A multi-national feasibility RCT involving adult ICUs in Canada, Saudi Arabia, Mexico, Argentina Australia/New Zealand. An overview of the study design is provided in Figure (see Figure ).
 The ability to recruit the desired patient population under pandemic conditions (i.e., the proportion of eligible patients enrolled in the CHAT Pilot Trial).
 Adherence to the medication administration regimen as outlined in the study protocol.
 The ability to collect the required primary and secondary endpoints for the planned full CHAT trial.
 The number of patients who receive open-label statins.
 The number of consent withdrawals.
 The impact of approved consent models on recruitment rates.
A dedicated research coordinator will screen patients for eligibility on a daily basis in the ICUs at participating sites. If the study inclusion criteria are fulfilled and no exclusion criteria are present, the research coordinator will identify the patient as a potential study participant. The attending physician or intensivist will confirm eligibility for participation in the CHAT Pilot RCT.
Criteria to identify potential candidates for study inclusion will include:
1) Critically ill adult patients ≥ 16 years of age admitted to an adult ICU for any reason with suspected, probable or confirmed novel swine origin influenza A/H1N1 infection (see
Additional File 1
2) Requiring mechanical ventilation (invasive or non-invasive)
3) Receiving antiviral therapy (any medication at any dose and for any intended duration) for ≤ 72 hours
4) Attending physician or intensivist must have a 'moderate' to 'high' index of suspicion for H1N1.
1) Age < 16 years
2) Do not resuscitate or re-intubate order documented on chart or anticipated withdrawal of life support
3) Weight < 40 kg
4) Unable to receive or unlikely to absorb enteral study drug (e.g., incomplete or complete bowel obstruction, intestinal ischemia, infarction, short bowel syndrome)
5) Rosuvastatin specific exclusions:
a. Already receiving a statin
b. Allergy or intolerance to statins.
c. Receiving niacin, fenofibrate, cyclosporine, gemfibrozil, any protease inhibitor (including but not limited to lopinavir and ritonavir) or planned use of oral contraceptives or estrogen therapy during the ICU stay.
d. CK exceeds 5,000 U/L or ALT exceeds 8 times the upper limit of normal (ULN).
6) Severe chronic liver disease (Child-Pugh Score 11-15) (see
Additional File 2
7) Previous enrolment in this trial
8) Pregnancy or breast feeding
9) At the time of enrolment, receipt of > 72 hours of antiviral therapy.
10) Known or suspected clinically significant myositis or myopathy.
Eligible, Non-Randomized Patients
We will record reasons why eligible patients are not randomized into the CHAT Pilot Trial under the following categories:
a) Substitute Decision Maker (SDM) consent refusal
b) Physician refusal of consent
c) SDM not available to provide consent and waived/deferred consent not permitted
d) SDM does not exist and waived/deferred consent not permitted
e) Coordinator workload
f) Coordinator not available during eligible time-window
g) Enrolment in a competing trial
h) Other (specification required)
To enhance trial feasibility and given the need to conduct a pragmatic trial, co-enrolment in other prospective observational studies or RCTs (not investigating similar or alternative H1N1 treatments) in operation in the ICU setting will be permitted and recorded in sites where permitted by the local Research Ethics Boards (REBs) [36
To preserve allocation concealment, participants will be randomized centrally. Randomization lists will be distributed by the study methods centre to the research pharmacies of participating centres. Stratified variable block randomization, based on centre alone, will be performed to take into consideration differences in patient characteristics at participating ICUs. Day one will be considered the day of study treatment initiation, which may or may not be the same day of randomization.
A waiver of consent is the preferred option for participant enrollment given the context of a global pandemic. We have constructed a consent algorithm to direct the consent process at sites where the local REB has not approved a waiver of consent (see
Additional File 3
). In this trial, we will request that patients be enrolled in the study, and consent be deferred to SDMs or to the patient (whomever is able to provide consent first), when it is not possible to obtain consent within 24 hours. Consent may be obtained in person or by telephone as per local practices. In the event that patients die before providing consent, we request permission from REBs to include data collected during study participation.
Study Treatment Overview
Using randomization lists provided by the study methods centre, research pharmacists will assign critically ill adults to once daily enteral administration of rosuvastatin or matched placebo for 14 days. Only the research pharmacy staff will be aware of the assigned treatment arm. The site investigators, research coordinator, clinical pharmacist involved in the care of the patient and all other study personnel will remain blinded to treatment assignment. An oral placebo for nasogastric administration, identical in appearance (colour and consistency matched) to crushed rosuvastatin, will be prepared by Pharmacy 1 (Toronto, Canada) and supplied to the study sites. All other aspects of patient management will be left to clinician discretion as per pragmatic trial design. The Applied Health Research Centre of the Keenan Research Centre and Li Ka Shing Knowledge Institute (St Michael's Hospital, Toronto, Ontario) will be the Study Methods Centre.
Study Drug Administration
Study drug will be administered once daily through an enteral feeding tube or orally if the patient is able to safely take oral medications. The type and placement of the enteral feeding tube (nasogastric, nasoenteric, percutaneous endoscopic gastrostomy, orogastric, oroenteric, etc.) will be at the discretion of the attending clinical team. The ability to safely take oral medications will be determined by the patient's primary care team.
The first study drug dose (rosuvastatin or placebo) will be administered within 4 hours of randomization as a loading dose of 40 mg unless the subject is of Asian (Chinese, Korean, Japanese, Phillipino, Vietnamese, or Asian-Indian) descent, age <18 years or has serum creatinine greater than or equal to 248 umol/L (2.8 mg/dL) (see requirements for dose adjustments below).
Thereafter doses of 20 mg will be administered at 22:00 hrs daily (+/- 4 hours) starting on the next calendar day (study day 2) as a maintenance dose. If the patient is of Asian descent, is <18 years, or serum creatinine is greater than or equal to 248 umol/L (2.8 mg/dL) dose adjustments will be required according to the dose adjustment algorithm (see requirements for dose adjustments below). Dose adjustment is only necessary for patients with renal impairment and not receiving dialysis. Once dialysis is started and serum creatinine remains elevated, dose adjustment is not required.
If for any reason a maintenance dose is not administered at the intended time, it may be administered subsequently but not more than 12 hours after the intended time of administration. If greater than 12 hours has elapsed since the last scheduled dose, the patient will receive another loading dose, and then maintenance dosing will resume on the next calendar day as outlined above. A missed dose, for reasons other than outlined under medication discontinuation will be considered a protocol violation.
The loading (40 mg) and daily maintenance (20 mg) doses will be reduced by 50% for patients:
a) who have at least one parent of Asian descent (loading 20 mg and daily 10 mg),
b) whose age < 18 years (loading 20 mg and daily 10 mg),
c) whose serum creatinine concentration is greater than or equal to 248 umol/L (2.8 mg/dL) who are not on renal replacement therapy (loading 20 mg and daily 10 mg), and by 75% for patients:
d) who have at least one parent of Asian descent and/or age < 18 years and serum creatinine is greater than or equal to 248 umol/L (2.8 mg/dL) (loading 10 mg and daily 5 mg).
Concomitant Medication Administration
Intermittent oral antacids should be administered no closer than 6 hours before or after administering rosuvastatin to avoid influencing study drug absorption [37
Duration of Treatment
Given the substantial potential for false negative influenza results, we will continue adjuvant treatment administration, regardless of H1N1 testing results (positive or negative), for 14 days or until a criterion for cessation is met. If patients are liberated from mechanical ventilation (invasive or non-invasive) and discharged from the ICU between days 1 and 9 they will be advanced to day 10 of study drug administration. In the event that patients remain in the ICU for observation (e.g., possible reintubation or initiation of non-invasive ventilation) then study drug administration will NOT be advanced to day 10 until they are discharged.
Completion of Study Drug Administration
Study drug administration will be stopped when one of the following conditions is met, whichever comes first:
1. 14 days after randomization
2. Hospital discharge (including transfer to an alternate care facility)
4. CK noted to exceed 5,000 U/L (in the absence of an alternative diagnosis) or patient is determined to have clinical myositis or myopathy (at the discretion of the primary care team, patient may be re-challenged with study drug if CK or clinical findings no longer meet this criterion).
5. Alanine aminotransferase (ALT) exceeds 8 times the ULN (in the absence of an alternative diagnosis)
6. Co-administration of any of the following: niacin, fenofibrate, cyclosporine, gemfibrozil, lopinavir, ritonavir, oral contraceptives or estrogen
7. Attending physician or intensivist or SDM request to stop treatment.
We will request for data collection to continue in patients withdrawn from therapy prematurely. Clinicians will be encouraged to continue study medication despite negative H1N1 testing due to the potential for false negative results and the potential role for an anti-inflammatory agent (rosuvastatin) in severe lung disease. Decisions regarding continuation or discontinuation of antiviral treatment will be left to the discretion of the attending physician or intensivist.
