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    Summary
    EudraCT Number:2021-003062-12
    Sponsor's Protocol Code Number:PA-ADPKD-301
    National Competent Authority:Italy - Italian Medicines Agency
    Clinical Trial Type:EEA CTA
    Trial Status:Prematurely Ended
    Date on which this record was first entered in the EudraCT database:2021-10-18
    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 ConcernedItaly - Italian Medicines Agency
    A.2EudraCT number2021-003062-12
    A.3Full title of the trial
    A Phase 3 Study of the Efficacy and Safety of Lixivaptan in Participants with Autosomal Dominant Polycystic Kidney Disease Consisting of a 1-year Double-blind, Placebo-controlled, Randomized Phase and a 1-year Open-Label Phase: The ACTION Study.
    Studio di fase 3 sull'efficacia e la sicurezza di lixivaptan in partecipanti affetti da malattia policistica renale autosomica dominante, che comprende una fase in doppio cieco, randomizzata, controllata con placebo della durata di 1 anno e una fase in aperto della durata di 1 anno: studio ACTION
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A clinical trial to look at how safe and how effective Lixivaptan in patients with kidney disease compared to a placebo treatment.
    Uno studio clinico per valutare la sicurezza e l'efficacia di Lixivaptan nei pazienti con malattia renale rispetto a un trattamento con placebo.
    A.3.2Name or abbreviated title of the trial where available
    ACTION
    ACTION
    A.4.1Sponsor's protocol code numberPA-ADPKD-301
    A.5.4Other Identifiers
    Name:INDNumber:136,419
    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 SponsorPalladio Biosciences, Inc.
    B.1.3.4CountryUnited States
    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 supportPalladio Biosciences Inc.
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationPalladio Biosciences Inc.,
    B.5.2Functional name of contact pointMilena Kanova
    B.5.3 Address:
    B.5.3.1Street Address5 Walnut Grove Drive, Suite 120
    B.5.3.2Town/ cityHorsham
    B.5.3.3Post codePA 19044
    B.5.3.4CountryUnited States
    B.5.4Telephone number447780430583
    B.5.6E-mailmkanova@palladiobio.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 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 nameLixivaptan
    D.3.2Product code [0C23]
    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 INNLixivaptan
    D.3.9.1CAS number 168079-32-1
    D.3.9.2Current sponsor code0C23
    D.3.9.4EV Substance CodeSUB32850
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number50
    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 Information not present in EudraCT
    D.3.11.3.2Gene therapy medical product Information not present in EudraCT
    D.3.11.3.3Tissue Engineered Product Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    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
    Autosomal Dominant Polycystic Kidney Disease
    Malattia policistica renale autosomica dominante
    E.1.1.1Medical condition in easily understood language
    Kidney disorder characterized by cyst formation and progressive enlargement in the kidney, liver, and other organs
    Malattia renale caratterizzata dalla formazione di cisti e progressivo
    ingrossamento di reni, fegato e altri organi
    E.1.1.2Therapeutic area Body processes [G] - Genetic Phenomena [G05]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10036046
    E.1.2Term Polycystic kidney, autosomal dominant
    E.1.2System Organ Class 100000004850
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    Primary Objective of Part 1:
    •To demonstrate the efficacy of lixivaptan compared to placebo in the slowing of deterioration in kidney function in participants with ADPKD as demonstrated by the annualized change from baseline in estimated glomerular filtration rate (eGFR).
    The key safety objective of Part 1:
    •To compare the incidences of liver chemistry test elevations in participants randomized to lixivaptan with participants randomized to placebo.

    Primary Objective of Part 2:
    •To demonstrate the continued efficacy of lixivaptan in the slowing of deterioration in kidney function in participants randomized to lixivaptan in the double-blind phase (Part 1) as measured by the annualized change from baseline (Part 2) in eGFR at the end of the open-label phase (Part 2).
    The key safety objective of Part 2:
    •To assess the incidence of liver chemistry test abnormalities during the open-label phase.
