Multi-Arm Multi-Stage Adaptive Platform Trial (APT) for the Acute Treatment of Traumatic Brain Injury
Effects of an Investigational Medication on Recovery from Traumatic Brain Injury
Jamie L. Bradbury, MD
Primary Investigator
Brief description of study
The purpose of this study is to determine if experimental drug treatment improves recovery after TBI as compared to a control (placebo) group. Changes in recovery will be measured throughout the study. The study drugs lare approved by the U.S. Food and Drug Administration (FDA) but are being used "off-label" in this study. This means that the drugs are not currently approved to treat TBI.
Detailed description of study
Multi-center, double-blind, placebo-controlled, adaptive platform, precision medicine trial conducted under a single multi-arm, multi-stage (MAMS) study with parallel groups. Participants will be randomized to receive one of four possible treatment interventions:
Atorvastatin calcium (ATOR)
Minocycline hydrochloride (MINO)
Candesartan cilexetil (CAND)
Matching Placebo
The study requirements consist of an eligibility surveillance, consenting, randomization, intervention, and follow-up phase, in that order. Participants shall receive all necessary standard of care while only receiving mITT (modified intent to treat) after signing (or LAR signing of) their respective consent form. The standard of care for a participant who has had a TBI is state and site specific, but may consist of a CT scan, a pregnancy test, a CBC, and Comprehensive metabolic panel. After these standard of care tests occur (which is a site specific trauma panel and may include a liver panel at some institutions) and the participant has been consented, a liver panel measuring alanine amino transferase (ALT) and aspartate amino transferase (AST) shall occur prior to randomization in order for the participant to be fully eligible for the study.
Each enrollment arm is expected to have approximately 6 months of patient participation. The total study length is approximately 48 months from first participant randomized until last participant’s final visit. Each participant will be followed in the study for a 6 month period.
Eligibility of study
You may be eligible for this study if you meet the following criteria:
- Conditions: Traumatic brain injury, TBI
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Age: 18 years - 65 years
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Gender: All
Inclusion Criteria:
- Adults (18-65 years of age, inclusive)
- Presents to a participating enrollment site and is able to receive first dose within 24 hours of non-penetrating head injury warranting clinical evaluation with a non-contrast head CT based on American College of Emergency Physicians (ACEP) Centers for Disease Control and Prevention (CDC) clinical policy for TBI imaging.
- Closest, prior to Randomization Glasgow Coma Scale (GCS) score of 9 to 15
- Acute trauma-related neuroimaging abnormality (subarachnoid hemorrhage, contusion, subdural hematoma, petechial hemorrhage, intraventricular hemorrhage) on cranial CT (CT+)
- Initial Glial Fibrillary Acidic Protein (GFAP) blood level >100 pg/ml ≤ 15,000 pg/ml determined using a for Research Use Only (RUO) assay(s) or an Investigation Use Only (IUO) assay(s)
- Persons of childbearing potential (i.e., those not postmenopausal or surgically sterile) may participate provided that they are using adequate birth control methods for the duration of investigational product administration (see manual of procedures for adequate birth control methods)
- Participants able to undergo Magnetic Resonance Imaging (MRI) scans, no contraindications
- Participants or legally authorized representative (LAR) willing and able to provide informed consent
- Participants or LAR able to read, speak, and understand English or Spanish (participating site dependent, where available), including the informed consent form (ICF)
- Willingness and ability to comply with all study procedures, treatment, and follow-up
Exclusion Criteria:
- Isolated epidural hematoma
- Pre-existing conditions including disabling developmental, neurologic, psychiatric, medical disorder that continues to produce functional disability up to the time of injury; or imminent death based on clinical judgement
- Current enrollment in another interventional study
- Currently pregnant or currently breastfeeding or planning on becoming pregnant in the next 6 months
- Current incarceration or in custody
- Currently prescribed one of the investigational products (or other drugs in the same class) prior to injury; or contra-indicated or as listed in the appendices
- Hypersensitivity or intolerance to investigational products or the investigational products' respective classes
- Renal dysfunction (Creatinine Clearance (CrCl) or estimated Glomerular Filtration Rate (eGFR) (<60 mL/minute/1.73 m2)
- Acute liver disease or hepatic dysfunction (ALT/AST >3 times upper limit of normal lab value)
- Hemodynamic instability, per participating site physician investigator clinical judgment
- Inability to swallow investigational product capsule
- Unable or unwilling to consume animal byproducts, has a gelatin allergy, and/or religious beliefs that do not permit consuming gelatin
- Intolerance to small amounts of lactose (less than ½ teaspoonful) daily
- Low likelihood of follow up or study compliance, or any other reason, in the opinion of the participating site investigator, the participants should not participate in the study
This study investigates the effects of an investigational medication on recovery from traumatic brain injury (TBI). Traumatic brain injury occurs when an external force injures the brain, often leading to long-term complications or death. The study aims to compare recovery outcomes between participants receiving investigational medications and those receiving a placebo. Participants will be randomized into one of four study arms to receive either atorvastatin calcium, minocycline hydrochloride, candesartan cilexetil, or a placebo, which is an inactive substance that looks like the investigational medicine but does not contain any medicine.
Participants will undergo several procedures throughout the study. These include eligibility surveillance, consenting, randomization, intervention, and follow-up phases. Standard medical care will be provided, including tests like CT scans and blood panels, to ensure participants meet the study criteria. Participants must be enrolled and receive their first dose of the investigational product within 24 hours of injury. The study will measure changes in recovery through various assessments and imaging tests.
- Who can participate: Adults aged 18 to 65 with a non-penetrating head injury are eligible if they can receive the first dose within 24 hours. Eligibility requires specific Glasgow Coma Scale scores and neuroimaging findings.
- Study details: Participants will be randomized to receive one of four treatments, including a placebo. The study involves standard care assessments and specific blood tests before randomization. Participants will follow study procedures, including receiving the investigational product and attending follow-up visits.
- Study timelines: The study will last approximately 48 months.
