NEWTON: Safety and Tolerability Study of EG-1962 in Aneurysmal Subarachnoid Hemorrhage

Sponsor

Edge Therapeutics Inc (Industry)

Overall Status

Completed

CT.gov ID

NCT01893190

Collaborator

(none)

Enrollment

Locations

Arms

Duration (Months)

3.2

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

Phase 1/2a Multicenter, Controlled, Randomized, Open Label, Dose Escalation, Safety, Tolerability, and Pharmacokinetic Study Comparing EG-1962 and Nimodipine in Patients with Aneurysmal Subarachnoid Hemorrhage

Condition or Disease	Intervention/Treatment	Phase
Ruptured Cerebral Aneurysm Ruptured Berry Aneurysm	Drug: Nimodipine Drug: Nimodipine Microparticles	Phase 1/Phase 2

Detailed Description

This is a Phase 1/2a multicenter, controlled, open label, and randomized, study.

Part 1 of the study is a single dose escalation period to determine the MTD of EG-1962. During this period, a maximum of 6 dose level cohorts with up to 12 patients per cohort will be enrolled. In each cohort, patients will be randomly assigned in a ratio of 3:1 to receive either intraventricular EG 1962 or enteral nimodipine, respectively. The first cohort will receive 100 mg EG 1962. Upon completion of the dose escalation period, a safe and tolerable dose will be selected for further study.

Part 2 of the study is a treatment period to assess the safety and tolerability of the selected dose of EG-1962.

The safety and tolerability of a single intraventricular dose of EG 1962 will be compared to enteral nimodipine (60 mg given every 4 hours orally or via nasogastric or gastrostomy tube) for 21 days.

Study Design

Study Type:

Interventional

Actual Enrollment :

73 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

Nimodipine Microparticles to Enhance Recovery While Reducing TOxicity After subarachNoid Hemorrhage: Phase I/IIa Multicenter, Controlled, Randomized, Open Label, Dose Escalation, Safety, Tolerability, and Pharmacokinectic Study Comparing EG-1962 and Nimodipine in Patients With Aneurysmal Subarachnoid Hemorrhage

Study Start Date :

Sep 1, 2013

Actual Primary Completion Date :

Jan 1, 2016

Actual Study Completion Date :

Jan 1, 2016

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Nimodipine Nimodipine 60mg q4h for 21 days - oral	Drug: Nimodipine Based upon Investigator Judgement Other Names: Nimodipine Softgel Nimodipine Tablet
Experimental: Nimodipine Microparticles Single intraventricular injection	Drug: Nimodipine Microparticles Based upon Investigator Judgement Other Names: EG-1962

Arm

Intervention/Treatment

Active Comparator: Nimodipine

Nimodipine 60mg q4h for 21 days - oral

Drug: Nimodipine

Based upon Investigator Judgement

Other Names:

Nimodipine Softgel

Nimodipine Tablet

Experimental: Nimodipine Microparticles

Single intraventricular injection

Drug: Nimodipine Microparticles

Based upon Investigator Judgement

Other Names:

EG-1962

Outcome Measures

Primary Outcome Measures

Dose Escalation Period [3 Months]
To determine the maximum tolerated dose (MTD) of intraventricular EG 1962.

Secondary Outcome Measures

PK measurements [3 Months]
To measure plasma and cerebrospinal fluid (CSF) concentrations of nimodipine

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 75 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Male or female between the ages of 18 to 75 years, inclusive;
WFNS Grade 2, 3, or 4 assessed after treatment of the aneurysm but prior to administration of EG-1962;
Ruptured saccular aneurysm confirmed by angiography (catheter or CTA) and treated by neurosurgical clipping or endovascular coiling;
Subarachnoid hemorrhage on baseline CT scan that is diffuse (clot present in both hemispheres) thick (>4 mm) or thin, or local thick;
External ventricular drain (EVD) in place;
The patient is able to receive EG-1962 within 60 hours of the onset of subarachnoid hemorrhage (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 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;
Weight >45 kg;
Hemodynamically stable after resuscitation with systolic blood pressure (SBP) ≥90 mm Hg without the use of inotropic agents;
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
Female patients of child bearing potential must have negative pregnancy test . 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.