    L’obiettivo primario della Parte 1 è:
    • Dimostrare l’efficacia di lixivaptan rispetto al placebo nel rallentare il deterioram della funzionalità renale in partecip affetti da ADPKD, dimostrata dalla variazione annualizzata rispetto al basale della velocità di filtr glomerulare stimata (eGFR).
    L’obiettivo di sicurezza princ della Parte 1 è:
    • Confrontare l’incidenza dell’aumento negli esami di funzionalità epatica in partecip randomizzati a lixivaptan rispetto a partecip randomizzati a placebo.
    L’obiettivo principale della Parte 2 è:
    • Dimostrare l’efficacia continua di lixivaptan nel rallentare il deterioram della funzionalità renale nei partecip randomizzati a lixivaptan nella fase in doppio cieco (Parte 1), misurata mediante la variaz annualizzata rispetto al basale (Parte 2) dell’eGFR al termine della fase in aperto (Parte 2).
    L’obiettivo di sicurezza principale della Parte 2 è:
    • Valutare l’incidenza delle alterazioni degli esami di funzionalità epatica durante la fase in aperto.
    E.2.2Secondary objectives of the trial
    The secondary objectives of Part 1:
    •To compare the rate of change (slope) in on-treatment eGFR in participants treated with lixivaptan to participants treated with placebo.
    •To assess the effect of lixivaptan on total kidney volume (TKV) as measured by magnetic resonance imaging (MRI) compared to placebo.
    The secondary safety objective of Part 1:
    •To assess the non-hepatic safety and tolerability of lixivaptan.
    The secondary objectives of Part 2 are:
    •To assess the rate of change (slope) in on-treatment eGFR in Part 2 in participants treated with lixivaptan in Part 1 and Part 2;
    •To assess the effect of lixivaptan on TKV as measured by MRI in Part 2 in participants treated with lixivaptan in Part 1 and Part 2.
    The secondary safety objective of Part 2:
    •To assess the non-hepatic safety and tolerability of lixivaptan.
    Gli obiettivi secondari della Parte 1 sono:
    • Confrontare la percentuale di variazione (curva) dell’eGFR durante il trattamento nei partecipanti trattati con lixivaptan rispetto ai partecipanti trattati con placebo;
    • Valutare l’effetto di lixivaptan sul volume renale totale (TKV) misurato mediante risonanza magnetica (RM) rispetto al placebo.
    L’obiettivo di sicurezza secondario della Parte 1 è:
    • Valutare la sicurezza non epatica e la tollerabilità di lixivaptan.
    Gli obiettivi secondari della Parte 2 sono:
    • Valutare la percentuale di variazione (curva) dell’eGFR durante il trattamento nella Parte 2 nei partecipanti trattati con lixivaptan nella Parte 1 e nella Parte 2;
    • Valutare l’effetto di lixivaptan sul TKV misurato mediante RM nella Parte 2 nei partecipanti trattati con lixivaptan nella Parte 1 e nella Parte 2.
    L’obiettivo di sicurezza secondario della Parte 2 è:
    • Valutare la sicurezza non epatica e la tollerabilità di lixivaptan.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1.Male or female, between 18 and 60 years of age (inclusive) at the time of Screening (Visit 1a).
    2.Diagnosis of ADPKD by modified Pei criteria:
    •For participants with family history of ADPKD, by ultrasound:
    - 18-39 years: =3 cysts, unilateral or bilateral;
    - 40-59 years: =2 cysts in each kidney;
    - 60 years: =4 cysts in each kidney; or
    •For participants with family history of ADPKD, by computerized tomography (CT) or MRI:
    - 18-40 years: =10 cysts in both kidneys; or
    •For participants without family history of ADPKD
    - a minimum of 10 cysts per kidney by any radiologic method and
    exclusion of other cystic kidney diseases (multiple simple kidney
    cysts, renal tubular acidosis, cystic dysplasia of the kidney,
    multicystic kidney, multilocular cysts of the kidney, medullary
    cystic kidney and acquired cystic disease of the kidney); or
    - genetic diagnosis of ADPKD.