It will not be feasible to protocolize ventilator and general clinical management under pandemic conditions. Adjunctive non-antibiotic, non-interventional management of sepsis, acute respiratory distress syndrome, and glycemic control will be at the discretion of the patient's primary clinicians. Key aspects of clinical management (such as choice of antiviral, dose of administration, duration of treatment, ventilator strategy, treatment with inhaled nitric oxide, HFO, prone positioning, ECMO, additional antiviral/anti-inflammatory treatments and treated episodes of infection) will be documented either as part of the Influenza A H1N1 (Swine Flu) ICU (Registry) Study for participating centres or on separate data forms for centres not participating in the registry. Antibiotic therapy may be prescribed for suspected or confirmed concomitant bacterial infection at the discretion of the attending physician.
Local testing procedures may be used to facilitate diagnosis of H1N1. Where no local testing procedures exist, we recommend using the following initial and repeat testing procedures. For all new admissions to adult ICUs meeting study inclusion criteria and having no exclusion criteria with non-confirmed H1N1 (i.e., all suspected or probable cases) or where uncertainty exists regarding prior testing, we request the following sequence of laboratory tests:
Initial Diagnostic Testing (assuming diagnosis not confirmed at ICU admission)
1. Paired deep nasopharyngeal (NP) swab AND either an endotracheal (ET) aspirate or bronchoalveolar (BAL) (or sputum if not intubated) for (a) influenza polymerase chain reaction (PCR) and (b) viral culture; and
2. Endotracheal aspirate (or sputum if not intubated) for gram stain, culture and sensitivity (C & S)
Repeat Testing (for patients with one positive test)
1. Repeat both tests (PCR and viral culture) from the site that was positive previously (i.e., ET or BAL or NP swab). If both ET and NP swab were positive, send repeat ET aspirate specimen at day 7 and at weekly intervals thereafter.
2. After the first negative specimen(s) from a previously positive site, send a repeat specimen from the same site at 48 hours after the first specimen was collected.
Drug Level Specimen Collection
To verify adequate absorption of rosuvastatin, we will draw venous blood for peak and trough plasma rosuvastatin concentrations (total of 2 specimens) on day 7 (+/- 1 day). Day 7 will be the preferred day for trough and peak specimen collection. A trough level specimen will be drawn prior to day 7 (+/- 1 day) dose. A peak concentration specimen will be drawn 3 to 5 hours after the dose of study drug is administered. A maximum of 80 patients will have blood drawn for drug concentration analysis; however, only patients randomized to rosuvastatin will have their samples analyzed. Samples will be labeled and batched at the site, for shipment to St Michael's Hospital (Toronto, Canada) for analysis after the study is unblinded.
Research staff will assess participants daily for adverse effects for the duration of treatment. CHAT study participants will have daily CK and liver function [aspartate aminotransferase (AST) and ALT] levels collected as part of the study protocol. Study drug will be discontinued if hypersensitivity is suspected (see Criterion 7 Completion of Study Drug Administration).
We will record the number of patients receiving full treatment and reasons for the inability to complete the assigned treatment duration (i.e., death, transfer to an alternate care facility, study withdrawal, etc). The study Data Safety and Monitoring Board (DSMB) will review all patients withdrawn from the study, safety data, and deaths.
All patients will be followed until death or hospital discharge. We will record the vital status of all patients at 90 days and hospital discharge, whichever occurs first. At day 60 patients remaining on the ventilator will be deemed ventilator dependent. Randomized patients will be considered successfully extubated when they remain off positive pressure ventilation (invasive or non-invasive ventilation) for 48 consecutive hours. If patients are re-intubated within 48 hrs following extubation, they will be followed until they achieve one of the aforementioned outcomes. Patients discharged from the ICU and requiring readmission and re-initiation of mechanical ventilation (invasive or non-invasive) will be treated according to usual practice and will not be randomized on a second occasion to this study.
 Proportion of eligible patients enrolled in the CHAT pilot study.
 Adherence to the medication administration regimen as outlined in the study protocol.
 Proportion of completed primary and secondary endpoints for the planned full CHAT trial that are collected.
 Number of patients who receive open-label statins.
 Number of consent withdrawals.
 Recruitment rates by approved consent model.
Sample Size Estimation (CHAT Pilot Trial)
Estimates are not available to allow precise sample size estimation of the primary outcome for the proposed CHAT pilot RCT. We propose to undertake a pilot study in a convenience sample of 80 patients with suspected, probable or confirmed H1N1 infection to assess trial feasibility.
