screening, randomization, intervention, event ascertainment, and follow-up. The primary endpoint is the 30-day composite of progression to severe COVID-19 disease as defined by the World Health Organization ordinal scale of clinical improvement and arterial/venous thromboembolic events. The secondary powered endpoint is the 30-day composite of death, respiratory failure requiring intubation, and myocardial injury. Conclusions The COLSTAT trial will provide evidence on the efficacy of repurposing colchicine and rosuvastatin for the treatment of hospitalized COVID-19 patients. Moreover, it is designed to be a pragmatic trial that will demonstrate the power of using electronic health records to improve efficiency and enrollment in clinical trials in an adapting landscape. Clinical Trial Registration: NCT04472611 (https://clinicaltrials.gov/ct2/show/NCT04472611).

The COVID-19 pandemic caused by the viral pathogen severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has infected more than 200 million people and resulted in 4 million deaths worldwide. SARS-CoV-2 causes severe disease through direct viral invasion, hyperinflammatory host responses, and micro/macro-thrombotic reactions. [1] [2] [3] [4] [5] [6] [7] [8] [9] Thus far, for hospitalized patients, 3 treatments have shown benefit in randomized clinical trials (RCTs) and have been adopted as standard of care (SOC): the antiviral remdesivir 10 and the antiinflammatory medications dexamethasone and tocilizumab [11] [12] [13] [14] . Despite this, mortality in treated hospitalized patients in these trials remains up to 30%, and there is an imperative to identify

The major inclusion criteria for this study are any patients 18 years or older with SARS-CoV-2 infection requiring admission to a non-intensive care unit (ICU) within 72 hours of randomization and able to provide informed consent. Major exclusion criteria include patients requiring ICU level care before randomization as defined by World Health Organization (WHO) disease severity scale ≥6 (Table 1) , 17 pregnant or nursing mothers, chronic colchicine therapy, known allergies to statins or colchicine, elevated transaminases, severely reduced glomerular filtration rate (GFR <30 mL/min), severe QTc prolongation, rhabdomyolysis based on creatine kinase (CK) elevation, or severe thrombocytopenia/leukopenia/anemia ( Table 2) . Prior statin use is not an exclusion criterion in this study, as it would exclude a large quantity of patients, particularly those at highest risk for severe disease.

Descriptor Score

No clinical or virological evidence of infection 0

No limitation of activities 1 Limitation of activities 2

Hospitalized, no oxygen therapy 3

Oxygen by mask or nasal prongs 4

Non-invasive ventilation or high-flow oxygen 5

Intubation and mechanical ventilation 6

Ventilation + additional organ support (pressors, RRT, ECMO) 7 Death Death 8 Table 1 : WHO ordinal scale of clinical improvement ECMO: extracorporeal membrane oxygenation, RRT: renal replacement therapy J o u r n a l P r e -p r o o f

Subjects must meet ALL of the following criteria to be eligible for inclusion in the study: 1. 18 years or older and confirmed SARS-CoV-2 infection by RT-PCR 2. Patient is admitted to the floor or step down (non-ICU) within 72 hours of hospital admission (WHO ordinal scale of clinical improvement 3-5) 3. The patient, or legally authorized representative, has been informed of the nature of the study, agrees to its provisions and has provided witnessed (by 2 independent members of the health care team) oral informed consent, or a photograph of the signed informed consent approved by the institutional review board

Subjects will be excluded if ANY of the following criteria apply: Eligible patients are electronically "pushed" to the Epic ® in-baskets of approved research coordinators to complete a manual screening of patients' charts for eligibility in the trial ( Figure   2 ). Criteria including transaminases, GFR, and CK, which may change rapidly over the course of 72 hours, were not used in automated screening to avoid inappropriate inclusion or exclusion of patients. Once patients are deemed eligible, they or their legal decision-maker are approached in person or by phone. The protocol allows for in-person or over-the-phone consenting that is witnessed by at least 2 healthcare providers and is documented in Epic ® . Consent status is further incorporated in the screening logic to exclude patients from re-inclusion.