    3.Mayo Clinic ADPKD classification of 1C, 1D, or 1E based on age and height-adjusted total kidney volume as determined by kidney MRI obtained during Screening, as assessed by the central imaging vendor.
    4.eGFR =25 mL/min/1.73 m2 and =90 mL/min/1.73 m2 based on the mean of 2 eGFR determinations (Visits 1a and 2 or Visits 1b and 2, if Visit 1b is required) calculated by the Chronic Kidney Disease Epidemiology Collaboration (CKD EPI) equation
    from serum creatinine values obtained during Screening (Appendix 1 (Section 13.1)) Note: This criterion will preliminarily be reviewed at Visit 2 based on Visit 1a or Visit 1b results (if Visit 1b is required). The criterion must be re-evaluated no later than Visit 3 when results for Visits 1a and 2 or Visits 1b and 2 are available.
    5.Appropriate control of hypertension including an angiotensin converting enzyme inhibitor or angiotensin receptor blocker (unless not considered appropriate for the participant) as suggested by the Kidney Disease Improving Global Outcomes (KDIGO) “Clinical Practice Guideline for the Management of Blood Pressure in Chronic Kidney Disease,” without the use of a diuretic.
    6.Body mass index (BMI) between 18 and 40 kg/m2 (inclusive) at the time of Screening.
    7.Female participants must:
    a. not be pregnant, lactating, or breastfeeding.
    b. be either postmenopausal (defined as amenorrhea for = 12 months), surgically sterile (defined as having undergone hysterectomy and/or bilateral oophorectomy) or, if of child-bearing potential (WOCBP), agree to practice acceptable methods of birth control or remain abstinent (only if this is the usual and preferred lifestyle of the participant) during the full duration of the trial and for 30 days after the last dose of study drug. Birth control methods that can be used during the study include the following:
    • hormonal contraception associated with inhibition of ovulation (i.e., oral, intravaginal, transdermal) progestogen-only hormonal contraception (i.e., oral, injectable, implantable)
    • intrauterine device (IUD), including progestin-containing intrauterine devices
    • intrauterine hormone-releasing system (IUS)
    • male sexual partner who has been vasectomized for at least 3 months prior to Screening and who has obtained a follow-up negative sperm count and is the sole sexual partner
    • bilateral tubal ligation
    • Essure® procedure (tubal occlusion)
    • male or female condom with spermicide (cream, spray, gel, suppository, or polymer film)
    • diaphragm, cervical cap, or contraceptive sponge with spermicide (with or without male condom)
    8.Male participants must agree to use an acceptable form of birth control (see list above) or remain abstinent (only if this is the usual and preferred lifestyle of the participant) during the full duration of the trial and for 30 days after the last dose of study drug.
    9.Have read, understood, and provided written informed consent after the nature of the study has been fully explained and must be willing to comply with protocol requirements and study-related procedures.
    1.Paziente di sesso maschile o femminile, tra i 18 e i 60 anni di età (comprese) al momento dello Screening (Visita 1a).
    2.Diagnosi di ADPKD secondo i criteri di Pei modificati:
    •Per i partecipanti con anamnesi familiare di ADPKD, mediante ecografia:
    -18-39 anni: =3 cisti, unilaterali o bilaterali;
    - 40-59 anni: =2 cisti in ciascun rene;
    - 60 anni: =4 cisti in ciascun rene; oppure
    •Per i partecipanti con anamnesi familiare di ADPKD, mediante tomografia computerizzata (TC) o RM:
    -18-40 anni: =10 cisti in ciascun rene; oppure
    - Per i partecipanti senza anamnesi familiare di ADPKD:
    - almeno 10 cisti per rene visualizzate mediante qualsiasi metodo radiografico ed esclusione di altre patologie cistiche renali (cisti renali multiple semplici, acidosi tubulare renale, displasia cistica renale, rene multicistico, cisti renale multiloculare, malattia cistica della midollare e malattia cistica renale acquisita); oppure
    •diagnosi genetica di ADPKD.
