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Safety and Feasibility of Minocycline in the Treatment of Traumatic Brain Injury (TBI)

This study is currently recruiting participants. (see Contacts and Locations)
Verified May 2014 by Wayne State University
Sponsor:
Information provided by (Responsible Party):
Jay M Meythaler, Wayne State University
ClinicalTrials.gov Identifier:
NCT01058395
First received: January 19, 2010
Last updated: May 11, 2014
Last verified: May 2014
  Purpose

The purpose of this study is:

  1. To assess the safety and feasibility of minocycline administration after TBI in a dose escalation study at two different doses over 7 days.
  2. To assess the pharmacokinetic characteristics of two different dosing regimens of minocycline in TBI patients, the effect on biochemical markers of neuroprotective mechanisms, and effect on neurobehavioral and functional outcome.
  3. To begin initial assessment of the efficacy of minocycline as a therapeutic agent for severe human TBI.

Condition Intervention Phase
Traumatic Brain Injury
Drug: Minocycline
Phase 1
Phase 2

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Phase I Study of Minocycline in a Dose Escalation Study as a Safe, Efficacious Therapeutic Intervention for Moderate and Severe TBI in Humans

Resource links provided by NLM:


Further study details as provided by Wayne State University:

Primary Outcome Measures:
  • Disability Rating Scale [ Time Frame: 3 months ] [ Designated as safety issue: Yes ]
  • Drug levels, toxicity. [ Time Frame: 7 days ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:
  • Liver enzymes and white-blood cell counts along with appropriate microbiologic cultures, Disability Rating Scale (DRS), Symbol Digit Modalities Test (SDMT), California Verbal Learning Test - 2nd Edition, Trails B, and SF-12 [ Time Frame: 7 days, 3 months ] [ Designated as safety issue: Yes ]

Estimated Enrollment: 14
Study Start Date: February 2010
Estimated Study Completion Date: January 2016
Estimated Primary Completion Date: September 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: 800 mg loading followed by 200 mg Q12
Physiologic data will be collected before, during and after study drug administration to monitor for drug effects and toxicity on 7 patients. Specifically, patients will be monitored for development of gastrointestinal irritation, diarrhea, and phototoxicity by history and physical examination. Hepatotoxicity and super-infections including pseudomembranous colitis will be monitored by serum studies of liver enzymes and white-blood cell counts along with appropriate microbiologic cultures.
Drug: Minocycline
Minocycline will be delivered in an open-label randomized study for seven days intravenously in one of two different dosing tiers to assess safety and toxicity per FDA recommendations. There will be tow different arms or groups differing by the amount of minocycline given over 7 days.
Experimental: 800 mg loading followed by 400 mg Q12
Physiologic data will be collected before, during and after study drug administration to monitor for drug effects and toxicity on 7 patients. Specifically, patients will be monitored for development of gastrointestinal irritation, diarrhea, and phototoxicity by history and physical examination. Hepatotoxicity and super-infections including pseudomembranous colitis will be monitored by serum studies of liver enzymes and white-blood cell counts along with appropriate microbiologic cultures.
Drug: Minocycline
Minocycline will be delivered in an open-label randomized study for seven days intravenously in one of two different dosing tiers to assess safety and toxicity per FDA recommendations. There will be tow different arms or groups differing by the amount of minocycline given over 7 days.

Detailed Description:

The purpose of this preliminary study is to test the hypothesis that administration of minocycline to humans with moderate and severe TBI is both safe and feasible in the acute post-injury setting, and to characterize its disposition and effects on biomarkers of traumatic CNS injury in a Phase IIa trial. The data collected will serve as the basis for a larger Phase IIb clinical trial in a randomized placebo-controlled parallel group design, to investigate further its potential safety and efficacy as a therapeutic agent for severe human TBI.

Tetracycline derivatives, including doxycycline and minocycline, have been shown to be neuroprotective when given after traumatic brain injury (TBI) and ischemia in rodents. In particular, reduced lesion volume and improved neurological outcome have been demonstrated following minocycline treatment of TBI. The proposed mechanism for these observations is multifactorial, and includes inhibition of microglial activation, caspase-mediated apoptosis, and the excitotoxic N-methyl-D-aspartic acid (NMDA) pathway. Because comparable inflammatory, excitotoxic and apoptotic pathways have also been implicated in human TBI, we hypothesize that administration of minocycline will confer neuroprotection after moderate to severe TBI in that milieu as well, with the potential for significant clinical benefit. Minocycline is highly lipophilic, and thus penetrates the human central nervous system (CNS). In addition, it has been shown to be safe when used in non-traumatic human neurological disorders.

  Eligibility

Ages Eligible for Study:   18 Years to 75 Years
Genders Eligible for Study:   Male
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Male , 18 to 75 years of age, irrespective of race;
  • Ability to provide written informed consent or have legal representative provide written informed consent;
  • Must be enrolled in the study within 6 of injury and meet the following criteria:

    • GCS score of 12 or less within the first 4 hours of injury;
    • Evidence of neurological injury on computer tomography (CT) of the head;
    • No known allergy to minocycline or other contraindication to receiving this medication.
  • Presence of central venous catheter;
  • Participants must not have a known life-threatening disease prior to the brain injury: However, individuals with a stable medical illness in the opinion of the investigator may be allowed to enter the study;
  • Participants are not to be on any other interventional studies aimed at enhancing neurorecovery;
  • Participants are not to be receiving immunosuppressant agents prior to study enrollment.

Exclusion Criteria:

  • Participant is a female;
  • Participants, guardians or legal representatives who are unwilling to cooperate with the investigation;
  • Participants who have received any other investigational drug within 30 days of injury;
  • Participants known to have severe ischemic heart disease or congestive heart failure, myocardial infarction, spinal cord injury with ongoing deficits, cancer or any other severe illnesses that in the opinion of the investigator would affect the assessment of therapy;
  • Participants with an ongoing neurological disease/condition or previous stroke or TBI;
  • Known clinical sequelae of spinal cord injury;
  • Massive cerebral hemisphere or brainstem hematoma, incompatible with survival;
  • History of major depression requiring the use of the medication at the time of injury;
  • Multiple trauma which in the opinion of the investigator, would jeopardize the assessment of therapy;
  • Participants who have any type of penetrating head injury;
  • Participants receiving chronic steroid treatment;
  • Participants receiving isotretinoin;
  • Lack of informed consent signed by either the participant or the subject's legal representative;
  • Prior TBI, brain tumor, cerebral vascular event, or other stable brain insult;
  • Prior history of Pseudotumor cerebri ;
  • Patients with known renal failure, BUN/ Creatinine 20:1; creatinine > 2 mg/dl;
  • Patients with known hepatic failure, AST/ALT> 3 x Upper Limit of Normal;
  • Thrombocytopenia < 75,000/mm;
  • Known allergy or sensitivity to any of the tetracyclines or any of the components of the product formulation.
  Contacts and Locations
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, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01058395

Contacts
Contact: Jay M Meythaler, MD 313-438-7373 jmeythal@med.wayne.edu
Contact: Kristina Freese, Physician Assistant 313-438-7373 Kfreese@med.wayne.edu

Locations
United States, Michigan
Oakwood Dearborn Hospital Recruiting
Dearborn, Michigan, United States, 48124
Contact: John M Fath, MD    313-982-5440    john.fath@oakwood.org   
Contact: Kristina Freese, PA    313-438-7373    kfreese@med.wayne.edu   
Principal Investigator: John Fath, MD         
Oakwood Southshore Hospital Active, not recruiting
Trenton, Michigan, United States, 48183
Sponsors and Collaborators
Wayne State University
Investigators
Principal Investigator: Jay M Meythaler, MD Wayne State University
Study Director: Kristina Freese, PA Wayne State University Dept. PM&R Oakwood
Principal Investigator: John Fath, MD Oakwood Hospital Dearborn, Trauma Surgery Director
Study Director: Allen Lamb, DO Oakwood Southshore Hospital
  More Information

No publications provided

Responsible Party: Jay M Meythaler, MD, Wayne State University
ClinicalTrials.gov Identifier: NCT01058395     History of Changes
Other Study ID Numbers: #H133A080044 -01, IND# 104298
Study First Received: January 19, 2010
Last Updated: May 11, 2014
Health Authority: United States: Food and Drug Administration

Keywords provided by Wayne State University:
Traumatic Brain Injury
Minocycline
Outcome

Additional relevant MeSH terms:
Brain Injuries
Brain Diseases
Central Nervous System Diseases
Craniocerebral Trauma
Nervous System Diseases
Trauma, Nervous System
Wounds and Injuries
Minocycline
Anti-Bacterial Agents
Anti-Infective Agents
Pharmacologic Actions
Therapeutic Uses

ClinicalTrials.gov processed this record on November 25, 2014