A Pilot Study of the Safety, Tolerability, and Effectiveness of Halo

This is a pilot study of the safety, tolerability, and effectiveness of Halo to prevent acute upper respiratory illness and respiratory virus infections. This study will be conducted at one site (University Hospitals Case Medical Center) in healthy adults during the upcoming respiratory virus season (12/15/11 to 3/14/12). The intervention will be with Halo, a commercial product which is FDA-approved for the treatment of xerostomia. The placebo will consist of the phosphate buffered saline plus the preservatives in the Halo formulation and without CPC - the active antiseptic. This placebo was chosen as the Halo formulation without CPC serves to act as a barrier to attachment of oral pathogens, and as such is an important contributing factor to its antimicrobial activity (see above). Also, the formulation without CPC with preservatives exhibits some antibacterial and antiviral activity. Moreover, the formulation without CPC and no preservatives is easily contaminated and not practical to utilize as the placebo in these studies.

Male and female participants 18-45 years of age will be recruited and monitored for the development of, duration, and severity of clinical symptoms and signs consistent with acute respiratory disease (defined below) captured daily through diaries, and PCR confirmation of important respiratory viruses including influenza, rhinoviruses, adenoviruses, and respiratory syncytial virus during episodes of acute respiratory disease during the length of the study will be undertaken. Secondary objectives will assess the tolerance, acceptability and adherence to Halo as well as the change in the bacterial (oral streptococci and Group A streptococcus) and fungal microflora in the oropharynx. School or work absenteeism, visits to physicians' offices, emergency departments and urgent care centers will also be captured. Conventional cultures for these bacterial and fungal organisms will be pursued (see below). Throughout the study period, the safety, tolerability, acceptability and adherence to study products will be assessed.

Significance and Background Respiratory tract disease is a major cause of morbidity and mortality throughout the world accounting for approximately 4 million deaths worldwide. Asthma, pneumonia, and acute bronchiolitis account for almost 22% of all pediatric hospitalizations in the United States. Pneumonia remains in the top ten causes for admission across all age groups in the United States. Much of which are directly caused by, or triggered from respiratory viruses including influenza, parainfluenza, respiratory syncytial virus (RSV), and adenovirus. In addition to these well-known pathogens, advancements in molecular and genomic techniques have increased our detection and identification of new respiratory viruses which also contribute to respiratory disease. There is also renewed attention on respiratory viruses previously considered benign, including the human rhinovirus and coronaviruses, as there is mounting evidence that these viruses can also lead to clinically severe disease. Influenza is one of the leading causes of infectious related deaths and hospitalizations in children and the 2009-10 H1N1 pandemic was especially severe in younger populations.

Respiratory disease can be caused by a variety of micro-organisms especially viruses. Despite the frequency and burden of acute respiratory infections worldwide and across all age groups, there has been limited progress in the management of treatment of respiratory virus infections aside from the use of anti-influenza drugs. The ability to prevent of acute respiratory disease has also been more limited except for the use of the influenza vaccine. The availability of a product that can be used with ease, is low cost but possesses broad spectrum antimicrobial and antiviral activity could play a major role in reducing the overall occurrence, morbidity and mortality associated with acute respiratory disease.

Moreover, upper respiratory infections are the leading cause of outpatient illness in U.S. military professionals and serve as the single greatest cause of lost workdays in the military. Unfortunately, these infections are not only prevalent, but also severe, constituting a primary cause of infectious disease hospitalization in U.S. military personnel including Navy shipboard and submarine personnel, and new recruits at basic training facilities. Military trainees and newly-mobilized troops are particularly subject to upper respiratory infection epidemic outbreaks due to their crowded living conditions, stressed working environments, and exposure to respiratory pathogens in disease-endemic areas. Additionally, the pulmonary disease resulting from ubiquitous infections are particularly impactful in high altitudes and other extreme environments common to Air Force/Navy activities.