    3.Classificazione ADPKD della Mayo Clinic di 1C, 1D o 1E in base all’età e al volume renale totale corretto per l’altezza, determinato mediante RM renale effettuata allo Screening, valutata dal fornitore centrale dei servizi di imaging.
    4.eGFR =25 ml/min/1,73 m2 e =90 ml/min/1,73 m2 basata sulla media di 2 determinazioni dell’eGFR (Visite 1a e 2 o Visite 1b e 2, se la Visita 1b è necessaria) calcolata utilizzando l’equazione Chronic Kidney Disease Epidemiology Collaboration (CKD EPI) con i valori di creatinina sierica ottenuti allo Screening. Nota: Questo criterio verrà riesaminato in maniera preliminare alla Visita 2 in base ai risultati della Visita 1a o Visita 1b (se la Visita 1b è necessaria). Il criterio deve essere riesaminato non più tardi della Visita 3 quando saranno disponibili i risultati delle Visite 1a e 2 o Visite 1b e 2.
    5.Controllo adeguato dell’ipertensione, compreso un inibitore dell’enzima convertitore dell'angiotensina o un antagonista del recettore per l'angiotensina (a meno che non sia controindicato per il partecipante) come suggerito dalle linee guida Kidney Disease Improving Global Outcomes (KDIGO) “Clinical Practice Guideline for the Management of Blood Pressure in Chronic Kidney Disease,” senza l’utilizzo di un diuretico.
    6.Indice di massa corporea (BMI) tra 18 e 40 kg/m2 (compresi) al momento dello Screening.
    7.Le partecipanti di sesso femminile devono:
    •non essere in stato di gravidanza, né allattare al seno.
    •essere in stato post-menopausale (definito da amenorrea = 12 mesi), chirurgicamente sterili (ovvero sottoposte a isterectomia e/o ovariectomia bilaterale) o, se in età fertile (WOCBP), accettare di utilizzare metodi contraccettivi accettabili o praticare l’astinenza (solo se fa parte dello stile di vita abituale e preferito della partecipante) per tutta la durata della sperimentazione e per 30 giorni dopo l’ultima dose di farmaco in studio. I metodi contraccettivi che possono essere utilizzati durante lo studio comprendono:
    •contraccettivi ormonali: contraccettivo ormonale combinato (contenente un estrogeno e un progestinico) che inibisce l’ovulazione (ad es. orale, intravaginale, transdermico) oppure contraccettivo ormonale solo progestinico (ad es. orale, iniettabile, impianto)
    •dispositivo intrauterino (IUD), compresi dispositivi intrauterini contenenti progestinico
    •sistema intrauterino a rilascio di ormoni (IUS) [...]
    8.I partecipanti di sesso maschile devono accettare di utilizzare un metodo contraccettivo accettabile (consultare l’elenco sopra) oppure di praticare l’astinenza (solo se fa parte dello stile di vita abituale e preferito del partecipante) per tutta la durata della sperimentazione e per 30 giorni dopo l’ultima dose di farmaco in studio.
    9.Aver letto, compreso e fornito il consenso informato scritto dopo che la natura di questo studio è stata spiegata in maniera completa ed avere la volontà di attenersi ai requisiti del protocollo e alle procedure correlate allo studio.
    E.4Principal exclusion criteria
    1.Advanced diabetes (e.g., glycosylated hemoglobin [HgbA1c] >7.5%, and/or glycosuria by dipstick, significant proteinuria [>300 mcg albumin/mg creatinine]), other significant kidney disease, kidney cancer, transplanted kidney, single kidney, kidney surgery within the past 6 months (including cyst drainage or fenestration) or acute kidney injury within 6 months prior to Screening.
    2.Clinically significant incontinence, overactive bladder, or urinary retention (e.g., benign prostatic hyperplasia).
    3.New York Heart Association Functional Class 3 or 4 heart failure or other significant cardiac or electrocardiogram (ECG) findings that could pose a safety risk to the participant.
    4.History of infection with HIV unless the participant is stable and doing well on a non-CYP interacting ART regimen and the participant has not required more than 2 changes in their ART regimen since treatment inception.
