Clinical Trials Register

Summary
EudraCT Number:	2020-005992-10
Sponsor's Protocol Code Number:	156-201-00307
National Competent Authority:	Germany - BfArM
Clinical Trial Type:	EEA CTA
Trial Status:
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

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A. Protocol Information

A.1

Member State Concerned

Germany - BfArM

A.2

EudraCT number

2020-005992-10

A.3

Full 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 18 years 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 18 Jahren mit autosomal-rezessiver polyzystischer Nierenerkrankung (ARPKD)

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

A trial to see if tolvaptan is safe in infants and children who at enrollment are 28 days to less than 18 years old with Autosomal Recessive Polycystic Kidney Disease (ARPKD)

Eine Studie zur Untersuchung der Sicherheit von Tolvaptan bei Säuglingen und Kindern, die bei Studienbeginn 28 Tage bis unter 18 Jahre alt sind und an einer autosomal rezessiven polyzystischen Nierenerkrankung (ARPKD) leiden Autosomal-rezessive polyzystische Nierenerkrankung (ARPKD)

A.4.1

Sponsor's protocol code number

156-201-00307

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT04782258

A.7

Trial is part of a Paediatric Investigation Plan

Yes

A.8

EMA Decision number of Paediatric Investigation Plan

P/002/2020

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Otsuka Pharmaceutical Development & Commercialization, Inc.
B.1.3.4	Country	United States
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Otsuka Pharmaceutical Development & Commercialization, Inc.
B.4.2	Country	United States
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Otsuka Pharmaceutical Development & Commercialization, Inc.
B.5.2	Functional name of contact point	Mathew Taylor
B.5.3	Address:
B.5.3.1	Street Address	2440 Research Boulevard
B.5.3.2	Town/ city	Rockville
B.5.3.3	Post code	MD 20850
B.5.3.4	Country	United States
B.5.4	Telephone number	+12407804266
B.5.5	Fax number	+13017218592
B.5.6	E-mail	mathew.taylor-cw@otsuka-us.com

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	SAMSCA 7.5 mg oral tablet
D.2.1.1.2	Name of the Marketing Authorisation holder	Otsuka Pharmaceutical Netherlands B.V.
D.2.1.2	Country which granted the Marketing Authorisation	European Union
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Tolvaptan 7.5 mg Tablet
D.3.2	Product code	OPC-41061
D.3.4	Pharmaceutical form	Tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Tolvaptan
D.3.9.1	CAS number	150683-30-0
D.3.9.2	Current sponsor code	OPC-41061
D.3.9.3	Other descriptive name	TOLVAPTAN (OPC-41061)
D.3.9.4	EV Substance Code	SUB22755
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	7.5
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 2
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	Jinarc® 15mg Tablet
D.2.1.1.2	Name of the Marketing Authorisation holder	Otsuka Pharmaceutical Netherlands B.V.
D.2.1.2	Country which granted the Marketing Authorisation	European Union
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Tolvaptan 15 mg Tablet
D.3.2	Product code	OPC-41061
D.3.4	Pharmaceutical form	Tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Tolvaptan
D.3.9.1	CAS number	150683-30-0
D.3.9.2	Current sponsor code	OPC-41061
D.3.9.3	Other descriptive name	TOLVAPTAN (OPC-41061)
D.3.9.4	EV Substance Code	SUB22755
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	15
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 3
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	Jinarc 30 mg Tablet
D.2.1.1.2	Name of the Marketing Authorisation holder	Otsuka Pharmaceutical Netherlands B.V.
D.2.1.2	Country which granted the Marketing Authorisation	European Union
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Tolvaptan 30 mg Tablet
D.3.2	Product code	OPC-41061
D.3.4	Pharmaceutical form	Tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Tolvaptan
D.3.9.1	CAS number	150683-30-0
D.3.9.2	Current sponsor code	OPC-41061
D.3.9.3	Other descriptive name	TOLVAPTAN (OPC-41061)
D.3.9.4	EV Substance Code	SUB22755
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	30
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 4
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Tolvaptan 50mg Granules
D.3.2	Product code	OPC-41061
D.3.4	Pharmaceutical form	Granules for oral suspension
D.3.4.1	Specific paediatric formulation	Yes
D.3.7	Routes of administration for this IMP	Nasogastric use (Noncurrent) Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Tolvaptan
D.3.9.1	CAS number	150683-30-0
D.3.9.2	Current sponsor code	OPC-41061
D.3.9.3	Other descriptive name	TOLVAPTAN (OPC-41061)
D.3.9.4	EV Substance Code	SUB22755
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	50
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another 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.1.1

