Clinical Trials Register

Summary
EudraCT Number:	2011-002502-74
Sponsor's Protocol Code Number:	NEU-01-02-01
Clinical Trial Type:	Outside EU/EEA
Date on which this record was first entered in the EudraCT database:	2014-05-12
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
H.4 THIRD COUNTRY IN WHICH THE TRIAL WAS FIRST AUTHORISED

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A. Protocol Information

A.2

EudraCT number

2011-002502-74

A.3

Full title of the trial

A multi-centre, randomised, double-blind, placebo-controlled Phase II study to evaluate the efficacy, safety, tolerability, and pharmacokinetics of 2-iminobiotin (2-IB) in neonates with gestational age of ≥36 weeks with moderate to severe perinatal asphyxia.

A.3.1

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

A study in newborn children in need for intensive treatment resulting from insufficient oxygen supply to the brain.

A.4.1

Sponsor's protocol code number

NEU-01-02-01

A.7

Trial is part of a Paediatric Investigation Plan

Yes

A.8

EMA Decision number of Paediatric Investigation Plan

P/035/2012

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Neurophyxia B.V.
B.1.3.4	Country	Netherlands
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	Neurophyxia B.V.
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	Neurophyxia B.V.
B.5.2	Functional name of contact point	VP regulatory and medical affairs
B.5.3	Address:
B.5.3.1	Street Address	Onderwijsboulevard 219
B.5.3.2	Town/ city	’s-Hertogenbosch
B.5.3.3	Post code	5223 DE
B.5.3.4	Country	Netherlands
B.5.4	Telephone number	31629056631
B.5.5	Fax number	31736274525
B.5.6	E-mail	info@neurophyxia.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/3/098/701
D.3 Description of the IMP
D.3.1	Product name	2-Iminobiotin
D.3.2	Product code	NEU-01
D.3.4	Pharmaceutical form	Solution for infusion
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	2-Iminobiotin
D.3.9.1	CAS number	13395-35-2
D.3.9.2	Current sponsor code	NEU-01
D.3.9.3	Other descriptive name	2-Iminobiotin
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	0.75
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

Perinatal asphyxia

E.1.1.1

Medical condition in easily understood language

Oxygen shortage during birth resulting in insufficient oxygen supply to the brain

E.1.1.2

Therapeutic area

Diseases [C] - Nervous System Diseases [C10]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	17.0
E.1.2	Level	LLT
E.1.2	Classification code	10003500
E.1.2	Term	Asphyxia neonatal
E.1.2	System Organ Class	100000004855

E.1.2 Medical condition or disease under investigation

E.1.2	Version	17.0
E.1.2	Level	LLT
E.1.2	Classification code	10004943
E.1.2	Term	Birth asphyxia
E.1.2	System Organ Class	100000004855

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 provide an early evaluation of the efficacy using magnetic resonance spectroscopy [MRS] and the combination of survival with amplitude-integrated electroencephalogram [aEEG]) of 2-IB

