None listed
Conditions
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.
Interventions
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 d
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.
Sponsors
PresSura Neuro Ltd
Study design
Allocation
Randomised controlled trial
Intervention model
Parallel
Primary purpose
Treatment
Masking
Blinded (masking used) (Subject, Caregiver, Outcomes Assessor)
Eligibility
Sex/Gender
Male
Age
18 Years to 45 Years
Healthy volunteers
Yes
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
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.
Outcome results
None listed