We will collect CHAT specific data starting at ICU admission using paper-based versions of the electronic data collection forms developed for the Influenza A H1N1 (Swine Flu) ICU (Registry) Study [7
]. The forms will document baseline characteristics, enrolment into concurrent influenza research studies, co-morbidities, illness severity (see
Additional File 4
), vaccination status, co-interventions, feasibility outcomes and clinical outcomes for the planned definitive trial (primary: the proportion of patients successfully weaned from mechanical ventilation in less than 10 days; secondary: impact of rosuvastatin on ICU, 60 and 90 day, and hospital mortality and on ICU free days at day 60). In addition to the data forms developed for the Influenza A H1N1 (Swine Flu) ICU study, we developed 13 additional forms including an (i) eligibility and randomization form, (ii) severity of illness form, (iii) consent form, (iv) drug administration form, (v) H1N1 diagnostic test results form, (vi) laboratory data form, (vii) drug level (serum) specimen collection form, (viii) 60 day and 90 day outcomes form, (ix) comments and end of study investigator sign off, (x) protocol violation form: biochemistry, (xi) protocol violation form: medication administration/discontinuation, (xii) adverse event form, (xiii) serious adverse event form in randomized patients. For centres not participating in the registry, we drafted 10 additional forms to capture necessary demographic, treatment and outcomes information. In addition, we drafted a form to capture demographic data and outcomes on eligible but not randomized patients.
Descriptive statistics will be used to summarize the data. For univariate analyses, we will use the Chi-square test (alternatively, Fisher's exact test when the expected cell size is ≤ 5) and Student's t-test (alternatively, the Mann-Whitney U-test, if normality assumptions are not satisfied) for binary and continuous outcomes, respectively. All analyses will be conducted on an intention-to-treat basis.
Feasibility for the pilot study will be assessed by metrics that reflect our capacity to ultimately recruit a representative sample of 1,050 patients in the planned full CHAT trial. We will consider the study to be feasible if we recruit at least 30% (commonly used threshold in ICU studies) of all eligible patients in participating ICUs through careful review of site screening logs. Additionally, we expect that: (i) less than 10% of medication doses will fail to be administered in the absence of meeting one of the medication discontinuation criteria; (ii) less than 5% of data forms will be missing important primary and secondary outcomes data required for the planned full CHAT trial and (iii) no more than 10% of enrolled patients will be withdrawn prematurely due to open label use of statins or withdrawal of consent. We will describe recruitment rates based on approved consent models. Since centres in Australia and New Zealand will be permitted to use Atorvastatin and matching placebo (instead of Rosuvastatin/matching placebo), we propose to conduct the planned primary and secondary analyses (i) using the pooled data (rosuvastatin plus atorvastatin) and (ii) using rosuvastatin (as the predominantly used statin in the CHAT Trial) data alone.
A DSMB will oversee the trial and will consist of 3 individuals with expertise in viral infectious diseases, statistics and clinical critical care of which one will be international. The DSMB will hold a teleconference after either 30 patients have evaluable data or approximately 8 months after study initiation. Should the trial be completed, feasibility data from the pilot study will be analyzed by the DSMB at the end of the study. This information will be conveyed to the Steering Committee. Together the DSMB and Steering Committee will formulate a decision whether to proceed with the full trial. Clinical outcomes will remain blinded by study group assignment with a view to including them in the planned larger trial.
Adverse Event Reporting
Investigators will evaluate any changes in laboratory values and physical signs and will determine if the change is clinically important and different from what is expected in the course of treatment of critically ill patients requiring mechanical ventilation for suspected, probable or confirmed influenza. If clinically important and unexpected adverse experiences occur, they will be recorded on an adverse event case report form. We will characterize adverse events (see
Additional File 5
) as expected, serious unexpected and study related or unanticipated.
We considered other factors (see
Additional File 6
) including patient withdrawals, consent (including telephone consent and waivers of consent) (see
Additional Files 7
), eligible non- randomized patients, equitable selection of subjects, justification for including vulnerable subjects, women of childbearing age, justification for excluding pregnant women, trial oversight and the trial data safety and monitoring board (see
Additional File 6
) in designing the CHAT Trial protocol. The investigators plan to make changes to the larger study protocol based on their experience in implementing the pilot trial. Regardless, we will publish the findings of the CHAT Pilot Trial, either alone or pooled with another trial evaluating the role of statins in a similar population, if recruitment ensues even if the study protocol is modified in important ways following conduct of the pilot trial or the planned larger trial never comes to fruition. Pilot trial data may also be combined with data from the larger trial if the latter trial comes to fruition, study personnel (including the data analyst) remain blinded to treatment assignment and no important modifications are made to the study protocol following the pilot trial.