E.2.2

Secondary objectives of the trial

• To evaluate the short term safety and tolerability of 2-IB;
• To evaluate the pharmacokinetic profile of 2-IB;
• To gather preliminary evidence on the long term efficacy of 2-IB, as measured by neurodevelopmental outcome at 24 months after birth;
• To gather preliminary evidence on the long term safety of 2-IB, as measured by serious adverse events reports up to 24 months after birth.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Subjects must meet all of the following requirements prior to inclusion in the study:
1. Neonates with ≥ 36 and <44 weeks gestation with at least one of the following:
• Apgar Score ≤ 5 at 10 minutes after birth
• Continued need for resuscitation, including endotracheal or mask ventilation at 10 minutes after birth
• Acidosis defined as either umbilical cord pH or any arterial, venous, capillary pH within 60 minutes of birth pH ≤ 7,00
• Acidosis defined as base deficit ≥ 16 mmol/l in umbilical blood sample or any blood sample within 60 minutes of birth (arterial or venous).
2. The presence of moderate/severe encephalopathy defined as:
• Altered state of consciousness (lethargy, stupor, coma) and at least one of the following:
- Hypotonia
- Abnormal reflexes including oculomotor or papillary abnormalities
- Weak or absent suck reflex
- Clinical seizures
• AND depression of the background pattern (lower margin≤ 5 µV meaning at least DNV or BS, CLV, FT) or the presence of seizure activity on the aEEG, registered for at least 30 minutes within 6 hours after birth.
3. Presence in hospital and ability to start treatment within 6 hours after birth.
4. Informed Consent Form signed before first study-related activity according to local law. The Law on Ethics of Biomedical research of the Republic of Lithuania Lithuanian law art. 7 para.2 , states that both parents of the minor should give informed consent before a minor can be included in a study. If there is only a mother (i.e. divorce, unknown father), the Informed Consent Form should be signed by the mother.
5. Receiving standard therapy without hypothermia.

E.4

Principal exclusion criteria

1. Major antenatally known- or congenital abnormalities, such as hernia diaphragmatica requiring ventilation.
2. Major antenatally known chromosomal abnormalities, such as trisomy 13 or 18 or neonates with evident syndromal appearances including brain dysgenesis.
3. Severe growth restriction with a birth weight below the 3rd percentile.
4. Inability to insert an indwelling catheter (umbilical venous catheter or percutaneously inserted central catheter, preferably multiple lumen).

E.5 End points

E.5.1

Primary end point(s)

Primary parameters as assessed by the Medical Adjudication Committee:
• The Lac/NAA ratio in the basal ganglia as measured by single voxel MRS.
Proton (1H) MRS of the basal ganglia lactate/N-acetyl aspartate (Lac/NAA) peak-area ratio is considered to be an accurate quantitative biomarker for prediction of neurodevelopmental outcome after Neonatal Encephalopathy (Thayyil et al, 2010).

• The composite endpoint of survival at 48h with a normal aEEG.
Electrocortical brain activity is measured by aEEG, starting as soon as possible after birth and before study medication has been initiated and continued until at least 72h after start of treatment. Every 4h the background pattern of the aEEG and the presence of seizures will be recorded in the eCRF. The aEEG will be classified as normal or abnormal at 48h after the start of treatment. The aEEG will be scored in five categories using pattern-recognition (Hellstrom-Westas et al, 2006): continuous normal voltage (CNV) and discontinuous normal voltage (DNV) being classified as normal (Thoresen et al, 2010), and burst suppression (BS), continuous extremely low voltage (CLV) and flat trace (FT) classified as abnormal.
To prevent bias due to death before 48h after start treatment, survival is added as parameter. Hence, for this primary endpoint, a good outcome is defined as survival in combination with a normal aEEG at 48h. A bad outcome is either death or abnormal aEEG at 48h after start treatment.
In this explorative Phase II study a composite endpoint is justifiable. In a large meta-analysis of non-cooled babies with perinatal asphyxia it was shown that the Lac/NAA ratio (as determined by MRS) is the most promising biomarker to predict the outcome at the age of 2 years old (Thayyil et al, 2010). However, in the TOBY trial (with newborns that have undergone hypothermia), the aEEG background pattern was one of the most prominent biomarkers of outcome (Thoresen et al 2010). We are going to explore the efficacy of 2-IB first in neonates without hypothermia and later also in neonates with hypothermia, and would like to see the effect of 2-IB on a broad number of outcome parameters, including two principle outcome parameters.

E.5.1.1

Timepoint(s) of evaluation of this end point

MRS will evaluated between 3 and 7 days after start treatment.
aEEG/mortality will evalluated at 48 hours after start of treatment

E.5.2

Secondary end point(s)

Secondary parameters for efficacy during hospitalization period:
• MRI: pattern of injury score
Neuro-imaging by Magnetic Resonance Imaging (MRI) between 3 and 7 days following birth. The scoring system used is the pattern of injury score (Rutherford et al, 2010 appendix) in 4 areas of the brain (cortex, basal ganglia and thalamus, white matter and posterior limb of the internal capsule (PLIC)). Abnormal MRI is reported to be a predictor of poor outcome when at least one of following occurs (Rutherford et al, 2010):
o Moderate or severe score in basal ganglia and thalamus
o Abnormal PLIC
o Severe white matter abnormalities

• MRI: DWI (diffusion weighted images): apparent diffusion coefficient (ADC) in basal ganglia and PLIC

• aEEG. Additional parameters derived from the aEEG recording will be assessed:
o aEEG at 36h after start of study drug administration (classified the same way as described for the primary endpoint at 48h)
o aEEG at 4-hour intervals until 48h after start of study drug administration (classified the same way as de described for the primary endpoint at 48h)
o Time to normal aEEG, defined as the first time a normal aEEG is seen after birth
o Time until the aEEG shows sleep-wake-cycling (Osredkar et al, 2005)
o Presence of (sub)clinical seizures (Glass et al, 2009, Bjorkman, 2010)
• Neurological examination at the moment of discharge from the Level III NICU (see Table 4)
• Mortality during first 7 days after birth (neonatal mortality)
• Length of stay at the NICU (Level III unit)

Safety parameters
o Frequency and nature of (severe) adverse events.
o Serum biochemistry and hematology at regular intervals conform schedule of assessment.
o Fluid balance will be monitored during the period at NICU.
o ECG at least once during the administration of 2-IB
o Continuous monitoring of the vital signs including blood pressure, heart rate, temperature, breathing rate, during stay at NICU.
o Daily clinical evaluation, including evaluation of all organ systems, measurement of weight and head circumference, length when possible.
o Local tolerance when a catheter becomes dysfunctional resulting in leakage on the skin.
o All cause mortality during first seven days after birth (neonatal mortality)

Pharmacokinetic parameters
The following parameters will be calculated on the basis of plasma concentration data: Cmax, Tmax, t1/2, AUC0-infinite, AUC0-24. A population pharmacokinetics approach will be used.
Plasma will be obtained at 30 minutes and 1 and 4 hours after start of the first 2-IB infusion and shortly before the start of the fourth infusion. Urine PK analysis will be performed on the urine collected at least until 72 hours after birth (when available).
Metabolomic parameters will be evaluated to gain more insight in the mode of action of 2-IB.

E.5.2.1

Timepoint(s) of evaluation of this end point

Secondary parameters
MRI(incl DWI):3-7 days after birth
aEEG: will be recorded as soon as possible after birth (at least before first administration study medication) till at least 72 hours after birth.
Neurological assessment will be performed during NICU stay
samples for metabolomics assessment will be taken before start of treatment, directly after the 6th infusion and at before discharge of the NICU. Metabolomics may also be performed in available urine and cerebral spinal fluid (CSF) samples.

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

Yes

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

Metabolomics

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

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

There is a open pilot phase with 6 subjects before the randomized double blind main phase.

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

Will this trial be conducted at a single site globally?

E.8.4

Will this trial be conducted at multiple sites globally?

Yes

E.8.6 Trial involving sites outside the EEA

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.6.3

Specify the countries outside of the EEA in which trial sites are planned

Turkey

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, or earlier if subject has dropped out or died.

E.8.9 Initial estimate of the duration of the trial

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)

Yes

F.1.1.2.1

Number of subjects for this age range:

F.1.1.3

Newborns (0-27 days)

Yes

F.1.1.3.1

Number of subjects for this age range:

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

F.3.3.6

Subjects incapable of giving consent personally

Yes

F.3.3.6.1

Details of subjects incapable of giving consent

Neonates of ≥36 and<44 weeks gestation

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.2

For a multinational trial

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)

G. Investigator Networks to be involved in the Trial

H.4 Third Country in which the Trial was first authorised
H.4.1	Third Country in which the trial was first authorised:	Turkey

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