Influenza
Conditions
Brief summary
Influenza (the 'flu') is a common virus infecting approximately 5-20% of the population in the United States and causing as many as 500,000 deaths worldwide each year. Currently, there are only a few treatments for influenza infection and none of these target inflammation that can be caused by the virus. This study will test whether the anti-inflammatory effects of statins, a class of drugs most often used to treat high cholesterol, will decrease the severity of illness in patients who are infected with influenza by testing markers of inflammation in the blood and recording resolution of influenza illness.
Interventions
DRUGAtorvastatin
DRUGPlacebo
Sponsors
National Institute of General Medical Sciences (NIGMS)
Beth Israel Deaconess Medical Center
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
(all must be present): 1. Adult patient (age \> 18 years) 2. Positive influenza DFA/RAT test result 3. \<12 hours from positive influenza test result
Exclusion criteria
1. Prior statin medication use (within 30 days of positive influenza test result) 2. Comfort measures only designation or anticipated withdrawal of life-support 3. Atorvastatin specific exclusions: 1. Documented liver cirrhosis or liver dysfunction (AST or ALT greater than 240) 2. Known allergy or intolerance to statins 3. Rhabdomyolysis (CPK elevation \> 6x normal) 4. Patients taking the following medications: cyclosporine, HIV protease inhibitors, hepatitis C protease inhibitor telaprevir, fibric acid derivatives (gemfibrozil), niacin, azole antifungals (itraconazole, ketoconazole) clarithromycin and colchicine 4. Patients unable to take oral or nasogastric medications or plan for no oral intake as part of medical course (eg. emergent surgical intervention) 5. Known pregnancy or active breastfeeding 6. Inability to provide written informed consent for any reason
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Inflammatory Markers From Time Zero to 72 Hours | Baseline to 72 hours | The primary IL- 6 measurements were at time zero and at 72 hours. Analysis was performed using a linear mixed effects model to make use of all biomarker timepoints as hospitalized patients had biomarkers measured at additional timepoints. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Severity of Illness Score Baseline to 72 Hours | Baseline and 72 hours | Composite score for 5 major symptoms (fever, cough, sore throat, headache, myalgia) ranked from 0 to 3 (none, mild, moderate, severe) for a score ranging from 0 to 15. Higher scores reflect more severe symptoms. |
Other
| Measure | Time frame | Description |
|---|---|---|
| ICU and Hospital Length of Stay | From date of randomization until the date of ICU discharge (in the event of ICU admission) and/or hospital discharge, based on an estimated average of 30 days | The investigators will assess the effect of statin therapy on hospital and ICU length of stay. |
| Progression to Shock State | From date of randomization until discharge from hospital | The investigators will assess the effect of statin therapy on rates of development of shock state |
| Severity of Illness | 24 hours post enrollment | The investigators will assess the effect of statin therapy on APACHE II scores |
| In-hospital Mortality | From date of randomization until the date of first documented discharge from hospital or date of death from any cause, whichever came first, assessed up to 1 year | The investigators will assess the effect of statin therapy on in-hospital mortality |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Atorvastatin Patients will be administered study medication (atorvastatin 40 mg) orally once daily for 5 days, for a maximum of 7 days for those who remain hospitalized.
Atorvastatin | 59 |
| Placebo Patients will be administered study medication (matched placebo) orally once daily for 5 days, for a maximum of 7 days for those who remain hospitalized.
Placebo | 57 |
| Total | 116 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lost to Follow-up | 5 | 5 |
| Overall Study | Withdrawal by Subject | 2 | 6 |
Baseline characteristics
| Characteristic | Atorvastatin | Placebo | Total |
|---|---|---|---|
| Age, Continuous | 34 years | 43 years | 37 years |
| BMI | 26.2 kg/m^2 | 28.4 kg/m^2 | 28.1 kg/m^2 |
| Race/Ethnicity, Customized Black/ African American | 20 Participants | 15 Participants | 35 Participants |
| Race/Ethnicity, Customized Other | 4 Participants | 2 Participants | 6 Participants |
| Race/Ethnicity, Customized White | 34 Participants | 40 Participants | 74 Participants |
| Sex: Female, Male Female | 33 Participants | 39 Participants | 72 Participants |
| Sex: Female, Male Male | 26 Participants | 18 Participants | 44 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 59 | 0 / 57 |
| other Total, other adverse events | 4 / 59 | 5 / 57 |
| serious Total, serious adverse events | 0 / 59 | 0 / 57 |
Outcome results
Primary
Change in Inflammatory Markers From Time Zero to 72 Hours
The primary IL- 6 measurements were at time zero and at 72 hours. Analysis was performed using a linear mixed effects model to make use of all biomarker timepoints as hospitalized patients had biomarkers measured at additional timepoints.
Time frame: Baseline to 72 hours
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Atorvastatin | Change in Inflammatory Markers From Time Zero to 72 Hours | Baseline | 2.4 pg/ml |
| Atorvastatin | Change in Inflammatory Markers From Time Zero to 72 Hours | 72 hours | 0.91 pg/ml |
| Placebo | Change in Inflammatory Markers From Time Zero to 72 Hours | Baseline | 3.46 pg/ml |
| Placebo | Change in Inflammatory Markers From Time Zero to 72 Hours | 72 hours | 0.57 pg/ml |
Comparison: We used a linear mixed-effects model which accounted for all measurements taken and the time that those measurements were taken.p-value: 0.611Mixed Models Analysis
Secondary
Severity of Illness Score Baseline to 72 Hours
Composite score for 5 major symptoms (fever, cough, sore throat, headache, myalgia) ranked from 0 to 3 (none, mild, moderate, severe) for a score ranging from 0 to 15. Higher scores reflect more severe symptoms.
Time frame: Baseline and 72 hours
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Atorvastatin | Severity of Illness Score Baseline to 72 Hours | Baseline | 8 score on a scale |
| Atorvastatin | Severity of Illness Score Baseline to 72 Hours | 72 hours | 2 score on a scale |
| Placebo | Severity of Illness Score Baseline to 72 Hours | Baseline | 8 score on a scale |
| Placebo | Severity of Illness Score Baseline to 72 Hours | 72 hours | 3 score on a scale |
Comparison: The primary comparison was at 72 hours for the self-reported influenza severity score.p-value: 0.029Mixed Models Analysis
Other Pre-specified
ICU and Hospital Length of Stay
The investigators will assess the effect of statin therapy on hospital and ICU length of stay.
Time frame: From date of randomization until the date of ICU discharge (in the event of ICU admission) and/or hospital discharge, based on an estimated average of 30 days
Other Pre-specified
In-hospital Mortality
The investigators will assess the effect of statin therapy on in-hospital mortality
Time frame: From date of randomization until the date of first documented discharge from hospital or date of death from any cause, whichever came first, assessed up to 1 year
Other Pre-specified
Progression to Shock State
The investigators will assess the effect of statin therapy on rates of development of shock state
Time frame: From date of randomization until discharge from hospital
Other Pre-specified
Severity of Illness
The investigators will assess the effect of statin therapy on APACHE II scores
Time frame: 24 hours post enrollment