| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Aneurysmal subarachnoid hemorrhage |
|
| E.1.1.1 | Medical condition in easily understood language |
| Aneurysmal subarachnoid hemorrhage |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cardiovascular Diseases [C14] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 17.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10042320 |
| E.1.2 | Term | Subarachnoid hemorrhage |
| E.1.2 | System Organ Class | 100000004852 |
|
| 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 |
•Dose Escalation Period
To determine the maximum tolerated dose (MTD) of intraventricular EG 1962.
•Treatment Period
To determine the safety and tolerability of the selected dose of intraventricular EG 1962 as compared to enteral nimodipine in patients with Aneurysmal subarachnoid hemorrhage.
|
|
| E.2.2 | Secondary objectives of the trial |
•To measure plasma and cerebrospinal fluid (CSF) concentrations of nimodipine.
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Male or female between the ages of 18 to 75 years, inclusive;
2. WFNS Grade 2, 3, or 4 assessed after treatment of the aneurysm but prior to administration of EG-1962;
3. Ruptured saccular aneurysm confirmed by angiography (catheter or CTA) and treated by neurosurgical clipping or endovascular coiling;
4. Subarachnoid hemorrhage on baseline CT scan that is diffuse (clot present in both hemispheres) thick (>4 mm) or thin, or local thick;
5. External ventricular drain (EVD) in place;
6. The patient is able to receive EG-1962 within 60 hours of the onset of SAH. Onset of SAH is defined as the time the patient experiences the first symptom of SAH (e.g., severe headache or loss of consciousness reported either by the patient or by a witness). If found unconscious, the onset of SAH is defined as the last time the patient was seen at baseline neurological state;
7. Weight >45 kg;
8. Hemodynamically stable after resuscitation with SBP ≥90 mm Hg without the use of inotropic agents;
9. Signed informed consent from the patient or the patient’s legal representative after the completion of aneurysm repair and after all study criteria are confirmed; and
10. Female patients of child-bearing potential must have negative pregnancy test (urine or serum) at screening and must agree to use adequate birth control during the study and up to 1 month after the discontinuation of the study drug treatment. Female patients are considered to be not of child-bearing potential if they have a history of tubal ligation or hysterectomy or are post-menopausal with a minimum of 2 years without natural menstrual cycle. Male patients must agree to use adequate birth control during the study and up to 1 month after the discontinuation of the study drug treatment. |
|
| E.4 | Principal exclusion criteria |
1. Subarachnoid hemorrhage due to causes other than a saccular aneurysm (e.g., trauma or rupture of fusiform or infective aneurysm);
2. WFNS Grade 1 or 5 assessed after the completion of aneurysm repair but prior to administration of EG-1962;
3. Increased intracranial pressure (ICP) >30 mm Hg in sedated patients lasting >4 hours anytime since admission;
4. Intraventricular or intracerebral hemorrhage in absence of SAH or with only local, thin SAH;
5. Angiographic vasospasm prior to aneurysm repair procedure, as documented by catheter angiogram or CT angiogram;
6. Major complication during aneurysm repair such as, but not limited to, massive intraoperative hemorrhage, brain swelling, arterial occlusion, or inability to secure the ruptured aneurysm;
7. Aneurysm repair requiring flow diverting stent or stent-assisted coiling and dual antiplatelet therapy;
8. Hemodynamically unstable prior to administration of study drug
(i.e., SBP <90 mm Hg, requiring >6 L colloid or crystalloid fluid resuscitation);
9. Cardiopulmonary resuscitation was required following SAH;
10. Female patients with positive pregnancy test (blood or urine) at screening;
11. History within the past 6 months and/or physical finding on admission of decompensated heart failure (New York Heart Association [NYHA] Class III and IV or heart failure requiring hospitalization);
12. Acute myocardial infarction within 3 months prior to the administration of the study drug;
13. Symptoms or electrocardiogram (ECG)-based signs of acute myocardial infarction or unstable angina pectoris on admission;
14. Electrocardiogram evidence and/or physical findings compatible with second or third degree heart block or of cardiac arrhythmia associated with hemodynamic instability;
15. Echocardiogram, if performed as part of standard-of-care before treatment, revealing a left ventricular ejection fraction (LVEF) <40%;
16. Severe or unstable concomitant condition or disease (e.g., known significant neurologic deficit, cancer, hematologic, or coronary disease), or chronic condition (e.g., psychiatric disorder) that, in the opinion of the Investigator, may increase the risk associated with study participation or study drug administration, or may interfere with the interpretation of study results;
17. Patients who have received an investigational product or participated in another interventional clinical study within 30 days prior to randomization. Patients participating in a non-interventional study that has no bearing on assessment of EG-1962 or enteral nimodipine can be enrolled per guidelines of the local Institutional Review Board (IRB)/Independent Ethics Committee (IEC);
18. Kidney disease as defined by plasma creatinine ≥2.5 mg/dl (221 μmol/l); liver disease as defined by total bilirubin >3 mg/dl (51.3 μmol/l); and/or known diagnosis or clinical suspicion of liver cirrhosis; or
19. Known hypersensitivity to nimodipine or other dihydropyridine calcium channelantagonists, PLGA, or hyaluronic acid. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Safety and Tolerability
• Safety monitoring and grading used for evaluating adverse events
will be based on the National Cancer Institute Common Terminology
Criteria for Adverse Events (NCI CTCAE, Version 4.0).
