Clinical trial NCT02723344: Biological Signatures, Probiotic Among Those With mTBI and PTSD
Official title: Biological Signature and Safety of an Immunomodulatory Probiotic Intervention for Veterans With Co-Occurring Mild TBI and PTSD
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Mild Traumatic Brain Injury
Post Traumatic Stress Disorder
Keywords: PTSD
Mild TBI
Probiotic
Inflammation
Lead sponsor: VA Office of Research and Development
Sponsor class: FED
First posted: 2016-03-30
Enrollment: 75
Sex: ALL
Minimum age (years): 18
Maximum age (years): 50
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Biologic
Primary purpose: OTHER

Brief summary: Exaggerated inflammation in the body and brain is thought to play a role in the vulnerability to and aggravation and perpetuation of adverse consequences among those with co-occurring mild TBI (mTBI) and post-traumatic stress disorder (PTSD). The proposed study begins the process of investigating the use of a natural immunoregulatory/anti-inflammatory probiotic to treat chronic symptoms associated with co-occurring mTBI and PTSD among Veterans. By looking at the impact of probiotic supplementation on biological signatures of increased inflammation, as reflected by the gut microbiota, gut permeability, and biomarkers of peripheral inflammation, this study may lead to the identification of a novel intervention for the treatment of symptoms associated with these frequently co-occurring conditions.

Detailed description: United States military Veterans from recent conflicts are coping with symptoms related to mild traumatic brain injury (mTBI), persistent post concussive (PPC) symptoms, and posttraumatic stress disorder (PTSD). Many Veterans are resistant to conventional health and mental health interventions (e.g., medication, psychotherapy), and often symptoms are not significantly improved by traditional treatments. Moreover, there are limited treatments for symptoms associated with both conditions, which frequently co-occur. Alternative treatment methods are needed. One potential common underlying feature of both mTBI and PTSD is exaggerated inflammation, both peripherally and in the central nervous system, which is thought to play an important role in the vulnerability to, aggravation of, and perpetuation of adverse consequences of these often co-occurring conditions. Therefore, a novel intervention strategy would be the use of immunoregulatory/anti-inflammatory probiotics to reduce inflammation. In this study, the investigators will investigate the effects of an immunoregulatory probiotic on both biological signatures of systemic inflammatory processes and proximal signatures of probiotic administration. Lactobacillus reuteri (L. reuteri), a commensal organism that colonizes the human gut mucosa, suppresses mucosal inflammation via inhibition of the production of proinflammatory cytokines, and is the probiotic of interest. Specific aims of the study are to determine the: 1) effects of L. reuteri on biological signatures of gut microbiota, gut permeability, systemic inflammation processes, and stress responses; 2) feasibility of L. reuteri supplementation; 3) acceptability of L. reuteri supplementation; and 4) tolerability and safety of L. reuteri supplementation. Project aims will be assessed using a longitudinal, double blind, randomized placebo-controlled design. Participants will be Veterans with PPC symptoms, PTSD, and evidence of elevated systemic inflammation (based on high baseline plasma C-reactive protein \[CRP\] concentrations). After initial evaluation procedures, 20 participants will be randomized to probiotic supplementation and 20 will be randomized to placebo supplementation. The proposed line of research addresses the Office of Rehabilitation Research and Development (RR\&D) Service's goal of identifying means of intervening to increase function among those with mTBI and co-occurring psychiatric conditions. Long-term, this study may lead to a paradigm shift in the manner by which the investigators target clinical symptoms associated with PPC and PTSD symptoms, by beginning the process of supporting a multitargeted, neuroprotective approach.

Eligibility criteria: Inclusion Criteria:

* History of at least one deployment in support of Operation Enduring Freedom (OEF)/Operation Iraqi Freedom (OIF)/Operation New Dawn (OND)
* History of mTBI per the Ohio State University (OSU) TBI-ID85 with any endorsement of post concussive symptoms (PCS) associated with an mTBI, which occurred at least 6 months prior to the baseline assessment
* Current symptoms in 3 or more of the following ICD-10 Post Concussive Symptom86 categories as measured by the Rivermead Post Concussive Symptom Questionnaire (RPCSQ87; score of 2 or greater per symptom to qualify):

  * headache
  * dizziness
  * malaise
  * fatigue
  * noise intolerance
  * irritability
  * depression
  * anxiety
  * emotional lability
  * subjective concentration
  * memory
  * intellectual difficulties
  * and/or insomnia
* Current diagnosis of PTSD per the Clinician Administered PTSD Scale-5 (CAPS-5)88
* Medical clearance by study physicians to participate in the protocol
* Age between 18 and 50
* Ability to provide informed consent
* Willingness not to take probiotic supplements (pills, tablets, oils, etc.) other than the product provided in the clinical study until all study procedures are completed
* Willingness to provide blood, as well as stool samples

