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    Summary
    EudraCT Number:2014-000988-41
    Sponsor's Protocol Code Number:UoL000977
    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:2014-08-01
    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 number2014-000988-41
    A.3Full title of the trial
    A randomized, controlled multi-centre trial of 26 weeks of subcutaneous Liraglutide (a GLP1 receptor agonist), with or without continuous positive airway pressure (CPAP), in patients with Type 2 Diabetes Mellitus (T2DM) and Obstructive Sleep Apnoea (OSA)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Continuous positive airway pressure with or without liraglutide in obstructive sleep apnoea and type 2 diabetes (ROMANCE)
    A.3.2Name or abbreviated title of the trial where available
    CPAP with or without liraglutide in sleep apnoea and diabetes(ROMANCE)
    A.4.1Sponsor's protocol code numberUoL000977
    A.5.1ISRCTN (International Standard Randomised Controlled Trial) NumberISRCTN16250774
    A.5.3WHO Universal Trial Reference Number (UTRN)U1111-1139-0677
    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 Liverpool
    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 Victoza 6 mg/ml solution for injection in pre-filled pen
    D.2.1.1.2Name of the Marketing Authorisation holderNovo Nordisk A/S
    D.2.1.2Country which granted the Marketing AuthorisationDenmark
    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 nameVictoza 6mg/ml solution for injection in pre-filled pens
    D.3.2Product code N/A
    D.3.4Pharmaceutical form Solution for injection in pre-filled pen
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPSubcutaneous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNHuman glucagon-like peptide-1
    D.3.9.4EV Substance CodeAS1
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    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
    Obstructive Sleep Apnoea and Type 2 Diabetes
    E.1.1.1Medical condition in easily understood language
    Obstructive Sleep Apnoea
    Type 2 Diabetes
    E.1.1.2Therapeutic area Diseases [C] - Hormonal diseases [C19]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10029983
    E.1.2Term Obstructive sleep apnoea syndrome
    E.1.2System Organ Class 100000014722
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level PT
    E.1.2Classification code 10067585
    E.1.2Term Type 2 diabetes mellitus
    E.1.2System Organ Class 10027433 - Metabolism and nutrition disorders
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    Primary objective
    To determine whether twenty six weeks of Liraglutide treatment (up to 1.8mg) can provide a useful treatment for obese patients with T2DM and OSA, either as a stand-alone treatment or as an add-on treatment to continuous positive airway pressure (CPAP). We are primarily concerned with change from baseline in AHI (the principal measure of OSA severity).

    E.2.2Secondary objectives of the trial
    Using entirely non-invasive measures to assess changes in fat volume and distribution (visceral adipose tissue (VAT), subcutaneous adipose tissue (SAT) and liver fat using MRI based techniques), cardiac function using transthoracic echocardiography and flow mediated dilatation.

    Additionally the trial will provide useful estimates of daytime sleepiness, quality of life, compliance and adverse events.

    There is an option for participants to provide additional samples for later biochemical analysis. Adipose tissue biopsies from anterior abdominal wall will be taken in a subset of 8 patients per group. If trial participants are interested the researcher will provide more information and there is a separate PIS and ICF for this procedure.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Age & reproductive status
    • Males or females, age 18-75 years.
    • Reproductive Status: Definition of Women of Child-Bearing Potential (WOCBP). WOCBP comprises women who have experienced menarche and who have not undergone successful surgical sterilization (hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or who are not post-menopausal (see definition below).

    • WOCBP must have a negative serum or urine pregnancy test result (minimum sensitivity 25 IU/L or equivalent units of HCG) within 0 to 72 hours before the first dose of study drug.

    Clinical requirements
    • A clinical diagnosis of type 2 diabetes.
    • Glycosylated haemoglobin (HbA1c) ≥ 47mmol/mol.
    * BMI ≥30 kg/m2
    • Currently treated with either diet or any combination of metformin and sulphonylureas (excluding patients treated with DPP-IV inhibitors*, pioglitazone or insulin).
    • No current use of Liraglutide treatment.
    • Patients with moderate-severe OSA as assessed by polysomnographic criteria, either by:
     Apnoea-hypopnea index (AHI) ≥15 events/hour) with overnight domiciliary multichannel sleep study (ResMed, Apnoea Link™ or other suitable alternative).
     Overnight desaturation index (pulse oximetry): ODI ≥10 (4% dip in oxygen saturation more than 10 events/hour)
     Currently symptomatic for OSA, with excessive daytime sleepiness.
    *Patients who are currently treated with DPP-IV inhibitors can be included providing the treatment is discontinued before Baseline tests.
    E.4Principal exclusion criteria
    1. Medical History and Concurrent Diseases
    • Females of childbearing age who are not using adequate contraceptive methods or who are planning a pregnancy in the next 6 months.
    • Treatment with DPP-IV inhibitors, pioglitazone or subcutaneous insulin injections or with the anti-obesity medication, orlistat.
    • Patients in whom there may be occupational implications to a diagnosis of OSA e.g. professional drivers or operating machinery
    • Type 1 diabetes mellitus.
    • Congestive heart failure class III-IV.
    • Renal impairment: eGFR less than 30 ml/minute/1.73m2.
    • Previous history of acute pancreatitis.
    • Hyperthyroidism
    • Hypothyroidism (subjects with a normal TSH and free T4, and on a stable dose of thyroxine for at least 3 months may be included).
    • Uncontrolled hypertension (blood pressure >170/120 mmHg).
    • Recent (< 6 months) myocardial infarction.
    • Previous stroke (with residual neurological deficit).
    • Significant cardiac dysrhythmias (including pacemaker or ICD).
    • Presence of any other medical condition that would, in the opinion of the investigator or their clinician preclude safe participation in the study. This decision should be informed by Liraglutide precautions for use statements which will be provided to all clinicians and the research team.
    • Alcohol consumption in excess of daily recommended limits (21 units/week females, 28 units/week males).
    • Any history of internal metal, pacemakers, or ferromagnetic metallic implants intraocular foreign bodies or cerebral aneurysm clips (exclusion from MR scanning).
    • History of seizures or unexplained syncope.
    • Severe sleepiness.

