RATIONALE AND SIGNIFICANCE:

The population of the US has no or limited immunologic memory to the swine flu, and thus the potential for serious or lethal infections is present. Genetic analysis has now indicated that the H1N1 swine flu is too different from human H1N1 for previous vaccinations or flu infections to offer much if any protection.

Research suggests that non-specific, or innate, immune factors-- especially Natural Killer (NK) cells—are important in controlling primary influenza infection. Although studies have not been done on swine flu strains, these processes may be even more important in these infections due to an absence of specific responses. Studies demonstrate that NK cells are essential in controlling lung virus titers early during an influenza virus infection and that NK cell function decreases with old age.

Enercel® has several properties that may make it ideal adjunct therapy for swine flu infections. Animal studies have revealed enhancement of NK function and limiting of acute Coxsackievirus infections in mice through immune mechanisms. Intranasal Enercel® has been shown to protect respiratory tissues from infection and immune-mediated damage. Furthermore, Enercel® enhances ACE pathways, potentially improving acute and post-viral malaise and fatigue. Finally, by providing a second antiviral mechanism (immune activation), drug resistance may be limited.

Analysis of its neuraminidase protein indicates that swine flu virus should be sensitive to the antiviral drug Tamiflu®, which targets this protein. This bears out clinical experience so far, which suggests that patients respond well to the drugs if initiated promptly after the onset of symptoms. However, it appears likely that persons with diminished natural immunity may respond less favorably. As with any severe, acute infection, lowered immunity—as in children, the immunocompromised or the elderly—increased morbidity and mortality.

Viruses with N1 neuraminidase appear to be more likely than other strains to develop resistance to antivirals, including Tamiflu®. In the community, resistance may develop before detection in the laboratory, potentially putting treated patients at risk for therapeutic failure. 

Antiviral treatment alone may not eliminate the risk of the virus triggering a massive immune reaction--a cytokine storm—which can prove particularly lethal in young, healthy persons. This is thought to have been the chief cause of death during the Spanish Flu of 1918-19, which was caused by an H1N1 strain.

The addition of Enercel® could prove to be beneficial to an antiviral regimen for swine flu for several reasons.

• Enercel® has been proven to improve immune function in acute infections, and may reduce mortality, length and severity of illness by strengthening immune responses-- in particular NK function-- to the infection

• Enercel® may mitigate the extreme fatigue associated with clinical swine flu due to its potentiation of ACE pathways

• By indirectly reducing viral replication from immune-mediated antiviral mechanisms, antiviral resistance may be limited

• Respiratory tract cellular resistance to infectious and immunologic damage may be enhanced by Enercel administration. The incidence of bacterial superinfections and pneumonia may be limited.

• Patients with antiviral resistance to Tamiflu® may still derive benefit from Enercel®

• Enercel® appears to be an immune modulator; therefore, cytokine-mediated cytotoxicity, Adult Respiratory Distress Syndrome (ARDS) and Disseminated Intravascular Coagulation (DIC) may all be limited.

STUDY OBJECTIVES:

• Comparison of the effect of Enercel® and Tamiflu® together with Tamiflu® alone on length of illness and severity of clinical signs and symptoms of swine flu  

• Mortality

• Effect on the incidence of pneumonia

• Toxicity

• Peripheral Blood Mononuclear Cell (PBMC) NK function

STUDY POPULATION:

Eighty adult patients between the ages of 18 and 65 with presumptive swine flu will be eligible for enrollment. Healthy persons and individuals with chronic diseases that are well-compensated and stable will qualify. Pregnant women are excluded. Subjects referred from outside physicians with the presumptive diagnosis of swine flu of 72 hrs. duration or less will be sequentially enrolled. A clinical constellation consistent with an influenza infection (fever, malaise, headache, myalgias, sore throat, cough) shall be confirmed by the Investigator prior to enrollment. A pharyngeal swab must be positive by rapid assay for Influenza A.

STUDY DESIGN:

This is a randomized open-label study to assess the benefits of Enercel® when added to Tamiflu® for presumptive swine flu. Adult subjects with symptoms of the swine flu for 72 hrs. or less will be eligible for enrollment. Preliminary diagnosis by a referring physician, signs and symptoms of swine flu validated by the investigator and pharyngeal swab specimen positive for Influenza A by rapid screening test are required for participation.

Patients will be interviewed on day 0 to determine their eligibility to participate in the study. Specifically, they must meet inclusion criteria and also provide a witnessed written consent for the study. A throat swab for rapid screening test of Influenza A must be positive. Eighty such sequentially informed consented patients will randomly select an available number from 1-80 that will become the patient study number. Forty subjects will be enrolled into group A and 40 into group B. Group A will receive Tamiflu® 75 mg orally bid for 5 consecutive days. Group B will receive Tamiflu® 75 mg orally bid and intranasal Enercel® 2 puffs tid for 5 consecutive days. There is no placebo arm due to concern over swine flu virulence.

Prior to administering any product, on day 0, the individuals will undergo a complete physical examination. Signs and symptoms of influenza infection (fever, pharyngitis, malaise, headache, sore throat, cough, myalgias, diarrhea, nausea and vomiting) will be scored on a scale of 0 to 4, with 0 being not present and 4 severe and/or continuous. A pharyngeal swab for detection Influenza A by rapid screening test will be obtained; a second swab will be sent to the CDC for confirmation of swine flu (viral culture and RT-PCR). A Chest X-ray will be taken. Approximately 2 tablespoons of blood will be drawn for CBC, Chemistry panel, NK function and banked serum. A urinalysis and urine pregnancy test for women of childbearing potential will be obtained. Qualifying subjects will be enrolled and given study 5 days of study medication(s).

All non-excluded medications the participants are receiving at the time of enrollment may be continued at the discretion of the investigators in consultation with the subjects’ physician. Oral antibiotics may be administered during the trial as clinically indicated. In addition, over-the-counter and prescription medications for influenza symptoms may be given. These include analgesics, aspirin, acetaminophen, non-steroidal anti-inflammatory agents, cough suppressants, antihistamines, decongestants, anti-nausea and anti-diarrhea drugs.

All dietary supplements with the exception of multivitamins and minerals must be held at the time of enrollment and for the duration of the trial.

Enrolled subjects will be re-evaluated at days 2, 4, 6, 8, 10 and weeks 2 and 3. At each visit, they will be similarly scored for signs and symptoms of influenza. A repeat CBC, Chemistry panel, and UA will be obtained at days 4, 10, and 2 and 3 weeks. Blood for NK function will be drawn at day 10 and 3 weeks. Remaining pill counts of Tamiflu® will be determined. Any new symptoms shall be reported to the study coordinator and recorded.

The subjects will be directed to take Enercel® as follows:  prior to each use, the bottle is to be succussed by pounding the base of the bottle against a firm surface (such as a firmly held hand) for 10 times within a 15 second period. Any immediate or delayed adverse effect potentially linked to the inhalation of the Enercel® will be reported to the study coordinator at the next visit.

Either the subject or the investigator may discontinue further participation in the study at any time. Subjects that have grade III/IV or greater clinical or laboratory toxicity during active treatment will  have their study medication(s) discontinued and will continue to be evaluated clinically as needed.

THERAPEUTIC ALTERNATIVES:

Relenza® is another neuraminidase inhibitor indicated for H1N1 influenza infections. The swine flu is resistant to the older antiviral agents Amantadine and Rimantadine. Biological Response Modifiers like Alpha Interferon have shown experimental promise against influenza. Time may reveal that the current swine flu strain is less virulent than expected; if so, the case may be made to treat healthy adults symptomatically only. Current vaccines do not confer any protection to swine flu.

FINANCIAL CONSIDERATIONS:

The study medications will be provided without charge to the study subjects. Clinical assessments and laboratory testing will also be done at no cost to the participants. There is no monetary reimbursement for participating, however.