MINOS: Study of a Neuroprotective Drug to Limit the Extent of Damage From an Ischemic Stroke

• Sponsor: David Hess, MD (Other)
• Overall Status: Completed
• CT.gov ID: NCT00630396
• Collaborator: National Institute of Neurological Disorders and Stroke (NINDS) (NIH), University of Kentucky (Other), Oregon Health and Science University (Other)
• Enrollment: 60
• Locations: 2
• Duration (Months): 20
• Patients Per Site: 30
• Patients Per Site Per Month: 1.5

Study Details

Study Description

Brief Summary

The primary aim of this study is to find out which of 4 different doses of minocycline are safe and well tolerated so that we will know the optimal dose to test in future patients.

Condition or Disease	Intervention/Treatment	Phase
Stroke, Acute	Drug: Minocycline	Phase 1/Phase 2

Detailed Description

Minocycline is a widely used antibiotic and is approved by the Food and Drug Administration (FDA) for treatment of infections and acne. However, doctors do not know whether minocycline will work in stroke patients. Its use in stroke patients is experimental. There is a lot of information from experimental stroke studies in animals that minocycline lessens the damage from a stroke and the animals recover better. Since minocycline is generally a very safe drug in humans and does not have a lot of side effects, investigators at Georgia Health Sciences University (formerly the Medical College of Georgia) believe that it might be a safe and effective drug to improve the outcome in patients with stroke.

Study Design

• Study Type: Interventional
• Actual Enrollment: 60 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Minocycline to Improve Neurologic Outcome in Stroke (MINOS)
• Study Start Date: May 1, 2008
• Actual Primary Completion Date: Jan 1, 2010
• Actual Study Completion Date: Jan 1, 2010

Outcome Measures

Primary Outcome Measures

1. Maximally Tolerated Dose of IV Minocycline [3 days]

   Investigators closely monitored each subject for evidence of minocycline intolerance. All adverse events were immediately reported for a decision whether to discontinue the study medication and/or reduce the dose. A computer program was used to determine the maximum tolerated dose. After entering information regarding doses and expected toxicities, results for each subject as they were collected were entered. The computer program informed as to (de)escalation, or maintenance of the same dose in the subsequent cohort of enrolled patients.

Secondary Outcome Measures

1. Half-life of IV Minocycline [For each subject blood samples were drawn before dose #1 and one hour after starting dose #1. Additional blood was drawn 1, 6, 12, 24, 48, and 72 hours after starting dose #6, which lasted approximately 6 days.]

   In eligible patients enrolled at Georgia Health Sciences University, blood samples were drawn for quantification of minocycline serum concentrations. This enabled the study team to determine the half life of the study drug.

2. 90 Day Modified Rankin Scale Score [3 months]

   The modified Rankin Scale (mRS) was performed in person at the 90 day clinic follow-up appointment. The modified Rankin Scale is a commonly used scale for measuring the degree of disability or dependence in the daily activities of people who have suffered a stroke. The scale runs from 0-6. 0 represents no symptoms. 1 represents no significant disability. 2 represents slight disability. 3 represents moderate disability. 4 represents moderately severe disability. 5 represents severe disability. 6 represents death.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 19 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• over 18 years of age

• acute onset focal neurologic deficit consistent with acute ischemic stroke, or computed tomographic scan consistent with acute cerebral ischemia

• onset of symptoms less than 6 hours

• measurable neurologic deficit (National Institutes of Health [NIH] Stroke Scale >/= 1)

Exclusion Criteria:

• allergy to tetracycline antibiotics

• women of child-bearing potential

• known hepatic and/or renal insufficiency

• Thrombocytopenia

• history of intolerance to minocycline

• dizziness at the time of stroke or in the past month (by self-report)

• aphasia likely to interfere with patients ability to report adverse effects

• previous functional disability

• stuporous or comatose

• presence of another serious illness likely to confound the study

• unlikely to be available for 90 day follow-up

• severe stroke (National Institutes of Health [NIH] Stroke Scale >22)

• undergoing an interventional neuro-radiological intervention in first 12 hour

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Kentucky	Lexington	Kentucky	United States	40506-0057
2	Oregon Health & Science University	Portland	Oregon	United States	97239

Sponsors and Collaborators

• David Hess, MD
• National Institute of Neurological Disorders and Stroke (NINDS)
• University of Kentucky
• Oregon Health and Science University

Investigators

• Principal Investigator: David C Hess, MD, Augusta University

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: David Hess, MD, Professor and Chairman, Augusta University
• ClinicalTrials.gov Identifier: NCT00630396
• Other Study ID Numbers: R01NS055728-01A1; 07-02-202
• First Posted: Mar 7, 2008
• Last Update Posted: Jan 13, 2012
• Last Verified: Dec 1, 2011

