Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12616001437459
Ethics application status
Approved
Date submitted
10/10/2016
Date registered
14/10/2016
Date last updated
22/03/2018
Type of registration
Prospectively registered

Titles & IDs
Public title
A double-blind Phase I study to investigate safety, tolerability, and
pharmacokinetics of single and repeated escalating doses of
EU-C-001 given as intravenous infusions and as oral
administrations in healthy male subjects
Scientific title
A double-blind Phase I study to investigate safety, tolerability, and
pharmacokinetics of single and repeated escalating doses of the NK1 receptor antagonist
EU-C-001 given as intravenous infusions and as oral
administrations in healthy male subjects
Secondary ID [1] 290183 0
Nil known
Universal Trial Number (UTN)
U1111-1187-8223
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Traumatic brain injury 300323 0
Condition category
Condition code
Neurological 300192 300192 0 0
Other neurological disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
EU-C-001:
Group 1: Single oral administration (5mg, 15mg, 45mg, 90mg, 150mg, 180mg)
Each subject will receive one single oral administration of the study medication, either EU-C-001 or placebo. At each dose levels, six male subjects will receive one oral
administration of either EU-C-001 (four or five subjects) or Placebo (one or two subjects).
Dose escalation will be stopped when the maximal tolerated dose is defined. However, higher dose levels might be investigated if the maximal tolerated dose has not been reached. In addition, smaller dose escalation steps may be explored if warranted by the safety data.
Stopping criteria are occurrence of abnormal results at safety assessments (e.g. laboratory values) and / or systemic adverse events all being of clinical relevance. It is anticipated that the maximum tolerated doses are reached after six dose escalations.
At the lowest dose level two subjects will be treated first, one subject will receive placebo and one subject will receive EU-C-001. If there are no clinically relevant adverse events related to the study medication (no NCI-CTC Grade 3 related toxicity and no NCI-CTC Grade 4 related toxicity) within 48 hours, the remaining subjects of the cohort will be
treated (3 on EU-C-001; 1 on placebo). Provided there are not more than two subjects with NCI-CTC Grade 3 related toxicity and no subject with NCI-CTC Grade 4 related toxicity in each cohort, dose escalation continues with one subject receiving placebo and five subjects receiving EU-C-001 from Cohort 2 (15mg) to Cohort 6 (180mg). When there are more than two subjects with NCI-CTC Grade 3 related toxicity and subjects with NCI-CTC Grade 4 related toxicity the maximum tolerated single oral dose is reached.

Group 2: Single 15 minute IV infusion (5mg, 15mg, 45mg, 60mg, 90mg)
Each subject will receive one single administration of the study medication, a 15-minute intravenous infusion. At the lowest dose level, six male subjects will receive one intravenous
administration of either EU-C-001 (four subjects) or Placebo (two subjects).
At each of the following dose levels, six male subjects will receive one intravenous administration of either EU-C-001 (five subjects) or Placebo (one subject).
Stopping criteria are occurrence of abnormal results at safety assessments (e.g. laboratory values), local injection reactions and / or systemic adverse events all being of clinical relevance. It is anticipated that the maximum tolerated doses are reached after six dose escalations.
At the lowest dose level two subjects will be treated first, one subject will receive placebo and one subject will receive EU-C-001. If there are no clinically relevant adverse events related to the study medication (no NCI-CTC Grade 3 related toxicity and no NCI-CTC Grade 4 related toxicity) within 48 hours after the intravenous infusion, the remaining
subjects of the cohort will be treated. Provided there are not more than two subjects with NCI-CTC Grade 3 related toxicity and no subject with NCI-CTC Grade 4 related toxicity in each cohort, dose escalation continues with one subject receiving placebo and five subjects receiving EU-C-001 from Cohort 2 (15mg) to Cohort 5 (90mg). When there are more than two subjects with NCI-CTC Grade 3 related toxicity and subjects with NCI-CTC Grade 4 related toxicity the maximum tolerated single intravenous dose is reached.

