Clinical Trials Register

Summary
EudraCT Number:	2013-003368-29
Sponsor's Protocol Code Number:	VAS203/III/1/04
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:	2016-05-03
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

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A. Protocol Information

A.1

Member State Concerned

Germany - BfArM

A.2

EudraCT number

2013-003368-29

A.3

Full title of the trial

EFFICACY OF VAS203 IN PATIENTS WITH MODERATE AND SEVERE
TRAUMATIC BRAIN INJURY. A confirmatory, placebo-controlled, randomised, double blind, multi-centre study.

A.3.1

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

EFFICACY OF VAS203 IN PATIENTS WITH MODERATE AND SEVERE
TRAUMATIC BRAIN INJURY. A confirmatory, placebo-controlled, randomised, double blind, multi-centre study.

A.3.2

Name or abbreviated title of the trial where available

NOSTRA Phase III Trial

A.4.1

Sponsor's protocol code number

VAS203/III/1/04

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	vasopharm GmbH
B.1.3.4	Country	Germany
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	vasopharm GmbH
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	vasopharm GmbH
B.5.2	Functional name of contact point	Frank Tegtmeier
B.5.3	Address:
B.5.3.1	Street Address	Friedrich-Bergius-Ring 15
B.5.3.2	Town/ city	Wuerzburg
B.5.3.3	Post code	97076
B.5.3.4	Country	Germany
B.5.4	Telephone number	499313590990
B.5.5	Fax number	4993135909912
B.5.6	E-mail	tegtmeier@vasopharm.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	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	Yes
D.2.5.1	Orphan drug designation number	EU/3/06/390 //EMEA/OD/035/06
D.3 Description of the IMP
D.3.1	Product name	VAS203
D.3.2	Product code	VAS203
D.3.4	Pharmaceutical form	Lyophilisate for solution for infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Ronopterin
D.3.9.1	CAS number	206885-38-3
D.3.9.2	Current sponsor code	VAS203
D.3.9.3	Other descriptive name	4-AMINO-(6R,S)-5,6,7,8-TETRAHYDRO-L-BIOPTERIN
D.3.9.4	EV Substance Code	SUB33337
D.3.10	Strength
D.3.10.1	Concentration unit	g gram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	1
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	Solution for infusion
D.8.4	Route of administration of the placebo	Intravenous use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Moderate and severe traumatic brain injury

E.1.1.1

Medical condition in easily understood language

Moderate and severe traumatic brain injury

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	20.1
E.1.2	Level	LLT
E.1.2	Classification code	10060690
E.1.2	Term	Traumatic brain injury
E.1.2	System Organ Class	100000004863

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 demonstrate efficacy of VAS203 on clinical outcome at 6 months (extended Glasgow Outcome Scale Interview, eGOS-I) in patients suffering from moderate and severe traumatic brain injury (TBI)

E.2.2

Secondary objectives of the trial

To demonstrate efficacy on
• Quality of Life after Brain Injury (QOLIBRI) at 6 months after TBI
• QOLIBRI overall scale (QOLIBRI-OS) at 6 months after TBI
• eGOS-I at 3 months after TBI
• QOLIBRI-OS at 3 months after TBI
• 24-hours value of Therapy Intensity Level (TIL) over 14 days after start of treatment
• number of craniectomies (one or both hemispheres)

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Inclusion criteria
1. Written informed consent from patient’s legal guardian or legal representative or deferred consent procedure, according to local requirements
2. 18 - 60 years of age, inclusive
3. Expected to survive more than 24 hours after admission
4. Traumatic Brain Injury (TBI) within the last 18 hours (infusion must not start earlier than 6 hours after the injury)
5. TBI with Glasgow Coma Score (GCS) ≥ 3 requiring intracranial pressure (ICP) monitoring according to the assessment of the treating physician.
6. Catheter placement (intraventricular or intraparenchymal, only) for monitoring and management of increased ICP
7. Systolic blood pressure ≥ 100 mmHg
8. Females of child-bearing potential must have a negative pregnancy test

