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    The EU Clinical Trials Register currently displays   43861   clinical trials with a EudraCT protocol, of which   7284   are clinical trials conducted with subjects less than 18 years old.   The register also displays information on   18700   older paediatric trials (in scope of Article 45 of the Paediatric Regulation (EC) No 1901/2006).

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    Summary
    EudraCT Number:2012-002199-15
    Sponsor's Protocol Code Number:12/0036
    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:2013-08-20
    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 number2012-002199-15
    A.3Full title of the trial
    A Phase III double-blind, randomised, placebo controlled trial of long term therapy on Exacerbation Rate in patients with stable COPD using Doxycycline
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    The effect of long term antibiotic therapy on exacerbation (flare-up) frequency in patients with Stable Chronic Obstructive Pulmonary Disease (COPD).
    A.3.2Name or abbreviated title of the trial where available
    Effects of Long Term Antibiotic Therapy on Exacerbation Rate in Stable COPD Patients
    A.4.1Sponsor's protocol code number12/0036
    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 SponsorImperial 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 for Health Research
    B.4.2CountryUnited Kingdom
    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
    B.5.3.4CountryUnited Kingdom
    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 Doxycycline 100
    D.2.1.1.2Name of the Marketing Authorisation holderActavis UK Ltd
    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 nameDoxycycline
    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 INNDoxycycline
    D.3.9.1CAS number 564250
    D.3.9.2Current sponsor codeN/A
    D.3.9.3Other descriptive nameN/A
    D.3.9.4EV Substance CodeAS3
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number100
    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
    COPD Chronic Obstructive Pulmonary Disease
    E.1.1.1Medical condition in easily understood language
    COPD is a name used to describe a collection of lung diseases where people have difficulty breathing because of long term damage to the airways in the lung.
    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 16.1
    E.1.2Level LLT
    E.1.2Classification code 10010952
    E.1.2Term COPD
    E.1.2System Organ Class 100000004855
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 16.1
    E.1.2Level LLT
    E.1.2Classification code 10010953
    E.1.2Term COPD exacerbation
    E.1.2System Organ Class 100000004855
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    The principal research question/objective is to assess whether the use of an antibiotic for 12 months by a group of patients with COPD reduces their rate of COPD exacerbations (periodic flare-ups of COPD symptoms) compared to a control group, taking a placebo.
    E.2.2Secondary objectives of the trial
    To assess the effect of Doxycycline on on:
    • Changes in spirometry (lung function measure) from baseline
    • Changes in respiratory health status from baseline, as measured by St. Georges Respiratory Questionnaire (SGRQ).
    • Changes in COPD health status from baseline, as measured by COPD Assessment Test (CAT).
    • Changes in lower airway bacteria concentration (cfu/ml) from baseline and compare that to placebo.
    • To collect further data on cost-effectiveness of antibiotics in preventing exacerbations which will be evaluated in a future work package(WP5). This includes EQ5D and SF12 questionnaires.
    • To collect further data on patient adherence to be analysed in as part of a future work package (WP6) (Questionnaires to include BMQ-12 general and BMQ-specific scale, PSM, MARS, AP-6/12).
    • Patient adherence to antibiotic/placebo treatment as measured by diary cards and pill counts at treatment end.
    • Changes in CRP levels (a systemic inflammatory marker, shown to be associated with
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Patients eligible for enrolment in the study must meet all the following criteria:
    • Informed Consent: Patients must give their signed and dated written informed consent to participate
    • Confirmed COPD diagnosis (Post bronchodilator spirometry spirometry: FEV1/FVC<0.70 with at least a 10 pack year history of smoking )
    • Severity of disease: Only patients with a measured FEV1<80% of predicted normal values as determined at screening will be enrolled. Three spirometry readings will be taken to assess FEV1 and FVC. The highest reading of FEV1 and the highest reading of FVC will be used to calculate the FEV1/FVC ratio, and for comparison with the predicted normal value
    • At least one treated exacerbation (Patient recalls an episode of symptomatic worsening which was treated and was consistent with a COPD exacerbation) in the previous year.
    • Age: ≥ 45 years of age at screening
    • Able to complete questionnaires for health status and symptoms and considered able to comply with the dosing regimen.
    • Patients who self-manage exacerbations must be willing to report these exacerbations and attend relevant exacerbation visits.
    E.4Principal exclusion criteria
    • Patients with known active TB or other clinically significant chronic respiratory disease (e.g. chronic asthma, bronchiectasis, pulmonary fibrosis) in the judgment of the study doctor.
    • Hepatic or renal impairment as defined as LFTs > 5XULN, and creatinine > 5 x ULN.
    • Patients with known hypersensitivity to the IMP and/or Placebo including their excipients.
    • Patients taking ongoing antibiotic therapy for COPD or other conditions.
    • Patients with uncontrolled clinically significant hypertension
    • Female patients who are pregnant or planning on becoming pregnant during the study, or are breastfeeding.
    • Clinically relevant abnormal electrolyes (sodium or potassium), renal function (urea and creatinine) or liver function (ALT, AST, ALP) that could interfere with the objectives of the trial or safety of the volunteer
    • Patient taking clinically significant contraindicated medication, as per the SmPC for Doxycycline.
    • Use of another experimental investigational medicinal product within 3 months of study enrolment. If the IMP used was as part of the NIHR WP2 study then entry to WP3 after a 6 week washout period is permissible.
    • Patients with any other condition precluding enrolment in the trial, according to the assessment of the study doctor. This will be documented at screening.