Group 3: Repeated oral administration (15mg, 45mg, 90mg, 180mg)
Each subject will receive once daily oral administrations of the study medication for 5 days. Six male subjects will receive oral administrations of either EU-C-001 (four or five subjects) or Placebo (one or two subjects). It is planned to administer 5 oral administrations at 24-hour
intervals. It is anticipated that the maximum tolerated doses are reached after three dose escalations. However, higher dose levels might be investigated if the maximal tolerated dose has not been reached. In addition, smaller dose escalation steps may be explored if warranted by the safety data.
At the lowest dose level two subjects will be treated first, one subject will receive placebo and one subject will receive EU-C-001. If there are no clinically relevant adverse events related to the study medication (no NCI-CTC Grade 3 related toxicity and no NCI-CTC Grade 4 related toxicity) 24 hours after the 2nd oral administration, the remaining subjects
of the cohort will be treated. Provided there are not more than two subjects with NCI-CTC Grade 3 related toxicity and no subject with NCI-CTC Grade 4 related toxicity in each cohort, dose escalation continues with one subject receiving placebo and five subjects receiving
EU-C-001 from Cohort 2 (45mg) to Cohort 4 (180mg). When there are more than two subjects with NCI-CTC Grade 3 related toxicity and more than one subject with NCI-CTC Grade 4 related toxicity after the oral administrations the maximum tolerated dose is reached for this route of repeated administrations.

Group 4: Repeated 15-minute intravenous infusions (5mg, 15mg, 45mg, 90mg)
Each subject will receive repeated once daily administrations of the study medication for 5 days, as 15-minute intravenous infusions. Six male subjects will receive 15-minute intravenous infusions of eitherEU-C-001 (five subjects) or Placebo (one subject). It is planned to administer the 5 injections at 24-hour intervals. It is anticipated that the
maximum tolerated doses are reached after three dose escalations. However, higher dose levels might be investigated if the maximal tolerated dose has not been reached. In addition, smaller dose escalation steps may be explored if warranted by the safety data.
At each dose level one subject will receive placebo and five subjects will receive EU-C-001. Provided there are not more than two subjects with NCI-CTC Grade 3 related toxicity and no subject with NCI-CTC Grade 4 related toxicity in each cohort, dose escalation continues in the same way for cohorts 2 (15mg) to 4 (90mg). When there are more than two subjects with NCI-CTC Grade 3 related toxicity and more than one subject with NCI-CTC Grade 4 related
toxicity after the intravenous administrations the maximum tolerated dose is reached for this route of repeated administrations.

All doses are administered at the site under controlled conditions by the investigators.

The subjects will be sequentially allocated to the different study groups.
The assignment of number and code for the subject’s identification is based on the need for
anonymity. Subjects will be identified only by their subject number, a study center subject
identification code and date of birth. The allocation of the treatment (EU-C-001 or placebo) to the subjects will be done in the morning of Day 1 immediately before the start of the first administration of the study medication according to a randomization list. The randomization list is prepared by an independent statistician from CPR Pharma Services not involved in the study and will be kept blind in the Study Files until the end of the study or individual random code sheets can be broken, if deemed necessary in medical emergency situations.
Intervention code [1] 295940 0
Treatment: Drugs
Comparator / control treatment
Placebo treated
IV placebo (80% propylene glycol set to a pH of 5 with NaOH). Identical volume of placebo to EU-C-001 is given in 100mL of sterile water for single infusion or in 200mL of 5% Glucose solution for repeated infusions.
The composition and the outer appearance of the placebo tablets is identical to the EU-C-001 tablets but without EU-C-001.
Group 1: Single oral administration
Group 2: Single 15 minute IV infusion
Group 3: Once daily oral administration for up to 5 days
Group 4: Once daily 15 minute IV infusion for up to 5 days
Please see above for administration protocol.
Control group
Placebo

Outcomes
Primary outcome [1] 299803 0
Determining the safety and tolerability of EU-C-001 following single and daily repeated administration for up to 5 days following oral and 15 minute IV infusion by measuring the following:
Vital signs: blood pressure, pulse rate and body temperature
Cardiac telemetry
Blood oxygen saturation by digital oximetry, physical examination
Biochemistry, haematology and urinalysis
Assessment of adverse events and concomitant medication
Timepoint [1] 299803 0
Vital signs: 0.5h, 1h, 2h, 4h, 8h,12h and 24h after dosing
Cardiac telemetry: continuous for 15 minutes prior and 6 hours after dosing
Blood oxygen saturation: 1h, 2h, 4h and 8h after dosing
Physical examination at 24 h after dosing
Secondary outcome [1] 328176 0
Determination of the pharmacokinetic profile of EU-C-001 and of its main
metabolites after oral and intravenous administrations in both plasma and urine. The pharmacokinetic parameters for EU-C-001 and its metabolites measured in plasma are:
AUC0-t , AUC0-infinity , Cmax , tmax , deltaz , and t1/2 under single dose conditions and under single as well as multiple dose conditions. These will be determined from samples taken from subjects in groups 1 to 4.
Absolute bioavailability. Accumulation factor.
The pharmacokinetic parameters for EU-C-001 and its metabolites
measured in urine are: Ae0-24.
Timepoint [1] 328176 0
Pharmacokinetics in plasma at 15 min, 30 min, 1 h, 1.5 h, 2 h, 2.5 h, 3h, 3.5 h, 4h, 5h, 6 h, 7h, 8h, 10h, 12h, 16h and 24 hours after administration by LS-MS/MS Assay.
Pharmacokinetics in urine during the following time intervals: 0h-4h, 4h-8h, 8h-12h, 12h-24h by the LC-MS/MS Assay.

