Study to Assess the Safety, Tolerability, and Preliminary Efficacy of B244 in Healthy Volunteers and Subjects With Seasonal Allergic Rhinitis

Study Overview
=================
Brief Summary
-----------------
This is a Prospective, Controlled, Double Blinded, Single Center, Randomized, 3 Arm, Parallel Assignment, Phase 1b/2a Study to assess the safety, tolerability, and preliminary efficacy of B244 delivered as an intranasal spray in healthy volunteers and subjects with seasonal allergic rhinitis.

Detailed Description
-----------------
This is a Prospective, Controlled, Double Blinded, Single Center, Randomized, 3 Arm, Parallel Assignment, Phase 1b/2a Study to assess the safety, tolerability, and preliminary efficacy of B244 delivered as an intranasal spray in healthy volunteers and subjects with seasonal allergic rhinitis. This will be a 2-part study. In Part 1, safety and tolerability will be evaluated during 14 days of study treatment twice-a-day followed by 4 weeks of follow-up in healthy volunteers. In Part 2, preliminary efficacy will be evaluated in subjects with a history of seasonal allergic rhinitis outside of the local pollen season. For Part 1 (safety and tolerability evaluation in healthy volunteers) we will enroll 24 subjects. Safety and tolerability will be assessed by reporting of AEs, physical examination and vital signs (blood pressure, heart rate, respiratory rate) during 14 days of treatment and up to 28 days of follow-up. An internal safety committee meeting will review the 2 week Part 1 safety data and, if there are no safety concerns, the study will proceed to Part 2 to evaluate preliminary efficacy in subjects with a history of seasonal allergic rhinitis (SAR) For Part 2 (preliminary efficacy evaluation in subjects with a history of SAR to ragweed pollen) will enroll 42 subjects. Safety and tolerability will be assessed in subjects with allergic rhinitis by reporting of AEs, physical examination and vital signs (blood pressure, heart rate, respiratory rate) during 14 days of treatment. For Part 2, study will be paused for safety review using the same stopping criteria as in Part 1. Rescue medications will not be allowed during the study.

Official Title
-----------------
A Prospective, Controlled, Double Blind, Multi-Center, Randomized, 3 Arm, Phase 1b/2a Study to Assess the Safety, Tolerability, and Preliminary Efficacy of B244 Delivered as an Intranasal Spray in Healthy Volunteers and Subjects With Seasonal Allergic Rhinitis

Conditions
-----------------
Allergic Rhinitis, Allergic Rhinitis Due to Grass Pollen, Healthy Volunteers

Intervention / Treatment
-----------------
* Biological: B244 suspension
* Biological: Vehicle


