Study to Evaluate Eye Function in Patients Taking Linezolid for Six Weeks or Greater

• Sponsor: Pfizer (Industry)
• Overall Status: Terminated
• CT.gov ID: NCT00359632
• Collaborator: (none)
• Enrollment: 34
• Locations: 12
• Arms: 2
• Duration (Months): 61
• Patients Per Site: 2.8
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

To understand and characterize the effects of linezolid on the optic nerve by observing and following patients who have been treated with linezolid for six weeks or longer for the development of signs or symptoms of visual disturbance or eye disorders.

Condition or Disease	Intervention/Treatment	Phase
Optic Nerve Diseases	Drug: Zyvox - linezolid; Drug: Matched control	Phase 3

Detailed Description

Characterize Optic Side Effect

Study Design

• Study Type: Interventional
• Actual Enrollment: 34 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Official Title: Prospective Study Of Ophthalmologic Function In Patients Receiving Linezolid For Six Weeks Or Greater
• Study Start Date: Nov 1, 2008
• Actual Primary Completion Date: Dec 1, 2013
• Actual Study Completion Date: Dec 1, 2013

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Linezolid Subjects have received at least 6 weeks of linezolid therapy (600 mg BID). Continued duration of linezolid treatment is based on treating physician's benefit/risk assessment. A matching control who did not receive linezolid will be selected for each linezolid treated subject.	Drug: Zyvox - linezolid; Observation and testing in patients for whom their treating physician has determined linezolid is an appropriate therapy. Eye tests performed for subjects who have received linezolid for at least 6 weeks and matching controls who have received other antibiotics for similar types of infections.
Active Comparator: Matched control Control subjects individually matched to linezolid subjects (on age, gender and type of infection) who received at least 6 weeks of antibiotics other than linezolid. Control group assessed only at baseline visit to assess presence of background abnormalities in the study test panel.	Drug: Matched control; Matched controls received an antibiotic other than linezolid for at least 6 weeks prior to baseline visit. The control group had only a baseline visit and there were no post baseline study visits.

Outcome Measures

Primary Outcome Measures

1. Percentage of Participants With an Adverse Event [Through and including 28 calendar days after the last administration of the investigational product]

Secondary Outcome Measures

1. Percentage of Participants by Clinical Outcome of Infection at End of Study [At End of Study visit]

   Clinical response was evaluated at the End of Study visit (30 days after last dose) as Cure, Improvement, Failure, Unknown or Other. Clinical response was based primarily on the global assessment of the clinical presentation of the subject made by the investigator at that evaluation timepoint. The clinical response classifications were defined as follows. Cure: Resolution of the clinical signs and symptoms of infection, when compared to Baseline. No additional antimicrobial treatment is required for the disease under study. Improvement: Improvement in 2 or more, but not all, of the clinical signs and symptoms of infection, when compared with Baseline. No additional antimicrobial treatment is required for the disease under study. Failure: Persistence or progression of Baseline clinical signs and symptoms of infection, or development of new clinical findings consistent with active infection. Unknown: Inability to assess clinical response.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Male and female subjects who are 18 years of age or older.

• Subjects in Treated Group:

• Subjects must have received linezolid 600 mg BID for six weeks or greater and be currently on drug (or have received linezolid within 7 days of baseline evaluation).

• Subjects who have current signs or symptoms compatible with linezolid toxicity (i.e. optic or peripheral neuropathy) may be enrolled in the study if they are on linezolid at time of baseline evaluation (or have received linezolid within 7 days of baseline evaluation).

• Linezolid may be discontinued at any time at the primary physician's discretion and remain on the study.

• Women of childbearing potential must use adequate contraception

• Subjects in Control Group:

• Subjects will have a diagnosis similar to patients in the treated group and similar important co-morbidities and epidemiologic factors if possible.

Exclusion Criteria:

• Subject in Treated Group:

• Subjects with a known presence of optic or peripheral nerve damage due to another illness, condition or medication.

• Subjects with a pre-existing or a diagnosis at time of screening visit of an ophthalmologic condition that would adversely affect the study testing protocol (e.g. dense cataracts, macular degeneration, retinitis pigmentosa).

• Subjects who are currently receiving or anticipated to receive another medication, antibiotic or other, that has known potential to produce ocular or neurologic toxicity indistinguishable from that caused by linezolid or lactic acidosis.

• Subjects with a history of significant exposure, in the opinion of the investigator and with prior discussion with the medical monitor, to medications known to produce optic or peripheral neuropathy.

• Subjects with an active communicable disease (i.e., tuberculosis assessed as currently communicable) and subjects on active treatment for tuberculosis or other mycobacterial disease that include drugs that have known potential to produce ocular or neurologic toxicity.