E.4

Principal exclusion criteria

Exclusion criteria
1. Penetrating head injury (e.g. missile, stab wound)
2. Concurrent, but not pre-existing, spinal cord injury
3. Bilateral fixed and dilated pupil (> 4 mm). However, inclusion with unilateral fixed and dilated pupil (> 4 mm) is possible when there are no signs of herniation in transtentorial or temporal brain area.
4. Cardiopulmonary resuscitation performed post injury, or extracranial injuries causing continuing bleeding likely to require multiple transfusions (> 4 units red blood cells)
5. Coma due to an exclusive epidural hematoma (lucid interval and absence of structural brain damage on CT scan)
6. Coma suspected to be primarily due to other causes than head injury (e.g. drug overdose intoxication, drowning/near drowning)
7. Known or CT scan evidence of pre-existing major cerebral damage
8. Patients who cannot be monitored with regard to their recovery (eGOS-I and QOLIBRI)
9. Patients and relatives of patients who don´t understand/speak Spanish, or English, or French, or German (if Israel is included: Hebrew, Russian, Arabic).
10. Decompressive craniectomy, planned prior to randomisation
Note:enrolment is possible, when osteoplastic craniectomy is performed for hematoma evacuation, only
11. Polytraumatic patients with Injury Severity Score non-head > 18
12. Rhabdomyolysis with CK > 5000 IU/L
13. Injuries to ascending aorta and/or carotid arteries and vertebral arteries
14. Serum creatinine values > 1.2 mg/dL (106 µmol/L) (women), or > 1.5 mg/dL (133 µmol/L) (men)
15. Estimated glomerular filtration rate (eGFR) < 60 mL/min as calculated by Chronic Kidney Disease Epidemiology Collaboration Formula
16. BMI < 18.5 kg/m2 and > 40 kg/m2, Body weight > 110 kg
17. Any severe concomitant condition (cancer; hematologic, renal, hepatic,
coronary disease; major psychiatric disorder; alcohol or drug abuse), that
can be ascertained at admission
18. Known to have received an experimental drug within 4 weeks prior to
current injury

E.5 End points

E.5.1

Primary end point(s)

Clinical outcome eGOS-I at 6 months after the TBI will be evaluated face to face with the patient and or a proxy by means of a standardized questionnaire in an interview

E.5.1.1

Timepoint(s) of evaluation of this end point

6 months

E.5.2

Secondary end point(s)

Secondary efficacy assessments
• QOLIBRI at 6 months after the TBI will be evaluated face to face with the patient and or
a proxy by means of a standardized questionnaire in an interview form

• QOLIBRI OS at 6 months after TBI will be evaluated face to face with the patient or a
proxy by means of a standardized questionnaire in an interview form
• eGOS-I at 3 months after TBI will be evaluated face to face with the patient and/or a proxy by means of a standardized questionnaire in an interview form
• QOLIBRI OS at 3 months after TBI will be evaluated face to face with the patient or a proxy by means of a standardized questionnaire in an interview form
• 24-hours value of TIL on a daily base over 14 days after start of treatment
• Number of decompressive craniectomies (one or both hemispheres)

E.5.2.1

Timepoint(s) of evaluation of this end point

14 days, 3 months and 6 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

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)

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

Last visit of last subject

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

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)

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

232

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 For clinical trials recorded in the database before the 10th March 2011 this question read: "Women of childbearing potential" and did not include the words "not using contraception". An answer of yes could have included women of child bearing potential whether or not they would be using contraception. The answer should therefore be understood in that context. This trial was recorded in the database on 2016-05-03.

Yes

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

Yes

F.3.3.6

Subjects incapable of giving consent personally

Yes

F.3.3.6.1

Details of subjects incapable of giving consent

Patients with moderate and severe traumatic brain injury.

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

100

F.4.2

For a multinational trial

F.4.2.1

In the EEA

232

F.4.2.2

In the whole clinical trial

232

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)

Continuation of Standard of Care procedures as per the treating facility.

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

2016-08-19

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2016-11-15

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2020-06-17

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