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

NCT ID: NCT01058395

Last Updated: 2018-09-17

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1/PHASE2
• Total Enrollment: 15 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2010-02-28
• Study Completion Date: 2016-01-31

Brief Summary

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.

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.

Conditions

Traumatic Brain Injury

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

800 mg loading then 200 mg Q12

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

Group Type: EXPERIMENTAL

Minocycline

Intervention Type: DRUG

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.

800 mg loading then 400 mg Q12

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

Group Type: EXPERIMENTAL

Minocycline

Intervention Type: DRUG

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.

Interventions

Minocycline

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.

Intervention Type: DRUG

Other Intervention Names

Minocin

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.

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 75 Years
• Eligible Sex: MALE
• Accepts Healthy Volunteers: No

Sponsors

Wayne State University

OTHER

Sponsor Role: lead

Responsible Party

Jay M Meythaler

MD

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Jay M Meythaler, MD

Role: PRINCIPAL_INVESTIGATOR

Wayne State University

Kristina Freese, PA

Role: STUDY_DIRECTOR

Wayne State University Dept. PM&R Oakwood

John Fath, MD

Role: PRINCIPAL_INVESTIGATOR

Oakwood Hospital Dearborn, Trauma Surgery Director

Allen Lamb, DO

Role: STUDY_DIRECTOR

Oakwood Southshore Hospital

Locations

Oakwood Dearborn Hospital

Dearborn, Michigan, United States

Oakwood Southshore Hospital

Trenton, Michigan, United States

Countries

United States

References

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.

Reference Type: DERIVED

PMID: 30744442 (View on PubMed)

Other Identifiers

IND# 104298

Identifier Type: REGISTRY

Identifier Source: secondary_id

#H133A080044 -01

Identifier Type: -

Identifier Source: org_study_id