| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| E.1.1.1 | Medical condition in easily understood language |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Ear, nose and throat diseases [C09] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 18.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10028735 |
| E.1.2 | Term | Nasal congestion |
| E.1.2 | System Organ Class | 10038738 - Respiratory, thoracic and mediastinal disorders |
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| 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 |
Efficacy Objective:
To evaluate and compare the nasal airways resistance (conductance) of fixed dose combination products containing 500 mg paracetamol and 3 mg phenylephrine hydrochloride (Maxiclear™ PE 3.0) or 500 mg paracetamol, 150 mg ibuprofen and 2.5 mg phenylephrine hydrochloride (Maxigesic® PE 2.5) with that of 12 mg phenylephrine hydrochloride and placebo.
Safety Objective:
To determine and compare the safety and tolerability of all treatment groups
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| E.2.2 | Secondary objectives of the trial |
•Subjective nasal congestion: nasal congestion will be measured subjectively by the participants in 10 minutes intervals over the first 60 minutes after the first dose of study medication on a 100 mm VAS scale (0 = nose completely clear and 100 = nose completely blocked).
•Peak subjective relief of nasal congestion: this will be measured on day 1 as the peak difference in VAS nasal congestion score from baseline (mm) within the first 60 minutes after the first dose study medication
•Time to peak subjective relief of nasal congestion: this will be measured on day 1 as the time (minutes) at which the peak difference in VAS nasal congestion score from baseline is achieved within the first 60 minutes after the first dose study medication
These endpoints will be compared between randomized groups.
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1)Male and/or female ≥ 18 years of age
2)Presents cold symptoms which began within 96 hours of the study entry
3)Has a minimum score of 2 from the list of the following URTI symptoms: runny nose, blocked nose, sore throat and cough
4)For females – must be sterile or using adequate contraception
5)Has a baseline NAR ≥ 0.25 Pa/cm3/sec
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| E.4 | Principal exclusion criteria |
1)Use of any nasal decongestant (systemic or topical) within the last 12 hours
2)Previous participation in this clinical trial
3)Is a member or relative of the study site staff
4)Consumption of alcohol within the last 6 hours
5)Use of menthol containing products within the last 6 hours
6)Has taken paracetamol or ibuprofen within the last 6 hours
7)Has a known history of allergic reaction or clinically significant intolerance to acetaminophen, ibuprofen or phenylephrine hydrochloride
8)Has a baseline NAR < 0.25 Pa/cm3/sec
9)Has experienced any surgical complications or other issues that, in the opinion of the investigator, could compromise the safety of the subject if he or she continues into randomized treatment or could confound the results of the study.
10)Has any clinically significant unstable cardiac, respiratory, neurological, immunological, haematological, or renal disease or any other condition that, in the opinion of the investigator, could compromise the subject’s welfare, ability to communicate with the study staff, or otherwise contraindicate study participation.
11)Has a history or current diagnosis of a significant psychiatric disorder that, in the opinion of the investigator, would affect the subject’s ability to comply with the study requirements.
12)Has anatomical nasal obstruction or gross anatomical deformity, including moderately or severely deviated septum or the presence of nasal polyps.
13)Has a history of bacterial sinusitis diagnosed in the previous two weeks prior to participating in this trial.
14)Has any clinically significant finding at Screening that, in the opinion of the investigator, contraindicates study participation.
15)Previously participated in another clinical study within 30 days before Screening.
16)Has used antibiotics within 10 days prior to entry
17)Has used tricyclic antidepressants or monoamine oxidase inhibitors within the last 30 days
18)Cannot abstain from smoking during the whole duration of the trial
19)Females of childbearing potential not using adequate contraception. A woman of childbearing potential is defined as any female who is less than 2 years post-menopausal or has not undergone a partial or total hysterectomy or surgical sterilisation.
20)Women that are lactating, or known to be pregnant or possibly pregnant
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| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary endpoint is the Area Under the Curve of Nasal Airflow Conductance between 0 and 4 hours after the first dose of study medication on day 1 (AUC NAC0-4), calculated by the trapezoidal rule.
For the primary efficacy endpoint, between-treatment differences will be tested by means of a one-way analysis of covariance (ANCOVA) model with treatment as a factor and the corresponding baseline (Day1) value as a covariate. A missing NAR value at 3 hours will be imputed by linear interpolation and a missing 4-hour value will be imputed by carrying forward the value from the preceding time point.
