Clinical trial NCT04003285: Allopregnanolone in Chronic Complex Traumatic Brain Injury
Official title: Novel Regenerative Therapeutic in Chronic Complex TBI
Study type: INTERVENTIONAL
Overall status: NOT_YET_RECRUITING
Phase: PHASE2
Conditions: Traumatic Brain Injury (TBI)
Keywords: Brain Injuries, Traumatic
Depression
Pain
Lead sponsor: VA Office of Research and Development
Sponsor class: FED
First posted: 2019-07-01
Enrollment: 132
Sex: ALL
Minimum age (years): 21
Maximum age (years): 62
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
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).
Primary purpose: TREATMENT

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).

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

Primary outcomes:
measure: Brief Pain Inventory, Short Form (BPI-SF) Change
timeFrame: 6 hours, 24 hours, 7 days, and 14 days
measure: Hamilton-Depression Inventory (HAM-D) Change
timeFrame: 6 hours, 24 hours, 7 days, and 14 days
Secondary outcomes:
measure: Short Form Health Survey (SF-36) Change
timeFrame: 6 hours, 24 hours, 7 days, and 14 days
Other outcomes:
Locations:
city: Durham
country: United States
facility: Durham VA Medical Center, Durham, NC
state: North Carolina
Study officials:
affiliation: Durham VA Medical Center, Durham, NC
name: Christine E. Marx, MD MA
role: PRINCIPAL_INVESTIGATOR
References: