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

Phase I Study of Minocycline in a Dose Escalation Study as a Safe, Efficacious Therapeutic Intervention for Moderate and Severe TBI in Humans

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.

Study Overview

• Status: Completed
• Conditions: Traumatic Brain Injury
• Intervention / Treatment: Drug: Minocycline

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.

• Study Type: Interventional
• Enrollment (Actual): 15
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • Michigan
    • Dearborn, Michigan, United States, 48124
      • Oakwood Dearborn Hospital
    • Trenton, Michigan, United States, 48183
      • Oakwood Southshore Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Male

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NON_RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: 800 mg loading then 200 mg Q12; Minocycline 800 mg. loading followed by 200 mg. Q 12 hours.	Drug: 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.; Other Names: Minocin
EXPERIMENTAL: 800 mg loading then 400 mg Q12; Minocycline 800 mg. loading followed by 400 mg. Q 12 hours.	Drug: 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.; Other Names: Minocin

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	4 weeks and 3 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	4 days after start

Collaborators and Investigators

• Sponsor: 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

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start: February 1, 2010
• Primary Completion (ACTUAL): September 1, 2015
• Study Completion (ACTUAL): January 1, 2016

Study Registration Dates

• First Submitted: January 19, 2010
• First Submitted That Met QC Criteria: January 27, 2010
• First Posted (ESTIMATE): January 28, 2010

Study Record Updates

• Last Update Posted (ACTUAL): September 17, 2018
• Last Update Submitted That Met QC Criteria: August 14, 2018
• Last Verified: August 1, 2018

More Information

Terms related to this study

• Keywords: Outcome; Traumatic Brain Injury; Minocycline
• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Wounds and Injuries; Craniocerebral Trauma; Trauma, Nervous System; Brain Injuries; Brain Injuries, Traumatic; Anti-Infective Agents; Anti-Bacterial Agents; Minocycline
• Other Study ID Numbers: #H133A080044 -01; IND# 104298 (REGISTRY: FDA)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No