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

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.

• B244 suspension (Biological): B244 suspension in 30ml/bottle
• Vehicle (Biological): Vehicle, 30ml/bottle

Primary outcomes

• Number of Participants With Treatment-related Adverse Events as Assessed by CTCAE v4.0 [Baseline to Day 28]: 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.

Secondary outcomes

• Change in Total Nasal Symptom Score (TNSS) After Prophylaxis Treatment [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.]: 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.
• Subjective Nasal Symptom Scores of Nasal Congestion After Prophylaxis Treatment [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.]: 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.
• Subjective Nasal Symptom Scores of Rhinorrhea After Prophylaxis Treatment [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.]: 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.
• Subjective Nasal Symptom Scores of Nasal Itching After Prophylaxis Treatment [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.]: 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.
• Subjective Nasal Symptom Scores of Sneezing After Prophylaxis Treatment [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.]: 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.
• Nasal Symptom-free Response Rate in Nasal Congestion Scores After Prophylaxis Treatment [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 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.
• Nasal Symptom-free Response Rate in Rhinorrhea Scores After Prophylaxis Treatment [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 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.
• Nasal Symptom-free Response Rate in Nasal Itching Scores After Prophylaxis Treatment [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 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.
• Nasal Symptom-free Response Rate in Sneezing Scores After Prophylaxis Treatment [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 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.
• Nasal Symptom-free Response Rate in TNSS After Prophylaxis Treatment [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.]: 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.

Other outcomes

• Change in Peak Nasal Inspiratory Flow (PNIF) [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.]: Peak Nasal Inspiratory Flow (PNIF) is a commonly used method for assessing nasal patency and provides an objective measurement of nasal airflow obstruction. The outcome is a direct representation of nasal congestion. Change in PNIF Observed Inverted Area Under the Curve (AUC) was measured between baseline and Visit 4. A decrease in PNIF Observed Inverted AUC(0-2 Hours) was considered an improvement in nasal airflow obstruction. Visit 3 was considered Baseline. Visit 2 was considered an alternate Baseline.
• Nasal Inflammation Score Using Otoscope [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 inflammation were graded by a clinician using a 0-3 nasal inflammation scale based on otoscope measurement where 0 = none, 1 = mild, 2 = moderate, and 3 = severe inflammation 120 minutes Post Nasal Allergen Challenge (Post-NAC).
• Intranasal Nitric Oxide Levels [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.]: Exhaled nasal nitric oxide (NO) was measured from the nasal cavity by a NO analyzer 120 minutes Post Nasal Allergen Challenge (Post-NAC).
• Change in Cytokine Concentration in Nasal Cavity and Blood [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.]: To evaluate if B244 administration will affect the levels of cytokine biomarkers in nasal cavity and blood.

Sex: All, ages: 18 Years to 65 Years, accepts healthy volunteers

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.

Participant flow

Outcome results

• Number of Participants With Treatment-related Adverse Events as Assessed by CTCAE v4.0 (Primary), Count of participants, Participants: Vehicle 0; B 244 1x (Low Dose) 0; B244 4x (Mid Dose) 0
• Change in Total Nasal Symptom Score (TNSS) After Prophylaxis Treatment (Secondary), Mean, score on a scale*hours: Vehicle -5.1 +/- 3.53; B 244 1x (Low Dose) -2.5 +/- 4.51; B244 4x (Mid Dose) -4.9 +/- 3.66
• Subjective Nasal Symptom Scores of Nasal Congestion After Prophylaxis Treatment (Secondary), Count of participants, Participants: Vehicle 4; B 244 1x (Low Dose) 2; B244 4x (Mid Dose) 5
• Subjective Nasal Symptom Scores of Rhinorrhea After Prophylaxis Treatment (Secondary), Count of participants, Participants: Vehicle 8; B 244 1x (Low Dose) 9; B244 4x (Mid Dose) 8
• Subjective Nasal Symptom Scores of Nasal Itching After Prophylaxis Treatment (Secondary), Count of participants, Participants: Vehicle 6; B 244 1x (Low Dose) 10; B244 4x (Mid Dose) 10
• Subjective Nasal Symptom Scores of Sneezing After Prophylaxis Treatment (Secondary), Count of participants, Participants: Vehicle 9; B 244 1x (Low Dose) 13; B244 4x (Mid Dose) 11
• Nasal Symptom-free Response Rate in Nasal Congestion Scores After Prophylaxis Treatment (Secondary), Count of participants, Participants: Vehicle 3; B 244 1x (Low Dose) 4; B244 4x (Mid Dose) 7
• Nasal Symptom-free Response Rate in Rhinorrhea Scores After Prophylaxis Treatment (Secondary), Count of participants, Participants: Vehicle 11; B 244 1x (Low Dose) 10; B244 4x (Mid Dose) 10
• Nasal Symptom-free Response Rate in Nasal Itching Scores After Prophylaxis Treatment (Secondary), Count of participants, Participants: Vehicle 11; B 244 1x (Low Dose) 11; B244 4x (Mid Dose) 13
• Nasal Symptom-free Response Rate in Sneezing Scores After Prophylaxis Treatment (Secondary), Count of participants, Participants: Vehicle 10; B 244 1x (Low Dose) 13; B244 4x (Mid Dose) 13
• Nasal Symptom-free Response Rate in TNSS After Prophylaxis Treatment (Secondary), Count of participants, Participants: Vehicle 9; B 244 1x (Low Dose) 6; B244 4x (Mid Dose) 12
• Change in Peak Nasal Inspiratory Flow (PNIF) (Other pre specified), Mean, L*Hr/min: Vehicle -60.8 +/- 57.83; B 244 1x (Low Dose) -8.6 +/- 39.62; B244 4x (Mid Dose) -60.9 +/- 57.48
• Nasal Inflammation Score Using Otoscope (Other pre specified), Count of participants, Participants: Vehicle 0; B 244 1x (Low Dose) 0; B244 4x (Mid Dose) 0
• Intranasal Nitric Oxide Levels (Other pre specified), Mean, ppb: Vehicle 61.9 +/- 57.77; B 244 1x (Low Dose) 33.9 +/- 26.68; B244 4x (Mid Dose) 81.9 +/- 104.88
• Change in Cytokine Concentration in Nasal Cavity and Blood (Other pre specified)

Adverse events

Time frame: Part 1: Baseline to end of study (Day 42). Part 2: Baseline to end of study (Day 28).

Other adverse events by term

• Study Protocol (PDF, 2018-08-29)
• Statistical Analysis Plan (PDF, 2018-01-03)

• Joel Neutel, MD, Principal investigator, Study PI