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    Summary
    EudraCT Number:2018-001650-98
    Sponsor's Protocol Code Number:AC1802
    National Competent Authority:UK - MHRA
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2018-08-29
    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 number2018-001650-98
    A.3Full title of the trial
    Alpha 2 agonists for sedation to produce better outcomes from critical illness (A2B Trial): A randomised, parallel-group, allocation concealed, controlled, open, phase 3 pragmatic clinical and cost- effectiveness trial with internal pilot
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Alpha-2 Agonists for sedation to produce better outcomes from critical illness (‘A2B Trial’)
    A.3.2Name or abbreviated title of the trial where available
    Alpha-2 agonists for sedation (A2B Trial)
    A.4.1Sponsor's protocol code numberAC1802
    A.5.1ISRCTN (International Standard Randomised Controlled Trial) NumberISRCTN18035454
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT03653832
    A.5.4Other Identifiers
    Name:Eudra CTNumber:2018-001650-98
    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 Edinburgh and NHS Lothian
    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 supportNIHR HTA
    B.4.2CountryUnited Kingdom
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationUniversity of Edinburgh
    B.5.2Functional name of contact pointO'Mahony
    B.5.3 Address:
    B.5.3.1Street AddressThe Queen's Medical Research Institute, 47 Little France Crescent
    B.5.3.2Town/ cityEdinburgh
    B.5.3.3Post codeEH16 4TJ
    B.5.3.4CountryUnited Kingdom
    B.5.4Telephone number01312429418
    B.5.5Fax number01312429447
    B.5.6E-mailfiach.o'mahony@ed.ac.uk
    B.Sponsor: 2
    B.1.1Name of SponsorNHS Lothian
    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 supportNIHR HTA
    B.4.2CountryUnited Kingdom
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationNHS Lothian
    B.5.2Functional name of contact pointKenneth Scott
    B.5.3 Address:
    B.5.3.1Street AddressThe Queen's Medical Research Institute, 47 Little France Crescent
    B.5.3.2Town/ cityEdinburgh
    B.5.3.3Post codeEH16 4TJ
    B.5.4Telephone number01312423325
    B.5.6E-mailaccord@nhslothian.scot.nhs.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 Information not present in EudraCT
    D.2.1.1.2Name of the Marketing Authorisation holderOr
    D.2.1.2Country which granted the Marketing AuthorisationFinland
    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 nameDexdor
    D.3.4Pharmaceutical form Solution for injection/infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNdexmedetomidine
    D.3.9.1CAS number 0113775-47-6
    D.3.9.2Current sponsor codeN/A
    D.3.9.4EV Substance CodeAS1
    D.3.10 Strength
    D.3.10.1Concentration unit µg/ml microgram(s)/millilitre
    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.IMP: 2
    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 Information not present in EudraCT
    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 nameCatapres
    D.3.4Pharmaceutical form Solution for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNclonidine
    D.3.9.1CAS number 4205-90-7
    D.3.9.4EV Substance CodeAS3
    D.3.10 Strength
    D.3.10.1Concentration unit µg/ml microgram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number150
    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.IMP: 3
    D.1.2 and D.1.3IMP RoleComparator
    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 Information not present in EudraCT
    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 nameDiprivan
    D.3.4Pharmaceutical form Emulsion for injection/infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNPropofol
    D.3.9.1CAS number 2078-54-8
    D.3.9.4EV Substance CodeAS2
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number10
    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
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Any patient requiring intensive care treatment due to critical illness.
    E.1.1.1Medical condition in easily understood language
    Any patient requiring treatment in an intensive care unit.
    E.1.1.2Therapeutic area Analytical, Diagnostic and Therapeutic Techniques and Equipment [E] - Anesthesia and Analgesia [E03]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.1
    E.1.2Level LLT
    E.1.2Classification code 10033305
    E.1.2Term Oversedation
    E.1.2System Organ Class 10029205 - Nervous system disorders
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level PT
    E.1.2Classification code 10039897
    E.1.2Term Sedation
    E.1.2System Organ Class 10029205 - Nervous system disorders
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.1
    E.1.2Level LLT
    E.1.2Classification code 10049124
    E.1.2Term Sedation during medical procedure
    E.1.2System Organ Class 100000004865
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.1
    E.1.2Level LLT
    E.1.2Classification code 10039898
    E.1.2Term Sedation excessive
    E.1.2System Organ Class 10029205 - Nervous system disorders
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    Our principal objective is:
    To determine whether the length of time critically ill adult patients require mechanical ventilation can be reduced when using two sedative drugs from the alpha2 agonist class, clonidine or dexmedetomidine, as compared with current usual care (sedation with the drug propofol).
    E.2.2Secondary objectives of the trial
    Secondary objectives are to assess the effects of dexmedetomidine and clonidine, compared with usual care, on other clinical, patient-centred, and economic outcomes in the ICU, hospital, and during up to 6 months follow up post-randomisation.

    Clinical and Person-centred objectives
    During ICU stay we will compare rates and duration of delirium, time to optimum sedation, average sedation depth, the ability of patients to communicate with staff and relatives, the quality of sedation, and duration of ICU stay. We will also compare safety based on pre-defined adverse events relevant to sedation and α2-agonist agents.
    Following discharge from the ICU we will compare patient outcomes for which sedation and ICU experience may be on the causal pathway, namely patients’ memories of their ICU stay, psychological well being, and cognitive function. We will follow up patients for 6 months for survival, HRQoL, and healthcare resource use.

