Allopregnanolone in Chronic Complex Traumatic Brain Injury

Traumatic Brain Injury (TBI) Clinical Trial

— ALLO  

Official title:

Novel Regenerative Therapeutic in Chronic Complex TBI

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT04003285
• Other study ID #: B2798-I
• Status: Not yet recruiting
• Phase: Phase 2
• Start date: March 1, 2024
• Est. completion date: September 30, 2024

Study information

• Verified date: October 2023
• Source: VA Office of Research and Development
• Contact: Christine E Marx, MD MA
• Phone: (919) 286-0411
• Email: christine.marx[@]va.gov
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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).

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 132
• Est. completion date: September 30, 2024
• Est. primary completion date: September 30, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 21 Years to 62 Years

Eligibility

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

Related Conditions & MeSH terms

• Brain Injuries
• Brain Injuries, Traumatic
• Traumatic Brain Injury (TBI)

Intervention

Drug:
• Placebo
ALLO 0 nM (placebo: loading dose, 4-hour infusion, taper)
• Allopregnanolone
ALLO 50 nM (lower dose ALLO: loading dose, 4 hour infusion, taper)
• Allopregnanolone
ALLO 150 nM (higher dose ALLO: loading dose, 4 hour infusion, taper)

Locations

Country	Name	City	State
United States	Durham VA Medical Center, Durham, NC	Durham	North Carolina

Sponsors (1)

Lead Sponsor	Collaborator
VA Office of Research and Development

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Brief Pain Inventory, Short Form (BPI-SF) Change	The Brief Pain Inventory, Short Form (BPI-SF) is a self-reported scale that measures the severity of pain and the interference of pain on function. The scores range from 0 (no pain) to 10 (pain as severe as you can imagine). There are 4 questions assessing worst pain, least pain, average pain in the past 24 hours, and pain right now. The Interference scores range from 0 (does not interfere) to 10 (completely interferes). There are 7 questions assessing the interference of pain in the past 24 hours for general activity, mood, walking ability, normal work, relations with other people, sleep, and enjoyment of life.	6 hours, 24 hours, 7 days, and 14 days
Primary	Hamilton-Depression Inventory (HAM-D) Change	The HAM-D measures the severity of depressive symptoms. It is a checklist of 17 items that are ranked on a scale of 0-4 or 0-2. The range for the total score (which is the sum of the scores of all 17 items) is 0-52; a higher score indicates greater severity of symptoms.	6 hours, 24 hours, 7 days, and 14 days
Secondary	Short Form Health Survey (SF-36) Change	The SF-36 is a health survey with an 8-scale profile embedded in 36 questions that measures physical and mental components of health. Each item is scored on a 0 to 100 range with the lowest and highest possible scores are set at 0 and 100, respectively. All of these items are scored so that a high score defines a more favorable health state.	6 hours, 24 hours, 7 days, and 14 days