    Females of childbearing potential must be willing to use an effective method of contraception from the time consent is signed until (6 weeks) after treatment discontinuation. These include:
    • Complete abstinence from screening to final visit
    • Male partner is sterile (vasectomy with documentation of azoospermia) prior to female subject entry into the study, and this male partner is the sole partner for the subject
    • Implants of levonorgestral inserted for at least 1 month prior to the study medication administration but not beyond the third successive year following insertion
    • Injectable progestogen administered for at least 1 month prior to study medication administration
    • Oral contraception (combined or progestogen only) administrated for at least one monthly cycle prior to study medication administration.
    • Double barrier methods: condoms or occlusive cap (diaphragm or cervical/vault caps) plus spermicidal agent (foam/get/film/cream/suppository)
    • An intrauterine device (IUD), inserted by a qualified physician, with published data showing that the highest expected failure rate is less than 1% per year
    • Estrogenic vaginal ring
    • Percutaneous contraceptive patches.
    Females of childbearing potential must have a negative pregnancy test within 7 days prior to receiving trial treatment.
    NOTE: Subjects are considered not of childbearing potential if they are surgically sterile (i.e. they have undergone a hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or they are postmenopausal.
    Females must not be breastfeeding.
    E.5 End points
    E.5.1Primary end point(s)
    The primary outcome will be the rate of exacerbations (COPD symptom flare ups) per person-year recorded from the date of drug issue until the date of end of treatment visit. Patients will be considered to not be at-risk of a repeat exacerbation until they have recovered from their most recent exacerbation and are no longer in the post-recovery period. The difference in exacerbation rate per person-year between the active treatment and control group will be analysed using zero inflated Poisson or negative binomial regression, depending on whether there is evidence of over dispersion and it characteristics.
    E.5.1.1Timepoint(s) of evaluation of this end point
    12 months
    E.5.2Secondary end point(s)
    • Lung function (spirometry) (FEV1, FVC, FEV1/FVC ratio, FEV1 as % Predicted).
    • Total and individual component(symptoms, activity, impact) SGRQ scores will be used to measure health status. Each range from zero (no impairment) to 100 (maximum impairment).
    • Respiratory health status across groups as measured from total number of symptoms in a day and prevalence of individual symptoms recorded on daily diary cards.
    • Airway bacteria numbers taken from a sputum sample, provided by a subset of patients, at months 3, 6, 9, 12 after drug issue. Sputum samples will be collected and analysed using routine culture methods, together with evaluation of any bacterial resistance by susceptibility testing.
    • CRP - changes in CRP levels from baseline.
    • Hospital admissions. This data will be collected from HES.
    • Time to 1st exacerbation measured by diary cards in both therapy and placebo groups.
    • Rate of exacerbations treated with steroids and antibiotics.
    • Adherence as measured using pill counts.
    • Antibiotic resistance measured in the subset of patients (able to produce sputum) from sputum based on standard NHS procedures (not resistant, intermediate, severe, resistant).
    E.5.2.1Timepoint(s) of evaluation of this end point
    12 months.
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis Yes
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    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) No
    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 trial2
    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 concerned2
    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 the trial will be defined as the date of the last telephone call to the last study participant.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years2
    E.8.9.1In the Member State concerned months4
    E.8.9.1In the Member State concerned days1
    E.8.9.2In all countries concerned by the trial years2
    E.8.9.2In all countries concerned by the trial months2
    E.8.9.2In all countries concerned by the trial days1
    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: 50
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 172
    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 Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    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 state222
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 222
    F.4.2.2In the whole clinical trial 222
    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 the study, the patient's respiratory care will be transferred back to the patient's primary care physician.

    Patients with more severe disease who require more specialist care will be followed up within the specialist COPD service in either London or Liverpool. The study medication will be discontinued at the end of study visit and further study medication will not be provided. ....
    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 Primary Care Research Network, London South Bank University
    G.4.3.4Network Country United Kingdom
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2013-09-26
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2013-07-25
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2017-07-20
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