Multi-Arm Multi-Stage Adaptive Platform Trial (APT) for the Acute Treatment of Traumatic Brain Injury

Study Overview
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Brief Summary
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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 listed below are 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.

Official Title
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Multi-Arm Multi-Stage Adaptive Platform Trial (APT) for the Acute Treatment of Traumatic Brain Injury

Conditions
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Traumatic Brain Injury

Intervention / Treatment
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* Drug: Atorvastatin Calcium
* Drug: Minocycline Hydrochloride
* Drug: Candesartan Cilexetil
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adults (18-65 years of age inclusive) Presents to an enrollment site within 12 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. Post-resuscitation Glasgow Coma Scale (GCS) of between 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 the participant is 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 or need for sedation Participants/legally authorized representative (LAR) willing and able to provide informed consent Participants or legally authorized representative able to read, speak, understand English or Spanish including the informed consent form (ICF) Willingness and ability to comply with all study procedures, treatment and follow-up Participants identified by site investigator as a good candidate for study participation Exclusion Criteria: Post-resuscitation GCS <9 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 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 Estimate Glomerular Filtration Rate (eGFR) <60 mL/minute/1.73 m2) Hepatic dysfunction (Alanine Transaminase (ALT)/Aspartate Transaminase (AST)) >3 times upper limit of normal lab value) Persistent hypotension, more than 30 minutes (Systolic Blood Pressure (SBP) <90 mmHg and Diastolic Blood Pressure (DBP) <60 mmHg) Inability to swallow investigational product capsule Low likelihood of follow up or study compliance, or any other reason, in the opinion of the site investigator, the participants should not participate in the study

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Intervention 1: Atorvastatin calcium (ATOR)<br>By Mouth (PO) Twice a day (BID) 80 mg/day, with no loading dose, for 28 days | Drug: Atorvastatin Calcium<br>* Capsule, 80 mg/day, with no loading dose, for 28 days<br>* Other names: ATOR;|
| Active Comparator: Intervention 2: Minocycline hydrochloride (MINO)<br>By Mouth (PO) Twice a day (BID) 200 mg loading dose on Day 1, then 100 mg twice daily for 6 days, then placebo twice daily for 21 days | Drug: Minocycline Hydrochloride<br>* Capsule, 200 mg loading dose on Day 1, then 100 mg twice daily for 6 days, then placebo twice daily for 21 days<br>* Other names: MINO;|
| Active Comparator: Intervention 3: Candesartan cilexetil (CAND)<br>By Mouth (PO) Twice a day (BID) 8 mg once on Day 1, then 16 mg daily for 27 days | Drug: Candesartan Cilexetil<br>* Capsule, 8 mg once on Day 1, then 16 mg daily for 27 days<br>* Other names: CAND;|
| Placebo Comparator: Matching Placebo<br>By Mouth (PO) Twice a day (BID) 2 capsules 2x/day | Drug: Placebo<br>* Capsule, 2x/day for 28 days<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Glasgow Outcome Scale-Extended (GOSE-TBI only) | Functional impairment due only to the TBI will be measured using the GOSE Scale. The score ranges from 1-8, with higher scores indicating better recovery. Change will be measured from Week 2 to Month 3 postinjury and compared to placebo. | 2 weeks to 3 months postinjury | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Blood-based biomarkers (Neurofilament light chain) | Neurofilament light chain (NfL) levels postinjury in participants with TBI will be measured and compared to placebo | Week 2 | 
| Blood-based biomarker (GFAP) | GFAP levels postinjury in participants with TBI as compared to placebo | Week 2 | 
| Imaging biomarkers | Comparison of MRI diffusion tensor imaging (DTI) Axial Diffusivity (AD) measure using the average of 4 long association/projections tracts: (i) Anterior Limb of Internal Capsule (ALIC); (ii) External Capsule (EC); (iii) Superior Corona Radiata (SCR); and (iv) Superior Longitudinal Fasciculus (SLF). Change will be measured from 2 Weeks to 3 Months postinjury. | 2 weeks to 3 months postinjury | 
| Post-TBI cognitive outcome (BTACT) | Neurocognitive impairment due to TBI will be measured using the Brief Test of Adult Cognition by Telephone (BTACT). Change will be measured by composite z-score from Day 3 to Week 4 postinjury | Day 3 to Week 4 postinjury | 
| Post-TBI symptom outcome (Rivermead) | Post-concussive symptoms due to TBI as measured by the change in Rivermead Post Concussion Symptoms Questionnaire (RPQ) Total score (0-64) from Day 3 to Week 4. Higher scores indicate more severe symptoms | Day 3 to Week 4 |