Clinical Trials Register

Summary
EudraCT Number:	2016-000222-19
Sponsor's Protocol Code Number:	H2020-PHC-18-2015-667224
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:	2017-01-30
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

2016-000222-19

A.3

Full title of the trial

Effect of ALlopurinol in addition to hypothermia for hypoxic-ischemic Brain Injury on Neurocognitive Outcome – a blinded randomized placebo-controlled parallel group multicenter trial for superiority (Phase III)

A.3.1

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

A European trial to evaluate the effect of Allopurinol administered very early after birth on brain injury in children with oxygen deficiency during birth

A.3.2

Name or abbreviated title of the trial where available

ALBINO

A.4.1

Sponsor's protocol code number

H2020-PHC-18-2015-667224

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	University Hospital Tuebingen
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	European Union
B.4.2	Country	European Union
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Center for Pediatric Clinical Studies
B.5.2	Functional name of contact point	Clinical Trial Center
B.5.3	Address:
B.5.3.1	Street Address	Frondsbergstr. 23
B.5.3.2	Town/ city	Tuebingen
B.5.3.3	Post code	72070
B.5.3.4	Country	Germany
B.5.4	Telephone number	004970712981469
B.5.5	Fax number	00497071294857
B.5.6	E-mail	albino@med.uni-tuebingen.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	ACEPURIN
D.2.1.1.2	Name of the Marketing Authorisation holder	ACE Pharmaceuticals
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	Yes
D.2.5.1	Orphan drug designation number	EU/3/15/1493
D.3 Description of the IMP
D.3.1	Product name	Allokid
D.3.4	Pharmaceutical form	Powder for solution for injection
D.3.4.1	Specific paediatric formulation	Yes
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	Allopurinol sodium
D.3.9.1	CAS number	17795-21-0
D.3.9.3	Other descriptive name	ALLOPURINOL SODIUM
D.3.9.4	EV Substance Code	SUB30291
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	100
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	Powder for solution for injection
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

Perinatal Asphyxia, hypoxic-ischemic brain injury

E.1.1.1

Medical condition in easily understood language

oxygen deficiency during birth

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	PT
E.1.2	Classification code	10028923
E.1.2	Term	Neonatal asphyxia
E.1.2	System Organ Class	10038738 - Respiratory, thoracic and mediastinal disorders

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
E.1.2	Level	PT
E.1.2	Classification code	10014633
E.1.2	Term	Encephalopathy neonatal
E.1.2	System Organ Class	10029205 - Nervous system 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

To evaluate whether in newborns with asphyxia and early clinical signs of hypoxic-ischemic encephalopathy, early postnatal allopurinol compared to placebo (mannitol) administered in addition to standard of care (including therapeutic hypothermia if indicated) reduces the incidence of death or severe neurodevelopmental impairment (as defined herein) at 24 months of age.

E.2.2

Secondary objectives of the trial

To evaluate the effect of allopurinol in addition to hypothermia (if indicated) on:
- components of the primary outcome variable
- brain injury assessed by magnetic resonance imaging,
- amplitude integrated electroencephalogram,
- full scale electroencephalogram,
- laboratory biomarkers and markers of peroxidation
- heart function assessed by echocardiography
To evaluate the safety of allopurinol in neonates treated with hypothermia.
To study pharmacokinetics of allopurinol (verum) and mannitol (placebo) in neonates treated with hypothermia and not treated with hypothermia

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

Near InfraRed Spectroscopy (NIRS)-monitored Cerebral Oxygen Saturation and Extraction (01/2016 V01.0/negative and positive predictive values at 12 h of life for outcome at 24 months. We hypothesize that early treatment of perinatally asphyxiated neonates with allopurinol (ALLO) have lower rScO2 values and higher cFTOE values as compared to placebo-treated asphyxiated neonates pointing to a better outcome at 24 months of age.

E.3

Principal inclusion criteria

Term and near-term infants with a history of disturbed labour who meet at least one sign of perinatal asphyxia and early clinical signs of potentially evolving encephalopathy as defined herein:
Perinatal asphyxia:
At least 1 out of the following 4criteria must be met
- Umbilical (or arterial or reliable venous) blood gas within 30 min after birth with pH<7.0
- Umbilical (or arterial or reliable venous) blood gas within 30 min after birth with base deficit ≥16 mmol/l (i.e. a base excess ≤ -16mmol/l)
- Need for ongoing cardiac massage at/beyond 5 min postnatally
- Need for adrenalin administration during resuscitation or APGAR score ≤5 at 10min

AND

Early clinical signs of potentially evolving encephalopathy:
At least 2 out of the following 4 criteria must be met:
- Altered state of consciousness (reduced or absent response to stimulation or hyperexcitability)
- Severe muscular hypotonia or hypertonia,
- Absent or insufficient spontaneous respiration (e.g., gasping only) with need for respiratory support at 10 min postnatally,
- Abnormal primitive reflexes (absent suck or gag or corneal or Moro reflex) or abnormal movements (e.g., potential clinical correlates of seizure activity)

