| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Seasonal Allergic Rhinitis |
|
| E.1.1.1 | Medical condition in easily understood language |
| Seasonal Allergic Rhinitis |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Respiratory Tract Diseases [C08] |
| MedDRA Classification |
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| The primary objective were to assess the efficacy of the combination of MFNS and oxymetazoline nasal spray (OXY) given concomitantly QD compared to OXY BID, MFNS QD, and placebo in subjects with seasonal allergic rhinitis (SAR) in relieving symptoms including nasal congestion. |
|
| E.2.2 | Secondary objectives of the trial |
| The secondary objectives was to assess the potential for the combination to produce tachyphylaxis and/or rebound congestion, and safety of the combination (e.g., subject-reported adverse events [AEs], vital signs, electrocardiograms [ECGs], and laboratory measurements). |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. A subject must be 12 years of age or older, of either sex, and of any race.
2. A subject must have at least a 2-year documented history of SAR which exacerbates during the time period over which the subject will be participating.
3. At screening (Visit 1), a subject must have a documented positive skin-prick test response to an appropriate seasonal allergen appropriate to the geographical vicinity in which the study is being carried out and over the period of time the subject is participating. Immunoglobulin E (IgE)-mediated
hypersensitivity to a seasonal allergen (eg, prevailing trees and/or grasses) must be by a positive response to the skin prick test with wheal diameter at least 3 mm larger than diluent control after 20 minutes.
4. A subject must be clinically symptomatic at the Screening Visit based upon NOW (instantaneous) allergy signs/symptom scores: nasal rhinorrhea must be ≥2, nasal congestion must be ≥2, and TNSS must be ≥6 (see Section 7.6 for details).
5. A subject must be clinically symptomatic at the Baseline Visit based upon NOW (instantaneous) allergy signs/symptom scores. For the 3 calendar days immediately before the Baseline Visit, the 7 twice-daily (AM plus PM, plus AM of the Baseline Visit) run-in diary NOW rhinorrhea score must be ≥14, nasal
congestion score must be ≥14, and TNSS must total ≥42.
6. A subject must be in general good health as confirmed by routine clinical and laboratory testing and ECG results. Clinical laboratory tests (complete blood count [CBC], blood chemistries, and urinalysis) must be within normal limits or clinically acceptable to the investigator and the sponsor.
7. A subject must be free of any clinically significant disease, other than SAR, which would interfere with the study evaluations.
8. A subject and/or a parent/guardian must be willing to give written informed consent and must be able to adhere to dosing and visit schedules and study requirements.
9. A female subject of child-bearing potential must have a negative serum pregnancy test (beta-human chorionic gonadotropin [β-hCG]) at screening. Nonsterile and premenopausal female subjects must be using a medically acceptable method of birth control, ie, double barrier method (eg, condom with spermicide), oral contraceptive, hormonal implant, medically prescribed intrauterine device (IUD), or depot injectable prior to screening and during the entire study.
10. A subject has the ability to transmit electronic diary data on a regular basis. |
|
| E.4 | Principal exclusion criteria |
1. A subject with a history of anaphylaxis and/or other severe local reaction(s) to skin testing.
2. A subject with asthma who require chronic use of inhaled or systemic corticosteroids.
3. A subject with current or history of frequent, clinically significant sinusitis or chronic purulent postnasal drip.
4. A subject with rhinitis medicamentosa.
5. A subject with glaucoma and/or increased intraocular pressure.
6. A subject who received a monoamine oxidase (MAO) inhibitor, β-blocker or tricyclic antidepressants with 14 days of the Screening Visit.
7. A subject with a history of allergies to more than 2 classes of medications or who are allergic to or cannot tolerate nasal sprays.
8. A subject who has had an upper respiratory tract or sinus infection that required antibiotic therapy without at least a 14-day washout prior to the Screening Visit, or who has had a viral upper respiratory infection within 7 days before the Screening Visit.
9. A subject who has nasal structural abnormalities, including large nasal polyps and marked septal deviations, which significantly interfere with nasal air flow.
10. A subject who, in the opinion of the investigator, is dependent on nasal, oral, or ocular decongestants, nasal topical antihistamines, or nasal steroids.
11. A subject who has used any drug in an investigational protocol in the 30 days before the Screening Visit.
12. A subject on immunotherapy (desensitization therapy), unless the subject is on a regular maintenance schedule prior to the Screening Visit and will stay on this schedule for the remainder of the study. A subject may not receive desensitization treatment within 24 hours before any visit.
13. A pregnant or nursing female.
14. A family member of the investigation study staff.
15. Members of the same family living in the same household.
16. A subject with current evidence of clinically significant hematopoietic, cardiovascular, hepatic, renal, neurologic, psychiatric, pulmonary, autoimmune disease, or other disease that precludes the subject’s participation in the study. Particular attention should be given to exclude subjects with conditions that
would currently interfere with the absorption, distribution, metabolism, or excretion of the study drug or interfere with the subject’s ability to complete or reliably complete the diaries.
