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    Clinical Trial Results:
    A phase 3 randomised, double blind, multiple dose, parallel group efficacy study of different doses of phenylephrine hydrochloride combined with paracetamol and/or ibuprofen in participants with nasal congestion associated with the common cold.

    Summary
    EudraCT number
    		 2015-002385-23
    Trial protocol
    		 GB  
    Global end of trial date
    23 Nov 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    04 Jan 2020
    First version publication date
    04 Jan 2020
    Other versions
    Summary report(s)
    		 Clinical study report

    Trial information

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    Trial identification
    Sponsor protocol code
    AFT-MXCF-03
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    AFT Pharmaceuticals Ltd
    Sponsor organisation address
    129 Hurstmere Road, Takapuna, Auckland, New Zealand, 0622
    Public contact
    Ioana Stanescu, AFT Pharmaceuticals Ltd, +64 9488 0232 712, ioana@aftpharm.com
    Scientific contact
    Ioana Stanescu, AFT Pharmaceuticals Ltd, +64 9488 0232 712, ioana@aftpharm.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    10 May 2019
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    23 Nov 2017
    Global end of trial reached?
    Yes
    Global end of trial date
    23 Nov 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    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
    Protection of trial subjects
    The informed consent process, the right to withdraw from the study at any time and the ethics committee review of the study protect the rights and benefits of the study participants.
    Background therapy
    		 -
    Evidence for comparator
    		 The relative nasal decongestant efficacy of Maxigesic® PE 2.5 and Maxiclear PE 3.0 compared with phenylephrine 12 mg alone and placebo. The lower doses of phenylephrine hydrochloride in both MaxiclearTM PE 3.0 and Maxigesic® PE 2.5 adjust for the interaction between paracetamol and phenylephrine hydrochloride and returns the phenylephrine exposure to that associated with approved phenylephrine hydrochloride doses (10-12 mg) when given as monotherapy (Atkinson et al., 2015a).
    Actual start date of recruitment
    15 Jan 2016
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United Kingdom: 165
    Country: Number of subjects enrolled
    New Zealand: 112
    Worldwide total number of subjects
    277
    EEA total number of subjects
    165
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    277
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 165 patients were enrolled and completed the study at the Common Cold and Nasal Research Centre, Cardiff School of Biosciences, Cardiff University, Cardiff CF10 3AX prior to the center’s closure. Consequently, another 112 participants were enrolled at the New Zealand based investigational site.

    Pre-assignment
    Screening details
    		 There were six screening failures, five from NAR < 0.25 Pa/cm3/sec, and one due to potential for tachycardia.

    Period 1
    Period 1 title
    Treatment period
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator
    Blinding implementation details
    Double blinding was achieved by the use of matching tablets and capsules packaged into identical blisters and cardboard outer containers. Two placebos were used in this study in a double dummy design. Two white capsules enabled double blinding of the study drugs provided by AFT Pharmaceuticals (Maxigesic® PE 2.5 and MaxiclearTM PE 3.0), and a yellow capsule enabled double blinding of the Sudafed® Blocked Nose capsules.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Maxigesic® PE 2.5
    Arm description
    		 Paracetamol 1000 mg + ibuprofen 300 mg + phenylephrine hydrochloride 5 mg (administered as 2 tablets of Maxigesic® PE 2.5) + 1 Placebo Capsule
    Arm type
    		 Experimental

    Investigational medicinal product name
    Maxigesic PE 2.5
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Two tablets every 4 hours

    Arm title
    		 Maxiclear PE 3.0
    Arm description
    		 Paracetamol 1000 mg + phenylephrine hydrochloride 6 mg /dose (administered as 2 tablets of Maxiclear™ PE 3.0) + 1 Placebo Capsule
    Arm type
    		 Experimental

    Investigational medicinal product name
    Maxiclear PE 3.0
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Two tablets every 4 hours

    Arm title
    		 Sudafed
    Arm description
    		 Phenylephrine hydrochloride 12 mg (Sudafed® Blocked Nose – 1 Capsule) + 2 Placebo tablets
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Sudafed Blocked Nose
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    One capsule every 4 hours

    Arm title
    		 Placebo
    Arm description
    		 Placebo (2 Placebo tablets + 1 Placebo capsule)
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Two tablets and one capsule every 4 hours

    Number of subjects in period 1
    		Maxigesic® PE 2.5 Maxiclear PE 3.0 Sudafed Placebo
    Started
    76
    76
    75
    50
    Completed
    76
    76
    75
    50
    Period 2
    Period 2 title
    Screening and randomization
    Is this the baseline period?
    		 Yes [1]
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator
    Blinding implementation details
    Double blinding was achieved by the use of matching tablets and capsules packaged into identical blisters and cardboard outer containers. Two placebos were used in this study in a double dummy design. Two white capsules enabled double blinding of the study drugs provided by AFT Pharmaceuticals (Maxigesic® PE 2.5 and MaxiclearTM PE 3.0), and a yellow capsule enabled double blinding of the Sudafed® Blocked Nose capsules.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Maxigesic® PE 2.5
    Arm description
    		 Paracetamol 1000 mg + ibuprofen 300 mg + phenylephrine hydrochloride 5 mg (administered as 2 tablets of Maxigesic® PE 2.5) + 1 Placebo Capsule
    Arm type
    		 Experimental