• Keywords provided by David Hess, MD, Professor and Chairman, Augusta University: stroke; ischemic; neuroprotection; minocycline; tissue plasminogen activator (tPA); biomarkers; pharmacokinetics; antiapoptotic; anti-inflammatory; treatment; matrix metalloproteinase-9 (MMP-9); thrombolysis; Minocycline to Improve Neurologic Outcome in Stroke (MINOS); cerebrovascular stroke; cerebrovascular accident; cerebral stroke; cerebrovascular accident (CVA)
• Additional relevant MeSH terms: Stroke; Minocycline

Study Results

Participant Flow

Recruitment Details	Recruitment occurred from June 3, 2008 to October 10, 2009. The study was completed ahead of schedule. Study subjects were enrolled in each recruiting centers' Emergency Department or stroke intensive care unit. Many subjects came as transfers from rural or outside hospitals to one of the enrolling centers for further care and study participation.
Pre-assignment Detail	Potential patients that met all of the inclusion criteria, did not meet any of the exclusion criteria, and were willing to participate were enrolled in the study. All study subjects were given one of the four doses of minocycline. The dose of minocycline given was assigned by a computer program.

Arm/Group Title	Minocycline
Arm/Group Description	All 60 participants were treated with minocycline. 11 participants were treated at 3mg/kg, 4 were treated at 4.5mg/kg, 4 were treated at 6mg/kg, and 41 were treated at 10mg/kg.
Period Title: Overall Study
STARTED	60
COMPLETED	53
NOT COMPLETED	7

Baseline Characteristics

Arm/Group Title	Minocycline
Arm/Group Description	All 60 participants were treated with minocycline. 11 participants were treated at 3mg/kg, 4 were treated at 4.5mg/kg, 4 were treated at 6mg/kg, and 41 were treated at 10mg/kg.
Overall Participants	60
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	30 50%
>=65 years	30 50%
Age (years) [Mean (Standard Deviation) ]
Overall age	65 (13.7)
Sex: Female, Male (Count of Participants)
Female	28 46.7%
Male	32 53.3%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	1 1.7%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	9 15%
White	50 83.3%
More than one race	0 0%
Unknown or Not Reported	0 0%
Region of Enrollment (participants) [Number]
United States	60 100%
Weight (Kg) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Kg]	81.6 (21.6)
Subjects receiving t-PA then minocycline (Number) [Number]
Total amount of subjects that received t-PA	36 60%
Total amount of subjects that did not receive t-PA	24 40%
NIH Stroke Scale at baseline (Units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Units on a scale]	8.7 (5.8)
Symptom onset to study drug infusion time (minutes) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [minutes]	307.4 (50.0)

Outcome Measures

1. Primary Outcome

Title	Maximally Tolerated Dose of IV Minocycline
Description	Investigators closely monitored each subject for evidence of minocycline intolerance. All adverse events were immediately reported for a decision whether to discontinue the study medication and/or reduce the dose. A computer program was used to determine the maximum tolerated dose. After entering information regarding doses and expected toxicities, results for each subject as they were collected were entered. The computer program informed as to (de)escalation, or maintenance of the same dose in the subsequent cohort of enrolled patients.
Time Frame	3 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Minocycline
Arm/Group Description	All 60 participants were treated with minocycline. 11 participants were treated at 3mg/kg, 4 were treated at 4.5mg/kg, 4 were treated at 6mg/kg, and 41 were treated at 10mg/kg.
Measure Participants	60
Number [mg/kg]	10

2. Secondary Outcome

Title	Half-life of IV Minocycline
Description	In eligible patients enrolled at Georgia Health Sciences University, blood samples were drawn for quantification of minocycline serum concentrations. This enabled the study team to determine the half life of the study drug.
Time Frame	For each subject blood samples were drawn before dose #1 and one hour after starting dose #1. Additional blood was drawn 1, 6, 12, 24, 48, and 72 hours after starting dose #6, which lasted approximately 6 days.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Minocycline
Arm/Group Description	All 60 participants were treated with minocycline. 11 participants were treated at 3mg/kg, 4 were treated at 4.5mg/kg, 4 were treated at 6mg/kg, and 41 were treated at 10mg/kg.
Measure Participants	22
Measure blood samples	176
Mean (Standard Error) [hours]	23.8 (1.9)

