Clinical Trials Register

Summary
EudraCT Number:	2014-005669-54
Sponsor's Protocol Code Number:	UKM2013-0034
National Competent Authority:	Germany - BfArM
Clinical Trial Type:	EEA CTA
Trial Status:	Trial now transitioned
Date on which this record was first entered in the EudraCT database:	2019-12-03
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

2014-005669-54

A.3

Full title of the trial

Clinical safety study on 5-Aminolevulinic acid (5-ALA) in children and adolescents with brain tumours

Klinische Prüfung zur Bewertung der Sicherheit von 5-Aminolävulinsäure (5-ALA) bei Kindern und Jugendlichen mit Hirntumoren

A.3.1

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

5-Aminolevulinic acid (5-ALA) in children and adolescents with differnt types of brain tumours

5-Aminolävulinsäure (5-ALA) bei Kindern und Jugendlichen mit Hirntumoren

A.3.2

Name or abbreviated title of the trial where available

5-ALA in children and adolescents

5-ALA bei Kindern und Jugendlichen

A.4.1

Sponsor's protocol code number

UKM2013-0034

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT04738162

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	Universität Münster c/o Universitätsklinikum Münster, Geschäftsbereich Personal und Recht
B.1.3.4	Country	Germany
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	medac Gesellschaft für klinische Spezialpräparate mbH
B.4.2	Country	Germany
B.4.1	Name of organisation providing support	photonamic GmbH & Co. KG
B.4.2	Country	Germany
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Universitätsklinikum Münster
B.5.2	Functional name of contact point	Klinik für Neurochirurgie
B.5.3	Address:
B.5.3.1	Street Address	Albert-Schweitzer-Campus 1, Geb. A1
B.5.3.2	Town/ city	Münster
B.5.3.3	Post code	48149
B.5.3.4	Country	Germany
B.5.4	Telephone number	+4925183 5555
B.5.5	Fax number	+492518347479
B.5.6	E-mail	5-ala-in-children.study@uni-muenster.de

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	Gliolan 30mg/ml
D.2.1.1.2	Name of the Marketing Authorisation holder	medac Gesellschaft für klinische Spezialpräparate mbH
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.3.4	Pharmaceutical form	Powder for oral solution
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	5-AMINOLEVULINIC ACID
D.3.9.1	CAS number	106-60-5
D.3.9.4	EV Substance Code	SUB12853MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
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.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

intra-axial brain tumor (malignant glioma, astrocytoma, malignant ependymoma, AT/RT, Oligodendroglioma, etc.)

intraaxiale Hirntumore (malignes Gliom, Astrozytom, malignes Ependymom, atypischer teratoider Rhabdoidtumor, Oligodendrogliom etc.)

E.1.1.1

Medical condition in easily understood language

different types of brain tumors

verschiedene Typen von Hirntumoren

E.1.1.2

Therapeutic area

Diseases [C] - Cancer [C04]

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	10006154
E.1.2	Term	Brain tumor NOS
E.1.2	System Organ Class	10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)

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 determine the safety of 5-ALA for fluorescence-guided resections in children and adolescents with intra-axial brain tumors

Bestimmung der Sicherheit fluoreszenzgestützter Resektion mit 5-ALA bei intra-axialen Hirntumoren bei Kindern und Jugendlichen

E.2.2

Secondary objectives of the trial

1. To determine whether fluorescing tissue truly signifies tumor (positive predictive value)
2. To determine extent of tumor resection on early post-operative MRI
3. Pharmacokinetics of 5-ALA in children and adolescents

1. Ermittlung, ob fluoreszierendes Gewebe Tumorgewebe entspricht.
2. Bestimmung des Resektionsausmaßes im Kontrastmittel-MRT nach Tumor-OP
3. Untersuchung der Pharmakokinetik von 5-ALA bei Kindern und Jugendlichen

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

• Age 3 - <18 years
• First radiological diagnosis of intra-axial, contrast-enhancing tumor on MRI or recurrent intra-axial brain tumor (malignant glioma, astrocytoma, malignant ependymoma, AT/RT, Oligodendroglioma, etc.)
• Resection is part of therapeutic strategy with an emphasis on neurological safety
• Informed consent by the parents or guardians and if possible assent of the patient after education of purpose and risks of study. Patients that are able to understand should provide assent to participate in the trial
• Female adolescents: not pregnant (pregnancy test required for adolescents of childbearing age) and not breast-feeding.
Female patients of childbearing potential and male patients who are sexually active must be practising a highly effective method of birth control up to 6 weeks after the tumor operation consistent with local regulations regarding the use of birth control methods for subjects participating in clinical trials.

•Alter 3 - < 18 Jahre
•Radiologische Erstdiagnose eines intra-axialen Kontrastmittel-aufnehmenden Hirntumor im MRT oder Rezidiv eines intra-axialen Hirntumors (malignes Gliom, Astrozytom, malignes Ependymom, atypischer teratoider Rhabdoidtumor, Oligodendrogliom etc.)
•Geplante Resektion des Tumors mit dem Ziel das umgebende gesunde Gewebe nicht zu schädigen, um zusätzliche neurologische Ausfälle zu vermeiden
•Unterzeichnete Einwilligungserklärung der Eltern oder des/der Sorgeberechtigten und sofern möglich die Zustimmung des Patienten nach Aufklärung über die Ziele und die Risiken der Studie. Der Wille des Patienten sollte berücksichtigt werden.
•Weibliche Studienteilnehmerinnen: nicht schwanger (ein Schwangerschaftstest wird für Jugendliche im gebärfähigen Alter benötigt) und nicht stillend (mindestens 24h nach Einnahme von Gliolan).
Bei gebärfähigen Frauen oder Männern mit gebärfähigen Partnerinnen: Bereitschaft eine zuverlässige Verhütungsmethode (Pearl-Index <1) bis zu 6 Wochen nach der Tumor-Operation anzuwenden.