    5.History of clinically significant drug or alcohol abuse in the 2 years prior to Screening Visit 1a.
    6.Contraindications to or interference with MRI assessments (e.g., ferromagnetic metal prostheses, aneurysm clips, severe claustrophobia, or large abdominal/back tattoos). Investigator should seek MRI safety guidance from the local MRI facility.
    7.Any malignancy within 5 years prior to Screening except for basal cell carcinoma successfully treated with local therapy or malignancies that are considered by the Investigator not to affect participant survival (after discussion with the medical monitor).
    8.Medical history or findings that preclude safe participation in the trial or participants who are likely to be non-compliant with trial procedures in the opinion of the Investigator or medical monitor.
    9.Clinically significant liver disease or impairment or ALT, AST, or total bilirubin values >1.2 x ULN during Screening. Note: This criterion will preliminarily be reviewed at Visit 2 based on Visit 1a and Visit 1b results (if Visit 1b is required). The criterion must be re-evaluated no later than Visit 3 when results for Visit 2 are available.
    10.Requirement for ongoing diuretic use.
    11.Participants who are currently taking, or are expected to be taking, strong or moderate CYP3A4 or CYP2C8 inhibitors or inducers including regular use of grapefruit juice, Seville oranges, or St. John’s wort. If applicable, there should be a 14-day washout of these treatments prior to Visit 2.
    12.Prior use of a sodium-glucose cotransporter 2 (SGLT2) inhibitor (e.g., canagliflozin, dapagliflozin, empagliflozin, etc.) within the 2 months prior to Screening Visit 1a or expected need for initiation of treatment with a SGLT2 inhibitor during the study.
    13. Prior use of a hypoxia-inducible factor prolyl hydroxylase (HIF-PH) inhibitor within the 2 months prior to Screening Visit 1a or expected need for initiation of treatment with a HIF-PH inhibitor during the study.
    14.Simvastatin at a total daily dose >10 mg or amlodipine at a total daily dose >5 mg.
    15.Prior use of tolvaptan or lixivaptan within the 2 months prior to Screening Visit 1a.
    16.Prior use of conivaptan, somatostatin analogs (e.g., lanreotide, pasireotide, octreotide, etc.), metformin (except for diabetes), nicotinamide, bardoxolone, demeclocycline, or mTOR kinase inhibitors (e.g., everolimus, sirolimus, etc.) within the 2 months prior to Screening Visit 1a.
    17.Participants who have taken any investigational drug or used an investigational device within 30 days, or 5 half-lives, whichever is longer, prior to Screening Visit 1a or plan to participate in an interventional trial during the study.
    18.Hypovolemia on physical examination at Screening.
    19.Abnormal serum sodium concentration at Screening.
    20.Positive test results for hepatitis B surface antigen (HBsAg).
    21.Positive test results for hepatitis C (HCV) antibody (Anti-HCV), with the exception of particip for whom the reflex HCV RNA titer test is negative.
    22.Known sensitivity or idiosyncratic reaction to lixivaptan and/or its excipients.
    1.Diabete avanzato (ad es. emoglobina glicata [HgbA1c] >7,5% e/o glicosuria misurata con stick reattivo, proteinuria significativa [>300 mcg albumina/mg creatinina]), altra patologia renale significativa, tumore renale, trapianto di rene, rene singolo, intervento chirurgico renale nei 6 mesi precedenti (compreso drenaggio cistico o fenestrazione) o danno renale acuto nei 6 mesi precedenti lo Screening.
    2.Incontinenza, vescica iperattiva o ritenzione urinaria clinic. significativa.
    3.Insufficienza cardiaca di classe funzionale 3 o 4 secondo la New York Heart Association o altra evidenza cardiaca o all’ECG significativa che potrebbe rappresentare un rischio di sicurezza per il partecip.
    4.Anamnesi di infez. da virus dell’HIV a meno che il partecipante non sia stabile e in buone condizioni in ART che non interagisce con CYP e che la terapia ART del partecip non abbia subito più di 2 modifiche dall’inizio del trattamento.