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Males and Females, 18 to 65 years of age (committed to consistent use of an acceptable method of birth control as described in Section 10). In good general health as determined by a thorough medical history and physical examination, and vital signs. Nonsmoker or ex-smoker (stopped >1 year prior to study entry). Subjects willing and able to provide written informed consent. Is willing and able to comply with the requirements of the protocol and must be available for the full duration of the study. For Part 1, subjects asymptomatic from any seasonal or perennial allergens. For Part 1, elevated systolic blood pressure greater than 120 but less than 160 and never been on antihypertensive medications or have been off any hypertensive treatment for a period of 12 weeks or longer. For Part 2, subjects with a well-documented history of seasonal allergic rhinitis (specifically ragweed pollen) with documentation of sensitivity by positive skin testing and/or IgE testing to the relevant allergens 12 months prior to enrollment that correlate with clinical history. For Part 2, a ragweed positive skin prick test with a wheal diameter at least 5 mm larger than the negative control and/or a ragweed specific IgE greater or equal to 0.7 kU/L. For Part 2, subjects with confounding allergies, or sensitization to cat epithelia, dog epithelia, Dermatophagoides farinae, or Dermatophagoides pteronyssinus or prevalent and relevant seasonal allergens as per the skin prick test may be included if sensitization is not clinically relevant (ie. subject is non-symptomatic and/or can avoid the allergen during the study) at the discretion of the Investigator. For Part 2, subjects with a baseline TNSS ≤ 3/12 at Visit 3 and a minimum qualifying TNSS score of a change of 6/12 from their baseline score after NAC #1 on at least 2 diary cards. For Part 2, subjects' average post diluents nasal congestion score must be < 1 at admission for each study visit. Exclusion Criteria: Pregnancy or breast-feeding Female of childbearing potential not using adequate contraceptive measures. Smoking within the past year or during the protocol. Systemic corticosteroid or other immunosuppressive medications use in the previous three months or during the protocol.* Intranasal corticosteroid use in the previous month or during the protocol.* Intranasal antihistamine or cromolyn use in the previous week or during the study.* Allergen immunotherapy during previous 12 months or during the protocol.* Omalizumab use in previous 12 months or during the protocol.* Systemic antihistamine or leukotriene modifying medication use in the previous week or during the protocol.* Use of antibiotics, NSAIDS, antihypertensives, beta-blockers, photosensitizing medications, or vitamin D supplements during study. Use of any intranasally administered over-the-counter product or nasal irrigation (e.g., neti pot) during study. Inability to give informed consent. Persistent asthma or any medical condition that in the opinion of the investigator may compromise the subject's ability to safely participate in the study. Subjects with any significant clinical abnormalities which may interfere with study participation. Prior use of AO+ Mist. Subjects with immunodeficiencies, nasal lesions, nasal polyps, or sinus infections. Use of an investigational drug within 30 days before screening Visit 1. * Exclusionary criterion due to 1) medication use as marker of persistent comorbid allergic or inflammatory condition that may increase subject risk with study participation, 2) potential of medication to interfere with study outcome measures or results.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Randomization will be 1:1:1 so that equal number of subjects will be treated in each arm of the study.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Vehicle<br>Intranasal application: 1 pump (140ul) per nostril BID for 14 days | Biological: Vehicle<br>* Vehicle, 30ml/bottle<br>|
| Active Comparator: B 244 1x (low dose)<br>Intranasal application: 1 pump (140ul) per nostril BID for 14 days | Biological: B244 suspension<br>* B244 suspension in 30ml/bottle<br>|
| Active Comparator: B244 4x (mid dose)<br>Intranasal application: 1 pump (140ul) per nostril BID for 14 days | Biological: B244 suspension<br>* B244 suspension in 30ml/bottle<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Treatment-related Adverse Events as Assessed by CTCAE v4.0 | Safety and tolerability endpoints will consist of all treatment-related adverse events reporting during the study duration for subjects only from Part 1 of the study. | Baseline to Day 28 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Total Nasal Symptom Score (TNSS) After Prophylaxis Treatment | Total Nasal Symptom Score (TNSS) is the sum of sub-scores for each of nasal congestion, sneezing, nasal itching, and rhinorrhea at each time point, using a four point scale (0-3; 0 = none; 1 = mild; 2 = moderate; 3 = severe), where 0 indicates no symptoms, a score of 1 for mild symptoms that are easily tolerated, 2 for awareness of symptoms which are bothersome but tolerable and 3 is reserved for severe symptoms that are hard to tolerate and interfere with daily activity. TNSS is calculated by adding the sub-score for each of the symptoms to a total out of 12. For TNSS and Area Under the Curve (AUC) analyses, an Analysis of Covariance with treatment and site as factors and Visit 3 (or Visit 2) value as a covariate was used to test for treatment effect at Visit 4. Observed AUC (0-2 Hours) was defined as TNSS from 0 to 120 minutes post Nasal Allergen Challenge (NAC). The Pre-NAC Adjusted AUC (0-2 Hours) was defined as the observed value minus the 0 minutes prior NAC value. | Visit 3 (or alternative baseline at Visit 2) to Visit 4 (14 days prophylaxis treatment). Visit 2 was used as an alternate baseline to report baseline values prior to any nasal allergen challenge (NAC) to minimize any potential priming effects. | 