Eligibility
Key inclusion criteria
-Gender Male
-Age: Between 18 and 45years
-Weight: 55–95 kg
-BMI: 19–29 kg/m2
-Medical history without clinically relevant pathologies
-Physical examination parameters without signs of clinically relevant pathologies
-Electrocardiogram recording without signs of clinically relevant pathology, in particular QTc (Bazett) <450 ms
-Values for hematology and for biochemistry tests of blood and urine within the normal
range or showing no clinically relevant deviation as judged by the medical investigator
(in particular normal values for ALT, AST, gamma-GT)
-Subjects must be willing to practice a medically approved method of contraception
(e.g., condom in combination with hormonal contraception or intrauterine device or a
diaphragm after the first drug administration and for one month after participation in
the study or are vasectomized since > 6 months or has a partner being sterilized since
> 6 months
- Having given written informed consent before any study-related activities are carried
out
Minimum age
18 Years
Maximum age
45 Years
Sex
Males
Can healthy volunteers participate?
Yes
Key exclusion criteria
-Evidence of clinically relevant pathology or disease
-Evidence of moderate or severe hypertension, hypotension or orthostatic hypotension
(fall in systolic blood pressure of >15 mmHg on standing up from semi-supine)
-Unwilling and/or incapable of giving informed consent
- Any history of clinically important psychiatric illness eg history of depression treated
with antidepressant or of any clinically important neurological or neuro-muscular
disorders and/or epilepsy
- Acute or chronic gastrointestinal disorders
- Presence or history of endocrine disorders
-Known hypersensitivity to the study drug or constituent of the study drug
- History of immediate hypersensitivity to any drug,
- Strict vegetarian or vegan
- Regular treatment with medications during three months prior to randomisation
- Receipt of any prescription or non-prescription medication, complementary therapies
including multi-vitamin preparations within 7 -10 days prior to randomization and for
the duration of the study with the exception of paracetamol at a dose less than or equal
to 2g per day
- Participation in a clinical study within 90 days prior to randomization or within 7 halflives
of a previous investigational agent
- Having already received EU-C-001
- Donation of blood within 90 days prior to randomisation
- Receipt of blood, blood products or plasma derivates one year prior to randomisation
- History of use of tobacco or nicotine-containing products within the past three months
- Any history of alcohol abuse or drug addiction
- Positive results at screen for drugs of abuse (cocaine, amphetamine /
methamphetamine, tetrahydrocannabiol, opiates) or alcohol (breath test) at screening
or on admission
- Positive screen results for HBsAg, anti-HCV, or anti-HIV1&2
- Consumption of abnormal quantities of coffee or tea or other caffeinated drinks (i.e.,
more than 5 cups per day [1 cup = 150 ml])
-Any disease which in the Investigator’s opinion would exclude the subject from the
study.

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Allocation is concealed. The assignment of number and code for the subject’s identification is based on the need for anonymity. Subjects will be identified only by their subject number, a study center subject identification code and date of birth.
The allocation of the treatment (EU-C-001 or placebo) to the subjects will be done in the
morning of Day 1 immediately before the start of the first administration of the study
medication according to a randomization list.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
The randomization list is prepared by an independent statistician from CPR Pharma Services not involved in the study and will be kept blind in the Study Files until the end of the study or individual random code sheets can be broken, if deemed necessary in medical emergency situations. Simple randomisation will be used by using a randomisation table. Subjects will be numbered with four-figure numbers in the order of their inclusion in the study.
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
Intervention assignment
Parallel
Other design features
Phase
Phase 1
Type of endpoint/s
Safety
Statistical methods / analysis
For the statistical analysis of safety, pharmacokinetic and pharmacodynamic parameters, a
descriptive statistical approach is foreseen.
Demographic parameters (age, height, weight) will be summarized by means of tabulated
descriptive statistics (the number of observations (N), arithmetic mean, median, SD, SEM,
minimum and maximum), by treatment groups and overall. Results of physical examination
will only be listed by subject, time point and body system.
The numerical values relating to safety and tolerability (ECG, blood pressure, pulse rate, and laboratory values) will be compiled by treatment descriptively in form of means with standard deviation (standard error), 95%-confidence intervals, maximum and minimum values calculated per time points on observed values and changes pre-dose/ post-dose.
All AEs recorded during the study will be coded according to the Medical terminology for Drug Regulatory Affairs (MedDRA) and assigned to an organ system class. AEs will be listed
individually per administration. Incidence of treatment emergent adverse events will be
summarized using frequency of events and number of subjects experiencing these events per administration, lowest level term, preferred term, system organ class and intensity.
The concomitant medications will be coded according to the WHO drug code. They will besummarized for each treatment by tabulating the number and percentages of subjects having received each treatment.
All pharmacokinetic concentrations and parameters will be presented descriptively for each administration and treatment group.
Descriptive statistics comprise N, mean, geometric mean, SD, SEM, median, coefficient of
variation (CV%,) minimum and maximum. Plasma concentrations will be described in addition per treatment and per time point. Values below LLQ will be taken as zero for descriptive statistics of concentrations.
Individual plasma concentration-time profiles will be plotted by treatment. Arithmetic mean of plasma concentrations will be plotted with SD per administration. Plots will be provided in linear and semi-logarithmic scale.
Pharmacokinetic dose proportionality for EU-C-001 and its metabolites will be assessed by
correlating pharmacokinetic parameters with dose, if possible.

