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Allopregnanolone in Chronic Complex Traumatic Brain Injury (ALLO)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details. Identifier: NCT04003285
Recruitment Status : Not yet recruiting
First Posted : July 1, 2019
Last Update Posted : June 17, 2020
Information provided by (Responsible Party):
VA Office of Research and Development

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.

Condition or disease Intervention/treatment Phase
Traumatic Brain Injury (TBI) Drug: Placebo Drug: Allopregnanolone Phase 2

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).

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 132 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: Participants will be randomized to receive 0 nM ALLO (placebo), 50 nM ALLO (lower dose ALLO) or 150 nM ALLO (higher dose ALLO).
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description: This is a randomized, double-blind, placebo-controlled trial. All roles will be masked with the exception of the research pharmacist
Primary Purpose: Treatment
Official Title: Novel Regenerative Therapeutic in Chronic Complex TBI
Estimated Study Start Date : January 1, 2021
Estimated Primary Completion Date : June 30, 2023
Estimated Study Completion Date : June 30, 2023

Resource links provided by the National Library of Medicine

Arm Intervention/treatment
Experimental: Placebo
ALLO 0 nM (placebo: loading dose, 4-hour infusion, taper)
Drug: Placebo
ALLO 0 nM (placebo: loading dose, 4-hour infusion, taper)

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

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

Primary Outcome Measures :
  1. Brief Pain Inventory, Short Form (BPI-SF) Change [ Time Frame: 6 hours, 24 hours, 7 days, and 14 days ]
    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.

  2. Hamilton-Depression Inventory (HAM-D) Change [ Time Frame: 6 hours, 24 hours, 7 days, and 14 days ]
    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.

Secondary Outcome Measures :
  1. Short Form Health Survey (SF-36) Change [ Time Frame: 6 hours, 24 hours, 7 days, and 14 days ]
    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.

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.

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Ages Eligible for Study:   21 Years to 62 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT04003285

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Contact: Christine E Marx, MD MA (919) 286-0411 ext 5112

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United States, North Carolina
Durham VA Medical Center, Durham, NC
Durham, North Carolina, United States, 27705
Contact: Bradley J Olson    919-286-6926   
Principal Investigator: Christine E. Marx, MD MA         
Sponsors and Collaborators
VA Office of Research and Development
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Principal Investigator: Christine E. Marx, MD MA Durham VA Medical Center, Durham, NC
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Responsible Party: VA Office of Research and Development Identifier: NCT04003285    
Other Study ID Numbers: B2798-I
First Posted: July 1, 2019    Key Record Dates
Last Update Posted: June 17, 2020
Last Verified: June 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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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
Keywords provided by VA Office of Research and Development:
Brain Injuries, Traumatic
Additional relevant MeSH terms:
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Brain Injuries
Brain Injuries, Traumatic
Wounds and Injuries
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Craniocerebral Trauma
Trauma, Nervous System
Central Nervous System Depressants
Physiological Effects of Drugs