Clinical trial NCT00978419
Conditions: Burns
Keywords: Statins Burns Sedatives Neurocognitive Septic Mortality C Reactive Protein Septic shock Sedation Neurocognitive function
Sponsor: Vanderbilt University Medical Center
Start date: 2010-03-01; Completion date: 2011-05-01
Enrollment: 40 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a 90 day study, with patients receiving either oral Rosuvastatin or placebo for up to 28 days. The study will assess the affect of statins administered soon after burn injury on C-reactive protein (CRP) levels, patient mortality and the incidence of septic shock. The investigators also seek to describe the correlation between exposure to statins and development of delirium and de-novo long-term cognitive impairment.

Hypothesis:

1. Statin administration within 96 hours of burn is safe, will decrease CRP, and will decrease septic shock and mortality in burn patients.
2. The investigators hypothesize that burn patients will have a de-novo long term cognitive impairment at 3 months after burn.
3. The investigators hypothesize the use of statins in burn patients will reduce the development and the degree of cognitive impairment at 3 months post burn.

Detailed description:
Infection and sepsis are the major causes of morbidity and mortality in burn patients. Several observational studies have shown that HMG-CoA reductase inhibitors, known as statins, before or after illness or injury results in decreased mortality and incidence of sepsis.

We performed a pilot retrospective chart review of 223 patients admitted to the Vanderbilt University Burn Service from 2006-2008 who were ≥55 years of age. Patients were identified as using statin drugs prior to burn, and compared to those who were not. There was a significant decrease in mortality of 83% (P=.004) in the statin group and a 50% reduction in septic shock (p=.155) that was not significant likely due to the low numbers of patients with septic shock (n=30). These effects were unchanged after controlling for cardiovascular comorbidities.

Animal studies have also shown decreased mortality and sepsis with pre-injury statin administration. Mechanisms of statin effect on mortality and septic shock are attributed to the so-called pleiotropic effects.

If the use of statins is potentially expected to reduce mortality, it is even more relevant to understand the long-term cognitive and functional outcomes of the survivors. In the last years researchers highlighted how survivors from acute respiratory distress syndrome (ARDS) largely experience cognitive and functional decline after their acute illness. More recently Jackson et al. advocated a relationship between delirium in intensive care unit (ICU) patients and cognitive impairment; more specifically 1 of 3 survivors of critically illness with delirium developed cognitive impairment. Though every year several patients are admitted to burn units in the United States, to date only one small report has been published addressing the long-term cognitive outcomes of burn ICU patients. In these preliminary data, Varney et al. found that of the eight patients all were found to have significant problems as evidenced in neuropsychological tests, activities of daily living, and from relatives' reports.

The causes of development of a de-novo cognitive impairment in this population are probably multifactorial and could be linked to the development of and duration of delirium or to the exposure to large amount of sedatives-analgesics used to assure the comfort of the patients on the ventilator and to control pain secondary to the burn. ICU delirium is a common acute brain dysfunction with a prevalence as high as 80% in critically ill surgical and medical ICU patients depending on the severity of illness and the instrument used to diagnose delirium. Different risk factors have been called to cause delirium including exposure to drugs. In particular, previous studies have shown how exposure to benzodiazepines (i.e. lorazepam and midazolam) and opiates have been associated to transition to delirium in medical and surgical ICU patients. If sedatives and analgesics are widely used in the medical and surgical ICUs, this is even more striking for the burn units where large amounts of drugs are infused for patient comfort and pain control. Therefore a large exposure to these drugs in burn patients has the potential to influence the prevalence of delirium even more.

Creatine kinase (CK) levels are known to be increased in the serum of burn patients. C-Reactive Protein (CRP) is an hepatically derived acute phase reactant, elevated in burn patients within the first 3 days, and decreases over time. Statins are known to decrease CRP and possibly mitigate the inflammatory response due to CRP.

Rosuvastatin (Crestor) was chosen as the study drug over others for pharmacokinetic and side effect profile.

1. Rosuvastatin has an elimination half-life of 19 hours, making it suitable for once a day dosing.
2. Rosuvastatin is excreted 90% unchanged in the stool, and the other 10% by the liver. (Rosuvastatin drug information, package insert).
3. Rosuvastatin, a hydrophilic statin, seems to be associated with fewer side effects than lipophilic statins and has fewer drug-drug interactions.