    5.Anamnesi di abuso di droghe o alcol clinicam. significativo nei 2 anni precedenti la Visita 1a di Screening.
    6.Controindicaz o interferenza con le valutaz. RM. Lo sperimentatore deve fare riferim alle linee guida di sicurezza locali.
    7.Patologie maligne nei 5 anni precedenti lo Screening, escluso carcinoma basocellulare trattato con successo con terapia locale o patologie maligne che secondo il PI non pregiudicano la sopravvivenza del partecip (dopo discussione con il MM).
    8.Anamnesi o evidenza clinica che preclude la partecipazione in sicurezza alla sperimentazione o partecipanti che probabilmente non si atterrebbero alle procedure della sperimentaz secondo lo Sperimentatore o il medical monitor.
    9.Patologia o danno epatico clinic. significativo o valori di ALT, AST o bilirubina totale >1,2 x ULN durante lo Screening. Nota: Questo criterio verrà riesaminato in maniera preliminare alla Visita 2 in base ai risultati della Visita 1a e Visita 1b (se la Visita 1b è necessaria). Il criterio deve essere riesaminato non più tardi della Visita 3 quando i risultati della Visita 2 sono disponibili.
    10.Necessità di trattam continuato con diuretici.
    11.Partecip che assumono attualmente, oppure che ci si attende dovranno assumere, inibitori o induttori forti o moderati di CYP3A4 o CYP2C8, compreso utilizzo regolare di succo di pompelmo, arance di Siviglia o iperico. Se applicabile, si dovrà effettuare un periodo di washout di 14 giorni da queste sostanze prima della Visita 2.
    12.Utilizzo precedente di un inibitore del co-trasportatore sodio-glucosio di tipo 2 (SGLT2) nei 2 mesi precedenti la Visita di Screening 1a o necessità prevista di avviare il trattamento con un inibitore del SGLT2 durante lo studio.
    13.Utilizzo precedente di un inibitore della prolil idrossilasi (HIF-PH) del fattore inducibile dall'ipossia nei 2 mesi precedenti la Visita di Screening 1a o necessità prevista di avviare il trattamento con un inibitore della HIF-PH durante lo studio.
    14.Simvastatina a una dose giornaliera totale >10 mg o amlodipina a una dose giornaliera totale >5 mg.
    15.Utilizzo preced. di tolvaptan o lixivaptan nei 2 mesi precedenti la Visita di Screening 1a.
    16.Utilizzo precedente di conivaptan, analoghi della somatostatina, metformina (tranne che per il diabete), nicotinamide, bardoxolone, demeclociclina o inibitori della protein-chinasi mTOR nei 2 mesi precedenti la Visita di Screening 1a.
    17.Partecip che hanno assunto farmaci sperimentali o usato un dispositivo sperimentale nei 30 giorni, o 5 emivite, qualunque dei due periodi sia il più lungo, prima della Visita di Screening 1a o che hanno in programma di partecip a una sperim interventistica.
    18.Ipovolemia all’esame obiettivo allo Screening.
    19.Concentraz alterata di sodio sierico allo Screening.
    20.Risultato + al test per l'antigene di superficie dell'epatite B (HBsAg).
    21.Risultato + al test per gli anticorpi (Anti-HCV) dell’epatite C (HCV), ad eccezione dei partecip con titolo HCV RNA negativo.
    22.Sensibilità o reazione idiosincrasica nota a lixivaptan e/o i suoi eccipienti.
    E.5 End points
    E.5.1Primary end point(s)
    Part 1:
    •The primary endpoint is the annualized change in eGFR calculated from the CKD-EPI equation for serum creatinine from baseline (mean of 3 eGFR determinations obtained during Screening and Placebo Run-in Periods (Visits 1a/1b (if required), Visit 2, and Visit 3) to final assessment (mean of 3 eGFR determinations obtained during Follow-up Period I or, for participants who discontinue treatment prior to Visit 22, during the Follow-up Period 8 to 28 days following study drug treatment discontinuation).