Oasis Health Care has developed a technology and product that combines microbial barrier abilities along with a broad spectrum anti-infective agent cetylpyridinium chloride (CPC) at 0.1%. This formulation called Halo is commercially available for the over-the-counter treatment of xerostomia. The spray formulation has high mucoadhesion properties and prolonged retention time in the oral cavity. Cetylpyridinium chloride like chlorhexidine is a quarternary ammonium salt. However, due it possesses certain advantages over the latter in that it targets pathogenic bacteria while sparing beneficial ones (see below). Due to its chemical structure, CPC demonstrates significant antiviral activity especially against respiratory viruses (see below). Toxicology studies have shown no evidence of acute or chronic toxicity in animal models or irritant effect, and over-the-counter mouthwashes containing cetylpyridinium chloride have been marketed for over 45 years. Expanding the indications for the use of a cetylpyridinium-based spray formulation (Halo) as a potential formulation to prevent respiratory virus infections (cold and flu) is the long term goal. This proposal will examine the effect of Halo on the frequency and duration of clinically apparent acute respiratory infections and on respiratory virus burden as measured by PCR in young healthy adults through the respiratory virus season in Cleveland, Ohio.

Selection and enrollment of participants Study Enrollment and Withdrawal One hundred two healthy male and female participants, ages 18-45 will be enrolled in two groups. It is estimated that 204 subjects will need to be screened (2:1 screened to eligible) to enroll 102 subjects. At screening/enrollment, subjects will be stratified as to whether they received inactivated or live influenza virus vaccination. Subjects will be recruited through customary IRB-approved methods. Children, pregnant women, prisoners and other vulnerable individuals will not be enrolled.

Clinical/Laboratory Evaluations and Study Schedule Screening/Enrollment Written informed consent will be obtained before any clinical evaluations are performed. As noted in the safety section:. the study product has an acceptable safety profile and poses no significant toxicological risk to individuals. The formulation consists of ingredients with a long history of safe use in oral healthcare products.

A posterior pharyngeal and nasal swab will be obtained to ascertain baseline bacterial and fungal organisms and a multiplex PCR for respiratory viruses. Study product (after randomization) will be provided until the next scheduled visit, study procedures will be again reviewed, contact information for reaching study personnel will be provided, and study diaries will be distributed. Appointments for the 1st monthly evaluation will be made.

Scheduled Follow-up Visits At these visits, an interval medical and concomitant medication history will be obtained. Solicited and unsolicited adverse reactions will be ascertained. The study diaries will be reviewed with participants. An oropharyngeal exam will be conducted by study clinicians and a fuller symptom-directed physical exam will be performed if indicated. A posterior pharyngeal and nasal swab will be obtained at each visit to ascertain bacterial and fungal organisms and a multiplex PCR for respiratory viruses. The enrollment and interim visit pharyngeal and nasal swabs will be analysed in real time, all other swabs will be stored for future use determined by funding. Study bottles will be collected and counted. Study product will be provided until the next scheduled visit, study procedures will be again reviewed, and contact information for reaching study personnel will be revisited. Appointments for the next monthly evaluation will be made.

Final Study Visit This study visit will be conducted within 2 months after completing the last dose of Halo/Placebo. At this visit, an interval medical and concomitant medication history will be obtained. Solicited and unsolicited adverse reactions will be ascertained. An oropharyngeal exam will be conducted by study clinicians and a fuller symptom-directed physical exam will be performed if indicated.

Interim Visits Subjects will be instructed to contact study personnel in the event they develop an acute upper respiratory disease as defined above within 72 hours of onset of symptoms and signs (this allows for weekends and holidays). At these visits, an interval medical and concomitant medication history will be obtained. Solicited and unsolicited adverse reactions will be ascertained. An oropharyngeal exam will be conducted by study clinicians and a fuller symptom-directed physical exam will be performed if indicated. If pharyngitis with exudate is observed or suspected, a rapid group A streptococcal (GAS) screen will be performed. Subjects positive for Group A streptococcal infection will be given a prescription for appropriate antibiotics and a referral for follow-up care as needed. If individuals present with symptoms and signs of acute influenza fever, sore throat, myalgias, headache and chills, they will be tested for influenza and prescribed Tamiflu as needed. A posterior pharyngeal and nasal swab will be obtained to ascertain baseline bacterial and fungal organisms and a multiplex PCR for respiratory viruses. Any visit to a physician's office, emergency department, urgent care center or the need for hospitalization will be recorded. Subjects will be carefully instructed to record the duration of each symptom and sign to be recorded in the study-supplied diaries.