    Physical and Laboratory Test Findings
    • Weight <140kg (due to limitations of MRI scanner).

    Allergies and Adverse Drug Reactions
    • Subjects with a history of any serious hypersensitivity reaction to GLP1-RA.

    Sex and Reproductive Status
    • WOCBP who are unwilling or unable to use an acceptable method to avoid pregnancy for the study duration plus 8 weeks after the last dose of study drug in such a manner that the risk of pregnancy is minimized.
    • Women who are pregnant or breastfeeding.

    Prohibited Treatments and/or Therapies
    • Diabetes treated with pioglitazone, GLP-1 analogues or insulin.
    • Use of other weight loss medication or any drug that might affect body weight or appetite (including anti-depressants, antipsychotics, corticosteroids).
    •
    Other Exclusion Criteria
    • Prisoners or subjects who are involuntarily incarcerated.
    • Subjects who are compulsorily detained for treatment of either a psychiatric or physical (e.g., infectious disease) illness.

    Eligibility criteria for this study have been carefully considered to ensure the safety of the study subjects and to ensure that the results of the study can be used. It is imperative that subjects fully meet all eligibility criteria.
    E.5 End points
    E.5.1Primary end point(s)
    Change in apnoea-hypopnea index (AHI) from baseline-post intervention.

    Although a number of studies using CPAP have instead used the ESS as the primary outcome measure, for the present study, analysis of the ESS may lead to misleading conclusions as excessive daytime sleepiness is very common in obese subjects and is not restricted to those with OSA - particularly in patients with poor glycaemic control (17).
    E.5.1.1Timepoint(s) of evaluation of this end point
    The trial will run for approximately 3-years. Pre - post measures will be collected from individual participants at 26-week time points prior to and following their respective intervention. See protocol for more detail.
    E.5.2Secondary end point(s)
    Using entirely non-invasive measures to assess changes in fat volume and distribution (visceral adipose tissue (VAT), subcutaneous adipose tissue (SAT) and liver fat using MRI based techniques), cardiac function using transthoracic echocardiography and flow mediated dilatation.

    1. HbA1c
    2. Oxygen desaturation index (ODI)
    3. Body Composition:
    Body weight (kg)
    Waist: hip ratio
    Visceral adipose tissue (VAT)
    Subcutaneous adipose tissue (SAT)
    Neck tissue volume
    Neck fat
    4. Cardiovascular measures:
    Flow-mediated dilation (FMD)
    Carotid intima-media thickness (cIMT)
    Left ventricular tissue velocity
    5. Quality of life:
    Epworth Sleepiness Scale (ESS)
    Calgary Sleep Apnoea Quality of Life (SAQLI)
    SF-36
    Oxford Sleep Resistance test (OSLER)

    Efficacy outcomes include:
    1. Compliance:
    Liraglutide: non-compliance is defined as administration of either less than 80% or more than 120% of their prescribed dose of investigational product.
    CPAP: non-compliance is defined as less than 2 hours usage.
    2. Proportion of adverse events
    E.5.2.1Timepoint(s) of evaluation of this end point
    The trial will run for approximately 3-years. Pre - post measures will be collected from individual participants at 26-week time points prior to and following their respective intervention. See protocol for more detail.
    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 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) 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 No
    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 No
    E.8.2.3Other Yes
    E.8.2.3.1Comparator description
    Mechanical device and control (no treatment)
    E.8.2.4Number of treatment arms in the trial4
    E.8.3 The trial involves single site in the Member State concerned Yes
    E.8.4 The trial involves multiple sites in the Member State concerned No
    E.8.4.1Number of sites anticipated in Member State concerned1
    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
    LVLS
    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 days1
    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 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: 116
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 36
    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 state152
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 0
    F.4.2.2In the whole clinical trial 0
    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)
    Once any given participant has finished the study their study doctor will decide what is the best treatment for the management of their diabetes and OSA. This might include Liraglutide as that is available on the NHS and has been approved by the National Institute for Health and Care Excellence (NICE).
    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 Decision2014-08-22
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2014-08-04
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2019-10-10
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