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    Summary
    EudraCT Number:2018-001100-11
    Sponsor's Protocol Code Number:14/0644
    National Competent Authority:UK - MHRA
    Clinical Trial Type:EEA CTA
    Trial Status:GB - no longer in EU/EEA
    Date on which this record was first entered in the EudraCT database:2018-06-08
    Trial results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedUK - MHRA
    A.2EudraCT number2018-001100-11
    A.3Full title of the trial
    Defining best Management in Adult Chronic RhinOsinusitis
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Defining Best Management in Adult Chronic RhinOsinusitis (MACRO) Trial
    A.3.2Name or abbreviated title of the trial where available
    The MACRO Trial
    A.4.1Sponsor's protocol code number14/0644
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorUniversity College London
    B.1.3.4CountryUnited Kingdom
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportNational Institute of Health Research (NIHR): Programme Grant for Applied Research Stream (PGfAR)
    B.4.2CountryUnited Kingdom
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationUniversity of Oxford
    B.5.2Functional name of contact pointSteffi le Conte
    B.5.3 Address:
    B.5.3.1Street AddressBotnar Research Centre, Old Road, Headington
    B.5.3.2Town/ cityOld Road, Headington
    B.5.3.3Post codeOX3 7LD
    B.5.3.4CountryUnited Kingdom
    B.5.4Telephone number01865737961
    B.5.6E-mailmacrotrial@nds.ox.ac.uk
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Clarithromycin
    D.2.1.1.2Name of the Marketing Authorisation holderAptil Pharma
    D.2.1.2Country which granted the Marketing AuthorisationUnited Kingdom
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameClarithromycin
    D.3.4Pharmaceutical form Capsule
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNClarithromycin
    D.3.9.1CAS number 81103-11-9
    D.3.9.3Other descriptive nameN/A
    D.3.9.4EV Substance CodeAS1
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number250 to mgs
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboCapsule
    D.8.4Route of administration of the placeboOral use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Chronic rhinosinusitis
    E.1.1.1Medical condition in easily understood language
    Chronic rhinosinusitis
    E.1.1.2Therapeutic area Diseases [C] - Ear, nose and throat diseases [C09]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10052106
    E.1.2Term Rhinosinusitis
    E.1.2System Organ Class 10021881 - Infections and infestations
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.1
    E.1.2Level PT
    E.1.2Classification code 10009137
    E.1.2Term Chronic sinusitis
    E.1.2System Organ Class 10021881 - Infections and infestations
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.1
    E.1.2Level PT
    E.1.2Classification code 10009137
    E.1.2Term Chronic sinusitis
    E.1.2System Organ Class 10021881 - Infections and infestations
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.1
    E.1.2Level LLT
    E.1.2Classification code 10009141
    E.1.2Term Chronic sinusitis, unspecified
    E.1.2System Organ Class 10021881 - Infections and infestations
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10031748
    E.1.2Term Other chronic sinusitis
    E.1.2System Organ Class 10021881 - Infections and infestations
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.1
    E.1.2Level LLT
    E.1.2Classification code 10009138
    E.1.2Term Chronic sinusitis, ethmoidal
    E.1.2System Organ Class 10021881 - Infections and infestations
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10009139
    E.1.2Term Chronic sinusitis, other
    E.1.2System Organ Class 10021881 - Infections and infestations
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.1
    E.1.2Level LLT
    E.1.2Classification code 10009140
    E.1.2Term Chronic sinusitis, sphenoidal
    E.1.2System Organ Class 10021881 - Infections and infestations
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To establish the comparative effectiveness of a prolonged course of antibiotics (clarithromycin) or endoscopic sinus surgery (ESS) in adult patients with CRS in terms of symptomatic improvement and costs to the NHS and patients, compared with standard medical care and each other at six months.
    E.2.2Secondary objectives of the trial
    • Measure clinical effectiveness using subjective self-reporting ratings and objective clinical measures
    • Compare the clinical effectiveness according to phenotype (CRSwNPs/CRSsNPs)
    • Record the incidence and details of adverse events in all treatment arms related to the trial medication or surgery intervention
    • Establish the cost effectiveness and cost utility over the 6 month trial duration
    • Embed a mixed methods evaluation into the main trial to identify factors and processes necessary for implementation of trial findings

    Internal recruitment pilot phase objectives
    • To randomise 72 participants at 6 pilot sites within 6 months. Recruitment will be deemed successful if ≥75% of expected, i.e. 54 patients are recruited
    • Undertake a MACRO Conversation Study (using qualitative methods) during the pilot phase to identify recruitment challenges and optimize recruitment during the main trial phase.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    • Adults aged 18 and over with a diagnosis of CRS according to European guidelines:
    *A minimum of 12 weeks history of inflammation of the nose and paranasal sinuses characterised by two or more symptoms, one of which should be either nasal blockage/obstruction/ congestion or nasal discharge (anterior/posterior nasal drip):
    - ± facial pain/pressure
    - ± reduction or loss of smell
    • Nasal endoscopy (within last 3 months) to determine CRS diagnosis and phenotype (CRSwNPs or CRSsNPs)
    • Non-contrast CT scan (within last 12 months) to determine Lund-Mackay score and confirm suitability for ESS
    • Moderate/severe symptoms; SNOT-22 score ≥ 20 within last 3 months
    • Symptom control not achieved following previous AMT, as deemed by the local Principal Investigator (PI) or Co-Investigator (Co-I), and therefore considered eligible for ESS
    • An understanding of the English language sufficient to understand written and verbal information about the trial, its consent process and the study questionnaires
    E.4Principal exclusion criteria
    • Lund-Mackay non-contrast CT scan score < 4
    • Macrolide antibiotic treatment for > 3 continuous weeks’ duration within the last 12 months
