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Biological Signatures, Probiotic Among Those With mTBI and PTSD

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. Read our disclaimer for details.
ClinicalTrials.gov Identifier: NCT02723344
Recruitment Status : Active, not recruiting
First Posted : March 30, 2016
Last Update Posted : May 13, 2019
Sponsor:
Information provided by (Responsible Party):
VA Office of Research and Development

Tracking Information
First Submitted Date  ICMJE March 1, 2016
First Posted Date  ICMJE March 30, 2016
Last Update Posted Date May 13, 2019
Actual Study Start Date  ICMJE August 1, 2016
Estimated Primary Completion Date May 31, 2019   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: March 23, 2016)
C-Reactive Protein [ Time Frame: Through study completion, an average of 8 weeks ]
Inflammation - Biological Signature (Blood) - The investigators will use high sensitivity ELISA assays, conducted in duplicate wells, from R&D Systems to measure a biological signature of exaggerated inflammation.
Original Primary Outcome Measures  ICMJE Same as current
Change History Complete list of historical versions of study NCT02723344 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: March 23, 2016)
Tumor Necrosis Facto [ Time Frame: Through study completion, an average of 8 weeks ]
Inflammation - Biological Signature (Blood) - The investigators will use high sensitivity ELISA assays, conducted in duplicate wells, from R&D Systems to measure a biological signature of exaggerated inflammation.
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures
 (submitted: March 23, 2016)
  • Interleukin 6 [ Time Frame: Through study completion, an average of 8 weeks ]
    Inflammation - Biological Signature (Blood) - The investigators will use high sensitivity ELISA assays, conducted in duplicate wells, from R&D Systems to measure a biological signature of exaggerated inflammation.
  • Gut Microbiome (Stool) [ Time Frame: Through study completion, an average of 8 weeks ]
    Biological Signature - Stool - Microbial DNA will be prepared with a QIAGEN high-throughput system (QIAsymphony SP) capable of handling 96 samples simultaneously. Microbes will be eluted from one of the two stool swabs in each tube (the second stored frozen as a contingency) and DNA prepared using the QIAGEN system.
  • qPCR quantification of 16S rDNA in plasma [ Time Frame: Through study completion, an average of 8 weeks ]
    Inflammation - Biological Signature (Blood) - The investigators will use high sensitivity ELISA assays, conducted in duplicate wells, from R&D Systems to measure a biological signature of exaggerated inflammation.
  • Heart Rate Variability [ Time Frame: Through study completion, an average of 8 weeks ]
    Stress Response - Centrally placed remote heart rate monitor around the base of the sternum will be used to collect this data
  • Galvanic Skin Response [ Time Frame: Through study completion, an average of 8 weeks ]
    Stress Response - will be with distal phalanges of the first and second fingers of the non-dominant hand.
  • Visual Analog Scale [ Time Frame: Through study completion, an average of 8 weeks ]
    Stress Response
  • Psychological Stress Measure-9 [ Time Frame: Through study completion, an average of 8 weeks ]
    Stress Response - 9 item self report measure
  • Adverse Events [ Time Frame: Through study, an average of 2 years ]
    Number of Adverse Events reported to IRB
  • Generic Assessment of Side Effects - Probiotics (GASE-P) [ Time Frame: Through study completion, an average of 8 weeks ]
    Tolerability - Consists of 36 symptom descriptions organized by body parts. Participants are asked to rate if these "symptoms" were either "not present", "mild", "moderate", or "severe" in the past week related to supplementation
  • Adult AIDS Clinical Trials Group (AACTG) [ Time Frame: Through study completion, an average of 8 weeks ]
    Feasibility - Adult AIDS Clinical Trials Group (AACTG). We will use only section G of this measure, which queries why one might not take a supplement as directed
  • Modified Morisky Medication-Taking Adherence Scale (MMAS). [ Time Frame: Through study completion, an average of 8 weeks ]
    Feasibility - The MMAS is designed to test whether or not a subject adheres to taking a particular medication or supplement, and has demonstrated concurrent and predictive validity in regard to the measurement of patient adherence in clinical studies.
  • Modified Treatment Satisfaction Questionnaire (TSQM v1.4) [ Time Frame: Through study completion, an average of 8 weeks ]
    Acceptability - The TSQM v1.4110 is a nine-item valid questionnaire that is designed to measure side effects associated with the supplement itself and the ease of administration of the supplement
Original Other Pre-specified Outcome Measures Same as current
 
Descriptive Information
Brief Title  ICMJE Biological Signatures, Probiotic Among Those With mTBI and PTSD
Official Title  ICMJE Biological Signature and Safety of an Immunomodulatory Probiotic Intervention for Veterans With Co-Occurring Mild TBI and PTSD
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.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:
Biologic
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Other
Condition  ICMJE
  • Mild Traumatic Brain Injury
  • Post Traumatic Stress Disorder
Intervention  ICMJE
  • Dietary Supplement: of Lactobacillus reuteri (L. reuteri; DSM 17938)
    Commercially available L. reuteri (deposited in the Deutsche Sammlung von Mikroorganismen und Zellkulturen (DSMZ) and referenced as DSM 17938; Gerber Soothe Colic Drops, 100 million CFU/5 drops; formerly known as L. reuteri ATCC 55730) will be used in the proposed study. L. reuteri (phylum Firmicutes) is a gram-positive anaerobic commensal bacteria found in the gut microbiome of humans. Independent testing of the viability of the commercial product will be conducted in our laboratories by diluting drops, plating on agar in triplicate, and anaerobic culturing at 37 oC. The commercial strain (DSM 17938) has been used to improve intestinal functions in infants and reduce symptoms of infantile colic.
  • Other: Sunflower and medium chain triglyceride oils
    Placebo
    Other Name: Placebo
Study Arms  ICMJE
  • Experimental: L. reuteri
    Commercially available L. reuteri (deposited in the Deutsche Sammlung von Mikroorganismen und Zellkulturen (DSMZ) and referenced as DSM 17938; Gerber Soothe Colic Drops, 100 million CFU/5 drops; formerly known as L. reuteri ATCC 55730) will be used in the proposed study. L. reuteri (phylum Firmicutes) is a gram-positive anaerobic commensal bacteria found in the gut microbiome of humans. Independent testing of the viability of the commercial product will be conducted in our laboratories by diluting drops, plating on agar in triplicate, and anaerobic culturing at 37 oC. The commercial strain (DSM 17938) has been used to improve intestinal functions in infants and reduce symptoms of infantile colic.
    Intervention: Dietary Supplement: of Lactobacillus reuteri (L. reuteri; DSM 17938)
  • Placebo Comparator: Sunflower and medium chain triglyceride oils
    Sunflower and medium chain triglyceride oils
    Intervention: Other: Sunflower and medium chain triglyceride oils
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Active, not recruiting
Estimated Enrollment  ICMJE
 (submitted: March 23, 2016)
60
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE June 1, 2019
Estimated Primary Completion Date May 31, 2019   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 50 Years   (Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02723344
Other Study ID Numbers  ICMJE N2232-P
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party VA Office of Research and Development
Study Sponsor  ICMJE VA Office of Research and Development
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Lisa Anne Brenner, PhD Rocky Mountain Regional VA Medical Center, Aurora, CO
PRS Account VA Office of Research and Development
Verification Date May 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP