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

Sponsor

University of California, San Francisco (Other)

Overall Status

Not yet recruiting

CT.gov ID

NCT05826912

Collaborator

United States Department of Defense (U.S. Fed)

672

Enrollment

Location

Arms

Anticipated Duration (Months)

14.9

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Traumatic Brain Injury	Drug: Atorvastatin Calcium Drug: Minocycline Hydrochloride Drug: Candesartan Cilexetil Drug: Placebo	Phase 2

Study Design

Study Type:

Interventional

Anticipated Enrollment :

672 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

Primary Purpose:

Treatment

Official Title:

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

Anticipated Study Start Date :

Aug 30, 2023

Anticipated Primary Completion Date :

May 30, 2027

Anticipated Study Completion Date :

May 30, 2027

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Intervention 1 Atorvastatin calcium (ATOR) PO 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) PO 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) PO 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: Placebo Matching placebo PO BID 2 capsules 2x/day	Drug: Placebo Capsule, 2x/day for 28 days

Outcome Measures

Primary Outcome Measures

Change in Glasgow Outcome Scale-Extended (GOSE-TBI only) [2 weeks to 3 months postinjury]
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.

Secondary Outcome Measures

Change in Blood-based biomarkers (Neurofilament light chain) [Week 2]
Neurofilament light chain (NfL) levels postinjury in participants with TBI will be measured and compared to placebo
Blood-based biomarker (GFAP) [Week 2]
GFAP levels postinjury in participants with TBI as compared to placebo
Imaging biomarkers [2 weeks to 3 months postinjury]
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.
Post-TBI cognitive outcome (BTACT) [Day 3 to Week 4 postinjury]
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
Post-TBI symptom outcome (Rivermead) [Day 3 to Week 4]
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

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 65 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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 (ALT/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