    Part 1 Key Safety Endpoint
    •Incidence of serum ALT levels >3 x ULN in participants randomized to lixivaptan compared to those randomized to placebo.

    Part 2 Key Comparison Endpoint
    •The primary endpoint of Part 2 is the annualized change in eGFR calculated from the CKD-EPI equation for serum creatinine from baseline (mean of 3 eGFR determinations obtained during Follow-up Period I) to final assessment (mean of 3 eGFR determinations obtained during Follow-up Period II).
    Part 2 Key Safety Endpoint:
    •Incidence of serum ALT levels > 3 x ULN in participants exposed to lixivaptan in Part 2.
    Parte 1:
    Endpoint di efficacia primario: Variazione annualizzata dell’eGFR calcolata mediante equazione CKD-EPI per la creatinina sierica dal basale (media di 3 determinazioni dell’eGFR ottenute durante i Periodi di Screening e di run-in con placebo (Visite 1a o 1b (se necessario), Visita 2 e Visita 3) alla valutazione finale (media di 3 determinazioni dell’eGFR ottenute durante il Periodo di follow-up I oppure, per i partecipanti che interrompono il trattamento prima della Visita 22, durante il Periodo di follow-up da 8 a 28 giorni dopo l’interruzione del trattamento con il farmaco in studio).
    Endpoint di sicurezza principale: Incidenza di livelli di ALT sierica >3 x ULN nei partecipanti randomizzati a lixivaptan rispetto a quelli randomizzati a placebo.

    Parte 2:
    Endpoint comparativo principale: Variazione annualizzata dell’eGFR dal basale (media di 3 determinazioni dell’eGFR ottenute durante il Periodo di follow-up I) alla valutazione finale post-trattamento nella Parte 2 (media di 3 determinazioni dell’eGFR ottenute durante il Periodo di follow-up II)
    Endpoint di sicurezza principale: Incidenza di livelli di ALT sierico >3 x ULN nei partecipanti esposti a lixivaptan nella Parte 2.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Throughout this study, the safety of participants will be closely monitored by an independent data monitoring committee (DMC). The DMC will comprise three disease experts and a biostatistician and will be governed by a DMC Charter. A Data Monitoring Committee will review safety and study data at specified intervals for the duration of the study.
    Durante questo studio, la sicurezza dei partecipanti sarà attentamente monitorata da un comitato indipendente per il monitoraggio dei dati (IDMC). Il DMC comprenderà tre esperti di patologie e un biostatistico e sarà disciplinato da un DMC charter. Un comitato di monitoraggio dei dati esaminerà la sicurezza e i dati dello studio a specifici intervalli durante il corso dello studio.
    E.5.2Secondary end point(s)
    Part 1:
    •The annualized rate of change (slope) in on-treatment eGFR, based on all on-treatment eGFR determinations during the Double-Blind, Randomized Treatment Period in Part 1, calculated from the CKD-EPI equation for serum creatinine;
    •The annualized rate of change from baseline in TKV, determined by MRI, during Follow-up Period I.

    Secondary Safety and tolerability of lixivaptan assessed through evaluation of:
    •Treatment-emergent adverse events (TEAEs);
    •Clinical laboratory findings (clinical chemistry including additional analyses of liver chemistry, hematology and urinalysis);
    •Vital signs;
    •12-lead electrocardiograms (ECG).

    Part 2:
    •The annualized rate of change in eGFR (calculated from the CKD-EPI equation for serum creatinine) from baseline (mean of 3 eGFR determinations obtained during Follow-up Period I) to Follow-up Period II;
    •The annualized rate of change in TKV determined by MRI.

    Secondary Safety and tolerability of lixivaptan assessed through evaluation of:
    •Treatment-emergent adverse events (TEAEs);
    •Clinical laboratory findings (clinical chemistry including additional analyses of liver chemistry tests), hematology and urinalysis);
    •Vital signs;
    •12-lead electrocardiograms (ECG).