17. A subject with significant medical condition(s) that, in the judgment of the investigator, might interfere with the study or require treatment (including eg, uncontrolled hypertension or diabetes).
18. A subject whose ability to provide informed consent (or, in the case of subjects less than the age of majority in their jurisdiction, their parent’s consent and their assent) is compromised.
19. A subject with a history of noncompliance with medications or treatment protocols. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
• Change from baseline in AM/PM NOW TNSS averaged over Days 1 to 15. The primary comparisons associated with this endpoint will be of the combinations (Groups 1 and 2) vs. OXY (Group 4). Baseline is the average of the seven twice-daily TNSS evaluations prior to the first dose (Days -3 to 1 AM, Days -3 to -1 PM).
• Standardized AUC (0-4 hr) of the change from baseline in nasal congestion score on Day 1. The primary comparisons associated with this endpoint will be of the combinations (Groups 1 and 2) vs. MFNS (Group 3). The AUC will be calculated using the trapezoid rule, then standardized by dividing the calculation by 4 hrs. Baseline is the average of the AM NOW nasal congestion scores that are assessed every 15 min for 1 hr prior
to dosing on Day 1 (ie, -1 hr, -45 min, -30 min, -15 min, and 0 hr). |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Change from baseline in AM/PM NOW TNSS averaged over Days 1 to 15.
Standardized AUC (0-4 hr) of the change from baseline in nasal congestion score on Day 1. |
|
| E.5.2 | Secondary end point(s) |
• Change from baseline in AM/PM NOW TNSS for each of Days 1, 2, 3, 4, 1 to 8, 9 to 15, and 16 to 22.
• Change from baseline in AM PRIOR (the subject’s status over the previous 12 hr [reflective]), AM NOW, PM PRIOR, PM NOW, and AM/PM PRIOR TNSS for each of Days 1, 2, 3, 4, 1 to 8, 9 to 15, 16 to 22, and 1 to 15.
• Change from baseline in AM PRIOR, AM NOW, PM PRIOR, PM NOW, AM/PM PRIOR, and AM/PM NOW total, ocular (eye watering/tearing, eye redness, and eye itching), and individual symptom scores for each of Days 1, 2, 3, 4, 1 to 8, 9 to 15, 16 to 22, and 1 to 15.
• Change from baseline in AM, PM, and AM/PM peak nasal inspiratory flow (PNIF) for each of Days 1, 2, 3, 4, 1 to 8, 9 to 15, 16 to 22, and 1 to 15.
• Change from baseline in standardized AUC(0-4 hr) of PNIF at Days 1, 15, and endpoint (the last treatment visit).
• Change from baseline in standardized AUC(0-4 hr) of the nasal congestion score at Days 15 and endpoint.
• Change from baseline in the subject’s evaluation of overall condition at Days 8, 15, endpoint, and follow-up
(based on the last day of the post-treatment period scheduled for Day 22).
• Subject evaluation of therapeutic response at Days 8, 15, and endpoint.
• Change from baseline in the investigator’s evaluation of overall condition at Days 8, 15, endpoint, and followup.
• Investigator evaluation of therapeutic response at Days 8, 15, and endpoint.
• Change from baseline in RQLQ total score at Day 15 and endpoint. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
• AM/PM NOW TNSS for each of Days 1, 2, 3, 4, 1 to 8, 9 to 15, and 16 to 22.
• AM PRIOR (the subject’s status over the previous 12 hr [reflective]), AM NOW, PM PRIOR, PM NOW, and AM/PM PRIOR TNSS for each of Days 1, 2, 3, 4, 1 to 8, 9 to 15, 16 to 22, and 1 to 15.
• AM PRIOR, AM NOW, PM PRIOR, PM NOW, AM/PM PRIOR, and AM/PM NOW total, ocular, and individual symptom scores for each of Days 1, 2, 3, 4, 1 to 8, 9 to 15, 16 to 22, and 1 to 15.
• AM, PM, and AM/PM peak nasal inspiratory flow (PNIF) for each of Days 1, 2, 3, 4, 1 to 8, 9 to 15, 16 to 22, and 1 to 15.
• Standardized AUC (0-4 hr) of PNIF at Days 1, 15, and endpoint (the last treatment visit).
Note: The time points of evaluation of secondary end points are noted in section E.5.2 |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | Yes |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
|
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 5 |
| E.8.3 |
Will this trial be conducted at a single site globally?
| No |
| E.8.4 | Will this trial be conducted at multiple sites globally? | Yes |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.2 | Trial being conducted completely outside of the EEA | Yes |
| E.8.6.3 | Specify the countries outside of the EEA in which trial sites are planned |
|
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.2 | In all countries concerned by the trial years | 0 |
| E.8.9.2 | In all countries concerned by the trial months | 4 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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