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

Primary Purpose

Traumatic Brain Injury

Status
Completed
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
Minocycline
Sponsored by
Wayne State University
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Traumatic Brain Injury focused on measuring Traumatic Brain Injury, Minocycline, Outcome

Eligibility Criteria

18 Years - 75 Years (Adult, Older Adult)MaleDoes not accept healthy volunteers

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.

Sites / Locations

  • Oakwood Dearborn Hospital
  • Oakwood Southshore Hospital

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Experimental

Arm Label

800 mg loading then 200 mg Q12

800 mg loading then 400 mg Q12

Arm Description

Minocycline 800 mg. loading followed by 200 mg. Q 12 hours.

Minocycline 800 mg. loading followed by 400 mg. Q 12 hours.

Outcomes

Primary Outcome Measures

Disability Rating Scale
The main outcome measure after the safety data was the Disability Rating Scale (DRS). It is a 29 point scale with 29 being a severe vegetative state. It is reliable across time and demonstrates better sensitivity than the Glasgow Outcome Scale.It has been a standard primary outcome measure for most pharmaceutical studies for TBI, and was required by the FDA for the IND approval.

Secondary Outcome Measures

Drug Levels
Serum samples were collected for assessment of minocycline concentrations at the estimated time of steady-state concentrations. Serum concentrations were assessed on Day 4. Data reported will be pKa levels 2 hours after AM dose.

Full Information

First Posted
January 19, 2010
Last Updated
August 14, 2018
Sponsor
Wayne State University
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1. Study Identification

Unique Protocol Identification Number
NCT01058395
Brief Title
Safety and Feasibility of Minocycline in the Treatment of Traumatic Brain Injury (TBI)
Acronym
TBI
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
Study Type
Interventional

2. Study Status

Record Verification Date
August 2018
Overall Recruitment Status
Completed
Study Start Date
February 2010 (undefined)
Primary Completion Date
September 2015 (Actual)
Study Completion Date
January 2016 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Wayne State University

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
The purpose of this study is: To assess the safety and feasibility of minocycline administration after TBI in a dose escalation study at two different doses over 7 days. 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. To begin initial assessment of the efficacy of minocycline as a therapeutic agent for severe human TBI.
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Traumatic Brain Injury
Keywords
Traumatic Brain Injury, Minocycline, Outcome

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
15 (Actual)

8. Arms, Groups, and Interventions

Arm Title
800 mg loading then 200 mg Q12
Arm Type
Experimental
Arm Description
Minocycline 800 mg. loading followed by 200 mg. Q 12 hours.
Arm Title
800 mg loading then 400 mg Q12
Arm Type
Experimental
Arm Description
Minocycline 800 mg. loading followed by 400 mg. Q 12 hours.
Intervention Type
Drug
Intervention Name(s)
Minocycline
Other Intervention Name(s)
Minocin
Intervention Description
Minocycline 800 mg loading followed by 200 mg Q12 or Minocycline 800 mg loading followed by 400 mg Q12 will be delivered in an open-label 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.
Primary Outcome Measure Information:
Title
Disability Rating Scale
Description
The main outcome measure after the safety data was the Disability Rating Scale (DRS). It is a 29 point scale with 29 being a severe vegetative state. It is reliable across time and demonstrates better sensitivity than the Glasgow Outcome Scale.It has been a standard primary outcome measure for most pharmaceutical studies for TBI, and was required by the FDA for the IND approval.
Time Frame
4 weeks and 3 months
Secondary Outcome Measure Information:
Title
Drug Levels
Description
Serum samples were collected for assessment of minocycline concentrations at the estimated time of steady-state concentrations. Serum concentrations were assessed on Day 4. Data reported will be pKa levels 2 hours after AM dose.
Time Frame
4 days after start

10. Eligibility

Sex
Male
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
75 Years
Accepts Healthy Volunteers
No
Eligibility 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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Jay M Meythaler, MD
Organizational Affiliation
Wayne State University
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Kristina Freese, PA
Organizational Affiliation
Wayne State University Dept. PM&R Oakwood
Official's Role
Study Director
First Name & Middle Initial & Last Name & Degree
John Fath, MD
Organizational Affiliation
Oakwood Hospital Dearborn, Trauma Surgery Director
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Allen Lamb, DO
Organizational Affiliation
Oakwood Southshore Hospital
Official's Role
Study Director
Facility Information:
Facility Name
Oakwood Dearborn Hospital
City
Dearborn
State/Province
Michigan
ZIP/Postal Code
48124
Country
United States
Facility Name
Oakwood Southshore Hospital
City
Trenton
State/Province
Michigan
ZIP/Postal Code
48183
Country
United States

12. IPD Sharing Statement

Plan to Share IPD
No
Citations:
PubMed Identifier
30744442
Citation
Meythaler J, Fath J, Fuerst D, Zokary H, Freese K, Martin HB, Reineke J, Peduzzi-Nelson J, Roskos PT. Safety and feasibility of minocycline in treatment of acute traumatic brain injury. Brain Inj. 2019;33(5):679-689. doi: 10.1080/02699052.2019.1566968. Epub 2019 Feb 12.
Results Reference
derived

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

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