Statistical Analysis Sample Size Calculations Initially, primary outcomes in the control group vs. the treatment group will be compared using the t-test for independent samples, and this technique was used to estimate sample sizes. Specifically, sample size calculations were carried out assuming that the two groups will be of equal size and that the random assignment will be balanced. Further, it was assumed that an average of 2 events would occur in the control group, contrasted against an average of 1.5 events in the treated group (SD = 1), and that the average duration of illness would be 4 days and 3 days in the control and treated groups, respectively (SD = 2). Taking alpha to be 0.05, a sample size of 23 per group would allow the detection of a 25% difference in primary outcomes between the two groups with 80% power. The sample size was increased to 51 per group to account for potential losses to follow-up.

29 Randomization Based on whether the enrolled study participants have received any type of flu shot within the past 3 months, the participants will be classified as influenza vaccine recipients and non-recipients. Within each category, they will be randomly assigned to the control group or treatment group. The assignment will be balanced so that equal numbers are assigned to each group.

Interim Analysis The investigators will carry out an interim analysis when all the patients recruited have been followed for one and a half months. Since this is a pilot study, this analysis will be carried out at a stringent level of significance.

Statistical Analysis Standard techniques of descriptive statistics will be used to compare demographics and other patient characteristics in the two treatment groups. Since an additional focus of this pilot study is to obtain accurate estimates of the moments of the distributions of the outcome variables, confidence intervals will also be provided. Descriptive summaries of the number of events and duration of infection will be generated for the two groups. As stated above, the t-test will be used to compare estimates of the average number of events per person as well as the average duration of illness between the two groups. To the extent that the small sample size allows it, the investigators will utilize regression techniques for count data, using SAS GENMOD, to model the number of events per person adjusting for relevant covariates.

Eligibility Criteria:
Inclusion Criteria:

1. Signed informed consent
2. Ages between 18-45 years, inclusive
3. Non-tobacco/nicotine use (at least 3 months)
4. BMI of 17-35 kg/m2 inclusive
5. Able to comply with all study procedures and follow-up
6. Healthy on the basis of screening medical exam, blood chemistries, hematology, and serum pregnancy tests for females (at screening )
7. Non-pregnant or breast-feeding

Exclusion Criteria:

1. History of current use of narcotics, or recreational drug use.
2. Use of \> 7 alcoholic beverages in 1 week
3. Any acute illness such as asthma, cardiovascular, respiratory, hepatic, renal, hematologic, gastrointestinal (including eating disorder), endocrine/metabolic, neurologic, dermatologic, or psychiatric disease.
4. Treatment with another investigational product in the past 30 days
5. Immunocompromised status including HIV by history
6. Use of any other intra-oral product (especially antiseptic).
7. Intended use of mouthwash during study duration
8. Laboratory (screening) of creatinine \> 1.5 X ULN, hemoglobin \< 10.5 g/dL, platelet count ≤ 99,000/mm3, absolute neutrophil count ≤1200/ mm3, serum glucose ≥ 150 mg/dl (Subject can enroll prior to receiving lab results. Subject will be contacted if lab results are an exclusion and discontinue from study)
9. Use of any systemic antibiotic or antifungal within 30 days of screening
10. Prior or current history of seasonal allergies, chronic sinusitis or rhinitis
11. Allergy to any component of Halo
12. Oral lesions
13. Dentures
14. Dental Treatment currently in progress (implants, root canals, complex restorative procedures)