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