After obtaining and documenting informed consent associated with the study in Epic ® , a randomization module restricted to IRB-approved providers (principal investigator or delegate listed on the study record) is triggered upon opening the patient's chart. The randomization best practice advisory (BPA) evaluates for presence of study-associated consent and appropriate clinician and uses simple randomization in a 1:1 ratio within the Epic EHR using an internal random number generator. Block randomization is not yet available through the Epic EHR. If the patient is assigned to the active arm (colchicine and rosuvastatin in addition to SOC) the BPA presents an order set with colchicine and rosuvastatin defaulted in addition to displaying the patients' relevant laboratory values, including GFR and liver function tests, that would trigger protocol-defined dose reductions ( Figure 2) . A research progress note using an EHR macro (Epic ® smart phrase) is left in each patient's chart to detail the informed consent process, the rationale of the trial, and potential adverse events to inform the in-hospital treatment teams. then switched back to the home medication at hospital discharge. For safety, doses of colchicine will be adjusted for concurrent use of CYP3A4 inhibitors or protease inhibitors, and doses for both colchicine and rosuvastatin will be adjusted for GFR <30 mL/min. Study drugs may be discontinued in a subject after review of all available data with the medical monitor and discussion with the investigator if any of the following occur: any serious adverse event or >Grade 3 adverse event is suspected to be related to treatment, any elevation of ALT >5× the upper limit of normal (ULN) confirmed by repeat testing, any elevation of CK >5× ULN confirmed by repeat testing or severe myalgias suspected related to statin therapy. Additionally, any subjects who develop renal or hepatic impairment and require a protease inhibitor or strong CYP3A4 inhibitor should discontinue colchicine, and subjects who develop new blood dyscrasia including leukopenia, granulocytopenia, thrombocytopenia, pancytopenia, and aplastic anemia should also discontinue colchicine. All protocol-defined adverse events are "pushed" to the EPIC in-basket of the principal investigators and coordinator regardless of randomized allocation. In addition, the adjudication of all clinician-reported adverse events, regardless of treatment, will be reviewed independently, blinded to treatment allocation.

After discharge if a patient returns to the Emergency Department, is admitted to any YNHH network hospital, or is marked as deceased in Epic, their chart is routed to the Epic research coordinators' in-baskets for further follow-up and adverse event reporting. In addition, all patients will be contacted at 30 days and 60 days after randomization for telephone follow-up. with about 42% of patients with PE having an identified DVT, 30 resulting in a composite event rate for DVT/PE of approximately 14.8%. The true incidence will likely be slightly higher given that some patients in trial will eventually be admitted to ICU and rates of DVT/PE are significantly higher in this population. This will be balanced by the fact that imaging is not mandated in all patients in the COLSTAT trial. Finally, the incidence of acute MI and/or ischemic stroke appears to be approximately 1% based on a recent large registry. 31 The absolute J o u r n a l P r e -p r o o f sum of these event rates is approximately 52%. Therefore, using a conservative 15% overlap in events, we expect the control event rate to be 44.2% with SOC.

At the time of the initiation of this trial, evidence from small RCTs and observational studies studying statin and colchicine use in COVID-19 patients suggested that a clinically relevant 30% relative difference in the primary endpoint was a reasonable assumption for the intervention arm. 20, 32 Under these assumptions, a total of 466 subjects (233 per arm) will provide ≥80% power to detect a 30% relative difference in the primary endpoint at an alpha level of 0.05 and assuming 10% of patients being lost to follow-up at 30 days. Loss to follow up will be mitigated through the use of Epic, which will allow follow-up of patients seen by any provider in the YNHH system.

Since the initiation of the COLSTAT trial, more recent trials have provided up-to-date event rates based on the new SOC. The more contemporary RECOVERY trial arm comparing colchicine to placebo in which 87% received steroids, 23% received remdesivir, and 13% received tocilizumab/sarilumab identified the following 28-day event rates based on preliminary results published on a preprint server: 25% incidence of mechanical ventilation and death in patients not requiring mechanical ventilation at time of randomization, 22% incidence of noninvasive ventilation in patients not receiving it at randomization, 4% incidence of renal replacement therapy (RRT), and 5.8% incidence of any thrombotic event (DVT/PE, MI, stroke). 33 Under similar assumptions of event overlap the control event rate using these incidences would be 48%, thus, the initial assumed event rate remains reasonable.

Assumptions for the secondary powered endpoint were made based on internal data from COVID-19 patients admitted to the YNHH system from March through June 2020. Of the 1,412 J o u r n a l P r e -p r o o f patients, >46% met the secondary powered endpoint. Using the same assumptions as above, the sample size of 466 patients would provide 85% power to detect a difference between the 2 arms.

The primary population for all analyses will be based on the intention-to-treat population defined by the assigned treatment at randomization regardless of the treatment actually received.

The primary efficacy endpoint analysis will be a test of superiority of colchicine and rosuvastatin in addition to SOC compared to SOC alone with regard to progression of COVID-19 disease as assessed by the primary endpoint using the z-test with pooled variance. A subject will be defined as progressed if they experience any of the events in the primary endpoint at any time through 30 days. Secondary analyses will be performed in the as-treated population defined by the treatment actually received (defined as at least 1 dose received) and the per-protocol population defined as patients meeting eligibility criteria without major protocol deviation and receiving the assigned treatment. Prespecified subgroup analyses will include diabetes, age (<65 years versus ≥65 years), sex, race, ethnicity, hypertension, coronary artery disease, cerebrovascular disease, chronic kidney disease, heart failure, statin naïve subjects, adjunctive treatments (dexamethasone, remdesivir, tocilizumab, monoclonal antibodies, ACEi/ARBs, anticoagulation, antiplatelet agents, vaccinations, etc.), SOFA score tertiles, and WHO score on admission.

Vaccinations were not widely available to the public at the time of trial initiation; however, a post hoc analysis by vaccination status at the time of enrollment will also be conducted.

