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Trial registered on ANZCTR


Registration number
ACTRN12618000482268
Ethics application status
Approved
Date submitted
4/03/2018
Date registered
3/04/2018
Date last updated
25/11/2019
Date data sharing statement initially provided
25/11/2019
Type of registration
Retrospectively registered

Titles & IDs
Public title
An open-label, parallel-group Phase I study to assess safety, tolerability, and pharmacokinetics of single doses of EU-C-001 administered with an apomorphine challenge, or when 90 mg EU-C-001 are administered alone twice (two times) a day (BID) for 7 doses in 12-hour intervals
Scientific title
An open-label, parallel-group Phase I study to assess safety, tolerability, and pharmacokinetics of single doses of EU-C-001 administered with an apomorphine challenge, or when 90 mg EU-C-001 are administered alone BID for 7 doses in 12-hour intervals
Secondary ID [1] 294227 0
Nil Known
Universal Trial Number (UTN)
U1111-1210-2622
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Traumatic brain injury 306889 0
Condition category
Condition code
Neurological 305988 305988 0 0
Other neurological disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Group [1]
(a) Five male subjects will receive one intravenous infusion of 90 mg EU-C-001.
(b) Five male subjects will receive one intravenous infusion of 15 mg EU-C-001.
(c) Five male subjects will receive one intravenous infusion of 5 mg EU-C-001 (To be investigated only if the 90 mg and the 15 mg doses show comparable activity in the apomorphine challenge).

The doses will be administered in descending ordered starting with the 90 mg dose (a) with staggered starts for the cohorts of at least 24 hours. The lowest dose of 5 mg EU-C-001 will only be investigated if the 90 mg and the 15 mg doses show comparable activity in the apomorphine challenge.. If the 90 mg and the 15 mg doses do not show comparable activity in the apomorphine challenge, Group c will not be administered the study drug..
Subjects will be monitored for clinically relevant gastrointestinal adverse events like e.g., nausea, vomiting, and retches when challenged with apomorphine 2 hours after the start of the EU-C_001 infusion.

Apomorphine challenge
Two hours (120 minutes) after start of the EU-C-001 infusion, the subjects will receive a subcutaneous injection of 50 µg/kg apomorphine.

After EU-C-001 infusion, subjects will be monitored during blood sampling for pharmacokinetecs at 15-20 minute intervals up to 1 hour, and for adverse events at 1.0, 1.5, 2, 2.5, 3.0, 4.0, 6.0, 8.0, 10., 12, and 24 hours.

Group [2]
Six male subjects (not included in Group 1) will each receive seven 30-minute intravenous infusions of 90 mg EU-C-001 in 12-hour intervals. Administration of study drug to Group 2 will start not less than 24 hours after Group 1 (a).
After EU-C-001 infusion, subjects will be monitored during blood sampling for pharmacokinetecs at 15-20 minute intervals up to 4 hours, and for adverse events at 1.0, 2, 4.0, 8.0, and 12 hours.
Stopping criteria are occurrence of abnormal results at safety assessments (e.g. laboratory values) and / or systemic adverse events all being of clinical relevance.

All doses are administered at a dedicated clinical trial facility under controlled conditions by the investigators.
The dose administrations will be made under direct medical supervision. The precise date and time of the administration shall than be documented in the CRF.
Intervention code [1] 300519 0
Treatment: Drugs
Comparator / control treatment
The comparator group for this study will be the Group 1 (a) administered 90 mg EU-C-001 before apomorphine challenge.
Control group
Dose comparison

Outcomes
Primary outcome [1] 305025 0
Pharmacodynamic assessment of the effect of EU-C-001 given as single slow intravenous infusions on apomorphine induced gastrointestinal adverse events. The inhibition of apomorphine-induced emesis will be used in this study as proof of receptor occupancy and EU-C-001 brain penetrance. When there are more than two subjects with 5 or more events of retching and/or vomiting within two hours after apomorphine injection at a given dose level, the minimum active single intravenous dose is reached.
A composite outcome will be assessed ::Pharmacodynamic assessment of EU-C-001, assessed using a composite of apomorphine-induced emesis, and safety parameters including vital signs and laboratory assessments.

Monitoring for adverse events will include:
vital signs -blood pressure, pulse rate
cardiac telemetry
laboratory investigations - haematology, biochemistry, urinalysis
Timepoint [1] 305025 0
Subjects will be specifically monitored for gastro-intestinal events at the time of apomorphine administration and at at 0.5, 1.0, 1.5, and 2.0 hours after apomorphine administation.
Occurrence of vomiting and number of retches and their time of occurrence will be recorded over 24 hours after apomorphine administration.
Secondary outcome [1] 343907 0
A composite outcome assesment will include determination of Safety and tolerability of EU-C-001 after one single 30-minute infusion of the study medication (group 1) and after seven single 30-minute infusions of the study medication in 12-hour (group 2)

assessments include:
vital signs -blood pressure and pulse rate
cardiac telemetry - 12 lead ECG
haematology analysis assessed against clinical laboratory normal ranges
Serum biochemistry analysis assessed against clinical laboratory normal ranges
Urinalysis assessed against clinical laboratory normal ranges

Hematology, Biochemistry, and Urinalysis will be performed in a NATA accredited laboratory.
Timepoint [1] 343907 0
Safety and tolerability assessments will be monitored from 1 hr post EU-C-001 infusion.
Vital signs
1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 6.0, 8.0, 12, and 24 hours after EU-C-001 infusion commences.
Cardiac telemetry
2.0, 4.0, 6.0, and 8 hours after EU-C-001 infusion commences.
Hematology, Biochemistry, and Urinalysis will be performed 24 hours after EU-C-001 infusion commences.
Secondary outcome [2] 344248 0
Determination of the Pharmacokinetics profile of EU-C-001 and its major metabolites in plasma via an LC-MS/MS assay. The pharmacokinetic parameters of EU-C-001 and its major metabolite measured in plasma are:
AUC 0-t , AUC 0-inf, Cmax, tmax, lamda z , and t 1/2 , as well as AUC(t), Cmax, tmax,
Lamda z , and t 1/2 after repeated dosing.
Timepoint [2] 344248 0
0, 0.25, 0.5, 0.67, 0.83, 1.0, 1.25, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 5.0, 6.0, 7.0, 8.0, 10, 12, 15, 24, 36, 48, 72 hours after the start of the EU-C-001 infusion

Eligibility
Key inclusion criteria
Healthy male subjects, age 18 to 45 years, healthy as defined by medical history, physical and biological examinations performed prior to inclusion.
1. Gender Male
2. Age: Between 18 and 45years
3. Weight: 55.0–95.0 kg
4. BMI: 19.0–29.0 kg/m2
5. Medical history without clinically relevant pathologies
6. Physical examination parameters without signs of clinically relevant pathologies
7. Electrocardiogram recording without signs of clinically relevant pathology, in particular QTc (Bazett) <450 ms
8. 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)
9. Having given written informed consent before any study-related activities are carried out
10. Willing and able to use a condom for all sexual intercourse and practice a medically approved method of contraception with female partners (e.g., condom in combination with hormonal contraception or intrauterine device or a diaphragm) throughout the study and for 1 month after the last study drug administration
Minimum age
18 Years
Maximum age
45 Years
Sex
Males
Can healthy volunteers participate?
Yes
Key exclusion criteria
Subjects will not be eligible for the study, if they fulfill one or more of the following exclusion criteria:
1. Evidence of clinically relevant pathology or disease
2. Evidence of moderate or severe hypertension, hypotension or orthostatic hypotension (fall in systolic blood pressure of >20 mmHg on standing up from supine)
3. Unwilling and/or incapable of giving informed consent
4. 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
5. Having had any previous traumatic brain injury, concussion or unexplained loss of consciousness
6. Acute or chronic gastrointestinal disorders
7. Presence or history of endocrine disorders
8. Known hypersensitivity to the study drug or constituent of the study drug
9. History of immediate hypersensitivity to any drug,
10. Strict vegetarian or vegan
11. Regular treatment with medications during three months prior to screening
12. Receipt of any prescription or non-prescription medication, complementary therapies including multi-vitamin preparations within 14 days prior to the day of the first pharmacokinetic assessment and for the duration of the study with the exception of paracetamol at a dose less than or equal to 2g per day
13. Participation in a clinical study within 90 days prior to randomization or within 7 half-lives of a previous investigational agent
14. Having already received EU-C-001
15. Donation of blood within 90 days prior to screening
16. Receipt of blood, blood products or plasma derivatives one year prior to randomization
17. History of use of tobacco or nicotine-containing products within the past three months
18. Any history of alcohol abuse or drug addiction
19. Positive results at screening for drugs of abuse (Methamphetamines / Opiates / Cocaine / Cannabinoids / Phencyclidine / Benzodiazepines / Barbiturates / Methadone / Tricyclic Antidepressants / Amphetamines) or alcohol (breath test) at screening or on admission
20. Positive screen results for HBsAg, anti-HCV, or anti-HIV1&2 (except for subjects vaccinated for hepatitis or subjects with past but resolved hepatitis)
21. Consumption of abnormal quantities of coffee or tea or other caffeinated drinks (i.e., more than 5 cups per day [1 cup = 150 ml])
22. Any disease which in the Investigator’s opinion would exclude the subject from the study.
23. Any indication of respiratory impairment