| Subjective Nasal Symptom Scores of Nasal Congestion After Prophylaxis Treatment | All measurements were taken 120 minutes Post-Nasal Allergen Challenge (Post-NAC) at Visit 4 and compared to Baseline Visit 3. Visit 3 was considered Baseline. Visit 2 was considered an alternate Baseline. Nasal congestion was categorized as None, Mild, Moderate, or Severe. | Visit 3 (or alternative baseline at Visit 2) to Visit 4 (14 days prophylaxis treatment). Visit 2 was used as an alternate baseline to report baseline values prior to any nasal allergen challenge (NAC) to minimize any potential priming effects. | 
| Subjective Nasal Symptom Scores of Rhinorrhea After Prophylaxis Treatment | All measurements were taken 120 minutes Post-Nasal Allergen Challenge (Post-NAC) at Visit 4 and compared to Baseline Visit 3. Visit 3 was considered Baseline. Visit 2 was considered an alternate Baseline. Rhinorrhea was categorized as None, Mild, Moderate, or Severe. | Visit 3 (or alternative baseline at Visit 2) to Visit 4 (14 days prophylaxis treatment). Visit 2 was used as an alternate baseline to report baseline values prior to any nasal allergen challenge (NAC) to minimize any potential priming effects. | 
| Subjective Nasal Symptom Scores of Nasal Itching After Prophylaxis Treatment | All measurements were taken 120 minutes Post-Nasal Allergen Challenge (Post-NAC) at Visit 4 and compared to Baseline Visit 3. Visit 3 was considered Baseline. Visit 2 was considered an alternate Baseline. Nasal itching was categorized as None, Mild, Moderate, or Severe. | Visit 3 (or alternative baseline at Visit 2) to Visit 4 (14 days prophylaxis treatment). Visit 2 was used as an alternate baseline to report baseline values prior to any nasal allergen challenge (NAC) to minimize any potential priming effects. | 
| Subjective Nasal Symptom Scores of Sneezing After Prophylaxis Treatment | All measurements were taken 120 minutes Post-Nasal Allergen Challenge (Post-NAC) at Visit 4 and compared to Baseline Visit 3. Visit 3 was considered Baseline. Visit 2 was considered an alternate Baseline. Sneezing was categorized as None, Mild, Moderate, or Severe. | Visit 3 (or alternative baseline at Visit 2) to Visit 4 (14 days prophylaxis treatment). Visit 2 was used as an alternate baseline to report baseline values prior to any nasal allergen challenge (NAC) to minimize any potential priming effects. | 
| Nasal Symptom-free Response Rate in Nasal Congestion Scores After Prophylaxis Treatment | Nasal symptom free response rate was assessed 120 minutes Post-Nasal Allergen Challenge (Post-NAC) to be scored as Yes or No to nasal congestion at Visit 4 (yes indicates subject is free from nasal congestion symptom and no indicates subject still has nasal itching symptom). Visit 3 was considered Baseline. Visit 2 was considered an alternate Baseline. | Visit 3 (or alternative baseline at Visit 2) to Visit 4 (14 days prophylaxis treatment). Visit 2 was used as an alternate baseline to report baseline values prior to any nasal allergen challenge (NAC) to minimize any potential priming effects. | 
| Nasal Symptom-free Response Rate in Rhinorrhea Scores After Prophylaxis Treatment | Nasal symptom free response rate was assessed 120 minutes Post-Nasal Allergen Challenge (Post-NAC) to be scored as Yes or No to rhinorrhea at Visit 4 (yes indicates subject is free from rhinorrhea symptom and no indicates subject still has nasal itching symptom). Visit 3 was considered Baseline. Visit 2 was considered an alternate Baseline. | Visit 3 (or alternative baseline at Visit 2) to Visit 4 (14 days prophylaxis treatment). Visit 2 was used as an alternate baseline to report baseline values prior to any nasal allergen challenge (NAC) to minimize any potential priming effects. | 
| Nasal Symptom-free Response Rate in Nasal Itching Scores After Prophylaxis Treatment | Nasal symptom free response rate was assessed 120 minutes Post-Nasal Allergen Challenge (Post-NAC) to be scored as Yes or No to nasal itching at Visit 4 (yes indicates subject is free from nasal itching symptom and no indicates subject still has nasal itching symptom). Visit 3 was considered Baseline. Visit 2 was considered an alternate Baseline. | Visit 3 (or alternative baseline at Visit 2) to Visit 4 (14 days prophylaxis treatment). Visit 2 was used as an alternate baseline to report baseline values prior to any nasal allergen challenge (NAC) to minimize any potential priming effects. | 
| Nasal Symptom-free Response Rate in Sneezing Scores After Prophylaxis Treatment | Nasal symptom free response rate was assessed 120 minutes Post-Nasal Allergen Challenge (Post-NAC) to be scored as Yes or No to sneezing at Visit 4 (yes indicates subject is free from sneezing symptom and no indicates subject still has nasal itching symptom). Visit 3 was considered Baseline. Visit 2 was considered an alternate Baseline. | Visit 3 (or alternative baseline at Visit 2) to Visit 4 (14 days prophylaxis treatment). Visit 2 was used as an alternate baseline to report baseline values prior to any nasal allergen challenge (NAC) to minimize any potential priming effects. | 
| Nasal Symptom-free Response Rate in TNSS After Prophylaxis Treatment | Number of subjects that had 25% and 50% reduction in Observed Area Under the Curve (AUC) (0-120 minutes)/Pre-NAC Adjusted AUC (0-120 minutes) at Visit 4 (Day 28) from Visit 2 Observed AUC (0-120 minutes)/Pre-NAC Adjusted AUC (0-120 minutes). For TNSS and Area Under the Curve (AUC) analyses, an Analysis of Covariance with treatment and site as factors and Visit 3 (or Visit 2) value as a covariate was used to test for treatment effect at Visit 4. Observed AUC (0-2 Hours) was defined as TNSS from 0 to 120 minutes post Nasal Allergen Challenge (NAC). The Pre-NAC Adjusted AUC (0-2 Hours) was defined as the observed value minus the 0 minutes prior NAC value. | Visit 3 (or alternative baseline at Visit 2) to Visit 4 (14 days prophylaxis treatment). Visit 2 was used as an alternate baseline to report baseline values prior to any nasal allergen challenge (NAC) to minimize any potential priming effects. |