• Subjects with severe liver disease or abnormal liver function test.

• Subjects in Control Group:

• Subjects must not currently be taking linezolid or have received it for more than 7 days at any time.

• Subjects with a known presence of optic or peripheral nerve damage due to another illness, condition or medication.

• Subjects with a pre-existing or a diagnosis at the screening visit of an ophthalmologic condition that would adversely affect the study testing protocol (e.g. dense cataracts, macular degeneration, retinitis pigmentosa).

• Subjects who are currently receiving another medication, antibiotic or other, that has known potential to produce ocular or neurologic toxicity indistinguishable from that caused by linezolid or lactic acidosis.

• Subjects with a history of significant exposure, in the opinion of the investigator and with prior discussion with the medical monitor, to medications known to produce optic or peripheral neuropathy.

• Subjects with an active communicable disease (i.e., tuberculosis assessed as currently communicable) and subjects on active treatment for tuberculosis or other mycobacterial disease that include drugs that have known potential to produce ocular or neurologic toxicity.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	St. Bernards Research Center	Jonesboro	Arkansas	United States	72401
2	Triple O Research Institute, PA	West Palm Beach	Florida	United States	33401
3	Ochsner Clinic Foundation	New Orleans	Louisiana	United States	70121
4	Henry Ford Health System	Detroit	Michigan	United States	48202
5	University of Minnesota, Department of Medicine/Division of Infectious Diseases	Minneapolis	Minnesota	United States	55455
6	Drexel University College of Medicine, Partnership Comprehensive Care Practice	Philadelphia	Pennsylvania	United States	19102
7	Associates in Infectious Disease and Tropical Medicine	Pittsburgh	Pennsylvania	United States	15206
8	Azienda Ospedaliera Universitaria di San Martino	Genova		Italy	16132
9	Ospedale San Martino, Clinica Malattie Infettive	Genova		Italy	16132
10	Università di Genova	Genova		Italy	16132
11	Clinica Malattie Infettive, Azienda Ospedaliero Universitaria Santa Maria della Misericordia	Udine		Italy	33100
12	Infektionskliniken 1-73, Karolinska Universitetssjukhuset Huddinge	Stockholm		Sweden	141 86

Sponsors and Collaborators

• Pfizer

Investigators

• Study Director: Pfizer CT.gov Call Center, Pfizer

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• To obtain contact information for a study center near you, click here.

Publications

None provided.

• Responsible Party: Pfizer
• ClinicalTrials.gov Identifier: NCT00359632
• Other Study ID Numbers: A5951110; 2006-002303-14
• First Posted: Aug 2, 2006
• Last Update Posted: Jun 26, 2015
• Last Verified: Jun 1, 2015

• Keywords provided by Pfizer: Optic neuropathy following long-term linezolid use
• Additional relevant MeSH terms: Nervous System Diseases; Optic Nerve Diseases; Linezolid

Study Results

Participant Flow

Recruitment Details	Nine centers (2 centers in Italy, 1 center in Sweden, and 6 centers in the US) enrolled subjects for inclusion in the study. Sites were selected based on their capability to perform the comprehensive testing and to treat types of infections that might require therapy with linezolid for 6 weeks or longer.
Pre-assignment Detail	There were separate selection criteria for subjects in the treated and control groups. At the Screening/Baseline visit (Day 1), subjects were eligible for the study after verification that they met the relevant inclusion/exclusion criteria and the study had been explained to them.

Arm/Group Title	Linezolid	Control
Arm/Group Description	Participants received linezolid either as tablets, by mouth (PO) or as an intravenous (IV) infusion at a dose of 600 milligrams (mg), twice daily (BID). Mode of administration and duration of treatment was at the discretion of the investigator, but for study purposes, the participant had to receive linezolid treatment for a minimum of 6 weeks (at least 42 days).	Control participants individually matched to linezolid participants (on age, gender, and type of infection) received antibiotics other than linezolid per standard of care at the discretion of the treating investigator, for at least 6 weeks (at least 42 days). The control group was only assessed at the baseline visit to identify the presence of background abnormalities in the study test panel.
Period Title: Overall Study
STARTED	24	9
COMPLETED	20	9
NOT COMPLETED	4	0

