Clinical trial NCT05995405: Safety and Tolerability of GTX-104 Compared with Oral Nimodipine in Patients with ASAH
Official title: 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
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE3
Conditions: Aneurysmal Subarachnoid Hemorrhage (aSAH)
Lead sponsor: Grace Therapeutics Inc.
Sponsor class: INDUSTRY
First posted: 2023-08-16
Enrollment: 100
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.


Eligibility criteria: Inclusion Criteria:

1. Male or female ≥18 years of age.
2. Diagnosis of aneurysmal subarachnoid hemorrhage (aSAH) based on CT scan and angiography (computed tomography angiography \[CTA\], magnetic resonance angiography \[MRA\], or digital subtraction angiography \[DSA\]).
3. Hunt and Hess score from I to V just prior to randomization.
4. 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.
5. 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.
6. 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.
7. 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:

1. Is at imminent risk of death and/or has Do Not Resuscitate (DNR) orders.
2. Required cardiopulmonary resuscitation within 4 days prior to randomization.
3. Has second- or third-degree atrio-ventricular block or bradycardia (heart rate ≤50 bpm) prior to randomization.
4. Has history of cirrhosis (Child-Pugh class B and C) prior to randomization.
5. Has alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) more than 2.5 times the upper limit of normal (ULN).
6. 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.
7. 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.
8. Has a history of recurrent syncope or hypotension that may interfere with the safety assessments of nimodipine.
9. Has a known hypersensitivity to nimodipine or capsule constituents or to GTX-104.
10. Is pregnant/has a positive serum or urine pregnancy test.
11. Has received more than 12 doses (or 720 mg) 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.
12. 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.
13. Is receiving or has received any other investigational agent(s)/device(s) in the last 30 days.

Primary outcomes:
measure: 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.
timeFrame: 90 days
Secondary outcomes:
measure: Total number of episodes of clinically significant hypotension
timeFrame: Day 1 - Day 90
measure: Duration of episodes of clinically significant hypotension
timeFrame: Day 1 - Day 90
measure: Incidence and severity of Adverse Events (AEs) based on the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE, Version 5.0).
timeFrame: Day 1 - Day 90
measure: Incidence of delayed cerebral ischemia (DCI)
timeFrame: Day 1 - Day 21
measure: Use of rescue therapy for DCI
timeFrame: Day 1 - Day 21
measure: Suicidal ideation using the Columbia-Suicide Severity Rating Scale (C-SSRS) score of ≥ 4
timeFrame: Day 1 - Day 90
Other outcomes:
measure: Number of intensive care unit (ICU) stays
timeFrame: Day 1 - Day 90
measure: Duration of intensive care unit (ICU) stays
timeFrame: Day 1 - Day 90
measure: Duration (calendar days) of mechanical ventilation
timeFrame: Day 1 - Day 90
measure: Therapeutic Intensity Scale (TIS)
timeFrame: Day 1 - Day 14
measure: Number of hospital stays
timeFrame: Day 1 - Day 90
measure: Duration of hospital stays
timeFrame: Day 1 - Day 90
measure: Hospital discharge disposition
timeFrame: Day 1 - Day 90
measure: Quality of Life as measured by EQ-5D-3L
timeFrame: Day 30 and Day 90
measure: Modified Rankin Scale (mRS)
timeFrame: Day 30 and Day 90
Locations:
city: Birmingham
country: United States
facility: The University of Alabama at Birmingham
state: Alabama
city: Phoenix
country: United States
facility: Brain and Spine Neurological Institute
state: Arizona
city: Fresno
country: United States
facility: Community Regional Medical Center
state: California
city: JacksonvIlle
country: United States
facility: Mayo Clinic Florida
state: Florida
city: Atlanta
country: United States
facility: Emory University School of Medicine Emergency Neurosciences
state: Georgia
city: Chicago
country: United States
facility: Northwestern Feinberg Pavillion Neuro and Spine ICU
state: Illinois
city: Indianapolis
country: United States
facility: Indiana University Health Methodist Hospital
state: Indiana
city: Lexington
country: United States
facility: University of Kentucky Hospital
state: Kentucky
city: Baltimore
country: United States
facility: University of Maryland Medical Center
state: Maryland
city: Boston
country: United States
facility: Beth Israel Deaconess Medical Center
state: Massachusetts
city: Saint Louis
country: United States
facility: Washington University
state: Missouri
city: New York
country: United States
facility: The Mount Sinai Hospital
state: New York
city: Chapel Hill
country: United States
facility: University of North Carolina
state: North Carolina
city: Durham
country: United States
facility: Duke University
state: North Carolina
city: Cincinnati
country: United States
facility: University of Cincinnati Medical Center
state: Ohio
city: Cleveland
country: United States
facility: University Hospitals Cleveland Medical Center
state: Ohio
city: Columbus
country: United States
facility: The Ohio State University Wexner Medical Center
state: Ohio
city: Portland
country: United States
facility: Oregon Health and Science University
state: Oregon
city: Memphis
country: United States
facility: Methodist University Hospital
state: Tennessee
city: Nashville
country: United States
facility: Vanderbilt University Medical Center
state: Tennessee
city: Houston
country: United States
facility: University of Texas Health Science Center at Houston
state: Texas
city: Richmond
country: United States
facility: Virginia Commonwealth University
state: Virginia
Study officials:
affiliation: Grace Therapeutics Inc.
name: R. Loch Macdonald, MD
role: STUDY_DIRECTOR
References: