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    Summary
    EudraCT Number:2015-004064-11
    Sponsor's Protocol Code Number:BETTER-BFeasibility
    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:2016-02-15
    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 number2015-004064-11
    A.3Full title of the trial
    BETTER-B (Feasibility)
    BETter TreatmEnts for Refractory Breathlessness: A feasibility study of the use of mirtazapine for refractory breathlessness
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    BETTER-B (Feasibility): Better Treatments for Refractory Breathlessness: A feasibility study of the use of mirtazapine for refractory breathlessness
    A.3.2Name or abbreviated title of the trial where available
    BETTER-B (Feasibility)
    A.4.1Sponsor's protocol code numberBETTER-BFeasibility
    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 SponsorKing's 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 supportMarie Curie Cancer Care Research Grant Scheme
    B.4.2CountryUnited Kingdom
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationClinical Trials Research Unit (CTRU)
    B.5.2Functional name of contact pointVictoria Hiley
    B.5.3 Address:
    B.5.3.1Street AddressCTRU, University of Leeds
    B.5.3.2Town/ cityLeeds
    B.5.3.3Post codeLS2 9JT
    B.5.3.4CountryUnited Kingdom
    B.5.4Telephone number00441133431477
    B.5.5Fax number00441133431471
    B.5.6E-mailbetter-b@leeds.ac.uk
    B.Sponsor: 2
    B.1.1Name of SponsorKing's College Hospital NHS Foundation Trust
    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 supportMarie Curie Cancer Care Research Grant Scheme
    B.4.2CountryUnited Kingdom
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationClinical Trials Research Unit (CTRU)
    B.5.2Functional name of contact pointVictoria Hiley
    B.5.3 Address:
    B.5.3.1Street AddressCTRU, University of Leeds
    B.5.3.2Town/ cityLeeds
    B.5.3.3Post codeLS2 9JT
    B.5.3.4CountryUnited Kingdom
    B.5.4Telephone number00441133431477
    B.5.5Fax number00441133431471
    B.5.6E-mailbetter-b@leeds.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 Mirtazapine
    D.2.1.1.2Name of the Marketing Authorisation holderMedreich Plc
    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 nameMirtazapine
    D.3.4Pharmaceutical form Capsule, hard
    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 INNmirtazapine
    D.3.9.1CAS number 85650-52-8
    D.3.9.3Other descriptive nameMIRTAZAPINE
    D.3.9.4EV Substance CodeSUB08996MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number15
    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, hard
    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
    Refractory breathlessness in patients diagnosed with cancer, chronic heart failure, or lung disease (chronic obstructive pulmonary disease (COPD) or interstitial lung disease (ILD)).
    E.1.1.1Medical condition in easily understood language
    Breathlessness that continues despite optimal management of the underlying causes and current symptom relief measures, in patients suffering from cancer, heart failure or lung disease.
    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 18.1
    E.1.2Level LLT
    E.1.2Classification code 10006345
    E.1.2Term Breathlessness
    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
    Is a large scale, randomised, double blind, placebo-controlled study of mirtazapine for refractory breathlessness feasible in terms of recruitment?
    E.2.2Secondary objectives of the trial
    1. Is a large-scale randomised, double-blind, placebo-controlled study of mirtazapine for refractory breathlessness feasible in terms of:
    a)Recruitment in different settings: outpatient, community services and inpatient settings?
    b) Acceptability of randomisation to patients?
    c) Ability to deliver placebo-control and maintain the double-blind?
    d) Ability to assess outcome measures and minimise missing data in a future large-scale trial?
    e) Patient eligibility to increase the dose of mirtazapine further at 28 days?
    f) Compliance with treatment?
    2. In order to further inform the sample size calculation for the future large-scale trial, what is the expected activity of mirtazapine?
    3. What is the toxicity profile of mirtazapine in patients with breathlessness?
    4. What is the potential impact on quality of life (QoL) and symptom management of mirtazapine for patients with breathlessness?
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    The aim of this sub-study is to qualitatively explore patient acceptability of the trial and recruitment processes to assist in optimisation of recruitment and follow-up strategies employed for a future large scale randomised controlled trial.
    E.3Principal inclusion criteria
    1. Male or female aged ≥ 18 years old
    2. Modified MRC dyspnoea scale grade 3 or 4
    3. Diagnosed with:
    • Cancer, or
    • Chronic obstructive pulmonary disease (COPD), or
    • Interstitial lung disease (ILD), or
    • Chronic heart failure (New York Heart Association (NYHA) class III or IV)
    4. On optimal treatment of the underlying condition in the opinion of the identifying clinician (see section 9.3.3 of protocol for guidance)
    5. Management of the underlying condition unchanged for the previous 1 week
    6. Reversible causes of breathlessness optimally treated in the opinion of the identifying clinician
    7. Expected prognosis of ≥2 months
    8. If female must be (as documented in the notes)
    a) postmenopausal (no menses for 12 months without an alternative medical cause), or
    b) surgically sterile (hysterectomy, bilateral salpingectomy or bilateral oophorectomy), or
    c) using acceptable contraception ii (which must be continued for 7 days after the last dose of IMP)
    9. Able to complete questionnaires and trial assessments
    10. Able to provide written informed consent
    ii Acceptable contraception is defined as one of the following: combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation (oral, intravaginal or transdermal); progestogen-only hormonal contraception associated with inhibition of ovulation (oral, injectable, implantable); intrauterine device (IUD); intrauterine hormone-releasing system (IUS); bilateral tubal occlusion; vasectomised partner; practising true abstinence (when this is in line with the preferred and usual lifestyle of the subject).
