Multi-Arm Multi-Stage Adaptive Platform Trial (APT) for the Acute Treatment of Traumatic Brain Injury (APT-TBI-01)

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.

Study Overview

• Status: Enrolling by invitation
• Conditions: Traumatic Brain Injury
• Intervention / Treatment: Drug: Atorvastatin Calcium; Drug: Minocycline Hydrochloride; Drug: Candesartan Cilexetil; Drug: Placebo

• Study Type: Interventional
• Enrollment (Estimated): 672
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • California
    • San Francisco, California, United States, 94110
      • University of California, San Francisco
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Indiana University Health
  • Kentucky
    • Lexington, Kentucky, United States, 40536
      • University of Kentucky
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital
  • North Carolina
    • Charlotte, North Carolina, United States, 28203
      • Atrium Health Wake Forest Baptist
    • Durham, North Carolina, United States, 27710
      • Duke University Medical Center
  • Ohio
    • Cincinnati, Ohio, United States, 45219
      • University of Cincinnati Medical Center
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • University of Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15213
      • University of Pittsburgh
  • Tennessee
    • Nashville, Tennessee, United States, 37203
      • Vanderbilt University Medical Center
  • Texas
    • Austin, Texas, United States, 78712
      • The University of Texas at Austin
    • Houston, Texas, United States, 77030
      • Baylor College of Medicine
    • Houston, Texas, United States, 77030
      • UTHealth Houston
  • Utah
    • Salt Lake City, Utah, United States, 84132
      • University of Utah
  • Virginia
    • Richmond, Virginia, United States, 23298
      • Virginia Commonwealth University
  • Washington
    • Seattle, Washington, United States, 98104
      • University of Washington
  • Wisconsin
    • Madison, Wisconsin, United States, 53792
      • UW Health University Hospital
    • Milwaukee, Wisconsin, United States, 53226
      • Medical College of Wisconsin

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Adults (18-65 years of age, inclusive)
2. 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.
3. Closest, prior to Randomization Glasgow Coma Scale (GCS) score of 9 to 15
4. Acute trauma-related neuroimaging abnormality (subarachnoid hemorrhage, contusion, subdural hematoma, petechial hemorrhage, intraventricular hemorrhage) on cranial CT (CT+)
5. 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)
6. 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)
7. Participants able to undergo Magnetic Resonance Imaging (MRI) scans, no contraindications
8. Participants or legally authorized representative (LAR) willing and able to provide informed consent
9. Participants or LAR able to read, speak, and understand English or Spanish (participating site dependent, where available), including the informed consent form (ICF)
10. Willingness and ability to comply with all study procedures, treatment, and follow-up

Exclusion Criteria:

1. Isolated epidural hematoma
2. 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
3. Current enrollment in another interventional study
4. Currently pregnant or currently breastfeeding or planning on becoming pregnant in the next 6 months
5. Current incarceration or in custody
6. 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
7. Hypersensitivity or intolerance to investigational products or the investigational products' respective classes
8. Renal dysfunction (Creatinine Clearance (CrCl) or estimated Glomerular Filtration Rate (eGFR) (<60 mL/minute/1.73 m2)
9. Acute liver disease or hepatic dysfunction (ALT/AST >3 times upper limit of normal lab value)
10. Hemodynamic instability, per participating site physician investigator clinical judgment
11. Inability to swallow investigational product capsule
12. Unable or unwilling to consume animal byproducts, has a gelatin allergy, and/or religious beliefs that do not permit consuming gelatin
13. Intolerance to small amounts of lactose (less than ½ teaspoonful) daily
14. 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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

4

Arms and Interventions

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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Glasgow Outcome Scale-Extended (GOSE 2-Way)	Functional impairment due only to the TBI will be measured using the GOSE Scale-Extended (GOSE 2-Ways). 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

Collaborators and Investigators

• Sponsor: University of California, San Francisco
• Collaborators: United States Department of Defense
• Investigators: Principal Investigator: Geoffrey Manley, MD PhD, University of California, San Francisco

Publications and helpful links

Helpful Links

• Related Info
• Related Info
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Study record dates

Study Major Dates

• Study Start (Actual): August 1, 2024
• Primary Completion (Estimated): August 31, 2028
• Study Completion (Estimated): August 31, 2029

Study Registration Dates

• First Submitted: April 12, 2023
• First Submitted That Met QC Criteria: April 12, 2023
• First Posted (Actual): April 24, 2023

Study Record Updates

• Last Update Posted (Actual): December 22, 2025
• Last Update Submitted That Met QC Criteria: December 18, 2025
• Last Verified: December 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Wounds and Injuries; Craniocerebral Trauma; Trauma, Nervous System; Brain Injuries; Brain Injuries, Traumatic; Organic Chemicals; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Fatty Acids; Lipids; Azoles; Hydrocarbons; Hydrocarbons, Cyclic; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Polycyclic Compounds; Naphthacenes; Pyrroles; Heptanoic Acids; Tetracyclines; Atorvastatin; Minocycline; candesartan cilexetil
• Other Study ID Numbers: APT-TBI-01

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Data will be made available through the Federal Interagency TBI Research (FITBIR) Database.
• IPD Sharing Time Frame: Shared scientific data will be made accessible as soon as possible, and no later than the time of an associated publication, or the end of performance period, whichever comes first.
• IPD Sharing Access Criteria: FITBIR qualified investigators will be provided access

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No