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    Summary
    EudraCT Number:2013-001490-25
    Sponsor's Protocol Code Number:3/016/13
    National Competent Authority:UK - MHRA
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2013-08-13
    Trial results View 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 number2013-001490-25
    A.3Full title of the trial
    A randomised, double-blind placebo controlled trial of the effectiveness of low dose oral theophylline as an adjunct to inhaled corticosteroids in preventing exacerbations of chronic obstructive pulmonary disease
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    TWICS - Theophylline with Inhaled Corticosteroids
    A.3.2Name or abbreviated title of the trial where available
    TWICS - Theophylline with Inhaled Corticosteroid
    A.4.1Sponsor's protocol code number3/016/13
    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 of Aberdeen
    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 HTA Programme
    B.4.2CountryUnited Kingdom
    B.4.1Name of organisation providing supportNapp Pharmaceuticals
    B.4.2CountryUnited Kingdom
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationUniversity of Aberdeen
    B.5.2Functional name of contact pointSeonaidh Cotton
    B.5.3 Address:
    B.5.3.1Street AddressThird Floor, HSB, Foresterhill
    B.5.3.2Town/ cityAberdeen
    B.5.3.3Post codeAB25 2ZD
    B.5.3.4CountryUnited Kingdom
    B.5.4Telephone number01224438178
    B.5.6E-mails.c.cotton@abdn.ac.uk
    B.Sponsor: 2
    B.1.1Name of SponsorNHS Grampian
    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 support
    B.4.2Country
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisation
    B.5.2Functional name of contact point
    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 Theophylline
    D.2.1.1.2Name of the Marketing Authorisation holderNapp Pharmaceuticals Ltd
    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 nameTheophylline
    D.3.4Pharmaceutical form Prolonged-release tablet
    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 INNTheophylline
    D.3.9.1CAS number 58-55-9
    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 number200
    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 placeboTablet
    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 Obstructive Pulmonary Disease (COPD)
    E.1.1.1Medical condition in easily understood language
    Chronic disease of the lungs where the airways narrow over time, limiting the airflow to and from the lungs, and causing shortness of breath
    E.1.1.2Therapeutic area Diseases [C] - Respiratory Tract Diseases [C08]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 16.0
    E.1.2Level PT
    E.1.2Classification code 10009033
    E.1.2Term Chronic obstructive pulmonary disease
    E.1.2System Organ Class 10038738 - Respiratory, thoracic and mediastinal disorders
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    The primary objective is to determine whether adding low-dose theophylline to existing treatment (inhaled corticosteroid therapy) in patients who have chronic obstructive pulmonary disease will reduce the number of exacerbations (or flare-ups) of the condition. If the treatment is effective, we will also assess whether it is cost effective.
    E.2.2Secondary objectives of the trial
    The secondary research objectives are to compare: - hospital admissions with a primary diagnosis of exacerbation of COPD - emergency hospital admissions - lung functon - all-cause and respiratory mortality - drug reactions and serious adverse events - health related quality of life - disease specific health status - total inhaled corticosteroid dose/useage - heath care utilisiation - incremental cost-per-exacerbation avoided - lifetime cost effectiveness based on extrapolation modelling - modelled lifetime incemental cost per Quality Adjusted Life Year
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    • Aged ≥ 40 years. • A smoking history of at least 10 pack years. • An established predominant respiratory diagnosis of COPD (post bronchodilator FEV1/FVC<0.7). • Current use of ICS therapy (irrespective of LABA and/or LAMA use). • A history of at least two exacerbations requiring treatment with antibiotics and/or oral corticosteroid use in the previous year, based on patient report. • Clinically stable with no COPD exacerbation for at least 4 weeks. • Able to swallow study medication. • Able and willing to give informed consent to participate. • Able and willing to participate in the study procedures; undergo spirometric assessment, complete study questionnaire.
    E.4Principal exclusion criteria
    • Severe or unstable ischaemic heart disease. • A predominant respiratory disease other than COPD. • Any other significant disease/disorder which, in the investigator’s opinion, either puts the patient at risk because of study participation or may influence the results of the study or the patient's ability to participate in the study. • Previous allocation of a randomisation code in the study or current participation in another interventional clinical study. • Theophylline use currently. • Known or suspected hypersensitivity to theophylline. • Current use of drugs known to interact with theophylline and/or increase serum theophylline: antimicrobials: aciclovir, clarithromiycin, ciprofloxacin, erythromycin, fluconazole, ketoconazole, levofloxacin, norfloxacin; cardiovascular: diltiazem, mexiletine, pentoxifylline, verapamil; neurological: bupropion, disulfiram, fluvoxamine, lithium; hormonal: medroxyprogesterone, oestrogens; immunological: methotrexate, peginterferon alpha, tacrolimus; miscellaneous: cimetidine, deferasirox, febuxostat, roflumilast, thiabendazole. • For women, current pregnancy or breast-feeding, or planned pregnancy during the study.
    E.5 End points
    E.5.1Primary end point(s)
    The primary clinical outcome measure will be the total number of exacerbations of COPD necessitating changes in management (minimum management change - use of oral corticosteroids and/or antibiotics) during the one year treatment period, as reported by the participant. The primary economic outcome measure will be cost-per-QALY gained during the one year treatment period.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Approximately 12 months after entry into the trial.
    E.5.2Secondary end point(s)
    • Total number of COPD exacerbations requiring hospital admission. • Total number of emergency hospital admissions (all causes). • Post bronchodilator lung function (FEV1, FVC). • All-cause and respiratory mortality. • Serious adverse events, adverse reactions. • Total dose of inhaled corticosteroid. • Utilisation of primary or secondary health care for respiratory events • Disease specific health status using the COPD Assessment Test (CAT). • The Hull Airways Reflux Questionnaire (HARQ) will be used at some sites to collect data on respiratory and GI symptoms. • Generic health related quality of life using EuroQoL 5D (EQ-5D) Index. • Modelled lifetime incremental cost per Quality Adjusted Life Year.
    E.5.2.1Timepoint(s) of evaluation of this end point
    Approximately 12 months after entry into 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) Yes
    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 No
    E.8.2.4Number of treatment arms in the trial1
    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 concerned7
    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 end of clinical follow-up for each participant is defined as completion of the follow-up visit at 12 months. The end of clinical follow-up is when the last participant completes the follow-up visit at 12 months. The end of the trial is defined as the end of funding.
    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 months0
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years3
    E.8.9.2In all countries concerned by the trial months5
    E.8.9.2In all countries concerned by the trial days31
    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: 700
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 724
    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 state1424
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 1424
    F.4.2.2In the whole clinical trial 1424
    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)
    Participants will be in the study for approximately 12 months. We do not plan to unblind individual participants at the end of their clinical follow-up. Thus, participants will not be told whether they were taking low dose theophylline or placebo. However, if a participant wishes to take low dose theophylline at the end of their clinical follow-up, the GP can be advised of this by letter. If the GP considers this appropriate, they can prescribe theophylline for the participant.
    G. Investigator Networks to be involved in the Trial
    G.4 Investigator Network to be involved in the Trial: 1
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2013-08-08
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2013-06-28
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2017-11-20
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