3. Secondary Outcome

Title	90 Day Modified Rankin Scale Score
Description	The modified Rankin Scale (mRS) was performed in person at the 90 day clinic follow-up appointment. The modified Rankin Scale is a commonly used scale for measuring the degree of disability or dependence in the daily activities of people who have suffered a stroke. The scale runs from 0-6. 0 represents no symptoms. 1 represents no significant disability. 2 represents slight disability. 3 represents moderate disability. 4 represents moderately severe disability. 5 represents severe disability. 6 represents death.
Time Frame	3 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Minocycline
Arm/Group Description	All 60 participants were treated with minocycline. 11 participants were treated at 3mg/kg, 4 were treated at 4.5mg/kg, 4 were treated at 6mg/kg, and 41 were treated at 10mg/kg.
Measure Participants	60
90 day mRS score of 0 overall	15 25%
90 day mRS score of 1 overall	15 25%
90 day mRS score of 2 overall	9 15%
90 day mRS score of 3 overall	11 18.3%
90 day mRS score of 4 overall	2 3.3%
90 day mRS score of 5 overall	3 5%
90 day mRS score of 6 overall	5 8.3%

Adverse Events

Time Frame	Adverse Events were collected for one year and seven months. This time period started when the first subject was enrolled and lasted until the 90 day follow-up was completed for the last subject enrolled.
Adverse Event Reporting Description	Investigators closely monitored each patient for evidence of study drug intolerance, particularly focusing on dizziness, gastrointestinal complaints, and infusion reactions.
Arm/Group Title	Minocycline
Arm/Group Description	All 60 participants were treated with minocycline. 11 participants were treated at 3mg/kg, 4 were treated at 4.5mg/kg, 4 were treated at 6mg/kg, and 41 were treated at 10mg/kg.
All Cause Mortality
	Minocycline
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Minocycline
	Affected / at Risk (%)	# Events
Total	29/60 (48.3%)
Cardiac disorders
Congestive Heart Failure exacerbation	1/60 (1.7%)	1
Rule out myocardial infarction (chest pain, nausea, shortness of breath)	1/60 (1.7%)	1
Congestive Heart Failure	1/60 (1.7%)	1
Paroxysmal atrial fibrillation	1/60 (1.7%)	1
Gastrointestinal disorders
Stomach cancer	1/60 (1.7%)	1
Infections and infestations
Urinary Tract Infection	3/60 (5%)	3
Rule out pneumonia	1/60 (1.7%)	1
Musculoskeletal and connective tissue disorders
Left hip fracture	1/60 (1.7%)	1
Nervous system disorders
Death	5/60 (8.3%)	5
Transient Ischemic Attack	1/60 (1.7%)	1
Acute Ischemic Stroke	3/60 (5%)	3
Worsening hallucinations and agitation	1/60 (1.7%)	1
Neuroworsening	3/60 (5%)	3
Intracerebral Hemorrhage	1/60 (1.7%)	1
Psychiatric disorders
Depression/suicide attempt	1/60 (1.7%)	1
Renal and urinary disorders
Hypotension	1/60 (1.7%)	1
Reproductive system and breast disorders
Scrotal edema	1/60 (1.7%)	1
Respiratory, thoracic and mediastinal disorders
Pulmonary emboli secondary to left lower extremity deep vein thrombosis	1/60 (1.7%)	1
Surgical and medical procedures
Carotid endarterectomy	1/60 (1.7%)	1
Other (Not Including Serious) Adverse Events
	Minocycline
	Affected / at Risk (%)	# Events
Total	50/60 (83.3%)
Blood and lymphatic system disorders
Reduced platelet count	4/60 (6.7%)	4
Cardiac disorders
Atrial Fibrillation	3/60 (5%)	3
Chest pain	4/60 (6.7%)	4
Tachycardia	3/60 (5%)	3
Gastrointestinal disorders
GI Symptoms	12/60 (20%)	22
General disorders
Pain	10/60 (16.7%)	13
Edema	3/60 (5%)	4
Infections and infestations
Urinary Tract Infection	3/60 (5%)	3
Aspiration pneumonia	3/60 (5%)	3
Nervous system disorders
Hemorrhagic transformation	3/60 (5%)	3
Neurological worsening	3/60 (5%)	3
Headache	15/60 (25%)	15
Vertigo	3/60 (5%)	4
Renal and urinary disorders
Elevated liver enzymes	4/60 (6.7%)	4
Hypotension	4/60 (6.7%)	4
Skin and subcutaneous tissue disorders
Skin reactions	13/60 (21.7%)	17

Limitations/Caveats

Some statistical tests could not be performed due to small sample size in the 4.5 and 6mg/kg dose tiers. The modified continual reassessment method (CRM) failed to identify the maximum tolerated dose of intravenous minocycline.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.