E.4

Principal exclusion criteria

- gestational age below 36 weeks
- birth weight below 2500 g
- postnatal age >30min at the end of the screening phase
- severe congenital malformation or syndrome requiring neonatal
surgery or affecting long-term outcome
- patient considered “moribund” or decision for “comfort care only”
before study drug administration
- parents declined study participation as response to community
engagment
- both parents are insufficiently fluent in the study site’s national language or English or do not have the intellectual capacity to understand the study procedures and to give consent as judged by the personel who had been in contact with the mother/father before delivery.
- both parents/guardians underaged, in case of single parent/guardian this one underaged

E.5 End points

E.5.1

Primary end point(s)

Death or severe neurodevelopmental impairment at the age of two years (where severe neurodevelopmental impairment is defined as any of the following: cognitive or language delay defined as mental developmental index (MDI) cognitive or language score on the Bayley Scales of Infant Development (3rd edition) < 85 and/or cerebral palsy according to SCPE criteria [SCPE Dev Med Child Neurol 2000].

E.5.1.1

Timepoint(s) of evaluation of this end point

at the age of two years

E.5.2

Secondary end point(s)

1) Death or neurodevelopmental impairment (NDI)
The primary endpoint will be reconstituted as dichotomised composite secondary endpoint (survival without NDI versus Death or language-composite-score < 85 or cognitive-composite-score <85 or cerebral palsy present). This will be analyzed by Cochrane-Mantel-Haenzel- X²-Test.
2) Incidence of death
Incidence of death will be analyzed by Cochrane-Mantel-Haenzel- X²-Test.
3) Incidence of CP
Incidence of CP will be analyzed by Cochrane-Mantel-Haenzel- X²-Test.
4) GMFCS-score
GMFCS-Score for quantification of the effects of cerebral palsy and other motor impairments (adapted from Palisano et al. [Palisano Med Child Neurol 1997]) using the ALBINO-GMFCS-score sheet (separate document not part of this protocol) will be analysed. GMFCS-score consists of six categories. Analysis will be done by using Wilcoxon-Mann-Whitney test.
5) Motor-Composite-Score (Bayley III)
The nummerical data of the motor-composite-score will be analysed using Wilcoxon-Mann-Whitney test. The use of this test accounts for the fact that data will be cut due to lack sensitivity below 50 points.
6) Motor-Composite-Score dichotomised (Bayley III)
The motor-composite-score will be dichotomised at the cut-off <85 versus ≥85 and analysed by Cochrane-Mantel-Haenzel- X²-Test.
7) Cognitive-Composite-Score (cognitive subscale, Bayley III)
The nummerical data of the cognitive-composite-score will be analysed using Wilcoxon-Mann-Whitney test. The use of this test accounts for the fact that data will be cut due to lack sensitivity below 50 points.
8) Cognitive-Composite-Score dichotomised (cognitive subscale, Bayley III)
The cognitive-composite-score will be dichotomised at the cut-off <85 versus ≥85 and analysed by Cochrane-Mantel-Haenzel- X²-Test.
9) Language-Composite-Score (language subscale, Bayley III)
The raw nummerical data of the language-composite-score will be analysed using Wilcoxon-Mann-Whitney test. The use of this test accounts for the fact that data will be cut due to lack sensitivity below 50 points.
10) Language-Composite-Score dichotomised (language subscale, Bayley III)
The language-composite-score will be dichotomised at the cut-off <85 versus ≥85 and analysed by Cochrane-Mantel-Haenzel- X²-Test.
11) Single Components of primary endpoint - Graph
Single components and observed combinations of the primary endpoint (healthy, death, CP, language-composite-score <85, cognitive-composite-score <85) will be displayed graphically stratified for the two treatment groups.

E.5.2.1

Timepoint(s) of evaluation of this end point

Secondary endpoints will be analysed at 24 months corrected age between the two treatment groups.

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

Yes

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

Yes

E.8.1.6

Cross over

E.8.1.7

Other

Yes

E.8.1.7.1

Other trial design description

multicenter trial

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

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

Switzerland

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 inclusion window will be 30 months, follow-up patients will be up till 24 months of age. Taking the last included patient into account, that means the duration of the trial will be 54months (4.5years) in total.

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

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:

846

F.1.1.1

In Utero

F.1.1.1.1

Number of subjects for this age range:

F.1.1.2

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

Yes

F.1.1.2.1

Number of subjects for this age range:

100

F.1.1.3

Newborns (0-27 days)

Yes

F.1.1.3.1

Number of subjects for this age range:

746

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)

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

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

newborn infants

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

280

F.4.2

For a multinational trial

F.4.2.1

In the EEA

806

F.4.2.2

In the whole clinical trial

846

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

G. Investigator Networks to be involved in the Trial
G.4 Investigator Network to be involved in the Trial: 1
G.4.1	Name of Organisation	Hypothermie-Netzwerk
G.4.3.4	Network Country	Germany

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

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2017-08-02

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2017-02-14

P. End of Trial
P.	End of Trial Status	Ongoing

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