Baseline Characteristics

Arm/Group Title	Linezolid	Control	Total
Arm/Group Description	Participants received linezolid either as tablets, PO or as an IV infusion at a dose of 600 mg, BID. Mode of administration and duration of treatment was at the discretion of the investigator, but for study purposes, the participant had to receive linezolid treatment for a minimum of 6 weeks (at least 42 days).	Control participants individually matched to linezolid participants (on age, gender, and type of infection) received antibiotics other than linezolid per standard of care at the discretion of the treating investigator, for at least 6 weeks (at least 42 days). The control group was only assessed at the baseline visit to identify the presence of background abnormalities in the study test panel.	Total of all reporting groups
Overall Participants	24	9	33
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	53.4 (13.38)	50.1 (11.86)	52.5 (12.89)
Sex: Female, Male (Count of Participants)
Female	10 41.7%	6 66.7%	16 48.5%
Male	14 58.3%	3 33.3%	17 51.5%

Outcome Measures

1. Primary Outcome

Title	Percentage of Participants With an Adverse Event
Time Frame	Through and including 28 calendar days after the last administration of the investigational product

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Linezolid	Control
Arm/Group Description	Participants received linezolid either as tablets, PO or as an IV infusion at a dose of 600 mg, BID. Mode of administration and duration of treatment was at the discretion of the investigator, but for study purposes, the participant had to receive linezolid treatment for a minimum of 6 weeks (at least 42 days).	Control participants individually matched to linezolid participants (on age, gender, and type of infection) received antibiotics other than linezolid per standard of care at the discretion of the treating investigator, for at least 6 weeks (at least 42 days). The control group was only assessed at the baseline visit to identify the presence of background abnormalities in the study test panel.
Measure Participants	24	9
Adverse events, %	83.3 347.1%	11.1 123.3%
Serious adverse events, %	25.0 104.2%	0 0%
Severe adverse events, %	12.5 52.1%	0 0%
Discontinued due to adverse events, %	29.2 121.7%	0 0%
Dose Reduced or Temporary Discontinuation, %	12.5 52.1%	0 0%

2. Secondary Outcome

Title	Percentage of Participants by Clinical Outcome of Infection at End of Study
Description	Clinical response was evaluated at the End of Study visit (30 days after last dose) as Cure, Improvement, Failure, Unknown or Other. Clinical response was based primarily on the global assessment of the clinical presentation of the subject made by the investigator at that evaluation timepoint. The clinical response classifications were defined as follows. Cure: Resolution of the clinical signs and symptoms of infection, when compared to Baseline. No additional antimicrobial treatment is required for the disease under study. Improvement: Improvement in 2 or more, but not all, of the clinical signs and symptoms of infection, when compared with Baseline. No additional antimicrobial treatment is required for the disease under study. Failure: Persistence or progression of Baseline clinical signs and symptoms of infection, or development of new clinical findings consistent with active infection. Unknown: Inability to assess clinical response.
Time Frame	At End of Study visit

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Linezolid
Arm/Group Description	Participants received linezolid either as tablets, PO or as an IV infusion at a dose of 600 mg, BID. Mode of administration and duration of treatment was at the discretion of the investigator, but for study purposes, the participant had to receive linezolid treatment for a minimum of 6 weeks (at least 42 days).
Measure Participants	21
Cure, %	47.6 198.3%
Improvement, %	42.9 178.8%
Failure, %	0 0%
Unknown, %	0 0%
Other, %	9.5 39.6%