Exclusion Criteria:

* Inability to adequately respond to questions regarding the informed consent procedure
* Currently involved in the criminal justice system as a prisoner or ward of the state
* Non-English speaking
* Current (past month) alcohol or substance abuse or dependence
* Lifetime history of bipolar disorder or psychosis or anxiety disorders (excluding PTSD)
* Current major depressive disorder (MDD)
* Consistent (e.g., 5x/week or greater) probiotic supplementation within the last month, including probiotic food products such as yogurt, as determined by phone screen interview and Probiotic Food Check List
* Receiving antibiotics within the last month; use of topical antibiotics or topical steroids on the face, scalp, or neck or on arms, forearms, or hands within the previous 7 days
* Receiving medications that interfere with gut motility (opiates, loperamide, stool softeners)
* Presence of central venous catheters (CVCs)
* Gastrointestinal (GI) barriers as identified by the 2-week run-in period as determined by the study team (e.g., daily GI discomfort with frequent diarrhea prior to supplementation)
* Participation in conflicting interventional research protocol
* Body mass index (BMI) greater than or equal to 35 or less than or equal to 18
* Vital signs outside of acceptable range, i.e., blood pressure \>160/100, oral temperature \>100 F, pulse \>100
* Use of any of the following drugs within the last 6 months:

  * systemic antibiotics
  * antifungals
  * antivirals or antiparasitics (intravenous, intramuscular, or oral)
  * oral
  * intravenous
  * intramuscular
  * nasal or inhaled corticosteroids
  * cytokines or cytokine inhibitors
  * methotrexate or immunosuppressive cytotoxic agents
* Acute disease at the time of enrollment (defer sampling until subject recovers)

  * Acute disease is defined as the presence of a moderate or severe illness with or without fever
* Chronic, clinically significant (unresolved, requiring on-going medical management or medication) pulmonary, cardiovascular, gastrointestinal, hepatic or renal functional abnormality, as determined by medical history or physical examination other than irritable bowel syndrome (IBS)
* History of cancer except for squamous or basal cell carcinomas of the skin that have been medically managed by local excision
* Unstable dietary history as defined by major changes in diet during the previous month, where the subject has eliminated or significantly increased a major food group in the diet
* Positive test for human immunodeficiency virus (HIV), Hepatitis B virus, or Hepatitis C virus
* Any confirmed or suspected condition/state of immunosuppression or immunodeficiency (primary or acquired) including HIV infection
* Major surgery of the GI tract, with the exception of cholecystectomy and appendectomy, in the past five years. Any major bowel resection at any time
* Regular urinary incontinence necessitating use of incontinence protection garments
* Female who is pregnant or lactating
* Treatment for or suspicion of ever having had toxic shock syndrome
* Those receiving immunosuppressive drugs or treatment including antineoplastic therapy, post-transplantation immunosuppressive therapy, and/or radiation therapy

Primary outcomes:
measure: C-Reactive Protein Change
timeFrame: Baseline and approximately 10 weeks
Secondary outcomes:
measure: Tumor Necrosis Factor Change
timeFrame: 2 weeks and approximately 10 weeks
Other outcomes:
measure: Visual Analog Scale
timeFrame: Approximately 10 weeks
measure: Interleukin 6 Change
timeFrame: 2 weeks and approximately 10 weeks
measure: Interleukin 10 Change
timeFrame: 2 weeks and approximately 10 weeks
measure: Intestinal Fatty Acid Binding Protein (IFABP) Change
timeFrame: 2 weeks and approximately 10 weeks
measure: D-amino Acid Oxidase (DAO) Change
timeFrame: 2 weeks and approximately 10 weeks
measure: Generic Assessment of Side Effects-Probiotics (GASE-P)
timeFrame: Time 1 (Baseline), Time 2 (2 weeks), and Time 3 (10 weeks)
Locations:
city: Aurora
country: United States
facility: Rocky Mountain Regional VA Medical Center, Aurora, CO
state: Colorado
Study officials:
affiliation: Rocky Mountain Regional VA Medical Center, Aurora, CO
name: Lisa A Brenner, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Brenner LA, Forster JE, Stearns-Yoder KA, Stamper CE, Hoisington AJ, Brostow DP, Mealer M, Wortzel HS, Postolache TT, Lowry CA. Evaluation of an Immunomodulatory Probiotic Intervention for Veterans With Co-occurring Mild Traumatic Brain Injury and Posttraumatic Stress Disorder: A Pilot Study. Front Neurol. 2020 Oct 20;11:1015. doi: 10.3389/fneur.2020.01015. eCollection 2020.