Exclusion Criteria:

Subarachnoid hemorrhage due to causes other than a saccular aneurysm (e.g., trauma or rupture of fusiform or infective aneurysm);
WFNS Grade 1 or 5 assessed after completion of the aneurysm repair but prior to administration of EG-1962;
Increased intracranial pressure >30 mm Hg in sedated patients lasting >4 hours anytime since admission;
Intraventricular or intracerebral hemorrhage in absence of SAH or with only local, thin SAH;
Angiographic vasospasm prior to aneurysm repair procedure, as documented by catheter angiogram or CT angiogram;
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;
Aneurysm repair requiring flow diverting stent or stent-assisted coiling and dual antiplatelet therapy;
Hemodynamically unstable prior to administration of study drug (i.e., SBP <90 mm Hg, requiring >6 L colloid, or crystalloid fluid resuscitation;
Cardiopulmonary resuscitation was required following SAH;
Female patients with positive pregnancy test (blood or urine) at screening;
History within the past 6 months and/or physical finding on admission of decompensated heart failure (New York Heart Association Class III and IV or heart failure requiring hospitalization);
Acute myocardial infarction within 3 months prior to the administration of the study drug;
Symptoms or electrocardiogram (ECG)-based signs of acute myocardial infarction or unstable angina pectoris on admission;
Electrocardiogram evidence and/or physical findings compatible with second or third degree heart block or of cardiac arrhythmia associated with hemodynamic instability;
Echocardiogram, if performed as part of standard-of-care before treatment, revealing a left ventricular ejection fraction <40%;
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;
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).
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 Known hypersensitivity to nimodipine or other dihydropyridine calcium channel antagonists, poly-D, L-lactide-co-glycolide (PLGA), or hyaluronic acid.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Barrow Neurological Institute	Phoenix	Arizona	United States	85013
2	Ronald Reagan UCLA Medical Center	Los Angeles	California	United States	90095-7436
3	Rush University Medical Center	Chicago	Illinois	United States	60612
4	University of Maryland Medical Cnter	Baltimore	Maryland	United States	21201
5	Hackensack University Medical Center	Hackensack	New Jersey	United States	07601
6	Overlook Medical Center	Summit	New Jersey	United States	07901
7	University of New Mexico	Albuquerque	New Mexico	United States	87131
8	Mount Sinai Medical Center	New York	New York	United States	10029
9	Columbia University	New York	New York	United States	10032
10	Lenox Hill Hospital	New York	New York	United States	10065
11	Duke University Medical Center	Durham	North Carolina	United States	27705
12	Mayfield Clinic Inc	Cincinnati	Ohio	United States	45219
13	The Cleveland Clinic Foundation	Cleveland	Ohio	United States	44195
14	Oregon Health and Science University	Portland	Oregon	United States	97239
15	Medical University of South Carolina (MUSC)	Charleston	South Carolina	United States	29425
16	Vanderbilt University	Nashville	Tennessee	United States	37232
17	University of Calgary, Foothills Medical Centre	Calgary	Alberta	Canada	T2N 1N4
18	University of Alberta Hospital	Edmonton	Alberta	Canada	T6G 2B7
19	St. Michael's Hospital	Toronto	Ontario	Canada	M5B 1W8
20	University Health Network - Toronto General Division, Toronto Western Hospital	Toronto	Ontario	Canada	M5T 2S8
21	University of Saskatchewan, Royal University Hospital	Saskatoon	Saskatchewan	Canada	S7N 0W8
22	Charles University, Department of Neurosurgery	Prague		Czechia	16902
23	Helsinki University Central Hospital	Helsinki		Finland	00260