Adverse Events

Time Frame	Through and including 28 calendar days after the last administration of the investigational product
Adverse Event Reporting Description	The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in 1 participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Arm/Group Title	Linezolid		Control
Arm/Group Description	Participants received linezolid either as tablets, PO or as an IV infusion at a dose of 600 mg, BID. Mode of administration and duration of treatment was at the discretion of the investigator, but for study purposes, the participant had to receive linezolid treatment for a minimum of 6 weeks (at least 42 days).		Control participants individually matched to linezolid participants (on age, gender, and type of infection) received antibiotics other than linezolid per standard of care at the discretion of the treating investigator, for at least 6 weeks (at least 42 days). The control group was only assessed at the baseline visit to identify the presence of background abnormalities in the study test panel.
All Cause Mortality
	Linezolid		Control
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Linezolid		Control
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	6/24 (25%)		0/9 (0%)
Blood and lymphatic system disorders
Erythropoiesis abnormal	1/24 (4.2%)	1	0/9 (0%)	0
Sideroblastic anaemia	1/24 (4.2%)	1	0/9 (0%)	0
General disorders
Condition aggravated	1/24 (4.2%)	1	0/9 (0%)	0
General physical health deterioration	1/24 (4.2%)	1	0/9 (0%)	0
Pyrexia	1/24 (4.2%)	1	0/9 (0%)	0
Infections and infestations
Sepsis	1/24 (4.2%)	1	0/9 (0%)	0
Nervous system disorders
Polyneuropathy	2/24 (8.3%)	2	0/9 (0%)	0
Vascular disorders
Hypertension	1/24 (4.2%)	1	0/9 (0%)	0
Other (Not Including Serious) Adverse Events
	Linezolid		Control
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	20/24 (83.3%)		1/9 (11.1%)
Blood and lymphatic system disorders
Anaemia	6/24 (25%)	6	0/9 (0%)	0
Leukopenia	1/24 (4.2%)	1	0/9 (0%)	0
Neutropenia	1/24 (4.2%)	1	0/9 (0%)	0
Eye disorders
Diabetic retinal oedema	1/24 (4.2%)	1	0/9 (0%)	0
Narrow anterior chamber angle	0/24 (0%)	0	1/9 (11.1%)	1
Optic neuropathy	1/24 (4.2%)	1	0/9 (0%)	0
Retinal disorder	1/24 (4.2%)	1	0/9 (0%)	0
Toxic optic neuropathy	1/24 (4.2%)	1	0/9 (0%)	0
Visual impairment	1/24 (4.2%)	1	0/1 (0%)	0
Gastrointestinal disorders
Abdominal pain upper	1/24 (4.2%)	1	0/9 (0%)	0
Diarrhoea	1/24 (4.2%)	1	0/9 (0%)	0
Gastrointestinal disorder	2/24 (8.3%)	2	0/9 (0%)	0
Nausea	3/24 (12.5%)	3	0/9 (0%)	0
Tooth discolouration	1/24 (4.2%)	1	0/9 (0%)	0
Vomiting	3/24 (12.5%)	3	0/9 (0%)	0
General disorders
Asthenia	2/24 (8.3%)	2	0/9 (0%)	0
Chest pain	1/24 (4.2%)	1	0/9 (0%)	0
Fatigue	1/24 (4.2%)	1	0/9 (0%)	0
Malaise	1/24 (4.2%)	1	0/9 (0%)	0
Oedema peripheral	1/24 (4.2%)	1	0/9 (0%)	0
Infections and infestations
Folliculitis	1/24 (4.2%)	1	0/9 (0%)	0
Oral candidiasis	1/24 (4.2%)	1	0/9 (0%)	0
Vulvovaginal mycotic infection	1/24 (4.2%)	1	0/9 (0%)	0
Injury, poisoning and procedural complications
Complications of transplant surgery	1/24 (4.2%)	1	0/9 (0%)	0
Investigations
Blood lactic acid increased	1/24 (4.2%)	1	0/9 (0%)	0
Haemoglobin decreased	1/24 (4.2%)	1	0/9 (0%)	0
Platelet count increased	2/24 (8.3%)	2	0/9 (0%)	0
Protein total increased	1/24 (4.2%)	1	0/9 (0%)	0
Vitamin B1 decreased	1/24 (4.2%)	1	0/9 (0%)	0
Vitamin B12 decreased	1/24 (4.2%)	1	0/9 (0%)	0
Weight decreased	1/24 (4.2%)	1	0/9 (0%)	0
Metabolism and nutrition disorders
Hepatic enzyme increased	1/24 (4.2%)	1	0/9 (0%)	0
Decreased appetite	1/24 (4.2%)	1	0/9 (0%)	0
Folate deficiency	3/24 (12.5%)	3	0/9 (0%)	0
Hyperkalaemia	1/24 (4.2%)	1	0/9 (0%)	0
Malnutrition	1/24 (4.2%)	1	0/9 (0%)	0
Vitamin B1 deficiency	2/24 (8.3%)	2	0/9 (0%)	0
Vitamin B12 deficiency	2/24 (8.3%)	2	0/9 (0%)	0
Vitamin B6 deficiency	2/24 (8.3%)	2	0/9 (0%)	0
Musculoskeletal and connective tissue disorders
Musculoskeletal chest pain	1/24 (4.2%)	1	0/9 (0%)	0
Nervous system disorders
Dysgeusia	1/24 (4.2%)	1	0/9 (0%)	0
Headache	1/24 (4.2%)	1	0/9 (0%)	0
Neuropathy peripheral	3/24 (12.5%)	3	0/9 (0%)	0
Paraesthesia	1/24 (4.2%)	1	0/9 (0%)	0
Polyneuropathy	1/24 (4.2%)	1	0/9 (0%)	0
Sinus headache	1/24 (4.2%)	1	0/9 (0%)	0
Somnolence	1/24 (4.2%)	1	0/9 (0%)	0
Respiratory, thoracic and mediastinal disorders
Cough	1/24 (4.2%)	1	0/9 (0%)	0

Limitations/Caveats

This pilot study was exploratory and not designed to be powered for safety or efficacy. Controls were not followed post-baseline whereas linezolid patients returned for multiple study visits. The study was terminated early due to slow enrollment.

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.