Completed Studies

Statins in Influenza


Description

Principal Investigator:

Maureen Chase MD, MPH

Status of Study:

Ongoing

Purpose of Protocol:

Influenza is a large-scale public health issue for which considerable focus has been placed on vaccination programs and on the development of antiviral therapies.

The objective of this study is to determine the potential effect of statin therapy for the treatment of acute influenza infection.  In addition, we will evaluate the mechanism by which statin therapy attenuates the host inflammatory response and the effect on clinical outcomes as follows:

Specific Aim #1: To determine if the administration of statin therapy to patients with acute influenza will attenuate the inflammatory cascade.

Specific Aim #2: To determine if the administration of statin drugs attenuates disease severity and improves time to clinical resolution of symptoms in patients with confirmed influenza.

Specific Aim #3: To determine the effect of influenza on host metabolic response to disease.

Significance and Background:

Influenza is associated with a high level of morbidity and mortality worldwide: The World Health Organization still estimates 3 to 5 million severe cases of influenza illness worldwide and attributes 250,000-500,000 deaths to seasonal influenza outbreaks each year. While a reported 90% of influenza-associated deaths occur among adults aged ≥65 years, the morbidity associated with 2009 swine-origin influenza A (H1N1) resulted in a shift in the ages and baseline health of patients who became ill and died. One epidemiologic study found that two-thirds of hospitalized patients and 40% of those who died had no pre-existing medical conditions. In addition, mortality rates in other major diseases also peak when influenza is circulating.

No universal influenza vaccine exists: The best means of controlling influenza outbreaks is the development of protective vaccines. Because it takes months to generate, produce and distribute a strain-specific vaccine, populations with no prior immunity may be left vulnerable in the event of pandemic-associated vaccine shortages.

Antivirals are currently the only primary defense: In the setting of inadequate vaccine supplies, the only line of treatment will be existing antiviral agents. There are challenges to using these agents including cost, utility late in disease, limited supplies and, perhaps most concerning with regard to using antivirals as a singular defense in influenza infection is emerging resistance.

Statins are inexpensive and widely available; if effective, statins may have a profound effect on the morbidity, mortality and economic burden associated with influenza worldwide. Thus, our investigation could lead to a practice-changing therapeutic intervention that complements the current strategies of prevention (vaccination) and direct antiviral therapy.

Design:

Prospective, double-blind, randomized clinical trial.

Inclusion Criteria:

  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

Treatment Protocol:

  • Patients will be administered study medication (either atrovastatin 40 mg or placebo) orally once daily for 5 days or  or for a maximum of 7 days for those remain hospitalized:
    • Patients seen in the ED will receive a 5 day supply of the study medication.
    • Patients who are hospitalized will receive a minimum of 5 day supply (7 days maximum for those who remain hospitalized after 5 days)
  • We will ask patients to provide an email address and telephone number for follow-up.
  • For patients who are in hospital study staff will go over the online diary at the bedside each day of the interventional period.
  • For patients who are not admitted to the hospital or discharged before Day10, they will receive email or telephone reminders daily up to Day 10 to complete the diary online. If internet access is not available, study stuff will fill out the diary with patients over the phone.
  • A 14-day telephone follow up interview will be conducted and patients will be asked about relapse, recurrence of symptoms or re-hospitalization.
  • Female patients of child bearing potential and males capable of fathering children will be asked to provide a method of contraception and advised to continue for 2 weeks after finishing the study drug.

Primary Outcome:

Specific Aim 1: To determine if the acute administration of statin drugs to patients with confirmed influenza will attenuate the inflammatory cascade.

  • The primary endpoint for this study is change in inflammatory biomarker IL-6 from the time of enrollment to 72 hours.
  • Secondary endpoints will include change on additional markers of inflammation including VegF and TNFa.

Specific Aim 2:  To determine if the administration of statin drugs attenuates disease severity and improves time to clinical resolution of symptoms in patients with confirmed influenza.

  • The primary endpoint in this aim will be the time to clinical resolution based on a daily composite score of recorded major influenza symptoms. Study subjects will record a diary of symptom severity, temperature, ability to perform normal activities, and use of relief medication twice daily for 10 days. The diary will be used to create a composite score for each of 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 15.80Clinical resolution of symptoms will be defined as time to alleviation in major symptoms recorded as no more than mild x 24 hours.
  • Secondary endpoints will be:

1.) Change in severity of illness (APACHE II) from enrollment to 24-hour follow-up

2.) Hospital and ICU lengths of stay

3.) Rates of progression to vasopressor-dependent shock

4.) In-hospital mortality

Specific Aim 3(Exploratory): To determine the effect of influenza on host metabolic response to disease.

  • The first exploratory endpoint (3a) will be to determine if influenza host response consists of a unique metabolic fingerprint for diagnostic or prognostic purposes. We will obtain a “metabolomic” fingerprint of all patients at baseline which will consist of over 250 metabolites. We will evaluate the association of the metabolic profiles to outcome measures including need for hospital or ICU admission and mortality. We will then evaluate the metabolomic profile as a prognostic indicator in comparison to other biomarker indices and severity of illness scoring.
  • The second exploratory endpoint (3b) will be to identify metabolic derangements and deficiencies that can serve as adjunctive therapies. Specifically, we will examine whether CoQ10 and other metabolic derangements may lead to adjunctive interventional therapies in influenza infection.

Measurements:

We will perform CoQ10 and metabolomic assessments on the first 50 patients enrolled in the trial. We will compare these results to those of controls in our data repository. A sample size of 50 patients per group will allow us to detect an effect size of 0.5 with 80% power (two-sided alpha 0.1).

Nivolumab in Septic Shock Phase Ib


Description

Principal Investigator:

Michael Donnino

Status of Study:

Completed

Purpose of Protocol:

The purpose of this Phase 1b study is to evaluate the safety, tolerability, and pharmacokinetics of single doses of BMS-936558 (nivolumab) in participants with severe sepsis or septic shock to inform feasibility of further study of nivolumab in his population. Data from a mouse model of sepsis and form samples from septic patients support a role for the PD-1/PD-L1 pathway in sepsis. Taking these data together with evidence of an immunosuppressive phase in severe sepsis associated with poor clinical outcomes, interventions with the potential to improve host immune function, such as nivolumab, should be studied.

The primary objectives are:

  • To assess the safety and tolerability of a single dose of nivolumab 480 mg or 960 mg in participants with severe sepsis or septic shock
  • To assess the pharmacokinetics of BMS-936558 in participants with severe sepsis or septic shock

The secondary objectives are:

  • To assess receptor occupancy of nivolumab following single dose administration
  • To assess the effect of a single dose of nivolumab on monocyte HLA-DR expression and absolute lymphocyte count
  • To assess the immunogenicity of nivolumab following single dose administration

Significance and Background:

Severe sepsis, defined as a systemic, deleterious host response to infection complication by acute organ dysfunction is a major health problem. In the US, severe sepsis is increasing in incidence, occurs in greater than 1,000,000 individuals annually, is recorded in 2% patients admitted to the hospital – half of whom are treated in the intensive care unit (ICU), and contributes to 1 in every 2 to 3 hospital deaths. Despite advances in early detection, ICU care, and implementation of guidelines-based care, for patients with severe sepsis, 90-day mortality rates remain close to 40%. Moreover, patients who survive their acute episode of severe sepsis have considerable incidence of re-hospitalization and ongoing morbidity and mortality beyond short-term endpoint.

Historically, organ dysfunction in patients with severe sepsis was thought to result from an exaggerated pro-inflammatory response. Accordingly, numerous randomized clinical trials examined therapies aimed at decreasing the pro-inflammatory response. With few exceptions, the results from these trials have been disappointing, and currently no specific therapeutic agent is approved for the treatment of patients with severe sepsis.

It is now appreciated that patients with severe sepsis mount simultaneous pro- and anti-inflammatory responses that perturb immune homeostasis. For many patients, an imbalance between these responses, with a predominant and/or protracted anti-inflammatory component, leads to a state of net immunosuppression. This immunosuppression is mediated by multiple mechanisms including reduction in the number of circulating lymphocytes and dendritic expression of negative co-stimulatory molecules, an increase in the numbers of regulatory T-cells and myeloid-derived suppressor cells, and a shift from a phenotype of pro-inflammatory type 1 helper T-cells to an anti-inflammatory phenotype of type 2 helper T cells. This immunosuppression has important clinical consequences including increased risk of secondary infection, viral reactivation, organ dysfunction, and mortality.

Design:

Prospective, randomized, double-blind, human clinical trial.

Treatment Protocol:

Nivolumab will be administered as a single dose infused using a volumetric pump at the protocol specific doses and rate through an intravenous solution infusion set with a sterile, non-pyrogenic, 0.2-micron pore size, low protein binding in line filter. Nivolumab will be infused at a rate of 2mL/min  over 90 minutes followed by a flush.

Primary Outcome:

For each subject, the study consists of four periods: (1) a screening period of up to 10 days, (2) baseline assessments within 24 hours prior to study treatment, (3) treatment with a single dose of nivolumab, and (4) a clinical study assessment period of up to 90 days. The total study duration is approximately 100 days for an individual subject. AE and SAE will be collected up to Day 90. The end of the study is defined as the last subject’s last assessment, or 90 days after last subject’s first dose, whichever is later.

Measurements:

Physical examinations, vital sign measurements, 12-lead electrocardiograms (ECG), and clinical safety laboratory assessments will be performed at selected times. Serial blood samples for pharmacokinetics, receptor occupancy, pharmacodynamics, biomarker, and immunogenicity analyses will be collected pre-dose and at selected time points post-dose.