Medical condition(s) being investigated

Autosomal Recessive Polycystic Kidney Disease (ARPKD)

Autosomal-rezessive polyzystische Nierenerkrankung (ARPKD)

E.1.1.1

Medical 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.1.1.2

Therapeutic area

Diseases [C] - Congenital, Hereditary, and Neonatal Diseases and Abnormalities [C16]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
E.1.2	Level	LLT
E.1.2	Classification code	10036047
E.1.2	Term	Polycystic kidney, autosomal recessive
E.1.2	System Organ Class	100000004850

E.1.3

Condition being studied is a rare disease

Yes

E.2 Objective of the trial

E.2.1

Main objective of the trial

To evaluate the safety of tolvaptan in pediatric subjects with ARPKD

Beurteilung der Sicherheit von Tolvaptan bei pädiatrischen Patienten mit ARPKD

E.2.2

Secondary objectives 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.2.3

Trial contains a sub-study

Yes

E.2.3.1

Full title, date and version of each sub-study and their related objectives

This is optional further research performed on the remainder of the samples collected during the study to understand the genetics of ARPKD

E.3

Principal inclusion criteria

1. Male or female subjects between 28 days and less than 18 years of age, with clinical features that are consistent with a diagnosis of ARPKD.
2. Ability for parent/legal 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. Ability to provide written informed assent from all subjects old enough per local laws to provide assent.

1. Männliche oder weibliche Studienteilnehmer im Alter zwischen28 Tagen und <18 Jahren mit klinischen und bildgebenden Merkmalen, die mit der Diagnose einer ARPKD übereinstimmen. Folgende Merkmale sind: Nephromegalie (> 2 Standardabweichungen von der altersgemäßen Norm im Ultraschall); multiple Nierenzysten; und eine Vorgeschichte von Oligohydramnion oder Anhydramnion in der Gebärmutter.
2. 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. Studienteilnehmer müssen in der Lage sein, ihre schriftliche Zustimmung zu geben, wenn sie nach den örtlichen Gesetzen alt genug sind, um ihre Zustimmung zu geben.

E.4

Principal exclusion criteria

1. Premature birth (≤ 32 weeks gestational age) for infants 28 days to <12 weeks of 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. Has splenomegaly or portal hypertension
6. Parents with renal cystic disease
7. Receiving chronic diuretic that could not be adjusted after tolvaptan initiation.
8. Cannot be monitored for fluid balance
9. Has or at risk of having sodium and potassium electrolyte imbalances, as determined by the investigator
10. Has or at risk of having significant hypovolemia (e.g. subjects that lack free access to water
[inability to respond to thirst, depending on age], without adequate fluid monitoring and
management) as determined by investigator
11. Clinically significant anemia, as determined by investigator
12. Platelets < 50000 μL
13. Severe systolic dysfunction defined as ejection fraction < 14%
14. Serum sodium levels < 130 mmol/L or >145 mmol/L (or the ULN of the local laboratory, whichever is lower)
15. Taking any other experimental medications
16. Require ventilator support
17. Taking medications known to induce CYP3A4
18. Having an active infection including viral that would require therapy disruptive to IMP dosing
19. Females who are breast-feeding or who have a positive pregnancy test result prior to receiving IMP.
20. Subjects with a history of substance abuse within the last 6 months (depending on age).
21. Subjects who have bladder dysfunction and/or difficulty voiding.
22. Subjects taking a vasopressin agonist (eg, desmopressin).
23. Subjects with a history of persistent non-compliance with antihypertensive or other important medical therapy
24. Subjects 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).
25. Subjects who do not agree to remain abstinent or assent to use a combination of two of the
following highly effective birth control methods for at least 28 days before the first dose of IMP,
during the trial (including during IMP dose interruptions), and for at least 30 days after the last
dose of IMP:
Barrier method of contraception: condoms with or without a spermicidal agent, diaphragm or cervical cap with spermicide, Intrauterine device, Hormone-based contraceptives which are associated with inhibition of ovulation.
26. Received or are scheduled to receive a liver transplant.
27. History of cholangitis within the last 6 months
28. Has findings consistent with clinically significant portal hypertension (eg, varices, variceal
bleeding, hypersplenism indicated by thrombocytopenia

1. Frühgeburt (≤ 32 Wochen Gestationsalter) für Kinder im Alter von 28 Tagen bis <12 Wochen
2. Anurie oder Nierenersatztherapie (RRT), definiert als intermittierende oder kontinuierliche Hämodialyse, Peritonealdialyse, Hämofiltration, Hämodiafiltration oder Nierentransplantation in der Vorgeschichte.
3. Hinweise auf syndromale Erkrankungen im Zusammenhang mit Nierenzysten (außer ARPKD)
4. Abnorme Leberfunktionstest, einschließlich ALT und AST > 1,2 × ULN
5. Vorliegen einer Splenomegalie oder portalen Hypertonie
6. Eltern mit zystischer Nierenerkrankung
7. Einnahme eines permanenten Diuretikums, das nach der Einführung von Tolvaptan nicht angepasst werden konnte.
8. Flüssigkeitshaushalt kann nicht überwacht werden
9. Durch den Prüfarzt festgestelltes Ungleichgewicht von Natrium, Kalium und Elektrolyten
10. 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
11. Durch den Prüfarzt festgestellte klinisch signifikante Anämie
12. Thrombozytenzahl < 50.000 µl
13. Schwere systolische Dysfunktion, definiert als Ejektionsfraktion < 14 %
14. Natriumspiegel im Serum < 130 mmol/l oder >145 mmol/l (oder ULN eines lokalen Labors, je nachdem welcher Wert niedriger ist)
15. Einnahme anderer experimenteller Medikamente
16. Erforderliche Atmungsunterstützung mit Beatmungsgerät
17. Einnahme von Medikamenten, die bekanntermaßen CYP3A4 induzieren
18. Aktive Infektion einschließlich Virusinfektion, die eine Therapie erforderlich macht, welche die IMP-Dosisgabe beeinträchtigen würde
19. Frauen, die stillen oder vor Einnahme des IMP einen positiven Schwangerschaftstest haben.
20. Patienten mit einer Vorgeschichte von missbräuchlicher Substanzeinnahme innerhalb der letzten 6 Monate (abhängig vom Alter).
21. Patienten mit einer Blasenfunktionsstörung und/oder Schwierigkeiten bei der Blasenentleerung.
22. Patienten, die einen Vasopressin-Agonisten (z. B. Desmopressin) einnehmen.
23. Patienten mit einer Vorgeschichte anhaltender Nicht-Compliance bei einer antihypertensiven oder anderen wichtigen medizinischen Therapie
24. Patienten, die Begleiterkrankungen haben oder Medikamente einnehmen, die die Endpunktbewertung beeinträchtigen können, einschließlich der Einnahme von zugelassenen (am Markt erhältlichen) Therapien zur Behandlung von PKD-Zysten wie Tolvaptan, Vasopressin-Antagonisten, Antisense-RNA-Therapien, Rapamycin, Sirolimus, Everolimus oder Somatostatin-Analoga (wie Octreotid, Sandostatin)
25. Patienten, die nicht bereit sind abstinent zu bleiben oder eine Kombination aus zwei der folgenden hochwirksamen Verhütungsmethoden anzuwenden. DIese sind anzuwenden mindestens 28 Tage vor der ersten Studienmedikamenten-Dosis, während der Studie (einschließlich der Unterbrechung der Studienmedikamenten-Dosis) und mindestens 30 Tage nach der letzten Dosis des Studienmedikamentes.
Barrieremethode zur Empfängnisverhütung: Kondome mit oder ohne Spermizid, Diaphragma oder Portiokappe mit Spermizid, Intrauterinpessar, hormonelle Verhütungsmittel die mit einer Hemmung des Eisprungs verbunden sind.
26. Eine Lebertransplantation wurde durchgeführt oder ist geplant
27. Cholangitis in der Anamnese innerhalb der letzten 6 Monate
28. Befunde, die auf eine klinisch signifikante portale Hypertension hindeuten (z. B. Varizen, Varizenblutungen, Blutungen, Hypersplenismus mit Thrombozytopenie

E.5 End points

E.5.1

Primary end point(s)

Safety assessments which will be summarized by descriptive statistics, and the endpoints will be
- Adverse events
- Vital signs
- Clinical laboratory assessments
- Serum transaminase elevations for frequency (2 ×, 3 ×, 5 × and 10 × ULN), time to onset, time to peak levels, time of offset (< 3 ×, 2 ×, or 1 × ULN), response to de-challenge and re-challenge and frequency of progression to Hy’s laboratory criteria (ALT or AST > 3 × ULN and BT, > 2 × ULN without alkaline phosphatase greater than or equal to 2 × ULN)
- Change from baseline in sNa+

Sicherheitsbewertungen, die durch deskriptive Statistiken zusammengefasst werden, mit folgenden Endpunkten:
- Unerwünschte Ereignisse
- Vitalparameter
- Klinische Laboruntersuchungen
- Erhöhte Serum-Transaminase-Werte nach Häufigkeit (2 ×, 3 ×, 5 × und 10 × ULN), Zeit bis zum Eintreten, Zeit bis zum Spitzenwert, Zeit bis zum Abklingen der Wirkung (< 3 ×, 2 × oder 1 × ULN), Reaktion auf De-Challenge und Re-Challenge und Häufigkeit der Progression zu den Kriterien von Hy’s Gesetz (ALT oder AST > 3 × ULN und BT > 2 × ULN ohne alkalische Phosphatase 2 × ULN)
Änderung vom Ausgangswert bei SNa+

E.5.1.1

Timepoint(s) of evaluation of this end point

Months 1, 6, 12, and 18

Monat 1, 6, 12 und 18

E.5.2

Secondary end point(s)

Annual rate of change of eGFR (eGFR Schwartz formula = 0.413 × height [or length, cm] /serum creatinine mg/dL) from baseline to post-treatment after 18 months of treatment
-Change from baseline of eGFR (eGFR
Schwartz formula = 0.413 × height [or length, cm] /serum creatinine mg/dL) while on treatment at Months 1, 6, 12, and 18
-Time to RRT
-Percentage of subjects who receive RRT

Jährliche Änderungsrate der eGFR (eGFR Schwartz-Formel = 0,413 × Größe [oder Länge in cm] / Serumkreatinin mg/dl) von Baseline bis zur Nachbehandlung nach 18 Monaten der Behandlung
-Veränderung von eGFR-Baseline (eGFR Schwartz-Formel = 0,413 × Größe [oder Länge in cm] / Serumkreatinin mg/dl) während der Behandlung im Monat 1, 6, 12 und 18
-Zeit bis Beginn der RRT
-Prozentsatz der Studienteilnehmer, die RRT erhalten

E.5.2.1

Timepoint(s) of evaluation of this end point

Months 1, 6, 12, and 18

Monat 1, 6, 12 und 18

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

Yes

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

Yes

E.6.13.1

Other scope of the trial description

Tolerability

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

E.7.3

Therapeutic confirmatory (Phase III)

Yes

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

E.8.1.1

Randomised

E.8.1.2

Open

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

E.8.1.5

Parallel group

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

E.8.2.3

Other

E.8.2.4

Number of treatment arms in the trial

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

E.8.5

The trial involves multiple Member States

Yes

E.8.5.1

Number of sites anticipated in the EEA

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

Yes

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.6.3

If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned

Canada

United Kingdom

United States

Belgium

Czechia

France

Germany

Italy

Poland

Spain

E.8.7

Trial 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

The overall trial duration is considered from the time the first ICF is signed to the final subject assessment and is expected to be approximately 3.5 years. All subjects may be followed for 18 months after the first dose of IMP, regardless of continued compliance with taking IMP.

Insgesamt gilt der Zeitraum ab Unterzeichnung der ersten Einwilligungserklärung bis zur abschließenden Beurteilung der Studienteilnehmer als Studiendauer. Er beträgt voraussichtlich ca. 3,5 Jahre. Alle Studienteilnehmer können in den 18 Monaten nach der ersten Dosis des Prüfarzneimittels beobachtet werden, unabhängig von der weiteren Compliance bei der Einnahme des Prüfarzneimittels.

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

E.8.9.2

In all countries concerned by the trial years

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

Yes

F.1.1

Number of subjects for this age range:

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

Yes

F.1.1.4.1

Number of subjects for this age range:

F.1.1.5

Children (2-11years)

Yes

F.1.1.5.1

Number of subjects for this age range:

F.1.1.6

Adolescents (12-17 years)

Yes

F.1.1.6.1

Number of subjects for this age range:

F.1.2

Adults (18-64 years)

F.1.3

Elderly (>=65 years)

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

Yes

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

Yes

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

Yes

F.3.3.6.1

Details of subjects incapable of giving consent

The population will consist of 10 male or female subjects, aged 28 days to less than 18 years at time of enrollment, with a clinical diagnosis of ARPKD

mindestens 10 männliche oder weibliche Patienten im Alter von 28 Tagen bis<18 Jahren zum Zeitpunkt des enrollments, mit einer klinischen Diagnose von ARPKD

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

F.4.2

For a multinational trial

F.4.2.1

In the EEA

F.4.2.2

In the whole clinical trial

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 and/or will have the option to enroll in an expanded access program to continue to receive tolvaptan as determined by the local regulations and at the sponsor's discretion dependant on safety data.

N/A

G. Investigator Networks to be involved in the Trial

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2021-12-03

Ethics Committee Opinion of the trial application

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

P. End of Trial
P.	End of Trial Status

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IMP with orphan designation in the indication
Orphan Designation Number:
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