A Pilot Study of the Safety, Tolerability, and Effectiveness of Halo
Condition: Healthy
Study type: Interventional

Summary: 
      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.
    

Detailed description: 
      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.
    

Intervention name(s): Halo Oral Spray; Halo Placebo
Intervention type(s): Drug; Drug
Intervention description(s): Three sprays per use, total = 9 sprays per day; Three sprays per use, total = 9 sprays per day
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Care Provider)
Primary purpose: Prevention
Keywords: Healthy volunteer