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    Summary
    EudraCT Number:2021-001626-22
    Sponsor's Protocol Code Number:RML-TB
    National Competent Authority:Spain - AEMPS
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2022-03-29
    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 ConcernedSpain - AEMPS
    A.2EudraCT number2021-001626-22
    A.3Full title of the trial
    A Multicentre Controlled Open Randomized Clinical Trial to evaluate the efficacy and safety profile of an anti-TB drug combination based on High Dose Rifampicin, High Dose Moxifloxacin and Linezolid daily for DS AFB smear positive pulmonary TB patients during the initial 8 weeks of treatment.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    New treatment for pulmonary TB with High dose Rifampicin, High dose Moxifloxacin and Linezolid
    A.3.2Name or abbreviated title of the trial where available
    RML-TB study
    A.4.1Sponsor's protocol code numberRML-TB
    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 SponsorVall d'Hebron Institute of Research
    B.1.3.4CountrySpain
    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 supportInstituto de Salud Carlos III
    B.4.2CountrySpain
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationVall d'Hebron Institute of Research
    B.5.2Functional name of contact pointAdrian Sanchez-Montalva
    B.5.3 Address:
    B.5.3.1Street AddressPasseig Vall d'Hebron 119-129. Edfici Mediterránea. desp 119
    B.5.3.2Town/ cityBarcelona
    B.5.3.3Post code08035
    B.5.3.4CountrySpain
    B.5.6E-mailadrian.sanchez.montalva@gmail.com
    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 Rifampicin
    D.2.1.1.2Name of the Marketing Authorisation holderSandoz Farmaceutica SA
    D.2.1.2Country which granted the Marketing AuthorisationSpain
    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.3.4Pharmaceutical form Capsule, hard
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    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
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Smear-positive rifampicin-sensitive pulmonary Tuberculosis
    E.1.1.1Medical condition in easily understood language
    pulmonary Tuberculosis
    E.1.1.2Therapeutic area Diseases [C] - Respiratory Tract Diseases [C08]
    MedDRA Classification
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    1.-Primary efficacy objective: To evaluate the efficacy of a treatment containing rifampicin at high doses (30mg/kg/day), moxifloxacin at high doses (600mg/day) and linezolid vs standard treatment for 8 weeks through the early sterilizing activity in not previously treated, uncomplicated, AFB smear-positive, drug susceptible pulmonary TB patients. The study regimen will be considered inferior to control arm if the proportion of participants with a negative sputum culture (sputum sterilization) in the experimental arm compared to control arm after 8 weeks of treatment does not meet the non-inferiority criteria.
    -Co-primary safety objective: To evaluate the safety of a regimen containing rifampicin at high doses, moxifloxacin at high doses and linezolid for 8 weeks. The intervention will be considered inferior to the control arm if proportion of participants with an AE grade =or> 3 in the experimental arm after 8 week of treatment does not meet the non-inferiority criteria.
    E.2.2Secondary objectives of the trial
    3.-Secondary objectives: a) To evaluate the tolerability (any adverse event) of high-dose rifampicin, high dose moxifloxacin and linezolid for 8 weeks. B)To evaluate the efficacy dynamics of the study intervention as time-dependent decline in sputum smear bacterial load and time-dependent increase in time-to-positivity of sputum culture between arms. C) To analyze the correlation between the AUC/MIC values for rifampicin, moxifloxacin and linezolid and the efficacy outcomes. D) To evaluate the quality of life using SF-12 and St Geroge’s respiratory questionnaire among participants and compare study arms. E) To conduct a cost-effectiveness study to explore the feasibility of implementing the experimental arm in the Spanish National Health System.