Rosuvastatin dose will be 40 mg loading dose first day, then 20mg by mouth or feeding tube daily.

Patients with thermal burn will be recruited on admission to the Vanderbilt University Burn Service within 96 hours from the time of the burn.

The trial will accrue 40 patients admitted to the Burn Service.

Sample size calculation:

alpha = 0.05 power = .80 delta= 200-(.64 \* 200) =72(expected difference statin and non-statin subjects) sigma = 80 (95% CI CRP burn patients at 3 days) m = 1 (ratio controls/experimental) Sample size=20

Informed consent will be obtained from the patient or surrogate prior to enrollment in the trial. No study procedures will be done without first obtaining informed consent.

After informed consent is obtained, patients will be assigned to Rosuvastatin or placebo group on a random 1:1 basis. The study will be double blind, with neither the participant, research staff nor clinical staff having knowledge of the treatment assignment until after the database has been locked. Assignment will be made by computer-generated randomization. Placebo will be an inactive tablet provided by the Vanderbilt Investigational Pharmacy that is not distinguishable in appearance from Rosuvastatin.

Patients will be considered to have completed the administration of the study drug when any of the following conditions is met:

1. 28 days after randomization
2. Discharge from the hospital
3. Death

Because CPK is routinely elevated in burn patients and myopathy from statins is very rare and is a delayed side effect, CKs before day 7 of treatment will not be used to trigger the rule for withholding/discontinuing study drug. Values greater than 10 times normal obtained after day 7 will trigger cessation of study drug. Study drug will also be discontinued if the patient develops ALT \> 8 times upper limit of normal after study day 1, or if the patient begins treatment with niacin, fenofibrate, cyclosporine, gemfibrozil, lopinavir, ritonavir or oral contraceptives. Data collection will continue as though therapy continued through study day 90.

1. Demographic data (age, sex, race)
2. Medical history, including cardiovascular comorbidities MI, CVA, arrhythmia, PVD, CHF, HTN, DM, COPD
3. Time of burn injury
4. Time of admission to the Burn Service
5. Injury type: burn only, burn plus smoke inhalation
6. Mechanism of burn

   1. structure fire
   2. trauma (i.e., MVA)
   3. scald/steam
   4. grease
   5. contact
   6. home oxygen
   7. flammable liquid
   8. cooking fire
   9. brush fire
   10. other (describe)
7. Extent of burn (% of BSA involved)
8. Physical assessment
9. Sedative drugs during admission, data collected daily.
10. Ventilator days.
11. Activities of Daily Living (ADLs), Instrumental activities of daily living (IADLs)
12. Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE)

Baseline (Day 0) Assessments

The following information will be recorded prior to dosing. If more than one value is available, the closest value prior to the time of dosing will be recorded: serum creatinine, bilirubin, glucose, CK, CRP, PT/PTT/INR and pre-albumin.

4.14 Follow-up Assessments

The following lab results will be recorded at the following timepoints:

1. Serum CK will be collected on days 3, 7, 14, 21, 28.
2. Serum ALT will be collected days 1, 7, 14, 21, 28.
3. Serum CRP will be collected on days 3, 7, 14.

RASS scoring will be assessed and documented at 0800 each day +/- 8 hours. (Appendix B)

Delirium will be evaluated daily with the Confusion Assessment Method in the ICU (CAM- ICU) up to 28 days. (Appendix C)

Type and total amount of sedatives and analgesic drugs will be collected daily up to 28 days.

The ADL 41 and the Mini Mental State Examination (MMSE) will be evaluated at hospital discharge. (Appendix D)

At a 3-month follow-up patients will be evaluated with the ADL, IADL, MMSE, Hospital Anxiety and Depression Scale (HADS), and the EuroQol.(Appendix E, F, G) The use of analgesics will also be collected.

Data will be analyzed using STATA 9 statistical program. Demographics, characteristics of burn, primary and secondary endpoints will be tabulated and compared across Rosuvastatin and placebo groups. CRP levels by Rosuvastatin use and occurrence of septic shock will be analyzed using area under the curve (AUC). Mortality and occurrence of septic shock adjusted for cardiovascular co-morbidities will be examined using multivariate logistic regression.