    E.4Principal exclusion criteria
    1. Existing antidepressant use, use of linezolid, or St John’s wort
    2. Known contraindication to mirtazapine
    3. Hypersensitivity to the active substance or to any of the components of the mirtazapine or placebo (e.g. lactose intolerance)
    4. Australia modified Karnofsky Performance Scale ≤40
    5. Pregnant or breast-feeding women(vi)
    6. Patients with acute cardiac events within 3 months of randomisation (myocardial infarction, unstable angina pectoris, or significant cardiac conduction disturbance)
    7. Patients with known hepatic impairment
    8. Patients with known renal impairment
    9. Patients with uncontrolled blood pressure
    10. Patients with uncontrolled diabetes mellitus
    11. Patients with uncontrolled seizures, epilepsy or organic brain syndrome
    12. Patients with severe depression or suicidal thoughts
    13. Patients with a history of psychotic illness (schizophrenia, bipolar disorder, mania or hypomania, or other psychotic disturbances)
    vi for women of childbearing potential (those not post-menopausal or surgically sterile) must be confirmed by a pregnancy test within 7 days prior to randomisation
    E.5 End points
    E.5.1Primary end point(s)
    The primary endpoint is the number of patients recruited into the trial across 3 trial sites over a 12-month period. This will be evaluated at the end of the trial.
    E.5.1.1Timepoint(s) of evaluation of this end point
    After 12 months recruitment
    E.5.2Secondary end point(s)
    Other outcome measures of feasibility will be assessed to determine whether the design of the future large-scale trial may need to be adapted to improve recruitment or reduce attrition. Physical activity and toxicity outcomes will be used to inform the design of the future trial, however they will not be used to inform the decision as to whether or not to proceed to a future large-scale trial. These are:
    • Number of patients screened for eligibility and reasons for non-eligibility
    • Proportion of eligible patients randomised and reasons for non-randomisation
    • Proportion of participants for which blinding is maintained
    • Proportion of research assessors for which blinding is maintained
    • Proportion of participants remaining on study for 28 days
    • Proportion of, and reasons for, participants with missing data for trial outcomes
    • Proportion of participants who would be eligible for dose escalation at 28 days
    • Treatment compliance over the period
    Feasibility outcome measures relating to recruitment will be assessed by the use of screening logs completed at each site.
    Blinding will be assessed using the Bang Blinding index.
    Missing data and study compliance will be assessed based on completed and received CRFs, summarised for each trial outcome measure.
    Eligibility for dose escalation will be assessed based on breathlessness intensity at day 28 and tolerability of treatment.
    3) Safety and Toxicity
    •Adverse events reported on days 7, 14, 21 and 28.
    •Safety will be reported based on the occurrence of SAEs, SARs and SUSARs.
    • Australia-modified KPS and mMRC at days 14 and 28
    •Opioid medication: on days 7, 14, 21 and 28.
    4) Symptoms and Quality of Life
    •Coping self-belief assessment on day 28.
    •Mobility, self-care, usual activities, pain/discomfort and anxiety/depression as assessed on day 28.
    •Palliative symptoms as assessed days 14 and 28.
    •Anxiety and depression as assessed on days 14 and 28.
    •QoL as assessed by CRQ at days 14 and 28.
    E.5.2.1Timepoint(s) of evaluation of this end point
    All secondary endpoints will be evaluated when all participants have been followed up for safety i.e. 7 days after last treatment dose.
    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 Yes
    E.6.13.1Other scope of the trial description
    Feasibility
    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 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 concerned3
    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 No
    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 trial is defined as the date of the collection of the last participant’s last data item, i.e. the last participant’s Follow-Up trial phone-call assessment, which will be no earlier than 7 days after the last participant has completed trial treatment.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years1
    E.8.9.1In the Member State concerned months0
    E.8.9.1In the Member State concerned days0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 30
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 30
    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 state60
    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)
    If participants believe they have had a benefit from the trial treatment, they may wish to take mirtazapine off-trial -
    mirtazapine is a relatively inexpensive and commonly used drug in the UK. Participants are advised that they may approach
    their GPs following trial completion for off-trial prescribing of mirtazapine.
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2016-02-16
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2016-02-16
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2017-12-13
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