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Trial registered on ANZCTR


Registration number
ACTRN12619000074190
Ethics application status
Approved
Date submitted
15/01/2019
Date registered
21/01/2019
Date last updated
30/05/2024
Date data sharing statement initially provided
21/01/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
A double-blind placebo-controlled study with an open-label pilot phase, assessing the efficacy, tolerability and safety of EU-C-001 in patients with moderate to severe traumatic brain injury
Scientific title
A double-blind placebo-controlled study with an open-label pilot phase, assessing the efficacy, tolerability and safety of EU-C-001 in patients with moderate to severe traumatic brain injury
Secondary ID [1] 296812 0
PresSura Neuro EU-C-001-II-01
Secondary ID [2] 297068 0
EUDRACT 2017-004890-15
Universal Trial Number (UTN)
UTN U1111-1226-7276
Trial acronym
PANGEA
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Traumatic Brain Injury 310698 0
Condition category
Condition code
Neurological 309399 309399 0 0
Other neurological disorders
Injuries and Accidents 309758 309758 0 0
Other injuries and accidents

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
The first fifteen patients will participate in an open-label pilot phase: in addition to the standard of care, patients will receive treatment with four infusions of EU-C-001, each administered as a single intravenous infusion over 15 minutes. The first seven patients will receive EU-C-001 90 mg four times over three days, at time-points 0 hours and 12 hours (Day 1), 36 hours (Day 2) and 60 hours (Day 3). The next four patients will receive EU-C-001 90 mg four times over two days, at time points 0 hours and 4 hours (Day 1) and 24 hours and 28 hours (Day 2). The last four patients will receive EU-C-001 four times over two days as a weight-adapted dose (WAD), calculated as 1.58 mg/kg times the patient's body weight in kg. The dosing schedule will remain as with the previous four patients (0 hours, 4 hours, 24 hours and 28 hours). The maximum dose of EU-C-001 to be administered in a single infusion is set at 140 mg.

After the open-label pilot phase, subsequent patients will be randomly assigned to one of two treatment arms in a double-blind phase, in addition to the standard of care:
Treatment Arm A: treatment consisting of EU-C-001 with weight-adapted dosing (1.58 mg/kg) at time-points 0 hours and 4 hours, on each of four consecutive days, administered as single intravenous infusions over 15 minutes.
Intervention code [1] 313100 0
Treatment: Drugs
Comparator / control treatment
Open-Label Pilot Phase: No control group

Double-Blind Phase:
Treatment Arm B: in addition to the standard of care, treatment consisting of placebo at time-points 0 hours and 4 hours, on each of four consecutive days, administered as single intravenous infusions over 15 minutes.
The placebo is equivalent to the vehicle used for the active drug, and is diluted in 5% glucose solution for administration.
Control group
Placebo

Outcomes
Primary outcome [1] 308363 0
Double-blind phase: AUEC(0-96h) for Therapy Intensity Level (TIL), measured every 4 hours after the start of infusion of study medication - Comparison between active and placebo groups for AUEC(0-96h) for TIL
Timepoint [1] 308363 0
96 h after start of first infusion.
Primary outcome [2] 308364 0
Open-label pilot phase: To assess the safety of EU-C-001 in the target population of the highest dose to be tested in the double-blind phase, based on adverse events, such as local tolerability, intravascular hemolysis, or central nervous system effects.
Timepoint [2] 308364 0
Day 5 after start of first dose
Secondary outcome [1] 354736 0
AUEC(0-96h) for ICP, measured using an ICP monitor
Timepoint [1] 354736 0
96 hours after the start of infusion of study medication.
Secondary outcome [2] 365647 0
AUEC(96-192h) for ICP, measured using an ICP monitor
Timepoint [2] 365647 0
192 hours after the start of infusion of study medication.
Secondary outcome [3] 365648 0
Cumulative time during which ICP, measured using an ICP monitor, is above 20 mm Hg, 22 mm Hg and 25 mm Hg
Timepoint [3] 365648 0
96 hours and 192 hours after the start of infusion of study medication.
Secondary outcome [4] 365651 0
AUEC(96-192) for TIL
Timepoint [4] 365651 0
192 hours after the start of infusion of study medication.
Secondary outcome [5] 365653 0
AUEC(0-t) for cerebral perfusion pressure, calculated from the ICP, measured using an ICP monitor, and arterial pressure, using an arterial pressure monitor.
Timepoint [5] 365653 0
96 hours and 192 hours after the start of infusion of study medication
Secondary outcome [6] 365654 0
Cerebral hypoperfusion index (the number of end-hourly measures of cerebral perfusion pressure, calculated from the ICP, measured using an ICP monitor, and arterial pressure, using an arterial pressure monitor, of <60 mm Hg divided by the total number of measurements, multiplied by 100) during the 48 hours and 120 hours after the start of infusion of study medication
Timepoint [6] 365654 0
96 hours after the start of infusion of study medication
Secondary outcome [7] 365655 0
AUEC(0-t) of brain tissue oxygenation (if Licox probe used routinely)
Timepoint [7] 365655 0
96 hours and 192 hours after the start of infusion of study medication
Secondary outcome [8] 365656 0
Glasgow Outcome Scale - Extended (GOS-E) Score
Timepoint [8] 365656 0
Week 12 after the start of infusion of study medication
Secondary outcome [9] 365657 0
Glasgow Coma Scale (GCS)
Timepoint [9] 365657 0
Days 1, 2, 3, 4, 5, 8 and Week 12 after the start of infusion of study medication
Secondary outcome [10] 365658 0
Proportion of patients in each treatment group surviving, based on the date of death entered in the case report form for those patients who die during the study.
Timepoint [10] 365658 0
Day 28 and Week 12 after the start of infusion of study medication
Secondary outcome [11] 365662 0
'Time to completion' of Trail Making Test, parts A & B
Timepoint [11] 365662 0
At discharge from hospital and at week 12 after the start of the infusion of study medication.
Secondary outcome [12] 365664 0
Quality of life assessed by the TBI - 36-Item Short Form Survey Instrument (SF-36)
Timepoint [12] 365664 0
At discharge from hospital and at week 12 after the start of the infusion of study medication.
Secondary outcome [13] 365665 0
Number of calendar days on ventilation after start of infusion of study medication, based on dates collected in the case report form.
Timepoint [13] 365665 0
Week 12 after the start of infusion of study medication
Secondary outcome [14] 365666 0
Mean change from baseline in total tau
Timepoint [14] 365666 0
Days 1, 2, 3, 4 and 5 after the start of infusion of study medication
Secondary outcome [15] 365667 0
PK (e.g. Cmax, Tmax, AUC, t1/2) of EU-C-001 and its main metabolite (desmethyl EU-C-001) in blood
Timepoint [15] 365667 0
Open-label phase: 0, 0.25, 1, 3, 8, 24 and 48 hours after start of the fourth infusion
Double-blind phase: immediately before and after each infusion, and after the last infusion at 17:00 and 08:00 each day, until 4 samples have been collected.
Secondary outcome [16] 365803 0
Number of calendar days in intensive care unit after start of infusion of study medication, based on the dates entered in the case report form.
Timepoint [16] 365803 0
week 12 after the start of infusion of study medication
Secondary outcome [17] 365804 0
Number of calendar days in hospital after start of infusion of study medication based on the dates collected in the case report form.
Timepoint [17] 365804 0
week 12 after the start of infusion of study medication
Secondary outcome [18] 365805 0
Mean change from baseline in Plasma substance P
Timepoint [18] 365805 0
Days 1, 2, 3, 4 and 5 after the start of infusion of study medication
Secondary outcome [19] 365806 0
Mean change from baseline in Serum glial fibrillary acidic protein (GFAP)
Timepoint [19] 365806 0
Days 1, 2, 3, 4 and 5 after the start of infusion of study medication
Secondary outcome [20] 435723 0
Percentage of patients requiring insertion of extra-ventricular drain (EVD), as collected in the case report form.
Timepoint [20] 435723 0
Secondary outcome [21] 435724 0
Percentage of patients requiring insertion of extra-ventricular drain (EVD), as collected in the case report form.
Timepoint [21] 435724 0
week 12 after the start of infusion of study medication

Eligibility
Key inclusion criteria
1. Male or female aged 18 to 70 years at the time the informed consent form is signed by either the patient or the patient’s legally authorized representative
2. Moderate to severe TBI due to blunt mechanism
3. Abnormal computerized tomography (CT) scan consistent with TBI due to blunt mechanism
4. Intracranial pressure monitor in situ, ICP >15 mm Hg at screening in the absence of potential external ICP stimuli, e.g., suctioning, coughing, and turning. The preferred method of ICP measurement is either intraventricular, intraparenchymal, or subdural, where possible
5. The GCS score at Screening is the most recent GCS score assessed at the hospital after resuscitation. If this is not available, the GCS score assessed by the ambulance personnel/paramedics prior to arrival at hospital will be used.
a. If the Total Score is assessable (range 3 to 15), a patient is eligible for inclusion if their score is in the range 3 to 12
b. If only the Eye and Motor scores are assessable (range 2 to 10), a patient is eligible for inclusion if their score is in the range 2 to 8
c. If only the Motor score is assessable (range 1 to 6), a patient is eligible for inclusion if their score is in the range 1 to 5
6. Onset of TBI within the last 72 hours
Minimum age
18 Years
Maximum age
70 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Documented continuously elevated ICP >20 mm Hg for >12 hours after elevated ICP was first measured/observed
2. Use of an extraventricular drain for ICP control
3. Injury deemed non-survivable by study team
4. Penetrating brain injury
5. Bilateral dilated, unresponsive pupils
6. Imminent cranial or extracranial surgery
7. Patients in whom a subdural and/or extradural haematoma are present and are considered by the investigator to be the predominant cause of raised ICP
8. Concomitant use of thiopentone
9. Cervical spinal cord injury
10. Cardiopulmonary resuscitation performed by medical personnel/paramedics
11. Life-threatening systemic injuries, additional injuries, or conditions requiring medical treatment which would confound the assessment of the effects and/or safety of study medication
12. Morbid obesity with body mass index =40 kg/m2
13. Severe or unstable pre-existing respiratory and hemodynamic conditions
14. Hypoxemia (oxygen saturation <80%, measured by pulse oximetry)
15. Hypotension (sustained systolic blood pressure <70 mm Hg despite adequate volume resuscitation and vasopressors)
16. Status epilepticus
17. Pregnancy
18. Clinically significant anemia (hemoglobin <7 g/dL)
19. History of blood clotting disorder; exclude if international normalized ratio (INR) >1.5 and/or thrombocytes <50,000/µL
20. Moderate to severe renal impairment with estimated glomerular filtration rate <60 mL/min
21. Hepatic dysfunction with total bilirubin >2 × upper limit of normal and INR >1.5
22. Any major neurological or psychiatric disorder associated with significant impairment of cognitive function or motor function, e.g., Alzheimer’s disease with dementia, Parkinson’s disease, Huntington’s disease, alcohol or substance abuse
23. Participating in or has participated in other investigational interventional studies (drug or device) within the last 30 days (or 5 times the half-life of the previously administered investigational compound, whichever is longer) prior to study treatment initiation, with the exception of studies assessing approved medicinal products. Exception is made for co-enrolment in the PATCH study of tranexamic acid, allowing inclusion if treatment with EU-C-001 is initiated not earlier than 7 half-lives (14 hours) after the end of the last administration of study drug from the PATCH study.
24. Wearing an opt out bracelet or is known not to wish to participate in this type of 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)
Central randomisation by Interactive Web Response System
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
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
The people analysing the results/data
Intervention assignment
Other
Other design features
Open label pilot phase followed by a 2-arm randomised trial
Phase
Phase 2
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis
For the double-blind phase, the primary endpoint will be the difference in the area under the effect curve for TIL between active and placebo treated patients during the 4 day treatment period.
Based on data from the open label part of the study and assuming repeated measures analysis of the 4 daily measurements of the predicted mean Area under the Curve for TIL, a sample size of 22 subjects per arm is estimated to have 80% power to detect a 33% reduction in the AUEC for TIL on active drug compared to placebo, at the two-sided alpha level of 5%. Assuming a dropout rate of approximately 12% a sample of 50 subjects in total will be included.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
21/01/2019
Actual
12/06/2019
Date of last participant enrolment
Anticipated
31/12/2024
Actual
Date of last data collection
Anticipated
31/03/2025
Actual
Sample size
Target
65
Accrual to date
15
Final
Recruitment in Australia
Recruitment state(s)
NSW,QLD,WA,VIC
Recruitment hospital [1] 12884 0
The Alfred - Prahran
Recruitment hospital [2] 12885 0
Royal North Shore Hospital - St Leonards
Recruitment hospital [3] 12886 0
Gold Coast University Hospital - Southport
Recruitment hospital [4] 12887 0
Princess Alexandra Hospital - Woolloongabba
Recruitment hospital [5] 12889 0
Royal Melbourne Hospital - City campus - Parkville
Recruitment hospital [6] 26621 0
Royal Perth Hospital - Perth
Recruitment postcode(s) [1] 25361 0
3004 - Prahran
Recruitment postcode(s) [2] 25362 0
2065 - St Leonards
Recruitment postcode(s) [3] 25363 0
4215 - Southport
Recruitment postcode(s) [4] 25364 0
4102 - Woolloongabba
Recruitment postcode(s) [5] 25365 0
3052 - Parkville
Recruitment postcode(s) [6] 42661 0
6000 - Perth
Recruitment outside Australia
Country [1] 21109 0
United Kingdom
State/province [1] 21109 0
Cambridgeshire, West Midlands, London, Edinburgh

Funding & Sponsors
Funding source category [1] 301385 0
Commercial sector/Industry
Name [1] 301385 0
Eustralis Pharmaceuticals Ltd, trading as PresSura Neuro
Country [1] 301385 0
Australia
Primary sponsor type
Commercial sector/Industry
Name
Eustralis Pharmaceuticals Ltd, trading as PresSura Neuro
Address
Compass Offices Level 26
360 Collins Street
Melbourne VIC 3000, Australia
Country
Australia
Secondary sponsor category [1] 301054 0
None
Name [1] 301054 0
Address [1] 301054 0
Country [1] 301054 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 302123 0
The Alfred Ethics Committee
Ethics committee address [1] 302123 0
Ethics committee country [1] 302123 0
Australia
Date submitted for ethics approval [1] 302123 0
27/09/2018
Approval date [1] 302123 0
12/12/2018
Ethics approval number [1] 302123 0
HREC/43447/Alfred-2018 (Local Reference: Project 481/18)

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 89194 0
Prof Jamie Cooper
Address 89194 0
Monash University, Department of Epidemiology and Preventative
Medicine, School of Public Health and Preventative Medicine, The
Alfred Centre, 99 Commercial Road, Melbourne, VIC 3004, Australia.
Country 89194 0
Australia
Phone 89194 0
+61 3 9903 0343
Fax 89194 0
Email 89194 0
jamie.cooper@monash.edu
Contact person for public queries
Name 89195 0
Peter Pursey
Address 89195 0
PresSura Neuro, Level 3, 62 Lygon Street Carlton VIC 3053, Australia
Country 89195 0
Australia
Phone 89195 0
+61 400 414 416
Fax 89195 0
Email 89195 0
peter.pursey@gmail.com
Contact person for scientific queries
Name 89196 0
Peter Pursey
Address 89196 0
PresSura Neuro, Level 3, 62 Lygon Street Carlton VIC 3053, Australia
Country 89196 0
Australia
Phone 89196 0
+61 400 414 416
Fax 89196 0
Email 89196 0
peter.pursey@gmail.com

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 info@pressuraneuro.com. 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

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
No additional documents have been identified.