Potential risks of study drug include:

1. Myopathy, defined as CK \> 10 times ULN, which has been reported in \< .01% of patients, is usually reversible with discontinuation of the statin. Rhabdomyolysis, severe myopathy, defined as CK \> 40 times ULN, can be expected in about a third of those, can lead to renal failure from myoglobin release, requires stopping the study drug, hydration and medical treatment.
2. Increase in liver enzymes (in our study ALT \> 8 times ULN) after day 1, reported in .08% after 4 months of statin use, and drug interactions. Simple discontinuation of the drug is sufficient as there is no evidence that liver failure will ensue.23
3. Additional uncommon risks of study drug include: headache, nausea, myalgia, asthenia, abdominal pain, dizziness, and constipation, from the package insert.

We will monitor CK and ALT levels and discontinue study drug if defined toxicity levels are reached. CK and ALT levels that meet toxicity levels will be reported as adverse events. Myopathy will be noted as an adverse event, but will not by itself stop study drug unless associated with CK levels as defined.

Adverse Event Recording Each adverse event occurring to a subject / patient, either spontaneously revealed by the patient / subject or observed by the Investigator, whether believed by the Investigator to be related or unrelated to the study drug, must be recorded on the adverse event information page of the CRF and on the patient / subject's hospital/center notes.

The Investigator will also determine the relationship of any adverse event to study drug and record it on the appropriate section of the CRF as well as their intensity, time of onset, duration, and the precautions carried out. The Investigator must record all adverse events, which occur during the study, regardless of their relationship to study drug and if they occur during a period without administration of study medication.

Adverse Event Reporting Investigators will assess the subject and medical record to determine if adverse experiences occur during the 60 day study or to hospital discharge, whichever occurs first. The investigator will determine if any changes in laboratory values or clinical signs are those expected in the course of a patient with burn injuries.

Always reported as adverse events:

CK\> 10 times ULN after study day 7 ALT\> 8 times ULN after study day 1

Serious Adverse Events will have to be reported according to the following special procedure:

The Investigator will report SAE's to the Vanderbilt Institutional Review Board per policy. All serious adverse events that occur in association with the study will be reviewed by study personnel and reported to the Vanderbilt Institutional Review Board (IRB) within 10 days of the Investigator's awareness of the event. Any new information that comes to light which may affect the subject or their caregiver's decision to continue to participate in the study will be passed on to them as soon as possible. This may also result in a change to the consent form and review by the IRB. Serious adverse events will also be reported to and reviewed by the data safety monitor.

8.0 Privacy/Confidentiality Issues

The Principal investigator will collect data and enter it into password protected computer in a locked office. Each patient will have a unique identifier number, with the key to the patient's medical record number kept in a locked cabinet in the office. Only research associates or those individuals directly involved with the study will have access to data. Information is for research purposes only and when used for publication purposes, all participants will have their names concealed. Access to identified patient information will be limited to the investigators listed within the IRB application. De-identified information with HIPAA identifiers removed will be available to other investigators following IRB approval. Confidentiality and security will be maintained for the database. The database is stored behind a firewall (in addition to the institutional firewall) with the highest level of protection, i.e. the same level of protection as the on-line hospital information system at Vanderbilt. This means that users must logon to a web server that sits between the institutional firewall and the firewall to the database, and only this application server is allowed to query the database. Only users approved through our institutional review board will be allowed access to patient identifiers. Other levels of authorization may exist for future approved users following IRB approval, e.g. access to de-identified data.

Data is initially collected in the medical record for each individual study participant. The information will be extracted from the patient's medical record and then transferred into the Case Report Form (CRF). The study data will be kept on site and in a securely locked room to protect patient confidentiality.

The CRFs do not include personal identifiers for any participant. Numbers and initials are assigned for each participant and these become the identifying information for each study participant. A master list is kept separately that identifies which names go with which numbers and initials.

Study personnel (PI and co-investigators) and government regulatory agencies have access to all research records as required by law. Others (such as law enforcement agencies) may have access to records as defined by law.

Follow-up and Record Retention

The study records will be stored for investigation for at least six years and may be retained indefinitely.

Arms: arm 1: Rosuvastatin arm 2: Placebo
Interventions: intervention 1: Rosuvastatin intervention 2: Placebo
Intervention descriptions: intervention 1: Loading dose 40mg by mouth first day, then 20 mg by mouth for up to 27 days intervention 2: Placebo administered every day for up to 28 days

Protocol documents: