Clinical Trials Register

Summary
EudraCT Number:	2016-002430-76
Sponsor's Protocol Code Number:	15OKG16
National Competent Authority:	Germany - BfArM
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2018-07-26
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

2016-002430-76

A.3

Full title of the trial

Double-blind, randomized, placebo controlled noninferiority intervention study to REduce STEroids in Relapsing Nephrotic syndrome

Multizentrische, doppeltblinde, randomisierte, placebokontrollierte Nicht-Unterlegenheits-Studie zur Reduktion von Korticosteroiden in der Behandlung des rezidivierenden nephrotischen Syndroms des Kindes- und Jugenalters

A.3.1

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

Less prednisone for a nephrotic syndrome relapse

Weniger Prednison zur Behandlung eines wiederkehrenden nephrotischen Syndroms

A.3.2

Name or abbreviated title of the trial where available

the RESTERN study

die RESTERN-Studie

A.4.1

Sponsor's protocol code number

15OKG16

A.5.4

Other Identifiers

Name:

Nederlands Trial Register

Number:

NTR5670

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Radboudumc, Amalia Children’s Hospital, Department of Pediatrics
B.1.3.4	Country	Netherlands
B.3.1 and B.3.2	Status of the sponsor	Non-Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Dutch Kidney Foundation
B.4.2	Country	Netherlands
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Radboudumc, Amalia Children’s Hospital
B.5.2	Functional name of contact point	Pediatric Drug Research Centre
B.5.3	Address:
B.5.3.1	Street Address	PO Box 9101
B.5.3.2	Town/ city	Nijmegen
B.5.3.3	Post code	6500 HB
B.5.3.4	Country	Netherlands
B.5.4	Telephone number	31243668957
B.5.5	Fax number	31243616428

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Comparator
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.2.1.2	Country which granted the Marketing Authorisation	Netherlands
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	Prednisolone
D.3.2	Product code	Prednisolone
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	Prednisolone
D.3.9.1	CAS number	52-21-1
D.3.9.3	Other descriptive name	PREDNISOLONE ACETATE
D.3.9.4	EV Substance Code	SUB04014MIG
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	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	Comparator
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.2.1.2	Country which granted the Marketing Authorisation	Netherlands
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	Prednisolone
D.3.2	Product code	Prednisolone
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	Prednisolone
D.3.9.1	CAS number	52-21-1
D.3.9.3	Other descriptive name	PREDNISOLONE ACETATE
D.3.9.4	EV Substance Code	SUB04014MIG
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	20
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
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Tablet
D.8.4	Route of administration of the placebo	Oral use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Nephrotic syndrome relapse in children

Rezidiv eines nephrotischen Syndroms des Kindesalter

E.1.1.1

Medical condition in easily understood language

Nephrotic syndrome relapse in children

Wiederkehrendes nephrotisches Syndrom des Kindesalters

E.1.1.2

Therapeutic area

Not possible to specify

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	21.1
E.1.2	Level	LLT
E.1.2	Classification code	10029172
E.1.2	Term	Nephrotic syndrome with unspecified pathological lesion in kidney
E.1.2	System Organ Class	10038359 - Renal and urinary disorders

E.1.2 Medical condition or disease under investigation

E.1.2	Version	21.1
E.1.2	Level	PT
E.1.2	Classification code	10029164
E.1.2	Term	Nephrotic syndrome
E.1.2	System Organ Class	10038359 - Renal and urinary disorders

E.1.2 Medical condition or disease under investigation

E.1.2	Version	21.1
E.1.2	Level	LLT
E.1.2	Classification code	10029168
E.1.2	Term	Nephrotic syndrome with lesion of minimal change glomerulonephritis
E.1.2	System Organ Class	10038359 - Renal and urinary disorders

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	10042826
E.1.2	Term	Syndrome nephrotic
E.1.2	System Organ Class	10038359 - Renal and urinary disorders

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

Primary Objective:
To study the effectiveness of a reduced steroid schedule for the treatment of a relapse in children with steroid sensitive nephrotic syndrome.

E.2.2

Secondary objectives of the trial

Secondary Objective(s):
• To study the influence of maintenance immunosuppressive therapy on the effectiveness of a reduced steroid schedule for the treatment of a relapse in children with steroid sensitive nephrotic syndrome;
• To study the course of relapses in children with nephrotic syndrome under the standard treatment regimen;
• To study the influence of maintenance immunosuppressive therapy on the course of relapses in children with nephrotic syndrome under the standard treatment regimen.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

• Age over 1 and less than 18 years;
• Steroid sensitive nephrotic syndrome;
• The last prednisolone or prednison use (at a dose over 10mg/m2 on alternate days) for the treatment of a previous episode was at least 4 weeks ago;
• Signed informed consent from the parent or legal assent and/or the patient, depending on the age of the patient.

E.4

Principal exclusion criteria

• Steroid resistant nephrotic syndrome;
• Daily prednisolone or prednison maintenance therapy at any dose;
• Alternate day prednisolone or prednison maintenance therapy at a dose over 4 mg/m2;
• Documented or suspected significant non-compliance;
• Pregnancy;
• Stimulant drug use;
• Comorbidity;
- Kidney transplant patients
- Any disease that requires the variation in oral prednisolone or prednison to be at the discretion of the treating physician(s);
• Concomitant use of drugs that induce CYP3A4: carbamazepine, phenobarbital, phenytoin and/or rifampicin;
• Concomitant use of drugs that inhibit CYP3A4: ketaconazole, itraconazole, ritonavir, indinavir, macrolide antibiotics (erythromycin), diltiazem, verapamil.

E.5 End points

E.5.1

Primary end point(s)

Time to first relapse after study randomization (censored at 12 and 24 months)

E.5.1.1

Timepoint(s) of evaluation of this end point

12 and 24 months

E.5.2

Secondary end point(s)

• Number of relapses after study randomization at 12 or 24 months
• Development of frequent relapsing nephrotic syndrome according to KDIGO criteria (four or more relapses in any 12-month period)
• Development of steroid dependent nephrotic syndrome according to KDIGO criteria (two consecutive relapses during corticosteroid therapy, or within 14 days of ceasing therapy)
• Cumulative dosage of prednisolone or prednison during study period (at 12 and 24 months)

E.5.2.1

Timepoint(s) of evaluation of this end point

12 and 24 months

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

Yes

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

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

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

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

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

Yes

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

E.8.4

The trial involves multiple sites in the Member State concerned

Yes

E.8.4.1

Number of sites anticipated in 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

E.8.6.2

Trial being conducted completely outside of the EEA

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 end of the trial is reached when the last patient has fulfilled the follow up of 24 months since the last day of the study medication.

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:

144

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:

100

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

Infants/toddlers/children

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

144

F.4.2.2

In the whole clinical trial

144

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. patient receive standard of care.

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

2019-07-25

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2019-10-10

P. End of Trial
P.	End of Trial Status	Completed

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