E.4

Principal exclusion criteria

• Extra-axial tumors such as craniopharyngeoma
• Tumors precluding surgical resection
• Acute or chronic porphyria
• Hypersensitivity to 5-ALA or porphyrins
• Renal insufficiency: serum creatinine > 2x upper limit of normal
• Hepatic insufficiency: serum bilirubine > 2x upper limit of normal, serum γ-GT > 2,5 x upper limit of normal, alanine transaminase (ALT) and aspartate transaminase (AST)> 2,5 upper limit of normal
• Blood clotting: INR out of acceptable limits
• Other malignant disease
• Patients with pre-existing cardiovascular diseases
• Co-administration with other potentially phototoxic substances (e.g. tetracyclines, sulfonamides, fluoroquinolones, hypericin extracts)
• Planned administration of potentially hepatotoxic substances within 24 hours after 5-ALA administration

•Extra-axiale Tumoren, wie z.B. Craniopharyngeome
• Inoperable Tumoren
•Akute oder chronische Porphyrie
•Bekannte Überempfindlichkeit gegen Porphyrine oder 5-ALA/Gliolan
•Nierenfunktion: Kreatinin > 2 x obere Normgrenze (ULN)
•Leberfunktion: Gesamtbilirubin > 2 x ULN, serum γ-GT > 2,5 ULN, alanin transaminase (ALT) und apspartat transaminase (ALT)> 2,5 ULN
•Blutgerinnung: INR außerhalb akzeptablem Limit
•Sonstige maligne Erkrankungen
•Bestehende kardiovaskuläre Erkrankungen
•Gleichzeitige Gabe mit anderen potentiell phototoxischen Substanzen (z.B. Tetrazykline, Sulfonamide, Fluorochinolone, Hypericinextrakte (z.B. Johanniskraut)
•Geplante Gabe von potentiell hepatotoxischen Substanzen im Zeitraum von 24h nach 5-ALA Gabe

E.5 End points

E.5.1

Primary end point(s)

Toxicological and clinical safety by measuring the incidence of adverse events of CTCAE grade III, IV or V (excluding chemotherapy-associated toxicities) during and after 5-ALA fluorescence-guided resections in children and adolescents with unifocal, contrast-enhancing intra-axial brain tumors (first diagnosis with unknown history, recurrent with malignant neuroepithelial histology)

Toxikologische und klinische Sicherheit gemessen als Inzidenz von unerwünschten Ereignissen CTCAE Grad III, IV, V (mit Ausnahme von Chemotherapie-assoziierten Nebenwirkungen) nach 5-ALA fluoreszenz-gestützter Tumorresektion bei Kindern und Jugendlichen mit Kontrastmittel-aufnehmenden intra-axialen Hirntumoren (Primärdiagnose oder Rezidiv)

E.5.1.1

Timepoint(s) of evaluation of this end point

Adverse events will be documented continuously from day of operation to 6 weeks afterwards.

Unerwünschte Ereignisse werden kontinuierlich erfasst vom Tag der Operation bis 6 Wochen danach.

E.5.2

Secondary end point(s)

1. True positive rate of fluorescence for indicating tumor

2. Extent of resection as assessed on early post-operative MRI

3. Pharmacokinetics (determination of protoporphyrin IX 3 times within 12h after 5-ALA-administration)

1. Ermittlung, ob fluoreszierendes Gewebe Tumorgewebe entspricht.

2. Bestimmung des Resektionsausmaßes im Kontrastmittel-MRT nach Tumor-OP.

3. Untersuchung der Pharmakokinetik von 5-ALA bei Kindern und Jugendlichen (Messung von Protoporphyrin IX 3x innerhalb von 12 Stunden nach 5-ALA-Gabe)

E.5.2.1

Timepoint(s) of evaluation of this end point

1. Biopsies are taken during the resection of the tumor
2. MRI is done until max. 72h post-OP
3. Samples for protoporphyrine IX analysis will be taken 3-6h, 6-9h, 9-12h after 5-ALA administration

1. Biopsien werden während der Resektion des Tumors entnommen
2. MRT bis zu 72 Stunden nach der OP
3. Blutproben zur Messung von Protoporphyrin IX werden in den Zeiträumen 3-6 Stunden, 6-9 Stunden und 9-12 Stunden nach 5-ALA-Gabe entnommen

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

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

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)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

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.8.3

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

LVLS

letzte Visite des letzten Patienten

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

E.8.9.2

In all countries concerned by the trial months

E.8.9.2

In all countries concerned by the trial days

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)

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

Children age 3 to < 18 years

Kinder im Alter von 3 bis 17 Jahren

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)

After the end of the study, patients will be treated according to the normal treatment of their condition

Nach Studienende erhalten die Patienten die gängige Behandlung für ihre Erkrankung.

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

2020-02-20

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2020-06-02

P. End of Trial
P.	End of Trial Status	Trial now transitioned

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