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    Summary
    EudraCT Number:2021-002311-64
    Sponsor's Protocol Code Number:SuloPrima
    National Competent Authority:Czechia - SUKL
    Clinical Trial Type:EEA CTA
    Trial Status:Prematurely Ended
    Date on which this record was first entered in the EudraCT database:2021-10-01
    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 ConcernedCzechia - SUKL
    A.2EudraCT number2021-002311-64
    A.3Full title of the trial
    Efficacy and safety of sulodexide in the treatment of chronic primary venous disease of the lower extremities: randomized double-blind placebo-controlled clinical trial
    Účinnost a bezpečnost sulodexidu v terapii chronického primárního žilního onemocnění dolních končetin: randomizované placebem kontrolované dvojitě zaslepené klinické hodnocení
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Treatment of patients with chronic venous disease of the lower extremities using sulodexide
    Terapie pacientů s chronickým žilním onemocněním dolních končetin pomocí sulodexidu
    A.3.2Name or abbreviated title of the trial where available
    SuloPrima
    A.4.1Sponsor's protocol code numberSuloPrima
    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 SponsorALFASIGMA CZECH s.r.o.
    B.1.3.4CountryCzechia
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportALFASIGMA CZECH s.r.o.
    B.4.2CountryCzechia
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationValue Outcomes s.r.o.
    B.5.2Functional name of contact pointClinical trials and regulatory dpt
    B.5.3 Address:
    B.5.3.1Street AddressVáclavská 316/12
    B.5.3.2Town/ cityPrague
    B.5.3.3Post code12000
    B.5.3.4CountryCzechia
    B.5.4Telephone number420727824059
    B.5.6E-mailjan.tuzil@valueoutcomes.cz
    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 Vessel
    D.2.1.1.2Name of the Marketing Authorisation holderAlfasigma S.p.A.
    D.2.1.2Country which granted the Marketing AuthorisationItaly
    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 nameVessel
    D.3.4Pharmaceutical form Capsule, soft
    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 No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    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, soft
    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
    Chronic primary venous disease of the lower limbs
    chronické primární žilní onemocnění dolních končetin
    E.1.1.1Medical condition in easily understood language
    Long-term venous disease of the lower limbs
    Dlouhodobé žilní onemocnění dolních končetin
    E.1.1.2Therapeutic area Diseases [C] - Cardiovascular Diseases [C14]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.1
    E.1.2Level LLT
    E.1.2Classification code 10066682
    E.1.2Term Chronic venous insufficiency
    E.1.2System Organ Class 100000004866
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    The primary objective is to estimate the efficacy of sulodexide therapy after 24 weeks of treatment measured as symptom reduction using the Revised Venous Clinical Severity Score (rVCSS).
    E.2.2Secondary objectives of the trial
    Secondary objectives measure extent of possible symptom reduction in several time periods and collects data on the quality of life. Exploratory objectives collect data on the work productivity, quality fo life, medication discontinuation or adherence and on the odds of adverse reactions with aim to detect predictors related to these factors and events.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    • Diagnosed primary venous disease of the lower limbs in stage C2 - C6 according to the CEAP classification, clinical involvement of the venous system of the lower limbs is verified by duplex ultrasonography
    • Presence of objective and subjective symptoms of the disease (classified according to rVCSS score ≥ 4)

    • The patient signed informed consent for inclusion in the clinical trial and consent to the processing of personal data
    • Patient over 18 years of age
    • Both male and female subjects will be enrolled. Female patients must be of non-childbearing potential, i.e.: post-menopausal (at least 2 years without spontaneous menses) or surgically sterile (bilateral tubal occlusion or hysterectomy or ablation of both ovaries); OR of childbearing potential but with a negative pregnancy test result at Visit 1 AND agrees to use a highly effective method of contraception
    • Diagnostikované primární žilní onemocnění dolních končetin ve stadiu C2 – C6 dle klasifikace CEAP, klinické postižení žilního systému dolních končetin je verifikované duplexní ultrasonografií
    • Přítomnost objektivních a subjektivních příznaků onemocnění (klasifikovaných dle rVCSS, skóre > 4)

    • Pacient podepsal informovaný souhlas se zařazením do klinického hodnocení a souhlas se zpracováním osobních údajů
    • Pacient starší 18 let
    • Do studie budou zařazování muži i ženy. Ženy budou zařazeny v případě, že již nemohou počít dítě t.j. postmenopausální (nejméně 2 roky bez spontánní menstruace) nebo chirurgicky sterilizované (bilaterální okluze vejcovodu nebo hysterektomie nebo ablace obou vaječníků) NEBO ženy které mohou počít dítě, ale mají negativní výsledek těhotenského testu na první návštěvě A ZÁROVEŇ souhlasí s použitím vysoce účinné metody antikoncepce
    E.4Principal exclusion criteria
    • Use of a drug with venoactive effect in the last month
    • Regular use of mechanical devices for reduction of oedema in the last month with the exception of compression therapy
    • Patients who had used compression therapy and stopped early before enrolment (for less than one month)
    • Heart Failure as per NYHA III and IV, congestive heart failure with peripheral oedemas
    • Chronic kidney disease with GF < 30 ml/min (< 0,5 ml/s) and/or proteinuria > 0,5 g/24 hours, nephrotic syndrome, renal oedemas
    • Advanced liver disease (Child-Pugh B and C or laboratory values of ALT or AST more than 3 times upper limit of normal range)
    • Deep venous thrombosis lower limb thrombosis and / or documented residual venous obstruction or deep venous reflux due to post-thrombotic changes in the deep venous system
    • Superficial venous thrombosis of the lower limbs in the previous 6 months
    • Congenital venous / venolymphatic venous malformation
    • Neuropathy of any aetiology
    • Diabetic foot syndrome
    • Refractory (uncontrollable) arterial hypertension (inability to achieve therapeutically systolic blood pressure ≤ 160 mmHg or diastolic blood pressure ≤ 100 mmHg)
    • Symptomatic ischemic disease of lower limbs
    • Lymphoedema: primary, posttraumatic, postoperative, post-radiation, malignant
    • Manual/instrumental lymphatic drainage in the last 6 months
    • Invasive procedure on the lower limbs in the last 6 months
    • Trauma of the lower extremity that has not fully healed
    • Use of oral/parenteral anticoagulants, dual antiplatelet therapy, diuretics, corticosteroids
    • Chronic pain treatment ≥ 14 days
    • Psychopharmaceuticals affecting fluid retention (antipsychotics, combined antidepressants)
    • Pathologic obesity (BMI > 40 kg/m2)
    • The patient is currently enrolled in another interventional or non-interventional study
    • Contraindications to the administration of sulodexide according to IB (haemorrhagic diathesis, hypersensitivity to the drug substance or any of the excipients, heparin, heparinoids or other glycosaminoglycans (GAGs), etc.)
    • Patients with active malignant disease or malignant disease in remission for less than 5 years
    • Pregnancy
    • Breastfeeding
    • Užívání léčiva s venoaktivním účinkem v posledním měsíci
    • Pravidelné použití mechanických prostředků pro snížení otoku v posledním měsíci s výjimkou kompresní terapie.
    • Pacienti, kteří používali kompresní terapii a ukončili její používání méně než 1 měsíc před zařazením do studie
    • Srdeční selhání III a IV dle klasifikace NYHA, městnavé srdeční selhání s periferními otoky
    • Chronické onemocnění ledvin s GF < 30 ml/min (< 0,5 ml/s) a/nebo proteinurií > 0,5 g/24 hodin, nefrotický syndrom, renální otoky
    • Pokročilé jaterní onemocnění (Child-Pugh B nebo laboratorní hodnoty ALT nebo AST více než trojnásobek horní hranice normálního rozmezí)
    • Hluboká žilní trombóza dolních končetin a/nebo dokumentovaná reziduální žilní obstrukce nebo hluboký žilní reflux v důsledku posttrombotických změn v hlubokém žilním systému
    • Povrchová žilní trombóza dolních končetin v předchozích 6 měsících
    • Vrozená venózní/venolymfatická žilní malformace
    • Neuropatie jakékoli etiologie
    • Syndrom diabetické nohy
    • Refrakterní (nekontrolovatelná) arteriální hypertenze (neschopnost dosáhnout terapií systolický krevní tlak ≤160 mmHg nebo diastolický krevní tlak ≤100 mmHg
    • Symptomatická ischemická choroba dolních končetin
    • Lymfedém primární, posttraumatický, pooperační, postradiační, maligní
    • Manuální/přístrojová lymfodrenáž v posledních 6 měsících
    • Invazivní výkon na dolních končetinách v posledních 6 měsících
    • Trauma dolní končetiny, které není kompletně zhojené
    • Používání orálních/parenterálních antikoagulancií, duální protidestičkové terapie, diuretik, kortikosteroidů
    • Chronická léčba bolesti ≥ 14 dní
    • Psychofarmaka ovlivňující retenci tekutin (antipsychotika, kombinovaná antidepresiva)
    • Patologická obezita (BMI > 40 kg/m2)
    • Pacient je v současné době zařazen do jiné intervenční nebo neintervenční studie
    • Kontraindikace podávání sulodexidu podle IB (hemoragická diatéza, přecitlivělost na léčivou látku nebo na kteroukoli pomocnou látku, heparin, heparinoidy nebo jiné glykosaminoglykany (GAG)atd.)
    • Pacienti s aktivním maligním onemocněním nebo maligním onemocněním v remisi po dobu kratší než 5 let
    • Těhotenství
    • Kojení
    E.5 End points
    E.5.1Primary end point(s)
    Efficacy of sulodexide therapy measured as symptom reduction using the Revised Venous Clinical Severity Score (rVCSS). The primary hypothesis is that more patients will achieve a decrease in rVCSS score of at least 4 points with sulodexide than with placebo.
