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    Summary
    EudraCT Number:2020-005991-36
    Sponsor's Protocol Code Number:156-12-204
    National Competent Authority:Germany - BfArM
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2021-05-26
    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 ConcernedGermany - BfArM
    A.2EudraCT number2020-005991-36
    A.3Full title of the trial
    A Phase 3b Multicenter Open-label Trial of the Safety, Tolerability, and Efficacy of Tolvaptan in Infants and Children 28 days to less than 12 weeks of Age with Autosomal Recessive Polycystic Kidney Disease (ARPKD)
    Multizentrische, offene Phase-3b-Studie zur Sicherheit, Verträglichkeit und Wirksamkeit von Tolvaptan bei Säuglingen und Kindern im Alter von 28 Tagen bis unter 12 Wochen mit autosomal-rezessiver polyzystischer Nierenerkrankung (ARPKD)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A trial to see if tolvaptan can delay dialysis in infants and children who at enrollment are 28 days to less than 12 weeks old with Autosomal Recessive Polycystic Kidney Disease (ARPKD)
    Die Studie untersucht, ob Tolvaptan bei Säuglingen und Kindern, die bei Studienbeginn 28 Tage bis unter 12 Wochen alt sind und an einer autosomal rezessiven polyzystischen Nierenerkrankung (ARPKD) leiden, die Dialyse verzögern kann
    A.4.1Sponsor's protocol code number156-12-204
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT04786574
    A.7Trial is part of a Paediatric Investigation Plan Yes
    A.8EMA Decision number of Paediatric Investigation PlanP/002/2020
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorOtsuka Pharmaceutical Development & Commercialization, 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 supportOtsuka Pharmaceutical Development & Commercialization, Inc.
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationOtsuka Pharmaceutical Development & Commercialization, Inc.
    B.5.2Functional name of contact pointMathew Taylor
    B.5.3 Address:
    B.5.3.1Street Address2440 Research Boulevard
    B.5.3.2Town/ cityRockville
    B.5.3.3Post codeMD 20850
    B.5.3.4CountryUnited States
    B.5.4Telephone number+12407804266
    B.5.5Fax number+13017218592
    B.5.6E-mailmathew.taylor@otsuka-us.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 nameTolvaptan 50mg Granules
    D.3.2Product code OPC-41061
    D.3.4Pharmaceutical form Granules for oral suspension
    D.3.4.1Specific paediatric formulation Yes
    D.3.7Routes of administration for this IMPOral use
    Nasogastric use (Noncurrent)
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNTolvaptan
    D.3.9.1CAS number 150683-30-0
    D.3.9.2Current sponsor codeOPC-41061
    D.3.9.3Other descriptive nameTOLVAPTAN (OPC-41061)
    D.3.9.4EV Substance CodeSUB22755
    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 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
    Autosomal Recessive Polycystic Kidney Disease (ARPKD)
    Autosomal-rezessive polyzystische Nierenerkrankung (ARPKD)
    E.1.1.1Medical condition in easily understood language
    Genetic disorder that causes numerous cysts to grow in the kidneys.
    Genetische Störung, bei der zahlreiche Zysten in den Nieren wachsen.
    E.1.1.2Therapeutic area Diseases [C] - Congenital, Hereditary, and Neonatal Diseases and Abnormalities [C16]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10036047
    E.1.2Term Polycystic kidney, autosomal recessive
    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
    To evaluate the effect of tolvaptan on the need for RRT in pediatric subjects with ARPKD
    Beurteilung der Wirkung von Tolvaptan in Bezug auf die Notwendigkeit einer RRT bei pädiatrischen Patienten mit ARPKD
    E.2.2Secondary objectives of the trial
    Evaluate changes in eGFR and palatability and acceptability of formulation
    Bewertung der Veränderungen bei eGFR sowie der Schmackhaftigkeit und Akzeptanz der Formulierung
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    Further research will be conducted on the remainder of the samples that are collected during the trial to understand the genetics of ARPKD
    E.3Principal inclusion criteria
    1. Male or female subjects between 28 days and < 12 weeks of age, inclusive.
    2. Must have clinical and imaging features that are consistent with a diagnosis of ARPKD with all the following characteristics:
    - Nephromegaly (> 2 standard deviations from age appropriate standard via ultrasound)
    - Multiple renal cysts
    - History of oligohydramnios or anhydramnios
    3. Ability for parent or guardian to provide written, informed consent prior to initiation of any trial related procedures, and ability, in the opinion of the principal investigator, to comply with all the requirements of the trial.
    1. Männliche oder weibliche Patienten im Alter zwischen 28 Tagen und < 12 Wochen.
    2. Klinische und bildgebende dokumentierte Eigenschaften, die mit der Diagnose einer ARPKD mit allen folgenden Merkmalen übereinstimmen:
    - Nephromegalie (> 2 Standardabweichungen vom altersentsprechenden Standard per Ultraschall)
    - Mehrere Nierenzysten
    - Vorgeschichte eines Oligohydramnions oder Anhydramnions
    3. Eltern/Erziehungsberechtigte müssen in der Lage sein, vor Einleitung studienbezogener Maßnahmen eine schriftliche Einwilligungserklärung abzugeben, und müssen nach Einschätzung des leitenden Prüfers in der Lage sein, alle Anforderungen der Studie einzuhalten.
    E.4Principal exclusion criteria
    1. Premature birth (≤ 32 weeks gestational age)
    2. Anuria or RRT defined as intermittent or continuous hemodialysis, peritoneal dialysis, hemofiltration, hemodiafiltration, or history of kidney transplantation
    3. Evidence of syndromic conditions associated with renal cysts (other than ARPKD)
    4. Abnormal liver function tests including ALT and AST, > 1.2 × ULN
    5. Parents with renal cystic disease
    6. Receiving chronic diuretic that could not be adjusted after tolvaptan initiation
    7. Cannot be monitored for fluid balance
    8. Has or at risk of having sodium and potassium electrolyte imbalances, as determined by the investigator
    9. Has or at risk of having significant hypovolemia (eg, subjects that lack free access to water, without adequate fluid monitoring and management) as determined by investigator
    10. Clinically significant anemia, as determined by investigator
    11. Severe systolic dysfunction defined as ejection fraction < 14%
    12. Serum sodium levels < 130 mmol/L or >145 mmol/L (or the ULN of the local laboratory, whichever is lower).
    13. Taking any other experimental medications
    14. Require ventilator support
    15. Taking medications known to induce CYP3A4
    16. Having an infection including viral that would require therapy disruptive to IMP dosing
    17. Platelet count <50,000 µL
    18. Has findings consistent with clinically significant portal hypertension (eg, varices, variceal bleeding, hypersplenism indicated by thrombocytopenia).
    19. Bladder dysfunction and/or difficulty voiding
    20. Taking a vasopressin agonist (eg, desmopressin)
    21. Having concomitant illnesses or taking medications likely to confound endpoint assessments, including taking approved (ie, marketed) therapies for the purpose of affecting PKD cysts such as tolvaptan, vasopressin antagonists, anti-sense RNA therapies, rapamycin, sirolimus, everolimus, or somatostatin analogs (ie, octreotide, sandostatin)
    22. History of cholangitis
    23. Received or are scheduled to receive a liver transplant
    1. Frühgeburt (≤ 32 Wochen Gestationsalter)
    2. Anurie oder RRT definiert als intermittierende oder kontinuierliche Hämodialyse, Peritonealdialyse,
    Hämofiltration, Hämodiafiltration oder Nierentransplantation in der Anamnese
    3. Hinweise auf syndromale Erkrankungen im Zusammenhang mit Nierenzysten (außer ARPKD)
    4. Abnorme Leberfunktionstest, einschließlich ALT und AST > 1,2 × ULN
    5. Eltern mit zystischer Nierenerkrankung
    6. Einnahme eines permanenten Diuretikums, das nach der Einführung von Tolvaptan nicht angepasst werden konnte
    7. Flüssigkeitshaushalt kann nicht überwacht werden
    8. Durch den Prüfarzt festgestelltes Ungleichgewicht von Natrium, Kalium und Elektrolyten
    9. Durch den Prüfarzt festgestelltes Risiko für signifikante Hypovolämie (z. B. bei Personen, die keinen freien Zugang zu Wasser haben[Unfähigkeit, auf Durst zu reagieren, abhängig vom Alter], ohne angemessene Flüssigkeitsüberwachung
    10. Durch den Prüfarzt festgestellte klinisch signifikante Anämie
    11. Schwere systolische Dysfunktion, definiert als Ejektionsfraktion < 14 %
    12. Natriumspiegel im Serum < 130 mmol/l oder >145mmol/l (oder die ULN des lokalen Labors, je nachdem welcher Wert niedriger ist)
    13. Einnahme anderer experimenteller Medikamente
    14. Erforderliche Atmungsunterstützung mit Beatmungsgerät
    15. Einnahme von Medikamenten, die bekanntermaßen CYP3A4 induzieren
    16. Infektion einschließlich Virusinfektion, die eine Therapie erforderlich macht, welche die Dosisgabe des Prüfarzneimittels beeinträchtigen würde
    17. Thrombozytenzahl < 50.000 µl
    18. Befunde, die auf eine klinisch signifikante portale Hypertension hindeuten (z. B. Varizen, Varizenblutungen, Hypersplenismus mit Thrombozytopenie).
    19. Blasenfunktionsstörung und/oder Blasenentleerungsstörungen
    20. Einnahme eines Vasopressin-Agonisten (z.B. Desmopressin)
    21. Begleitende Erkrankungen oder Einnahme von Medikamenten, die die Endpunktbewertung beeinträchtigen können, einschließlich der Einnahme von zugelassenen (d. h. vermarkteten) Therapien zur Beeinflussung von PKD-Zysten wie Tolvaptan, Vasopressin-Antagonisten, Anti-Sense-RNA-Therapien, Rapamycin, Sirolimus, Everolimus oder Somatostatin-Analoga (d. h. Octreotid, Sandostatin)
    22. Cholangitis in der Anamnese
    23. Eine Lebertransplantation wurde durchgeführt oder ist geplant
    E.5 End points
    E.5.1Primary end point(s)
    Percentage of subjects having RRT by 1 year of age
    Prozentanteil der Studienteilnehmer mit RRT bei Vollendung des 1. Lebensjahres
    E.5.1.1Timepoint(s) of evaluation of this end point
    12 Months
    12 Monate
    E.5.2Secondary end point(s)
    - Rate of change of eGFR (eGFR Schwartz formula = 0.413 × height [or length, cm] /serum creatinine mg/dL) from pretreatment to post-treatment after 2 years of treatment
    - Age-appropriate assessment of acceptability and palatability of formulation
    - Änderungsrate der eGFR (eGFR Schwartz-Formel = 0,413 × Größe [oder Länge in cm] / Serumkreatinin mg/dl) vor der Behandlung bis nach 2 Jahren Behandlung
    - Altersgerechte Bewertung der Akzeptanz und Schmackhaftigkeit der Formulierung
    E.5.2.1Timepoint(s) of evaluation of this end point
    pre-treatment to post treatment after 2 years of treatment
    vor der Behandlung bis 2 Jahre nach Behandlung
    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 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 Yes
    E.6.13.1Other scope of the trial description
    Tolerabiltiy
    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 No
    E.8.1.1Randomised No
    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) No
    E.8.2.2Placebo No
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial1
    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 Yes
    E.8.5.1Number of sites anticipated in the EEA10
    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 No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Canada
    United States
    France
    Poland
    Spain
    Czechia
    Germany
    Italy
    Belgium
    United Kingdom
    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
    Expected trial participation duration for each subject to be approximately 2 years with the option to continue to receive tolvaptan treatment for 12 additional months
    Die voraussichtliche Dauer der Studienteilnahme für jeden Patienten beträgt etwa 2 Jahre mit der Option, für weitere 12 Monate die Behandlung mit Tolvaptan fortzusetzen
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years4
    E.8.9.1In the Member State concerned months11
    E.8.9.1In the Member State concerned days15
    E.8.9.2In all countries concerned by the trial years5
    E.8.9.2In all countries concerned by the trial months0
    E.8.9.2In all countries concerned by the trial days0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 Yes
    F.1.1Number of subjects for this age range: 20
    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) Yes
    F.1.1.4.1Number of subjects for this age range: 20
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) No
    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 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 Yes
    F.3.3.6.1Details of subjects incapable of giving consent
    Approximately 20 male or female subjects, 28 days to ≤12 weeks
    of age at time of enrolment
    Ungefähr 20 männliche oder weiblichen Patienten, die zum Zeitpunkt des Einschlusses 28 Tage bis ≤12 Wochen alt sind
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state4
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 12
    F.4.2.2In the whole clinical trial 20
    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)
    The subjects will be treated with standard of care by their healthcare provider. Subjects who complete 36 months of treatment in this trial will have the option to enroll in an expanded access program to continue to receive tolvaptan as determined by local regulations and at the sponsor discretion dependent on safety data.
    Die Patienten werden mit den Standardmedikamenten behandelt (von Ihren Krankenkassen). Patienten die die Studie nach 36 monatiger Behandlung abschließen, haben die Möglichkeit, an einem erweiterten Zugangsprogramm teilnehmen, um weiterhinTolvaptan zu erhalten. Dies ist nur möglich, wenn dies gemäß den örtlichen Vorschriften und nach Ermessen des Sponsors aufgrund von Sicherheitsdaten zulässig ist.
    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 Decision2022-01-06
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2022-10-07
    P. End of Trial
    P.End of Trial StatusOngoing
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