Clinical trial NCT01893190: Safety and Tolerability Study of EG-1962 in Aneurysmal Subarachnoid Hemorrhage
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 type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Ruptured Cerebral Aneurysm
Ruptured Berry Aneurysm
Keywords: Ruptured saccular aneurysm
nimodipine
safety
tolerability
Subarachnoid hemorrhage
Lead sponsor: Edge Therapeutics Inc
Sponsor class: INDUSTRY
First posted: 2013-07-08
Enrollment: 73
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Dose Escalation Period
timeFrame: 3 Months
Secondary outcomes:
measure: PK measurements
timeFrame: 3 Months
Other outcomes:
Locations:
city: Phoenix
country: United States
facility: Barrow Neurological Institute
state: Arizona
city: Los Angeles
country: United States
facility: Ronald Reagan UCLA Medical Center
state: California
city: Chicago
country: United States
facility: Rush University Medical Center
state: Illinois
city: Baltimore
country: United States
facility: University of Maryland Medical Cnter
state: Maryland
city: Hackensack
country: United States
facility: Hackensack University Medical Center
state: New Jersey
city: Summit
country: United States
facility: Overlook Medical Center
state: New Jersey
city: Albuquerque
country: United States
facility: University of New Mexico
state: New Mexico
city: New York
country: United States
facility: Mount Sinai Medical Center
state: New York
city: New York
country: United States
facility: Columbia University
state: New York
city: New York
country: United States
facility: Lenox Hill Hospital
state: New York
city: Durham
country: United States
facility: Duke University Medical Center
state: North Carolina
city: Cincinnati
country: United States
facility: Mayfield Clinic Inc
state: Ohio
city: Cleveland
country: United States
facility: The Cleveland Clinic Foundation
state: Ohio
city: Portland
country: United States
facility: Oregon Health and Science University
state: Oregon
city: Charleston
country: United States
facility: Medical University of South Carolina (MUSC)
state: South Carolina
city: Nashville
country: United States
facility: Vanderbilt University
state: Tennessee
city: Calgary
country: Canada
facility: University of Calgary, Foothills Medical Centre
state: Alberta
city: Edmonton
country: Canada
facility: University of Alberta Hospital
state: Alberta
city: Toronto
country: Canada
facility: St. Michael's Hospital
state: Ontario
city: Toronto
country: Canada
facility: University Health Network - Toronto General Division, Toronto Western Hospital
state: Ontario
city: Saskatoon
country: Canada
facility: University of Saskatchewan, Royal University Hospital
state: Saskatchewan
city: Prague
country: Czechia
facility: Charles University, Department of Neurosurgery
city: Helsinki
country: Finland
facility: Helsinki University Central Hospital
Study officials:
affiliation: HHU
name: Daniel Hanggi
role: PRINCIPAL_INVESTIGATOR
References:
citation: Macdonald RL, Hanggi D, Strange P, Steiger HJ, Mocco J, Miller M, Mayer SA, Hoh BL, Faleck HJ, Etminan N, Diringer MN, Carlson AP, Aldrich F; NEWTON Investigators. Nimodipine pharmacokinetics after intraventricular injection of sustained-release nimodipine for subarachnoid hemorrhage. J Neurosurg. 2019 Dec 6;134(1):95-101. doi: 10.3171/2019.9.JNS191366. Print 2021 Jan 1.
citation: Hanggi D, Etminan N, Aldrich F, Steiger HJ, Mayer SA, Diringer MN, Hoh BL, Mocco J, Faleck HJ, Macdonald RL; NEWTON Investigators. Randomized, Open-Label, Phase 1/2a Study to Determine the Maximum Tolerated Dose of Intraventricular Sustained Release Nimodipine for Subarachnoid Hemorrhage (NEWTON [Nimodipine Microparticles to Enhance Recovery While Reducing Toxicity After Subarachnoid Hemorrhage]). Stroke. 2017 Jan;48(1):145-151. doi: 10.1161/STROKEAHA.116.014250. Epub 2016 Dec 8.
citation: Hanggi D, Etminan N, Macdonald RL, Steiger HJ, Mayer SA, Aldrich F, Diringer MN, Hoh BL, Mocco J, Strange P, Faleck HJ, Miller M. NEWTON: Nimodipine Microparticles to Enhance Recovery While Reducing Toxicity After Subarachnoid Hemorrhage. Neurocrit Care. 2015 Oct;23(2):274-84. doi: 10.1007/s12028-015-0112-2.