Study design
Purpose of the study
Treatment
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Other
Other design features
The subjects will be sequentially allocated to the different study groups.
Phase
Phase 1
Type of endpoint/s
Pharmacodynamics
Statistical methods / analysis
Sample sizes to be used in this exploratory study are consistent with other Phase I studies. The sample sizes are not based upon statistical considerations of power for comparative inference.

For the statistical analysis of safety, pharmacokinetic and pharmacodynamic parameters, a descriptive statistical approach is foreseen.

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
9/04/2018
Actual
6/03/2018
Date of last participant enrolment
Anticipated
7/05/2018
Actual
12/08/2018
Date of last data collection
Anticipated
17/05/2018
Actual
7/11/2018
Sample size
Target
21
Accrual to date
Final
22
Recruitment in Australia
Recruitment state(s)
SA
Recruitment postcode(s) [1] 21919 0
5000 - Adelaide

Funding & Sponsors
Funding source category [1] 298861 0
Commercial sector/Industry
Name [1] 298861 0
PresSura Neuro
Country [1] 298861 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] 298072 0
None
Name [1] 298072 0
None
Address [1] 298072 0
None
Country [1] 298072 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 299807 0
Bellberry Human Research Ethics Committee
Ethics committee address [1] 299807 0
129 Glen Osmond Road Eastwood South Australia 5063
Ethics committee country [1] 299807 0
Australia
Date submitted for ethics approval [1] 299807 0
Approval date [1] 299807 0
06/02/2018
Ethics approval number [1] 299807 0
2017-12-964

Summary
Brief summary
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.
This is the first in-man study planned to assess the pharmacodynamic potency as well as safety and tolerability and pharmacokinetics in man after a single intravenous administration when given together with apomorphine. The ability of EU-C-001 to penetrate the human brain is an important prerequisite for efficacy in its core indications. The inhibition of apomorphine-induced emesis will be used in this study as proof of receptor occupancy and EU-C-001 brain penetrance.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 81622 0
Dr Thomas Polasek
Address 81622 0
CMAX Clinical Research
Level 5, 18a North Terrace
Adelaide, SA, 5000, Australia
Country 81622 0
Australia
Phone 81622 0
+61 8 7088 7900
Fax 81622 0
+61 8 7088 7999
Email 81622 0
[email protected]
Contact person for public queries
Name 81623 0
Peter Pursey
Address 81623 0
PresSura Neuro Ltd.
Level 2
470 Collins street
3000 Melbourne
Australia
Country 81623 0
Australia
Phone 81623 0
(+61) 414 776 804
Fax 81623 0
Email 81623 0
[email protected]
Contact person for scientific queries
Name 81624 0
Klaus Kutz
Address 81624 0
Accel Pharm
Hebelstrasse 15A, 4056 Basel,
Country 81624 0
Switzerland
Phone 81624 0
(+41) 79 543 21 52
Fax 81624 0
Email 81624 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
What data in particular will be shared?
Individual participant data that underlie the results reported in the primary journal article containing the study results, after deidentification (text, tables, figures, appendices).
When will data be available (start and end dates)?
Beginning 6 months and ending 5 years following publication of the primary journal article containing the study results
Available to whom?
Researchers who provide a methodologically sound proposal
Available for what types of analyses?
To achieve aims in the approved proposal
How or where can data be obtained?
Proposals should be directed to [email protected]. To gain access, data requestors will need to sign a data access agreement.


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

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