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    Clinical Trial Results:
    Efficacy and safety of the combination of ibuprofen and paracetamol versus ibuprofen in monotherapy in acute Low Back Pain (LBP)

    Summary
    EudraCT number
    		 2020-005278-86
    Trial protocol
    		 IT   PL  
    Global end of trial date
    05 Oct 2022

    Results information
    Results version number
    		 v1(current)
    This version publication date
    09 May 2024
    First version publication date
    09 May 2024
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    147(Z)WO20157
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT05222724
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Angelini Pharma S.p.A
    Sponsor organisation address
    Via Amelia 70, Rome, Italy, 00181
    Public contact
    Martina Barcaroli, Angelini Pharma S.p.A., +39 3472274815, martina.barcaroli@angelinipharma.com
    Scientific contact
    Martina Barcaroli, Angelini Pharma S.p.A., +39 3472274815, martina.barcaroli@angelinipharma.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
    05 Oct 2022
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    05 Oct 2022
    Global end of trial reached?
    Yes
    Global end of trial date
    05 Oct 2022
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of the study is to assess the pain improvement in patients with uncomplicated non-specific acute low back pain after a 3-day treatment period with paracetamol/ibuprofen FDC compared to ibuprofen.
    Protection of trial subjects
    The study was conducted, in compliance with the protocol, regulatory requirements, good clinical practice (GCP) (including up-to-date versions) and the ethical principles of the latest revision of the Declaration of Helsinki as adopted by the World Medical Association. All patients provided written informed consent to participate in the study before any study-related procedures. The patients were given a copy of the ICF for their information. The original copy of the informed consent was kept in a confidential file in the Investigator’s site records. Patients were also informed by the Investigator of all aspects related to their personal data processing, as well as their rights on this matter.
    Background therapy
    		 Not applicable
    Evidence for comparator
    		 The Reference was Ibuprofen 600 mg film-coated tablets (Brufen 600 mg film-coated tablets) that is a NSAIDs effective to relieve the pain and to improve functionality in the treatment of Low Back Pain (LBP).
    Actual start date of recruitment
    26 Oct 2021
    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
    Poland: 170
    Country: Number of subjects enrolled
    Italy: 5
    Worldwide total number of subjects
    175
    EEA total number of subjects
    175
    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)
    174
    From 65 to 84 years
    1
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 A total of 179 patients were enrolled and 175 of them were randomized 1:1 to one of the following two treatment groups: Group 1: paracetamol 500 mg/ibuprofen 150 mg and Group 2: ibuprofen 600 mg and 3 patients of 175 didn't assume any dose of study treatment. A total of 172 patients were treated.

    Pre-assignment
    Screening details
    		 The Investigator assigned to patients fulfilling eligibility criteria the randomization number, by removing the upper layer of the label of the first available randomization number on the Randomization Label Form, where the assigned treatment was indicated.

    Period 1
    Period 1 title
    OVERAL TRIAL (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded
    Blinding implementation details
    Not applicable. This was an open-label study

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Test: Tachifene 500mg/150mg
    Arm description
    		 Subjects treated with the Fixed-Dose Combination (FDC) of 500 mg/ibuprofen 150 mg, two film-coated tablets (Tachifene® 500 mg/150 mg)
    Arm type
    		 Experimental

    Investigational medicinal product name
    Paracetamol 500 mg/ ibuprofen 150 mg
    Investigational medicinal product code
    Sponsor code 147(Z)
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    The patient took two tablets 3 times daily for 3 days (i.e., every 8 hours ± 1 hour) until Day 3 (± 1) according to the relevant Summary of Product Characteristics (SmPC). Tablets were swallowed without chewing. Ingestion could be helped by a small amount of water.

    Arm title
    		 Reference: Brufen 600 mg
    Arm description
    		 Subjects treated with Ibuprofen 600 mg (Brufen 600 mg film-coated tablets).
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Ibuprofen 600 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    The patient took one tablet of Ibuprofen 600 mg 3 times daily for 3 days (i.e., every 8 hours ± 1 hour). Tablets were swallowed without chewing. Ingestion could be helped by a small amount of water.