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
2/11/2016
Actual
2/11/2016
Date of last participant enrolment
Anticipated
16/05/2017
Actual
3/07/2017
Date of last data collection
Anticipated
29/05/2017
Actual
30/08/2017
Sample size
Target
114
Accrual to date
Final
114
Recruitment in Australia
Recruitment state(s)
SA
Recruitment postcode(s) [1] 14414 0
5000 - Adelaide

Funding & Sponsors
Funding source category [1] 294632 0
Commercial sector/Industry
Name [1] 294632 0
PresSura Neuro Ltd
Country [1] 294632 0
Australia
Primary sponsor type
Commercial sector/Industry
Name
PresSura Neuro Ltd
Address
470 Collins Street, Suite 3, Level 2
Melbourne 3000, Victoria, Australia
Country
Australia
Secondary sponsor category [1] 293496 0
None
Name [1] 293496 0
None
Address [1] 293496 0
None
Country [1] 293496 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 296093 0
Bellberry Human Research Ethics Committee
Ethics committee address [1] 296093 0
129 Glen Osmond Road, Eastwood SA 5063
Ethics committee country [1] 296093 0
Australia
Date submitted for ethics approval [1] 296093 0
14/09/2016
Approval date [1] 296093 0
17/10/2016
Ethics approval number [1] 296093 0
2016-09-678

Summary
Brief summary
In this trial, the safety and tolerability of a EU-C-001 is being evaluated. Additionally the amount of study drug and its metabolites is being measured in blood and urine after it is administered by different routes and at different dose levels. This is a phase 1 study in healthy subjects. It is planned to develop the drug for reducing pressure in the brain of patients with a traumatic brain injury (TBI). Increased pressure following TBI can lead to death or can cause permanent disability. There are currently no medications that are approved for improving outcomes after TBI. The drug will also be tested for improving clinical outcome in patients that suffered a concussion.
The study drug being evaluated is called EU-C-001 and is being developed by an Australian company called PresSura Neuro. Studies in animals have shown that EU-C-001 may reduce pressure in the brain. Therefore, it is thought that EU-C-001 may improve outcomes in patients with TBI by increasing the amount of oxygen available to brain tissue. In other studies it was shown that the EU-C-001 may also have potential to improve outcomes in patients with concussion.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 69142 0
Prof Sepehr Shakib
Address 69142 0
Phase I Unit of IDT CMAX
Level 5, 18a North Terrace
Adelaide, SA, 5000, Australia
Country 69142 0
Australia
Phone 69142 0
(+61) 8 7088 7900
Fax 69142 0
(+61) 8 7088 7999
Email 69142 0
[email protected]
Contact person for public queries
Name 69143 0
Mr Peter Pursey
Address 69143 0
PresSura Neuro Ltd.
Level 2
470 Collins street
3000 Melbourne
Australia
Country 69143 0
Australia
Phone 69143 0
(+61) 414 776 804
Fax 69143 0
Email 69143 0
[email protected]
Contact person for scientific queries
Name 69144 0
Prof Klaus Kutz
Address 69144 0
AccelPharm
Hebelstrasse 15A, 4056 Basel, Switzerland
Country 69144 0
Switzerland
Phone 69144 0
(+41) 79 543 21 52
Fax 69144 0
Email 69144 0
[email protected]

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