• Hypotension defined as mean SBP <80 mm Hg, lasting over
15 minutes, and requiring treatment other than IV fluid resuscitation,
and occurring any time after drug administration up to and including
Day 21.
• Death within 90 days of aSAH. The reason(s) of death will be
recorded carefully.
• Occurrence of adverse events of specific interest (i.e.,
hydrocephalus, meningitis, ventriculitis, hypotension, elevated liver
enzymes [increase in ALT or AP >2 × ULN], renal injury [increase in
serum creatinine >2 × baseline]) within 28 days of study drug
administration.
• Average daily change from baseline in SBP, diastolic blood pressure
(DBP), and heart rate for up to and including Day 21, or until
discharge from hospitalization, whichever occurs first. Baseline is the
average of 3 measurements performed before induction
Pharmacokinetics
Nimodipine concentration will be determined in plasma and CSF.
Pharmacokinetic evaluations will include, but not necessarily be limited
to, maximum drug concentration in plasma (Cmax), time to reach
maximum drug concentration in plasma (Tmax), area under the
concentration-time curve (AUC) from study drug administration to
Day 14-21 depending on data (AUCend), and until last measurement
(AUCinf), apparent total body clearance of drug from plasma (CL),
apparent terminal half-life (t½) and mean residence time (MRT) in
plasma and CSF, where appropriate.
Clinical Outcome
Clinical outcome will be assessed 3 months after aSAH and will be
measured on the basis of eGOS, mRS, Barthel Index, TICS, MoCA,
NIHSS, and all-cause mortality.
Delayed cerebral infarction will be measured as number and volume of
infarcts present in CT 28 days to 42 days after administration of
EG-1962 that were not present on CT <24 hours after the aneurysm
repair.
Incidence of DCI will be measured on the basis of mGCS or NIHSS in
patients in whom the neurologic scales are assessable and on the basis
of Investigator-initiated rescue therapy in patients in whom the
neurologic scales are not assessable.
Angiographic vasospasm will be detected by catheter or CTA. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| MTD: 21 days. Hypotension: lasting more than 15 minutes and occurring any time after drug administration up to and including Day 21•Death: within 90 days of aSAH•Adverse events of specific interest: within 28 days of study drug administration•Average daily change from baseline in SBP, diastolic blood pressure, and heart rate for up to and including Day 21 or until acute hospitalization or discharge whichever occurs first |
|
| E.5.2 | Secondary end point(s) |
| To measure plasma and cerebrospinal fluid (CSF) concentrations of nimodipine. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Nimodipine concentration: in plasma every 6 hours for the first 24 hours after administration of study drug, then daily up to and including Day 14 or until hospital discharge, at Day 21 (±3 days), and at the f-up visit on Day 30 (±7 days); in the CSF: daily starting 6 hours after the administration of study drug for up to and including Day 21 or until the ventricular catheter is removed |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | No |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | Yes |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | Yes |
| E.7.1.3.1 | Other trial type description |
| Dose Escalation, safety,tolerability and pharmacokinetic study |
|
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 2 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Canada |
| Czech Republic |
| Finland |
| United States |
|
| 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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