    Number of subjects in period 1
    		Test: Tachifene 500mg/150mg Reference: Brufen 600 mg
    Started
    87
    88
    Completed
    82
    85
    Not completed
    5
    3
         Patient requests to be excluded from the study (in
    -
    1
         Additional therapy for LBP
    1
    -
         Lost to follow-up
    3
    -
         Protocol deviation
    1
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    OVERAL TRIAL
    Reporting group description
    		 -

    Reporting group values
    		 OVERAL TRIAL Total
    Number of subjects
    		 175 175
    Age categorical
    Patients with uncomplicated and localized acute LBP or acute exacerbation of chronic LBP (not radiating below the gluteal fold), with moderate/severe pain at baseline. Minimum visual analogue scale (VAS) score ≥ 40 mm at screening visit.
    Units: Subjects
        In utero
    		 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0
        Newborns (0-27 days)
    		 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0
        Children (2-11 years)
    		 0 0
        Adolescents (12-17 years)
    		 0 0
        Adults (18-64 years)
    		 174 174
        From 65-84 years
    		 1 1
        85 years and over
    		 0 0
    Gender categorical
    Male and female patients of any ethnic origin between 18 and 64 years of age (limits included)
    Units: Subjects
        Female
    		 102 102
        Male
    		 73 73
    Subject analysis sets

    Subject analysis set title
    Safety population (SP)
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    The Safety Population (SP) was defined as all randomized patients who took at least one dose of the study medication.

    Subject analysis set title
    m-ITT population
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    The modified Intention-to-Treat (m-ITT) population: all randomized patients who took at least one dose of the study medication and had at least baseline (Day 0) and one post baseline evaluation on the LBP assessment. The Last Observation Carried Forward (LOCF) method was implemented as imputation scheme for missing data in the m-ITT population.

    Subject analysis set title
    PP Population
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    The PP population was defined as all randomized patients who took at least one dose of the study medication and had at least baseline (Day 0), Day 4 (± 1) and Day 8 (± 1) evaluations on the LBP assessment, with no major protocol violations.

    Subject analysis sets values
    		 Safety population (SP) m-ITT population PP Population
    Number of subjects
    172
    171
    152
    Age categorical
    Patients with uncomplicated and localized acute LBP or acute exacerbation of chronic LBP (not radiating below the gluteal fold), with moderate/severe pain at baseline. Minimum visual analogue scale (VAS) score ≥ 40 mm at screening visit.
    Units: Subjects
        In utero
    0
    0
    0
        Preterm newborn infants (gestational age < 37 wks)
    0
    0
    0
        Newborns (0-27 days)
    0
    0
    0
        Infants and toddlers (28 days-23 months)
    0
    0
    0
        Children (2-11 years)
    0
    0
    0
        Adolescents (12-17 years)
    0
    0
    0
        Adults (18-64 years)
    171
    170
    151
        From 65-84 years
    1
    1
    1
        85 years and over
    0
    0
    0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    ( )
    ( )
    ( )
    Gender categorical
    Male and female patients of any ethnic origin between 18 and 64 years of age (limits included)
    Units: Subjects
        Female
    100
    99
        Male
    72
    72

    End points

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    End points reporting groups
    Reporting group title
    Test: Tachifene 500mg/150mg
    Reporting group description
    		 Subjects treated with the Fixed-Dose Combination (FDC) of 500 mg/ibuprofen 150 mg, two film-coated tablets (Tachifene® 500 mg/150 mg)

    Reporting group title
    Reference: Brufen 600 mg
    Reporting group description
    		 Subjects treated with Ibuprofen 600 mg (Brufen 600 mg film-coated tablets).

    Subject analysis set title
    Safety population (SP)
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    The Safety Population (SP) was defined as all randomized patients who took at least one dose of the study medication.

    Subject analysis set title
    m-ITT population
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    The modified Intention-to-Treat (m-ITT) population: all randomized patients who took at least one dose of the study medication and had at least baseline (Day 0) and one post baseline evaluation on the LBP assessment. The Last Observation Carried Forward (LOCF) method was implemented as imputation scheme for missing data in the m-ITT population.

    Subject analysis set title
    PP Population
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    The PP population was defined as all randomized patients who took at least one dose of the study medication and had at least baseline (Day 0), Day 4 (± 1) and Day 8 (± 1) evaluations on the LBP assessment, with no major protocol violations.

    Primary: SPID 0-3 days

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    End point title
    		 SPID 0-3 days
    End point description
    The primary endpoint was the area under the pain intensity difference-versus-time curve of LBP scores up to three days of treatment (sum of the pain intensity differences [SPID] 0-3 days). The pain intensity difference was considered the difference in visual analogue scale (VAS) pain intensity between one time point and the baseline. The SPID was the sum of the average of two consecutive pain intensity differences multiplied by the time-interval between two time points.
    End point type
    Primary
    End point timeframe
    0-3 days
    End point values
    		 Test: Tachifene 500mg/150mg Reference: Brufen 600 mg
    Number of subjects analysed
    83 [1]
    88 [2]
    Units: number
        arithmetic mean (standard deviation)
    -45.18 ( 33.01 )
    -40.96 ( 29.65 )
    Attachments
    		 Additional Results (Secondary end points)
    Notes
    [1] - Subjects beloning to m-IIT population
    [2] - Subjects belonging m-ITT population
    Statistical analysis title
    		 ANCOVA
    Statistical analysis description
    ANCOVA model with center and baseline as covariates
    Comparison groups
    Test: Tachifene 500mg/150mg v Reference: Brufen 600 mg
    Number of subjects included in analysis
    171
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1038
    Method
    		 ANCOVA
    Confidence interval

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From 26 October 2021 to 5 October 2022
    Adverse event reporting additional description
    The AEs are divided into two categories, based on the time of AE occurrence: Pre-treatment adverse events (PTAE) and treatment-emergent adverse events (TEAE). Only TEAE as any AE occurring or worsening after the first dose of a medicinal product are reported
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    23.1
    Reporting groups
    Reporting group title
    Reference: Brufen 600mg
    Reporting group description
    		 -

    Reporting group title
    Test: Tachifene 500mg/150mg
    Reporting group description
    		 -