    Účinnost terapie sulodexidem hodnocená měřením redukce symptomů pomocí skóre Revised Venous Clinical Severity Score (rVCCS). Primární hypotézou je, že snížení skóre rVCSS alespoň o 4 body dosáhne více pacientů v rameni sulodexidu než v rameni placeba.
    E.5.1.1Timepoint(s) of evaluation of this end point
    24 Weeks ± 4 weeks
    24 týdnů ± 4 týdny
    E.5.2Secondary end point(s)
    Secondary efficacy:
    • More patients will achieve a decrease in rVCSS score of at least 4 points with sulodexide than with placebo after 4, 8 and 12 weeks of treatment.
    • More patients will achieve a decrease in lower limb volume with sulodexide than with placebo after 4, 8, 12 and 24 weeks of treatment.
    • Mean pain (Visual Analogue Scale VAS) in sulodexide group will be lower than in placebo group after 4, 8, 12 and 24 weeks of treatment.
    • Mean productivity and activity impairment (measured by the Work Productivity and Activity Impairment WPAI questionnaire) in sulodexide group will be lower than in placebo group after 8 and 24 weeks of treatment.
    • Mean functional limitation (measured by the Venous Disability Score VDS) in sulodexide group will be lower than in the placebo group after 8 and 24 weeks of treatment.
    • Mean generic quality of life (measured by the EQ-5D questionnaire) in sulodexide group will be higher than in the placebo group after 8 and 24 weeks of treatment.
    • Mean disease-specific quality of life (measured by the Chronic Venous Insufficiency Quality of Life CIVIQ-20 questionnaire) in the sulodexide group will be higher than in the placebo group after 8 and 24 weeks of treatment.
    • Time to rVCSS worsening of at least 4 points will be longer with sulodexide than with placebo.
    • Time to compression therapy initiation will be longer with sulodexide than with placebo.
    • Time to compression therapy discontinuation in patients using compression therapy at baseline will be shorter with Sulodexide than with placebo.


    Secondary exploratory:
    • Estimating the odds of discontinuation of the treatment, the odds of adherence (total number of soft capsules used in 24 weeks) and the odds of adverse reactions at 24 weeks and detecting the predictors of these types of events, especially the influence of stratification criteria (gender, age and CEAP)
    • Regression models estimating the WPAI score and the EQ-5D score at 24 weeks and detecting the predictors of these types of events, especially the influence of stratification criteria (gender, age and CEAP)
    Sekundární účinnostní cíle:
    • Po 4, 8 a 12 týdnech léčby dosáhne snížení skóre rVCSS alespoň o 4 body více pacientů pomocí sulodexidu než pomocí placeba.
    • Po 4, 8, 12 a 24 týdnech léčby dosáhne snížení objemu dolních končetin více pacientů pomocí sulodexidu než pomocí placeba.
    • Střední hodnota bolesti (Visual Analogue Scale VAS) ve skupině se sulodexidem bude nižší než ve skupině s placebem po 4, 8, 12 a 24 týdnech léčby.
    • Průměrné zhoršení produktivity a aktivity (měřeno dotazníkem WPAI Work Productivity and Activity Impairment) ve skupině se sulodexidem bude po 8 a 24 týdnech léčby nižší než ve skupině s placebem.
    • Průměrné funkční omezení (měřeno podle Venous Disability Score VDS) ve skupině se sulodexidem bude po 8 a 24 týdnech léčby nižší než ve skupině s placebem.
    • Průměrná obecná kvalita života (měřená dotazníkem EQ-5D) ve skupině se sulodexidem bude po 8 a 24 týdnech léčby vyšší než ve skupině s placebem.
    • Průměrná pro onemocnění specifická kvalita života (měřená dotazníkem CIVIQ-20 Chronic Venous Insufficiency Quality of Life) ve skupině s sulodexidem bude po 8 a 24 týdnech léčby vyšší než ve skupině s placebem.
    • Čas do zhoršení rVCSS o nejméně 4 body bude delší u sulodexidu než u placeba
    • Čas do nasazení kompresivní terapie bude delší u sulodexidu než u placeba
    • Doba do ukončení kompresivní terapie u pacientů, kteří na začátku léčby používali kompresivní terapii, bude kratší u Sulodexidu než u placeba.

    Sekundární exploratorní cíle:
    • Odhad pravděpodobnosti přerušení léčby, pravděpodobnosti adherence (celkový počet tobolek užitých za 24 týdnů) a pravděpodobnosti nežádoucích účinků po 24 týdnech a detekce prediktorů těchto typů událostí, zejména vliv stratifikačních kritérií (pohlaví, věk a CEAP)
    • Regresní modely odhadující skóre WPAI a skóre EQ-5D ve 24 týdnech za účelem identifikace prediktorů a vlivu stratifikačních kritérií (pohlaví, věk a CEAP)
    E.5.2.1Timepoint(s) of evaluation of this end point
    The timepoints are specific for each endpoint and are described in the E.5.2 above
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis Yes
    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 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 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 concerned15
    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: 145
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 145
    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 state290
    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
    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 Decision2021-10-01
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2021-09-23
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
    P.Date of the global end of the trial2023-08-01
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