    Investigational medicinal product name
    Maxigesic PE 2.5
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Two tablets every 4 hours

    Arm title
    		 Maxiclear PE 3.0
    Arm description
    		 Paracetamol 1000 mg + phenylephrine hydrochloride 6 mg /dose (administered as 2 tablets of Maxiclear™ PE 3.0) + 1 Placebo Capsule
    Arm type
    		 Experimental

    Investigational medicinal product name
    Maxiclear PE 3.0
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Two tablets every 4 hours

    Arm title
    		 Sudafed
    Arm description
    		 Phenylephrine hydrochloride 12 mg (Sudafed® Blocked Nose – 1 Capsule) + 2 Placebo tablets
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Sudafed Blocked Nose
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    One capsule every 4 hours

    Arm title
    		 Placebo
    Arm description
    		 Placebo (2 Placebo tablets + 1 Placebo capsule)
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Two tablets and one capsule every 4 hours

    Notes
    [1] - Period 1 is not the baseline period. It is expected that period 1 will be the baseline period.
    Justification: Periods were entered in the wrong order. They can not be reordered without affecting other completed forms.
    Number of subjects in period 2
    		Maxigesic® PE 2.5 Maxiclear PE 3.0 Sudafed Placebo
    Started
    76
    76
    75
    50
    Completed
    76
    76
    75
    50

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Maxigesic® PE 2.5
    Reporting group description
    		 Paracetamol 1000 mg + ibuprofen 300 mg + phenylephrine hydrochloride 5 mg (administered as 2 tablets of Maxigesic® PE 2.5) + 1 Placebo Capsule

    Reporting group title
    Maxiclear PE 3.0
    Reporting group description
    		 Paracetamol 1000 mg + phenylephrine hydrochloride 6 mg /dose (administered as 2 tablets of Maxiclear™ PE 3.0) + 1 Placebo Capsule

    Reporting group title
    Sudafed
    Reporting group description
    		 Phenylephrine hydrochloride 12 mg (Sudafed® Blocked Nose – 1 Capsule) + 2 Placebo tablets

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo (2 Placebo tablets + 1 Placebo capsule)

    Reporting group values
    		 Maxigesic® PE 2.5 Maxiclear PE 3.0 Sudafed Placebo Total
    Number of subjects
    		 76 76 75 50 277
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 76 76 75 50 277
    Gender categorical
    Units: Subjects
        Female
    		 43 45 51 32 171
        Male
    		 33 31 24 18 106

    End points

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    End points reporting groups
    Reporting group title
    Maxigesic® PE 2.5
    Reporting group description
    		 Paracetamol 1000 mg + ibuprofen 300 mg + phenylephrine hydrochloride 5 mg (administered as 2 tablets of Maxigesic® PE 2.5) + 1 Placebo Capsule

    Reporting group title
    Maxiclear PE 3.0
    Reporting group description
    		 Paracetamol 1000 mg + phenylephrine hydrochloride 6 mg /dose (administered as 2 tablets of Maxiclear™ PE 3.0) + 1 Placebo Capsule

    Reporting group title
    Sudafed
    Reporting group description
    		 Phenylephrine hydrochloride 12 mg (Sudafed® Blocked Nose – 1 Capsule) + 2 Placebo tablets

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo (2 Placebo tablets + 1 Placebo capsule)
    Reporting group title
    Maxigesic® PE 2.5
    Reporting group description
    		 Paracetamol 1000 mg + ibuprofen 300 mg + phenylephrine hydrochloride 5 mg (administered as 2 tablets of Maxigesic® PE 2.5) + 1 Placebo Capsule

    Reporting group title
    Maxiclear PE 3.0
    Reporting group description
    		 Paracetamol 1000 mg + phenylephrine hydrochloride 6 mg /dose (administered as 2 tablets of Maxiclear™ PE 3.0) + 1 Placebo Capsule

    Reporting group title
    Sudafed
    Reporting group description
    		 Phenylephrine hydrochloride 12 mg (Sudafed® Blocked Nose – 1 Capsule) + 2 Placebo tablets

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo (2 Placebo tablets + 1 Placebo capsule)

    Primary: Area Under the Curve of Nasal Airflow Conductance

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    End point title
    		 Area Under the Curve of Nasal Airflow Conductance
    End point description
    End point type
    Primary
    End point timeframe
    0-4 hours after the first does of study medication
    End point values
    		 Maxigesic® PE 2.5 Maxiclear PE 3.0 Sudafed Placebo
    Number of subjects analysed
    76
    76
    75
    50
    Units: AUC NAC
        arithmetic mean (standard error)
    905.3 ± 274.7
    901.4 ± 274
    922.3 ± 273.8
    872 ± 232.4
    Statistical analysis title
    		 ANCOVA
    Statistical analysis description
    Between-treatment differences were tested by means of a one-way analysis of covariance (ANCOVA) model with treatment as a factor and the corresponding baseline (Hour 0, Day 1) value as a covariate
    Comparison groups
    Placebo v Sudafed v Maxiclear PE 3.0 v Maxigesic® PE 2.5
    Number of subjects included in analysis
    277
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 ≤ 0.05
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Confidence interval
    Variability estimate
    Standard error of the mean

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Day 1-2 of study
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    20.0
    Reporting groups
    Reporting group title
    Maxigesic® PE 2.5
    Reporting group description
    		 Paracetamol 1000 mg + ibuprofen 300 mg + phenylephrine hydrochloride 5 mg (administered as 2 tablets of Maxigesic® PE 2.5) + 1 Placebo Capsule

    Reporting group title
    Maxiclear PE 3.0
    Reporting group description
    		 Paracetamol 1000 mg + phenylephrine hydrochloride 6 mg /dose (administered as 2 tablets of Maxiclear™ PE 3.0) + 1 Placebo Capsule

    Reporting group title
    Sudafed
    Reporting group description
    		 Phenylephrine hydrochloride 12 mg (Sudafed® Blocked Nose – 1 Capsule) + 2 Placebo tablets

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo (2 Placebo tablets + 1 Placebo capsule)

    Serious adverse events
    		 Maxigesic® PE 2.5 Maxiclear PE 3.0 Sudafed Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 76 (0.00%)
    0 / 75 (0.00%)
    0 / 50 (0.00%)
         number of deaths (all causes)
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Maxigesic® PE 2.5 Maxiclear PE 3.0 Sudafed Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    9 / 76 (11.84%)
    9 / 76 (11.84%)
    4 / 75 (5.33%)
    4 / 50 (8.00%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 76 (0.00%)
    0 / 75 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Somnolence
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 76 (0.00%)
    0 / 75 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Dizziness
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 76 (0.00%)
    0 / 75 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    0
    0
    1
    Migraine
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 76 (0.00%)
    1 / 75 (1.33%)
    0 / 50 (0.00%)
         occurrences all number
    0
    0
    1
    0
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    2 / 76 (2.63%)
    0 / 76 (0.00%)
    1 / 75 (1.33%)
    0 / 50 (0.00%)
         occurrences all number
    2
    0
    1
    0
    Gastrointestinal disorders
    Dyspepsia
         subjects affected / exposed
    1 / 76 (1.32%)
    1 / 76 (1.32%)
    0 / 75 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    1
    1
    0
    0
    Gastroesophageal reflux disease
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 76 (1.32%)
    0 / 75 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Diarrhea
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 76 (1.32%)
    0 / 75 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Nausea
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 76 (0.00%)
    0 / 75 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Abdominal pain upper
         subjects affected / exposed
    2 / 76 (2.63%)
    0 / 76 (0.00%)
    0 / 75 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    2
    0
    0
    1
    Feces soft
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 76 (0.00%)
    0 / 75 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    0
    0
    1
    Abdominal pain lower
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 76 (0.00%)
    0 / 75 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    0
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Epistaxis
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 76 (0.00%)
    1 / 75 (1.33%)
    1 / 50 (2.00%)
         occurrences all number
    0
    0
    1
    1
    Nasal congestion
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 76 (1.32%)
    0 / 75 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Nasal discomfort
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 76 (1.32%)
    0 / 75 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Dry throat
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 76 (0.00%)
    0 / 75 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    0
    0
    1
    Cough
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 76 (1.32%)
    0 / 75 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Skin and subcutaneous tissue disorders
    Dry skin
         subjects affected / exposed
    1 / 76 (1.32%)
    1 / 76 (1.32%)
    0 / 75 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    1
    1
    0
    0
    Psychiatric disorders
    Agitation
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 76 (0.00%)
    0 / 75 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 76 (0.00%)
    0 / 75 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Infections and infestations
    Conjunctivitis
         subjects affected / exposed
    0 / 76 (0.00%)
    2 / 76 (2.63%)
    0 / 75 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Ear infection
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 76 (1.32%)
    0 / 75 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Oral herpes
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 76 (0.00%)
    1 / 75 (1.33%)
    0 / 50 (0.00%)
         occurrences all number
    0
    0
    1
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    24 Mar 2017
    Premature closure of the Cardiff Investigational site interrupted the trial and led to the opening of the New Zealand trial site.
    07 Jun 2017

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    Participants were required to have a cold in order to participate in the trial. The common cold is self-limiting, with symptoms lasting 7-10 days, peaking on day two or three.
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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