Allopregnanolone in Chronic Complex Traumatic Brain Injury

NCT ID: NCT04003285

Last Updated: 2025-08-12

Basic Information

• Recruitment Status: NOT_YET_RECRUITING
• Clinical Phase: PHASE2
• Total Enrollment: 132 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2026-02-01
• Study Completion Date: 2027-02-01

Brief Summary

This study will determine if allopregnanolone (ALLO) improves depression and pain symptoms in patients who have a history of mild traumatic brain injury (TBI) [primary endpoints]. The investigators will also determine if ALLO improves functional outcome [secondary endpoint]. Participants in this study will receive an intravenous infusion of either ALLO or placebo. Behavioral assessments will be conducted during the infusion and at several time points post-infusion.

Detailed Description

ALLO is a neurosteroid that exhibits multiple actions highly relevant to the treatment of chronic complex TBI. The investigators' recent human data suggest that ALLO is decreased in patients with TBI, suggesting that ameliorating deficits of this neurosteroid may be clinically therapeutic. In addition, multiple groups have reported ALLO reductions in patients with conditions that frequently co-occur with TBI, including depression and pain disorders. 132 Veterans with a history of mild TBI with co-occurring depression and pain symptoms (chronic complex TBI) will be randomized to either intravenous placebo or ALLO (3 groups/44 participants per group: placebo, lower dose ALLO, higher dose ALLO). Following a loading dose, Veterans will receive placebo or ALLO infusion targeted to achieve serum ALLO levels of 0 nM (placebo), 50 nM (ALLO lower dose), or 150nM (ALLO higher dose). Behavioral assessments will be conducted during the infusion, post-taper, and 24 hours post-infusion. In addition, the investigators will conduct behavioral assessments 7 days and 14 days post-infusion.

The investigators hypothesize that ALLO will be well-tolerated in patients with complex TBI, and that this intervention may reduce depression and pain symptoms (in addition to potentially improving function).

Conditions

Traumatic Brain Injury (TBI)

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

Placebo

ALLO 0 nM (placebo: loading dose, 4-hour infusion, taper)

Group Type: EXPERIMENTAL

Placebo

Intervention Type: DRUG

ALLO 0 nM (placebo: loading dose, 4-hour infusion, taper)

ALLO 50 nM

ALLO 50 nM (lower dose ALLO: loading dose, 4 hour infusion, taper)

Group Type: EXPERIMENTAL

Allopregnanolone

Intervention Type: DRUG

ALLO 50 nM (lower dose ALLO: loading dose, 4 hour infusion, taper)

ALLO 150 nM

ALLO 150 nM (higher dose ALLO: loading dose, 4 hour infusion, taper)

Group Type: EXPERIMENTAL

Allopregnanolone

Intervention Type: DRUG

ALLO 150 nM (higher dose ALLO: loading dose, 4 hour infusion, taper)

Interventions

Placebo

ALLO 0 nM (placebo: loading dose, 4-hour infusion, taper)

Intervention Type: DRUG

Allopregnanolone

ALLO 50 nM (lower dose ALLO: loading dose, 4 hour infusion, taper)

Intervention Type: DRUG

Allopregnanolone

ALLO 150 nM (higher dose ALLO: loading dose, 4 hour infusion, taper)

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

• 21-62 years of age, any ethnic group, either sex
• History of mild TBI since 2001 and service in the U.S. Military since 9/11/01 (OEF/OIF/OND era)
• The investigators will adhere to the operational definition of mild TBI suggested by the World Health Organization Task Force, with the exception of seizure and Glasgow Coma Scale score criteria (not available for these participants) with 1 or more of the following:

• confusion or disorientation
• loss of consciousness for 30 minutes or less
• post-traumatic amnesia for less than 24 hours
• and/or other transient neurological abnormalities such as focal signs, and intracranial lesion not requiring surgery
• Ability to participate fully in the informed consent process
• HAM-D score 14 (HAM-D range for moderate depression=14-18)
• Participants will meet DSM-5 criteria for major depressive disorder (by SCID)

• The presence of psychotic features will be exclusionary
• Single episodes or recurrent episodes will be permissible for study entry (the investigators will examine treatment responses in those who have had single depressive episodes versus those who have had multiple depressive episodes in exploratory sensitivity analyses
• BPI (Brief Pain Inventory, Short Form) 'current' pain intensity rating item score 4 (scale of 0-10)

• Pain must be musculoskeletal in nature
• No anticipated need to alter psychiatric medications for 14-day duration of study involvement
• No changes in psychotropic or behavioral interventions during the study or in the 2 weeks prior to study enrollment
• Concomitant medications for co-occurring medical conditions are permissible for stable medical conditions that are reasonably well-controlled

• for example, hypertension medications, statins, and oral hypoglycemic medications would generally be permissible if they appear to be effectively treating the underlying condition

Exclusion Criteria

• Participants with current suicidal or homicidal ideation necessitating clinical intervention or representing an imminent concern
• Medications that could potentially confound study outcomes (for example, prednisone) are exclusionary
• Current DSM-5 diagnosis of bipolar disorder, schizophrenia or other psychotic disorder, or cognitive disorder due to a general medical condition other than TBI
• Female participants who are pregnant or breast-feeding
• Known allergy to study medication
• Benzodiazepine, barbiturate, or opioid use within the last 2 weeks is exclusionary
• Substance use disorder (DSM-5), other than nicotine use disorder
• A serious medical illness, defined as an illness that requires hospitalization for additional care at the time of screening or one that has required hospitalization in the last month.

• Any co-occurring medical illness should have a history of stable outpatient management
• Report of a history of seizures, a history of stroke, a history of prostate cancer (or any other cancer other than non-melanoma skin cancer), a history of myocardial infarction, the presence of congestive heart failure, or any other serious health condition that would likely preclude safe study participation in the medical opinion of the PI or in consultation with the participant's PCP/other health care provider
• Use of oral contraceptives, a hormone-releasing IUD, or other hormonal supplementation such as estrogen or progesterone, as there is a theoretical risk that a metabolite such as ALLO could potentially impact efficacy of oral contraceptives or estrogen replacement

• Minimum Eligible Age: 21 Years
• Maximum Eligible Age: 62 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

VA Office of Research and Development

FED

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Christine E. Marx, MD MA

Role: PRINCIPAL_INVESTIGATOR

Durham VA Medical Center, Durham, NC

Locations

Durham VA Medical Center, Durham, NC

Durham, North Carolina, United States

Countries

United States

Central Contacts

Christine E Marx, MD MA

Role: CONTACT

christine.marx@va.gov

(919) 286-0411 ext. 5112

Facility Contacts

Christine E Marx, MD MA

Role: primary

christine.marx@va.gov

919-286-0411 ext. 5112

Other Identifiers

B2798-I

Identifier Type: -

Identifier Source: org_study_id