Safety and Tolerability of GTX-104 Compared With Oral Nimodipine in Patients With aSAH

Study Overview
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Brief Summary
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The purpose of this study is to deliver nimodipine via IV directly into the bloodstream and to determine if this is as safe and tolerable as oral nimodipine capsules.

Official Title
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Safety and Tolerability of GTX-104 (Nimodipine Injection for IV Infusion) Compared With Oral Nimodipine in Patients Hospitalized for Aneurysmal Subarachnoid Hemorrhage (aSAH): a Prospective, Randomized Trial

Conditions
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Aneurysmal Subarachnoid Hemorrhage (aSAH)

Intervention / Treatment
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* Drug: GTX-104
* Drug: Nimotop 30 MG Oral Capsule


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female ≥18 years of age. Diagnosis of aneurysmal subarachnoid hemorrhage (aSAH) based on CT scan and angiography (computed tomography angiography [CTA], magnetic resonance angiography [MRA], or digital subtraction angiography [DSA]). Hunt and Hess score from I to V just prior to randomization. Subject or the subject's legal representative has signed informed consent (either in person or by fax, scan, or email) before any study-specific procedures are performed. Able to start IP within 96 hours from the onset of aSAH. Note 1: The onset of aSAH is defined as the time when the subject experienced the first symptom of aSAH (e.g., severe headache or loss of consciousness reported either by the subject or by a witness). Note 2: If found unconscious or the time of first symptoms is unknown, the onset of aSAH will be defined as the last time the subject was seen at baseline neurological state. If a woman of childbearing potential (WOCBP), must have a negative pregnancy test during the pre-randomization phase (screening). A woman is not of childbearing potential if she has undergone surgical sterilization (total hysterectomy, or bilateral tubal ligation, or bilateral oophorectomy at least 6 weeks before taking IP) or if she is abstinent (see below) or postmenopausal and has had no menstrual bleeding of any kind including menstrual period, irregular bleeding, spotting, etc., for at least 12 months, with an appropriate clinical profile, and there is no other cause of amenorrhea (e.g., hormonal therapy, prior chemotherapy). WOCBP and males whose sexual partners are WOCBP must agree to use barrier contraception and a second form of contraception while receiving IP and for 30 days following their last dose of IP. Alternatively, total abstinence is also considered a highly effective contraception method when this is in line with the preferred and usual lifestyle of the subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception. Sexually active males must use a condom during intercourse while taking IP and for 30 days after the last dose of IP and should not father a child during this period. A condom is required to be used also by vasectomized men as well as during intercourse with a male partner to prevent delivery of the IP via seminal fluid. Exclusion Criteria: Is at imminent risk of death and/or has Do Not Resuscitate (DNR) orders. Required cardiopulmonary resuscitation within 4 days prior to randomization. Has second- or third-degree atrio-ventricular block or bradycardia (heart rate ≤50 bpm) prior to randomization. Has history of cirrhosis (Child-Pugh class B and C) prior to randomization. Has alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) more than 2.5 times the upper limit of normal (ULN). Has history of malabsorption syndrome, recent ileus (in the last 3 months), or other gastrointestinal (GI) conditions that would interfere with absorption of nimodipine, in the opinion of the Investigator. Has a severe or unstable concomitant condition or disease other than what may be attributed to the SAH that, in the opinion of the Investigator, may increase the risk associated with study participation or nimodipine administration, or may interfere with the interpretation of study results. Has a history of recurrent syncope or hypotension that may interfere with the safety assessments of nimodipine. Has a known hypersensitivity to nimodipine or capsule constituents or to GTX-104. Is pregnant/has a positive serum or urine pregnancy test. Has received more than 5 doses of oral nimodipine (as a solution [e.g., Nymalize] or capsules) as part of the standard of care (SOC) for the ruptured aneurysm prior to randomization. Is receiving strong inhibitors of CYP3A4 such as some macrolide antibiotics (e.g., clarithromycin, telithromycin), some anti-HIV protease inhibitors (e.g., delavirdine, indinavir, nelfinavir, ritonavir, saquinavir), some azole antimycotics (e.g., ketoconazole, itraconazole, voriconazole), and some antidepressants (e.g., nefazadone). See Appendix 5. Is receiving or has received any other investigational agent(s)/device(s) in the last 30 days.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: GTX-104<br>GTX-104 is a sterile concentrate of 10 mg nimodipine/5 mL (2 mg/mL), to be diluted in normal saline to obtain a dosing solution composed of dispersed micelles containing nimodipine for IV infusion. It will be administered as a continuous IV infusion of 0.15 mg/hour and a 30-minute IV bolus of 4 mg every 4 hours for up to 21 days | Drug: GTX-104<br>* Nimodipine IV infusion<br>|
| Active Comparator: Oral nimodipine<br>Oral nimodipine is a soft gelatin capsule. The dose is 60 mg (two 30 mg capsules) every 4 hours for up to 21 consecutive days. | Drug: Nimotop 30 MG Oral Capsule<br>* Oral nimodipine capsules<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence (% or proportion) of subjects with at least one episode of clinically significant hypotension with a reasonable possibility that GTX-104/oral nimodipine caused the event, according to the Endpoint Adjudication Committee. | Hypotension events requiring medical treatment | 90 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Total number of episodes of clinically significant hypotension |  | Day 1 - Day 90 | 
| Duration of episodes of clinically significant hypotension | Calendar days | Day 1 - Day 90 | 
| Incidence and severity of Adverse Events (AEs) based on the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE, Version 5.0). |  | Day 1 - Day 90 | 
| Incidence of delayed cerebral ischemia (DCI) | Delayed cerebral ischemia will be evaluated and defined by the following: For subjects in whom changes in the mGCS and Abbreviated National Institutes of Health Stroke Scale (aNIHSS) are assessable: a decrease of at least 2 points on the mGCS or an increase of at least 2 points on the aNIHSS, lasting for at least 2 hours, where other medical or surgical causes are excluded. The deterioration is measured relative to the best score attained after aneurysm repair. For subjects in whom the neurologic scales are not assessable: radiological evidence and clinical judgement. | Day 1 - Day 21 | 
| Use of rescue therapy for DCI | Rescue therapy is defined as induced hypertension, selective intraarterial infusion of vasodilator drugs or balloon angioplasty. | Day 1 - Day 21 | 
| Suicidal ideation using the Columbia-Suicide Severity Rating Scale (C-SSRS) score of ≥ 4 |  | Day 1 - Day 90 |