    Serious adverse events
    		 Reference: Brufen 600mg Test: Tachifene 500mg/150mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 84 (0.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Frequency threshold for reporting non-serious adverse events: 2%
    Non-serious adverse events
    		 Reference: Brufen 600mg Test: Tachifene 500mg/150mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    23 / 88 (26.14%)
    19 / 84 (22.62%)
    Investigations
    Aspartate
         subjects affected / exposed
    0 / 88 (0.00%)
    1 / 84 (1.19%)
         occurrences all number
    0
    1
    Blood triglycerides increased
         subjects affected / exposed
    0 / 88 (0.00%)
    1 / 84 (1.19%)
         occurrences all number
    0
    1
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    1 / 88 (1.14%)
    0 / 84 (0.00%)
         occurrences all number
    1
    0
    Urine phosphorus abnormal
         subjects affected / exposed
    1 / 88 (1.14%)
    0 / 84 (0.00%)
         occurrences all number
    1
    0
    Injury, poisoning and procedural complications
    Intentional product misuse
         subjects affected / exposed
    0 / 88 (0.00%)
    1 / 84 (1.19%)
         occurrences all number
    0
    1
    Medication error
         subjects affected / exposed
    2 / 88 (2.27%)
    3 / 84 (3.57%)
         occurrences all number
    2
    3
    Overdose
         subjects affected / exposed
    1 / 88 (1.14%)
    3 / 84 (3.57%)
         occurrences all number
    1
    3
    Vascular disorders
    Hypertension
         subjects affected / exposed
    1 / 88 (1.14%)
    0 / 84 (0.00%)
         occurrences all number
    1
    0
    Nervous system disorders
    Headache
         subjects affected / exposed
    4 / 88 (4.55%)
    0 / 84 (0.00%)
         occurrences all number
    4
    0
    Migraine
         subjects affected / exposed
    0 / 88 (0.00%)
    1 / 84 (1.19%)
         occurrences all number
    0
    1
    Somnolence
         subjects affected / exposed
    1 / 88 (1.14%)
    2 / 84 (2.38%)
         occurrences all number
    1
    2
    Blood and lymphatic system disorders
    Iron deficiency anaemia
         subjects affected / exposed
    1 / 88 (1.14%)
    0 / 84 (0.00%)
         occurrences all number
    1
    0
    Thrombocytopenia
         subjects affected / exposed
    1 / 88 (1.14%)
    0 / 84 (0.00%)
         occurrences all number
    1
    0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    0 / 88 (0.00%)
    1 / 84 (1.19%)
         occurrences all number
    0
    1
    Feeling cold
         subjects affected / exposed
    0 / 88 (0.00%)
    1 / 84 (1.19%)
         occurrences all number
    0
    1
    Swelling face
         subjects affected / exposed
    0 / 88 (0.00%)
    1 / 84 (1.19%)
         occurrences all number
    0
    1
    Eye disorders
    Eyelid oedema
         subjects affected / exposed
    0 / 88 (0.00%)
    1 / 84 (1.19%)
         occurrences all number
    0
    1
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    2 / 88 (2.27%)
    1 / 84 (1.19%)
         occurrences all number
    2
    1
    Abdominal pain lower
         subjects affected / exposed
    1 / 88 (1.14%)
    0 / 84 (0.00%)
         occurrences all number
    1
    0
    Abdominal pain upper
         subjects affected / exposed
    3 / 88 (3.41%)
    1 / 84 (1.19%)
         occurrences all number
    3
    1
    Diarrhoea
         subjects affected / exposed
    3 / 88 (3.41%)
    0 / 84 (0.00%)
         occurrences all number
    3
    0
    Dry mouth
         subjects affected / exposed
    0 / 88 (0.00%)
    1 / 84 (1.19%)
         occurrences all number
    0
    1
    Dyspepsia
         subjects affected / exposed
    1 / 88 (1.14%)
    0 / 84 (0.00%)
         occurrences all number
    1
    0
    Flatulence
         subjects affected / exposed
    1 / 88 (1.14%)
    0 / 84 (0.00%)
         occurrences all number
    1
    0
    Haemorrhoids
         subjects affected / exposed
    0 / 88 (0.00%)
    1 / 84 (1.19%)
         occurrences all number
    0
    1
    Nausea
         subjects affected / exposed
    3 / 88 (3.41%)
    0 / 84 (0.00%)
         occurrences all number
    3
    0
    Oesophageal discomfort
         subjects affected / exposed
    0 / 88 (0.00%)
    1 / 84 (1.19%)
         occurrences all number
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Sinus p
         subjects affected / exposed
    1 / 88 (1.14%)
    0 / 84 (0.00%)
         occurrences all number
    1
    0
    Throat irritation
         subjects affected / exposed
    1 / 88 (1.14%)
    0 / 84 (0.00%)
         occurrences all number
    1
    0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    1 / 88 (1.14%)
    1 / 84 (1.19%)
         occurrences all number
    1
    1
    Infections and infestations
    COVID-19
         subjects affected / exposed
    1 / 88 (1.14%)
    0 / 84 (0.00%)
         occurrences all number
    1
    0
    Oral herpes
         subjects affected / exposed
    1 / 88 (1.14%)
    0 / 84 (0.00%)
         occurrences all number
    1
    0
    Respiratory tract infection
         subjects affected / exposed
    0 / 88 (0.00%)
    1 / 84 (1.19%)
         occurrences all number
    0
    1
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 88 (1.14%)
    2 / 84 (2.38%)
         occurrences all number
    1
    2
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    0 / 88 (0.00%)
    1 / 84 (1.19%)
         occurrences all number
    0
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    11 Mar 2022
    The substantial amendment (Amendment nº 7 of 11/Mar/2022 ) was made after first patient enrolled in the study. According to the opinion of the Investigators involved in the study and after a careful analysis performed by the Sponsor, a few exclusion criteria ( n. 7, 8 and 9) were better detailed for the definition of patients’ eligibility. Hungary was deleted from the countries involved in the clinical study. In addition, some changes for safety reasons (related to the difficulty for patients to step up on the platform) were done to modify the procedure for patient mobility restriction assessment. The description of the “PGIC scale” was aligned with the validated one effectively submitted for the study.

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
    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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