Similarly, although data on SARS-CoV-2 strain is not available, a post hoc subgroup analysis will also be conducted stratifying patients based on the predominant strain in Connecticut at a given time. Finally, a sensitivity analysis only including patients who had an imaging evaluation to rule out DVT/PE will be done to address concerns about ascertainment bias.

An independent clinical events committee (CEC) will adjudicate all primary and major secondary clinical events potentially meeting endpoint criteria in an ongoing fashion during the trial. An independent data and safety monitoring board (DSMB) will be responsible for the oversight of the study, as well as the scientific merit of the trial based on evaluation of an interim analysis. There is no protocol planned prespecified interim analyses for the purposes of altering the study design; however, interim data are provided exclusively to the data safety monitoring board.

The primary dataset will be obtained as a direct export from Epic. For all patients, data from the index admission, including vitals, oxygen/ventilation requirements, discharge status (alive/deceased), lab values, and imaging will be exported from Epic with the assistance of the Joint Data Analytics Team (JDAT). A subset of JDAT exported data will be validated against a parallel standard Research Electronic Data Capture (REDCap) database with traditional manual data entry.

The trial was reviewed by FDA and exempt from IND requirement and was approved by a single In the early stages of the pandemic, colchicine was a promising medication for the treatment of COVID-19. It is an oral anti-inflammatory agent that inhibits tubulin polymerization and microtubule formation, which inhibits any process that requires intracellular trafficking along microtubules, cell mitosis, and cell migration. 36, 37 Colchicine downregulates multiple inflammatory pathways including the NLRP3 inflammasome implicated in acute lung injury 17, 38 and modulates innate immunity. 36, [39] [40] [41] [42] Because of its anti-inflammatory effects, colchicine is indicated for the treatment of gout, Behcet's syndrome, familial Mediterranean fever, and pericarditis. 43, 44 It has also been found to improve outcomes in patients with stable coronary artery disease or recent myocardial infarction. 23, 24 With regard to COVID-19 in particular, colchicine may indirectly improve outcomes through its anti-inflammatory effects and directly by interfering with SARS-CoV-2 viral endocytosis and disrupting viral exit from the cell by preventing spike protein binding to microtubules. 15 investigated the effect of colchicine on non-hospitalized COVID-19 patients and found that it reduced the rate of death and hospitalization compared with placebo (4.6% versus 6.0%, p=0.04). 45 Lastly, a meta-analysis of the RCTs above and select observational studies found that colchicine improved mortality (RR 0.62, 95% CI 0.48-0.81, p<0.001). 32 It should be noted, however, that the vast majority of these studies were conducted before dexamethasone and tocilizumab were SOC. Indeed, the preliminary results of the contemporary arm of the large RECOVERY trial comparing colchicine to placebo (>10,000 patients) did not find any benefit with regard to any 28-day event including death (21% in colchicine arm versus 21% in placebo J o u r n a l P r e -p r o o f arm, p=0.77), noninvasive ventilation (21% versus 23%, p=0.14), mechanical ventilation (7% versus 6%, p=0.06), or thrombotic events (5.7% versus 5.9%). 33 This may be because colchicine does not provide any additional anti-inflammatory benefit to hospitalized COVID-19 patients given the other strong anti-inflammatory medications they now receive as SOC.

Statins have multiple pleiotropic effects beyond lipid lowering that could be beneficial during acute infections, including anti-inflammatory and antithrombotic effects, mitigation of endothelial dysfunction, and cardiac and lung protection through increased angiotensinconverting-enzyme 2 (ACE2) expression. 46 The COVID-19 pandemic has emphasized the need for streamlining research infrastructure in order to answer important questions more quickly and efficiently. One such method is leveraging the power of her, which can be used for faster screening and enrollment, randomization, intervention delivery, and easy remote follow-up for endpoint ascertainment and monitoring. EHR is increasingly being used in clinical trials to some degree 59, 60 . The vast majority of clinical trials to date that utilize EHR specifically test EHR-based interventions such as alerts or clinical decision support tools 59, 61 , although trials testing non-EHR-based interventions such as medical treatments have begun to utilize EHR as well at various stages. 62, 63 J o u r n a l P r e -p r o o f

The pragmatic COLSTAT trial is among the first trials to fully use EHR in all phases of the trial and demonstrates its utility moving forward for trials in other domains as well.

This is an open-label pragmatic trial based on standard of care, which comes with inherent limitations of ascertainment, measurement, and observer expectancy bias. Furthermore, the rapidly evolving nature of the pandemic, with new treatments, vaccinations, and virus variants will likely result in a heterogenous population enrolled in the trial. The sensitivity analyses in the various subgroups detailed above will be used to identify if any of these factors significantly affected the results.

The goal of the COLSTAT trial is to identify if 2 commonly available, well studied medications can reduce the severity of COVID-19 in hospitalized patients. Despite inherent limitations of rapidly evolving treatments, disease variants and severity of disease, COLSTAT is designed to be a pragmatic trial and will demonstrate the power of using the EHR to improve efficiencies and enrollment in clinical trials in an adapting landscape.

The study was funded in part by a grant from the American Diabetes Association (#7-20-COVID-162).

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