    Economic evaluation
    We will include a detailed cost-effe
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    Mechanistic Sub-study - in a sub-group of participants with sepsis, who have given their consent, 2 blood samples will be collected at baseline and 60 hours. We will use several methods to explore whether there are differences in inflammation and/or immune function between the trial sub-groups with sepsis at baseline, and how these relate to trial outcomes. When consent has been provided, we will also explore whether changes in gene expression occur that are modified by alpha2-agonists, for example using whole blood transcriptomics. Where appropriate, we will also measure a panel of circulating pro- and anti-inflammatory mediators in order to explore whether alpha2-agonists have anti-inflammatory properties that might contribute to or mediate some of their beneficial effects during critical illness.
    E.3Principal inclusion criteria
    1. Patient requiring MV in an ICU
    2. Aged 18 or over
    3. Within 48 hours of first episode of mechanical ventilation in ICU
    4. Requiring sedation with propofol
    5. Expected to require a total of 48 hours of MV or more in ICU
    6. Expected to require a further 24 hours of MV at the time of randomisation in the opinion of the responsible clinician
    E.4Principal exclusion criteria
    1. Acute brain injury
    2. Post-cardiac arrest
    3. Status epilepticus
    4. Continuous therapeutic neuromuscular paralysis at the time of screening or randomisation
    5. Guillain-Barre Syndrome
    6. Myasthenia gravis1
    7. Home ventilation
    8. Fulminant hepatic failure
    9. Patient not expected to survive 24 hours by responsible clinician
    10. Decision to provide only palliative or end-of-life care
    11. Pregnancy
    12. Known allergy to one of the study drugs
    13. Patient known to have experienced a period with heart rate <50 beats per minute for 60 minutes or longer since commencing mechanical ventilation in the ICU
    14. Untreated second or third degree heart block3
    15. Transferred from another Intensive Care Unit in which MV occurred for >6 hours
    16. Prisoners
    17. Enrolled on another CTIMP
    18. Previously enrolled on the A2B Trial
    E.5 End points
    E.5.1Primary end point(s)
    Time to successful extubation post-randomisation (hours).
    For the purpose of the trial, a successful first extubation from mechanical ventilation (MV) will be defined as follows:

    a. For patients with an Endotracheal tube:
    time of successful extubation will be the time of the first extubation that is followed by 48 hours of spontaneous breathing without mechanical support (i.e. the start time of the 48 hours of spontaneous breathing)

    b. For patients with a tracheostomy:
    time of successful extubation will be the start time of the patient’s first period of 48 hours of spontaneous breathing, where spontaneous breathing is defined as receiving support not exceeding 5 cmH2O PEEP/CPAP with ≤ 5 cmH2O pressure support above PEEP

    c. For patients who are receiving non-Invasive mechanical ventilation (NIV):
    time of successful extubation will be the start time of the patient’s first period of 48 hours of spontaneous breathing, where spontaneous breathing is defined as receiving support not exceeding 5 cmH2O CPAP via mask/hood (NB NIV patients receiving any pressure supported breaths will not be considered to be spontaneously breathing unassisted)
    NB: The use of high flow nasal oxygen will not be counted as mechanical ventilation, so patient on high nasal flow oxygen alone will be considered to be spontaneously breathing unassisted.

    The 48 hours of successful extubation is included in the definition in order to exclude patients with early failed extubations, i.e. those patients requiring reintubation within 48 hours. If a re-intubation occurs within this time window it is likely to be related to the original episode of respiratory failure requiring intubation. In this situation patients should continue to be followed for the start time at which a successful extubation occurs according to the above definitions
    E.5.1.1Timepoint(s) of evaluation of this end point
    Daily until successful extubation achieved
    E.5.2Secondary end point(s)
    1) Length of ICU stay
    2) Delirium prior to successful extubation
    3) Sedation and analgesia quality
    4) Time to first optimum sedation
    5) Patient's ability to communicate pain and ability to cooperate with care
    6) Relative/partner/friend assessment (PerLR) of comfort and communication
    7) Drug related adverse events
    8) Mortality
    9) Patient experience of ICU care
    10) Anxiety and depression
    11) Post-traumatic stress
    12) Cognitive function
    13) Health related quality of life
    E.5.2.1Timepoint(s) of evaluation of this end point
    1) ICU discharge
    2) Twice daily during ICU stay until primary outcome reached
    3) Four hourly during ICU stay until primary outcome reached
    4) Daily during the intervention period
    5) Twice daily until primary outcome reached
    6) Daily until primary outcome reached
    7) Daily during the intervention period
    8) ICU, hospital, 30, 90 and 180 days post randomisation
    9) 30 and 90 days post randomisation
    10) 90 and 180 days post randomisation
    11) 90 and 180 days post randomisation
    12) 90 and 180 days post randomisation
    13) 30, 90 and 180 days post-randomisation and recalled prior to hospital admission (measured at 30 days)
    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 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 Yes
    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 Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group Yes
    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) Yes
    E.8.2.2Placebo No
    E.8.2.3Other No
    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 concerned50
    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
    LVLS: The end of the trial will be after the final enrolled patient has completed follow up 180 days post-randomisation
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years3
    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 months0
    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: 580
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 1157
    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 No
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation Yes
    F.3.3.6Subjects incapable of giving consent personally Yes
    F.3.3.6.1Details of subjects incapable of giving consent
    Critically ill patients receiving sedation in intensive care
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state1737
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 1737
    F.4.2.2In the whole clinical trial 1737
    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)
    None. The intervention will be given only while the participant is in ICU and on mechanical ventilation or for a period shortly thereafter.
    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 Decision2018-12-10
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2018-08-21
    P. End of Trial
    P.End of Trial StatusOngoing
    As of 1.2.2020, the UK is no longer an EU Member State. However, EU law still applies to the UK during the transition period
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