The objective of the study is to test whether MaxiclearTM PE 30 and Maxigesic® PE 2.5 provide effective nasal decongestive relief which is comparable with that achieved with Phenylephrine 12 mg (Sudafed® Blocked Nose). To address this objective both MaxiclearTM PE 30 and Maxigesic® PE 2.5 will be compared with the placebo group and with Phenylephrine 12 mg (Sudafed® Blocked Nose). The two pairwise comparisons with placebo will be tested using a two-tailed p-value <0.05. No adjustment of the type I error rate is made here as these are considered two separate hypotheses relating to two independent products. The pair-wise non-inferiority comparisons with phenylephrine 12 mg (Sudafed® Blocked Nose) will use a one-sided 95% non-inferiority limit of a 15% difference in the NAC (AUC0-4). For either MaxiclearTM PE 30 or Maxigesic® PE 2.5 to be declared non-inferior the one-tailed upper 95% limit of the difference (Phenylephrine 12 mg (Sudafed® Blocked Nose) minus comparator; with larger values indicating greater efficacy) in the NAC (AUC0-4) must be less than 15% of the mean AUC0-4 of Sudafed® PE.
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
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| E.5.2 | Secondary end point(s) |
•Area Under the Curve of subjective nasal congestion measured on the VAS (0 = no congestion, 100 = complete congestion) over the first hour after dosing (AUC VAS0-1)
•Peak subjective relief of nasal congestion, measured as peak difference in VAS score from baseline (mm) within the first 60 minutes of the first dose of study medication
•Time (minutes) to peak subjective relief of nasal congestion within the first 60 minutes of the first dose of study medication
As with the primary efficacy endpoint, between-treatment differences in the AUC and peak of subjective nasal congestion relief will be tested by means of one-way analysis of covariance (ANCOVA) model with treatment as a factor and the corresponding baseline (Day 1) value as a covariate. The time to peak subjective nasal congestion relief will be summarised using Kaplan-Meier curves and compared between groups using log-rank tests.
Intermittent missing VAS values will be imputed by linear interpolation. A missing VAS value at 60-minutes will be imputed by carrying forward the value from the preceding time point.
Exploratory Endpoints
The Exploratory Endpoints of this study are:
•Area Under the Curve of Nasal Airflow Conductance between 0 and 1 hour, 0 and 2 hours, and 0 and 3 hours after the first dose of study medication on Day 1 (AUC NAC0-1, AUC NAC0-2, AUC NAC0-3), calculated by the trapezoidal rule.
•Area Under the Curve of subjective nasal congestion measured on the VAS (0 = no congestion, 100 = complete congestion) over the first 2, 3 and 4 hours after the first dose of study medication on Day 1 (AUC VAS0-2, AUC VAS0-3, AUC VAS0-4), calculated by the trapezoidal rule
As with the primary and secondary efficacy endpoints (with the exception of time to peak subjective relief), the exploratory endpoints will be compared between randomized groups using an ANCOVA model with treatment as a factor and the corresponding baseline values as a covariate. Missing VAS values will be imputed as per the secondary endpoint. In addition, a missing 4-hour value will be imputed by carrying forward the value from the preceding time point. Exploratory analyses will test the associations between objective NAC measures and the subjective measures of congestion relief using Pearson’s correlation coefficients incorporating data from all randomized groups.
Safety Endpoints
Data listings will be provided for protocol specified safety data. The Medical Dictionary for Regulatory Activities (MedDRA) (Version 9.1 or higher) will be used to classify all AEs with respect to system organ class and preferred term. Adverse event summaries will include only treatment emergent AEs, which will be summarized for each treatment group. Fisher’s 2 sided exact test may be used to compare the rates of occurrence between all treatment groups.
For vital sign measurements, descriptive statistics will be provided at each scheduled time point for each treatment group. Changes from baseline of vital signs will be calculated for each subject, and descriptive statistics will be provided on changes in vital signs from baseline for each treatment group at each scheduled time point after baseline.
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
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| 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) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| 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 | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 4 |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| 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
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 0 |
| E.8.9.1 | In the Member State concerned months | 12 |
| E.8.9.1 | In the Member State concerned days | 0 |
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