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    PK/PD substudy
    E.3Principal inclusion criteria
    1) Diagnosis of AFB smear-positive pulmonary TB. 2) Age ≥ 18 years. 3) Sign informed consent. 4) Negative pregnancy test (women of childbearing age)
    E.4Principal exclusion criteria
    1) Contact of a patient with multidrug-resistant TB. 2) Multidrug-resistant TB or monoresistance to any first-line drugs (except ethambutol). 3) AFB smear-positive pulmonary TB with negative mycobacterial culture. 4) Barthel <60 or if the investigator considers that there is a risk of death in the following month. 5) Weight <40 kg. 6) Treatment with drugs that may prolong QT in the last month before randomization for more than 7 days: randomization: azithromycin, chloroquine, chlorpromazine, cisapride, clarithromycin, domperidone, droperidol, erythromycin, halofantrine, haloperidol, lumefantrine, mefloquine, methadone, pentamidine, procainamide, quinidine, quinine, sotalol, sparfloxacin, thioridazine, amiodarone. 7) Cirrhosis Child C. 8) User of abuse drugs (including alcohol) according to investigator criteria. 9) Patients with solid organ or bone marrow transplantation. 10) Patients under treatment with anti-TNF or other immunosuppressive drugs. 11) Patients with oncohematological diseases. 12) Advanced lung disease according to investigator criteria. 13) Epilepsy or uncontrolled psychiatric disorder according to the investigator criteria. 14) History of ischemic heart disease or severe arrhythmia in the last 6 months. 15) Long QT syndrome or family history of sudden death. 16) Patient living in HIV infection. 17) Breastfeeding women. 18) Intolerance or allergy to any of the study drugs. 19) History of TB in the previous year. 20) Laboratory alterations: a) AST or ALT> 3x Upper limit of normality b) Bit> x3 Upper limit of normality c) Hb <6.5g/dl d) Platelets <40000/mm3 e) Potassium <3.2 mmol/L f) Glomerular filtration <30 mL /min/1.73m2. 21) ECG alterations: a) QTcF > 0.5s b) Other clinically relevant changes in the ECG according to investigator criteria. 22) Treatment with any of the study drugs in the last month for more than 7 days.
    E.5 End points
    E.5.1Primary end point(s)
    The efficacy outcome is defined as the proportion of patients with sputum sterilization in liquid media culture at 8 weeks after treatment onset. Sputum culture negativization / sterilization: a participant with positive culture at the beginning of the treatment, but who has a negative culture at 8 weeks after treatment onset. Participants without signs or symptoms of active TB at 8 weeks after treatment onset and unable to produce a sputum specimen. Efficacy subset (per protocol): group of participants that have completed 75% of the treatment dosages and have provided 8-week sputum sample. Efficacy subset (Intention to treat): group of patients randomized to the experimental or standard arm regardless treatment adherence. Participants with no sample collected at 8-week will be considered as having sputum positive culture at 8 weeks (includes death due to TB, lost to follow up, referrals). Participant with treatment shift will also be considered as having sputum positive culture at 8 weeks. Decrease in linezolid dose is permitted during the first two weeks and will not be considered treatment shift. Non-assessable: participants who die due to a cause not related to TB or the study treatment. Participant will be considered with sputum culture negativization at 8 weeks if the last known sputum culture was negative. The safety outcome is defined as the proportion of patient with grade 3 or superior adverse event. Safety / Toxicity: a patient experiencing a severe adverse event (grade 3 or superior according to the CTEAE version 5). Tolerability: a patient experiencing any adverse event according to the CTCAE version 5. Safety subset (per protocol): includes all participants who completed assigned follow up and are at least 75% adherent to the treatment. Safety subset (intention to treat): includes all participants that received at least one dose of the study drugs. Modified safety subset (per procotol): includes all participants who completed assigned follow up and are at least 75% adherent to the treatment and adverse event is attributable to any of the study drugs. Modified safety subset (intention to treat): includes all participants that received at least one dose of the study drugs and adverse event is attributable to any of the study drugs
    E.5.1.1Timepoint(s) of evaluation of this end point
    8 weeks
    E.5.2Secondary end point(s)
    a) To evaluate the tolerability (any adverse event) of high-dose rifampicin, high dose moxifloxacin and linezolid for 8 weeks. B)To evaluate the efficacy dynamics of the study intervention as time-dependent decline in sputum smear bacterial load and time-dependent increase in time-to-positivity of sputum culture between arms. C) To analyze the correlation between the AUC/MIC values for rifampicin, moxifloxacin and linezolid and the efficacy outcomes. D) To evaluate the quality of life using SF-12 and St Geroge’s respiratory questionnaire among participants and compare study arms. E) To conduct a cost-effectiveness study to explore the feasibility of implementing the experimental arm in the Spanish National Health System.
    E.5.2.1Timepoint(s) of evaluation of this end point
    8 weeks
    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 Yes
    E.6.7Pharmacodynamic Yes
    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) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    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 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) Yes
    E.8.2.2Placebo No
    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 concerned12
    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
    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 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: 100
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 20
    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 state120
    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)
    After the subject has ended the participation, he or she will be treated according to the protocol of each participating site.
    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 Decision2022-03-28
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2022-03-22
    P. End of Trial
    P.End of Trial StatusOngoing
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