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    Summary
    EudraCT Number:2014-002018-21
    Sponsor's Protocol Code Number:FOL12-01
    National Competent Authority:Italy - Italian Medicines Agency
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2014-10-16
    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 ConcernedItaly - Italian Medicines Agency
    A.2EudraCT number2014-002018-21
    A.3Full title of the trial

    5-Metyl-tetrahydrofolate in the treatment of portal hypertension in cirrhotics in pharmacologic prophylaxis of variceal bleeding with beta-blockers: a double-blind randomized controlled trial

    5-metil-tetraidrofolato di calcio nel trattamento dell’ipertensione portale nei pazienti cirrotici in profilassi farmacologica del sanguinamento da varici con beta-bloccanti: studio in doppio cieco, randomizzato e controllato
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language

    5-Metyl-tetrahydrofolate in the treatment of portal hypertension in cirrhotics in pharmacologic prophylaxis of variceal bleeding with beta-blockers: a double-blind randomized controlled trial

    5-metil-tetraidrofolato di calcio nel trattamento dell’ipertensione portale nei pazienti cirrotici in profilassi farmacologica del sanguinamento da varici con beta-bloccanti: studio in doppio cieco, randomizzato e controllato
    A.4.1Sponsor's protocol code numberFOL12-01
    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 SponsorAOU di Bologna Policlinico S.Orsola-Malpighi
    B.1.3.4CountryItaly
    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 supportUniversity of Bologna - research programe
    B.4.2CountryItaly
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationAOU di Bologna Pliclinico S.Orsola-Malpighi
    B.5.2Functional name of contact pointU.O. Semeiotica Medica
    B.5.3 Address:
    B.5.3.1Street AddressVia Massarenti 9
    B.5.3.2Town/ cityBologna
    B.5.3.3Post code40138
    B.5.3.4CountryItaly
    B.5.6E-mailranka.vukotic2@unibo.it
    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 No
    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 name5-methil tetrahydrofolate
    D.3.2Product code 5-MTHF
    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 INN5-METHYLTETRAHYDROFOLATE DI CALCIUM PENTAHYDRATE
    D.3.9.3Other descriptive name5-METHYLTETRAHYDROFOLATE DI CALCIUM PENTAHYDRATE
    D.3.9.4EV Substance CodeSUB64132
    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
    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
    portal hypertension in cirrhotic patients
    ipertensione portale nei pazienti cirrotici
    E.1.1.1Medical condition in easily understood language
    portal hypertension in cirrhotic patients
    ipertensione portale nei pazienti cirrotici
    E.1.1.2Therapeutic area Not possible to specify
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 17.0
    E.1.2Level HLT
    E.1.2Classification code 10036201
    E.1.2Term Portal hypertensions
    E.1.2System Organ Class 100000004866
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 17.0
    E.1.2Level LLT
    E.1.2Classification code 10009211
    E.1.2Term Cirrhosis liver
    E.1.2System Organ Class 100000004871
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To evaluate if a 3-months association of oral 5-MTHF to ‘non selective’ β-blockers can allow a significantly higher HVPG reduction in patients with liver cirrhosis in primary prophylaxis of variceal bleeding than β-blockers alone
    Valutare l’efficacia del trattamento di 3 mesi con 5-MTHF in associazione con propranololo rispetto a propranololo + placebo, in termini di riduzione dell’HVPG nei pazienti cirrotici con IP.
    E.2.2Secondary objectives of the trial
    1) To evaluate the tolerability of 5-MTHF n patients with cirrhosis and portal hypertension
    2) To evaluate if there is an improvement of intrahepatic vascular tone mediated through diminished oxidative stress and major NO bioavailability in the hepatic microcirculation in patients with cirrhosis treated with propranolol+5-MTHF compared to patients treated with propranolol alone. This outcome will be evaluated by testing ADMA, tHcy and BH4 levels at baseline and after 3 months of oral administration of propranolol+5-MTHF or propranolol+placebo and by comparing the respectively obtained biomarkers levels in the two groups of patients
    1. Valutare la tollerabilità di 5-MTHF nei pazienti cirrotici con IP
    2. Valutare se vi è un miglioramento del tono vascolare intraepatico attraverso la diminuzione dello stress ossidativo e maggiore biodisponibilità di NO (espressi dai livelli sierici di ADMA, tHcy, BH4, 5-MTHF) nei pazienti con cirrosi e IP trattati per 3 mesi con propranololo + 5-MTHF rispetto a quelli trattati con propranololo + placebo.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Liver cirrhosis demonstrated in terms of clinical, biochemical, imaging (echo-doppler upper abdomen, liver elastography). In the case of doubtful diagnosis is scheduled to run hepatic histology
    • HVPG ≥ 12 mmHg
    • Presence of esophageal varices requiring the prophylaxis of bleeding from rupture (as indicated by guidelines Baveno V [7])
    • Aged between 18 and 80 years
    • Females and males
    • Signature of informed consent
    • Cirrosi epatica dimostrata dal punto di vista clinico, biochimico, di imaging (eco-doppler addome superiore, elastometria epatica). Nel caso di diagnosi dubbia è prevista l’esecuzione di esame istologico epatico