    Parte 1:
    •Il tasso di variazione annualizzato (pendenza) dell'eGFR durante il trattamento, basato su tutte le determinazioni di eGFR durante il periodo di trattamento in doppio cieco, randomizzato nella Parte 1, calcolato dall’equazione CKD-EPI per la creatinina sierica;
    • Il tasso di variazione annualizzato del TKV a partire dal baseline, determinato mediante RM, durante il periodo di follow-up I.

    Sicurezza secondaria e tollerabilità del lixivaptan valutate attraverso valutazione di:
    •Eventi avversi emergenti dal trattamento (TEAE);
    •Risultati clinici di laboratorio (chimica clinica inclusi ulteriori esami epatochimici, di ematologia e analisi delle urine);
    •Segni vitali;
    •elettrocardiogramma (ECG) a 12 derivazioni.

    Parte 2:
    •Il tasso di variazione annualizzato dell'eGFR (calcolato dall’equazione CKD-EPI per la creatinina sierica) a partire dal baseline (media di 3 determinazioni eGFR ottenute durante il periodo di follow-up I) fino al periodo di follow-up II;
    •Il tasso annualizzato di variazione del TKV determinato mediante risonanza magnetica.

    Sicurezza secondaria e tollerabilità del lixivaptan valutate attraverso valutazione di:
    •Eventi avversi emergenti dal trattamento (TEAE);
    •Risultati clinici di laboratorio (chimica clinica inclusi ulteriori esami epatochimici, di ematologia e analisi delle urine);
    •Segni vitali;
    •elettrocardiogramma (ECG) a 12 derivazioni.
    E.5.2.1Timepoint(s) of evaluation of this end point
    Secondary efficacy endpoints will be displayed by study
    visit, using summary statistics including the number of observations, the mean, median, standard deviation, and range for continuous measures and counts and percentages for categorical measures. Actual values as well as change from baseline will be presented.
    Supportive and exploratory efficacy measures will be analyzed similarly as above. Details of the analysis methods will be outlined in the statistical analysis plan (SAP).
    In addition, a responder analysis (based on change in serum bile acid
    levels and bilirubin) will also be considered. The response definition and its appropriate analysis methodology will be outlined in the SAP for the study.
    Gli endpoint secondari di efficacia verranno visualizzati per visita di studio, utilizzando statistiche riassuntive compreso il numero di osservazioni, media, mediana, deviazione standard e range per misure continue e conteggi e percentuali per le misure categoriali. Verranno presentati valori effettivi così come il cambiamento rispetto al baseline.
    Le misure di efficacia di supporto ed esplorative saranno analizzate in maniera simile come sopra. I dettagli dei metodi di analisi saranno delineati nel piano di analisi statistica (SAP).
    Inoltre, verrà considerata anche un'analisi del responder (basata sulla variazione dei livelli di acido biliare sierico e bilirubina). La definizione di risposta e la sua metodologia di analisi appropriata sarà delineata nel SAP per lo studio.
    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 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) 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 Yes
    E.8.1.7.1Other trial design description
    Studio suddiviso in due parti: Parte 1 in doppio cieco controllato con placebo e Parte 2 in aperto
    Study in two parts: Part 1 double blind placebo controlled and Part 2 open label
    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 concerned6
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA70
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA Information not present in EudraCT
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Australia
    Brazil
    Canada
    Chile
    Colombia
    Georgia
    Israel
    Mexico
    Peru
    Serbia
    Turkey
    Ukraine
    United States
    Belgium
    Bulgaria
    France
    Hungary
    Italy
    Poland
    Romania
    Slovakia
    Spain
    United Kingdom
    Argentina
    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
    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 months6
    E.8.9.1In the Member State concerned days7
    E.8.9.2In all countries concerned by the trial years2
    E.8.9.2In all countries concerned by the trial months6
    E.8.9.2In all countries concerned by the trial days7
    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: 1200
    F.1.3Elderly (>=65 years) No
    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 state40
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 372
    F.4.2.2In the whole clinical trial 1200
    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
    Nessuno
    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 Decision2022-01-20
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2021-11-09
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
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