    • ESS in previous 6 months or visible, open sinus cavities from previous surgery
    • Maintenance oral steroids or biologics
    • Rare/complex sinus conditions:
    *CRS secondary to systemic disease - cystic fibrosis, granulomatous diseases
    *Suspected malignancy
    • Allergic fungal rhinosinusitis confirmed or suspected on CT imaging (expansion and mixed density opacification) necessitating immediate surgery
    • Severe asthma (high doses of inhaled steroids i.e. >1.5mg per day)
    • Females who are pregnant or breastfeeding, females of reproductive potential not prepared to use a reliable means of contraception (e.g. hormonal contraceptive patch, intrauterine device, physical barrier or abstinence, if preferred and usual lifestyle of the patient) at trial entry or those females wanting to start a family during the initial 3 months of the trial
    • Known immunodeficiency states including HIV and selective and multiple antibody deficiency states
    • Severe septal deviation preventing endoscopic examination
    • Contraindications to surgery (significant medical co-morbidity)
    • Any absolute contraindications to clarithromycin (risk factors to be assessed at screening include history of ischaemic heart disease, prolonged Q-T interval on ECG, diabetes and age over 65 or any medications known to interact with clarithromycin unless these can be discontinued during the 3 months of clarithromycin/placebo treatment)
    • Known allergies to the IMP and excipients of IMP and placebo
    • Inability to give consent (significant cognitive impairment or language issues), or to understand and comply with trial instructions
    • Participation in another Randomized Clinical Trial in the past 4 months
    E.5 End points
    E.5.1Primary end point(s)
    Disease-specific health related quality of life (HRQoL) using the SNOT-22 Patient Reported Outcome Measure (PROM) Questionnaire at six months
    E.5.1.1Timepoint(s) of evaluation of this end point
    Baseline, 6 weeks, 3 and 6 months. Those participants who opted to be followed-up on a long term basis will be contacted annually for a further 5 years after completing the trial.
    E.5.2Secondary end point(s)
    • Endoscopic score, including grade of polyps (0 – 3) if present (Lund-Kennedy Score)
    • Health-related quality of life and quality-adjusted life-years (QALYs), measured by the SF-12 and EQ-5D-5L questionnaires
    • Need for rescue oral steroids or antibiotic use for acute exacerbations, recorded by patient diaries
    • Olfactory function measured using Sniffin’ Sticks
    • Upper and lower respiratory function, measured using peak expiratory flow rate, peak nasal inspiratory flow rate
    • Treatment needed to control symptomatic reversible airway disease, measured using the Asthma Control Test
    • Adverse effects of treatment and readmissions relating to allocated treatment
    • Healthcare resource use, including medications and visits to primary and secondary care, recorded using patient diaries
    • Days of work missed, recorded using patient diaries
    • Overall cost and incremental cost per quality-adjusted life-year gained, from the cost perspective of the NHS and PSS, calculated using quality of life scores
    • Budget impact of treatment
    E.5.2.1Timepoint(s) of evaluation of this end point
    Baseline, weekly, 6 weeks, 3 and 6 months. Those participants who opted to be followed-up on a long term basis will be contacted annually for a further 5 years after completing the trial.
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety No
    E.6.5Efficacy No
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) Yes
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo Yes
    E.8.2.3Other Yes
    E.8.2.3.1Comparator description
    Endoscopic sinus surgery
    E.8.2.4Number of treatment arms in the trial3
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned17
    E.8.5The trial involves multiple Member States No
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.7Trial has a data monitoring committee Yes
    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
    The expected duration of recruitment and follow-up for the primary outcome data collection point is the trial is 52 months from recruitment of the first patient. For regulatory purposes the trial will be deemed ended on the date when all data has been received, cleaned and queries have been resolved at site.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years4
    E.8.9.1In the Member State concerned months5
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years4
    E.8.9.2In all countries concerned by the trial months5
    E.8.9.2In all countries concerned by the trial days0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1Number of subjects for this age range: 0
    F.1.1.1In Utero No
    F.1.1.1.1Number of subjects for this age range: 0
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.2.1Number of subjects for this age range: 0
    F.1.1.3Newborns (0-27 days) No
    F.1.1.3.1Number of subjects for this age range: 0
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.4.1Number of subjects for this age range: 0
    F.1.1.5Children (2-11years) No
    F.1.1.5.1Number of subjects for this age range: 0
    F.1.1.6Adolescents (12-17 years) No
    F.1.1.6.1Number of subjects for this age range: 0
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 500
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 100
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations No
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception No
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state600
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 600
    F.4.2.2In the whole clinical trial 600
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    At the end of each trial participant's follow-up period of 6 months, the participant will return to normal NHS care. If at the end of the trial the participant has not had any improvement in their CRS, they can discuss with their ENT doctor what course of treatment is best for them next.Participants allocated to medical treatment will not be told if they had clarithromycin or placebo capsules, except in the case of an emergency.
    G. Investigator Networks to be involved in the Trial
    G.4 Investigator Network to be involved in the Trial: 1
    G.4.1Name of Organisation North Thames CRN
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2018-07-13
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2018-07-11
    P. End of Trial
    P.End of Trial StatusGB - no longer in EU/EEA
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