    • HVPG ≥ 12 mmHg
    • Presenza di varici esofagee che necessitano la profilassi del sanguinamento da rottura (indicazione come da linee guida Baveno V [7])
    • Età compresa tra i 18 e 80 anni
    • Femmine e maschi
    • Firma del consenso informato
    E.4Principal exclusion criteria
    Presence of HCC at the time of enrollment or within 3 months prior
    • The presence of portal vein thrombosis at the time of enrollment or within 3 months prior
    • Presence of acute infections or conditions compromising hemodynamic stability at the time of enrollment or during the previous month
    • Serum creatinine> 2.5 mg / dL at enrollment
    • Direct bilirubin> 6 mg / dL at enrollment
    • Contraindications to beta-blockers at enrollment
    • Women who are pregnant and / or lactating at the time of enrollment
    • Known or suspected hypersensitivity to the drug or drug class in studio
    • Patients with serious medical conditions at enrollment who, in the opinion of the investigator, contraindicate the patient's participation in the study
    • Use of experimental drugs in the last 3 months before inclusion in the study
    • Treatment for hepatitis C in place at the time of study or in the previous 3 months
    • Treatment for hepatitis B undertaken by less than 3 months at the time of enrollment
    • Presenza di epatocarcinoma al momento dell’arruolamento o nei 3 mesi precedenti
    • Presenza di trombosi della vena porta al momento dell’arruolamento o nei 3 mesi precedenti
    • Presenza di infezioni acute o condizioni compromettenti la stabilità emodinamica al momento dell’arruolamento o nel mese precedente
    • Creatinina sierica> 2,5 mg/dL al momento dell’arruolamento
    • Bilirubina diretta> 6 mg/dL al momento dell’arruolamento
    • Controindicazioni ai beta-bloccanti al momento dell’arruolamento
    • Donne in gravidanza e/o in allattamento al momento dell’arruolamento
    • Nota o sospetta ipersensibilità al farmaco o alla classe farmacologica in studio
    • Pazienti con gravi condizioni cliniche al momento dell’arruolamento che, a giudizio dello sperimentatore, controindicano la partecipazione del paziente allo studio
    • Utilizzo di farmaci sperimentali negli ultimi 3 mesi prima dell’inclusione nello studio
    • Trattamento per l’epatite C in atto al momento dell’arruolamento nello studio o nei 3 mesi precedenti
    • Trattamento per l’epatite B intrapreso da meno di 3 mesi al momento dell’arruolamento
    E.5 End points
    E.5.1Primary end point(s)
    To evaluate if a 3-months association of oral 5-MTHF to ‘non selective’ β-blockers can allow a significantly higher HVPG reduction in patients with liver cirrhosis in primary prophylaxis of variceal bleeding than β-blockers alone.
    Valutare l’efficacia del trattamento di 3 mesi con 5-MTHF in associazione con propranololo rispetto a propranololo + placebo, in termini di riduzione dell’HVPG nei pazienti cirrotici con IP.
    E.5.1.1Timepoint(s) of evaluation of this end point
    3 months + 2 weeks follow-up
    3 mesi + 2 settimane FU
    E.5.2Secondary end point(s)
    To evaluate the tolerability of 5-MTHF n patients with cirrhosis and portal hypertension
    2) To evaluate if there is an improvement of intrahepatic vascular tone mediated through diminished oxidative stress and major NO bioavailability in the hepatic microcirculation in patients with cirrhosis treated with propranolol+5-MTHF compared to patients treated with propranolol alone. This outcome will be evaluated by testing ADMA, tHcy and BH4 levels at baseline and after 3 months of oral administration of propranolol+5-MTHF or propranolol+placebo and by comparing the respectively obtained biomarkers levels in the two groups of patients.
    1. Valutare la tollerabilità di 5-MTHF nei pazienti cirrotici con IP
    2. Valutare se vi è un miglioramento del tono vascolare intraepatico attraverso la diminuzione dello stress ossidativo e maggiore biodisponibilità di NO (espressi dai livelli sierici di ADMA, tHcy, BH4, 5-MTHF) nei pazienti con cirrosi e IP trattati per 3 mesi con propranololo + 5-MTHF rispetto a quelli trattati con propranololo + placebo.
    E.5.2.1Timepoint(s) of evaluation of this end point
    3 months + 2 weeks follow-up
    3 mesi + 2 settimane FU
    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 No
    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) 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 No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    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) 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 Yes
    E.8.4 The trial involves multiple sites in the Member State concerned No
    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
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years
    E.8.9.1In the Member State concerned months24
    E.8.9.1In the Member State concerned days
    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: 40
    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 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)
    Normal care
    Normale percorso assistenziale
    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 Decision2014-12-22
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2015-02-10
    P. End of Trial
    P.End of Trial StatusOngoing
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