Amantadine to Stimulate Wakefulness Following Post-Anoxic Encephalopathy


Description

Principal Investigator:

Michael Donnino MD

Status of Study:

Ongoing

Purpose of Protocol:

The overall aim of this study is to determine if amantadine (a neurostimulant) will improve the rate of awakening in comatose post-cardiac arrest patients. In order to achieve this goal, we will perform a randomized, controlled, double-blind trial of amantadine for patients who remain comatose 72 hours after cardiac arrest.  The primary aim of the study will be rate of awakening in this comatose population. This short-term primary outcome is selected to test for safety and signal of efficacy that would justify a large trial powered to measure long-term outcomes.

Specific aim #1: Determine if amantadine administration to patients who remain comatose 72 hours after resuscitation from cardiac arrest promotes awakening compared to placebo.

Specific aim #2: Determine if the number of serious adverse events differ between subjects randomized to amantadine and subjects randomized to placebo. The null hypothesis is that adverse events do not differ between groups

Significance and Background:

Cardiac arrest results in approximately 382,000 deaths per year in North America. After

resuscitation from cardiac arrest, the majority of deaths in-hospital are secondary to brain injury.

Standardized post arrest care plans, including temperature management, early coronary

revascularization and delayed neurologic prognostication improve outcomes.  Despite these

advances, the most common cause for withdrawal of life sustaining therapy is failure to awaken. In many cases, decisions to withdraw life sustaining treatment may occur earlier than accurate

prognosis is possible.

 

One method to accelerate awakening from coma is the use of neurostimulant medications, such as

amantadine. Neurostimulant medications stimulate consciousness in comatose traumatic brain injury patients. We have previously demonstrated these medications are tolerated and are associated with awakening in cardiac arrest patients.

The results of this work are significant and will directly influence care and outcomes for 120,000 post-cardiac arrest patients admitted to hospitals each year. The approach is innovative and provides a pragmatic approach to enrollment. The investigative group is expert in clinical care and regularly uses a standardized post-arrest care bundle including multimodal neurologic prognostication. This will be the first trial to accelerate awakening and to compare awakening with neuroanatomic injury patterns.

Design:

Multicenter, randomized-controlled, double-blinded trial to test whether early neurostimulant administration increases the rate of awakening after resuscitation from cardiac arrest.

Inclusion Criteria:

  1. Non traumatic cardiac arrest
  2. Age 18 and older
  3. Defibrillation and/or chest compressions by healthcare providers
  4. Return of spontaneous circulation
  5. Comatose, e.g. unresponsive to verbal stimuli and no purposeful response to pain

 

Exclusion Criteria:

  1. Written do not attempt resuscitation (DNAR) reported to providers before randomization
  2. Known prisoner or pregnancy
  3. Lack of motor response to pain and absent N20 response on SSEP prior to randomization
  4. Initial CT demonstrating brain edema (defined as grey white ratio <1.2)
  5. Presence of malignant pattern on EEG at time of randomization. (Including those with a history of seizures)
  6. Next of kin/LAr unwilling to provide supportive care for at least one week after enrollment
    1. At 72 hours after cardiac arrest, neuroprognostication and a family meeting to determine goals of care are the typical approach.  If a family determines that care will be withdrawn and/or unwilling to consider continuation of care for at least a week after enrollment, then the patient will be excluded.  Note, that if a family changes their mind during the protocol and wishes to withdraw support on a patient, the study team will not intervene in this decision or discussion.
  7. Creatinine clearance <50mL/min
  8. Presently using other dopaminergic agent

 

Treatment Protocol:

  • The trial will have 2 arms: one enteral control and one active 100mg enteral amantadine treatment arm, each administered over approximately 15 minutes twice daily (0600 and 1200) for up to seven days beginning 72 hours of resuscitation.

 

  • Neither the investigators nor the research participants will know to which arm the participant has been assigned. The pharmacist who mixes the treatment solution will not be blinded; however, this individual will have no study-related contact with the study participants.

 

Subjects will continue to undergo clinical routine procedures such as EEG testing. A study physician will complete a neurologic examination upon hospital arrival and again once the subject has rewarmed to a core temperature of >36°C.

Primary Outcome:

Awakening during hospitalization is the primary outcome for this trial to determine whether there is any potential signal of benefit that is meaningful to patients from early neurostimulant administration.

Measurements:

Blood samples will be collected at 8 timepoints (5 mLs each time for a total of 40 mL):

  1. Daily “peak” levels 1-2 h following the afternoon dose on days 1-4
  2. “Trough” levels immediately prior to 6 AM dose on days 2-5

Improving patient lives by advancing the field of resuscitation medicine