E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
This study is designed to understand the effects of Linezolid on the Optic nerve by observing subjects who have been treated with linezolid for two months or longer for the development of signs or symptoms of visual disturbance or eye disorders. |
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MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 9.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10061323 |
E.1.2 | Term | Optic neuropathy |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To prospectively identify and characterize optic nerve toxicity in subjects receiving long-term (2 months or greater) linezolid therapy. |
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E.2.2 | Secondary objectives of the trial |
To examine the association of abnormal ophthalmologic screening tests suggesting the presence of optic nerve toxicity with neuro-ophthalmologic tests confirming optic nerve toxicity; To examine the reversibility of any optic nerve toxicity; To relate occurrence of toxicity to duration of therapy, mitochondrial genetics, co-morbid conditions and other epidemiologic factors; To assess the overall long-term safety of linezolid including development of peripheral neuropathy and lactic acidosis |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Male and female, in- or out-patient subjects who are 18 years of age or older; 2. Subjects must have received linezolid 600 mg BID for two months or greater (ie, at least 60 days) and be currently on drug (or have received linezolid for two months or greater and have discontinued use within 7 days of baseline evaluation);Subjects who have current signs or symptoms compatible with linezolid toxicity (ie, optic or peripheral neuropathy) may be enrolled regardless of whether treatment will be continued. The decision to continue linezolid treatment in the presence of signs of optic or peripheral neuropathy will be at the discretion of the treating physician based on his/her assessment weighing the continued risk of progression of these findings against the medical need for continued treatment with linezolid; 4. Subjects must give informed consent by signing and dating an informed consent form prior to study entry; 5. Subjects must be willing to complete all study-related activities and follow-up visits required by the protocol; 6. Women of childbearing potential must use adequate contraception, defined as hormonal contraception, intrauterine device, or barrier methods (condoms or vaginal diaphragm) with spermicide, throughout the study. Within 24 hours prior to study entry, the pregnancy test (urine or serum gonadotropin) must be negative. Women who have been surgically sterilized or are at least two years postmenopausal may be enrolled and do not have to use birth control. |
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E.4 | Principal exclusion criteria |
1. Subjects of childbearing potential who are unable to take adequate contraceptive precautions, have a positive pregnancy test result within 24 hours prior to study entry, are otherwise known to be pregnant, or are currently breastfeeding an infant; 2. Subjects with a known presence of optic nerve damage due to another illness, condition or medication other than linezolid; 3. Subjects with a known presence of peripheral nerve damage due to another illness or medication other than linezolid. Those with mild diabetic neuropathy (ie a modified Nerve Test Score of ≤2) may be included. 4. Subjects with a pre-existing or a diagnosis at the screening visit of an ophthalmologic condition that would adversely affect the study testing protocol (eg, dense cataracts, macular degeneration, congenital color vision deficiency, nystagmus, high myopia, retinitis pigmentosa); 5. 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; 6. Subjects who are currently receiving or anticipated to receive another medication, antibiotic or other, that has a strong potential to produce optic nerve toxicity (eg, ethambutol) or peripheral nerve toxicity, (eg, metronidazole and isoniazid). A list of medications known to be associated with optic and/or peripheral neuropathies is provided in Appendix 2; 7. Subjects with deficiency states, particularly of thiamine, vitamin B12, folate, induced either by starvation, malabsorption, or alcoholism which may cause optic neuropathy; 8. Subjects with evidence of lactic acidosis or have a condition (eg, mitochondrial enzyme defects, hepatic failure, and/or metastatic cancer) or on a medication that causes it (eg, nucleoside analogues). A list of medications known to be associated with lactic acidosis is provided in Appendix 3; 9. Subjects with an active communicable disease (ie, tuberculosis assessed as currently communicable); 10. Subjects with a mental condition or use of alcohol and/or other drugs that would result in his/her inability to participate in the trial and all study visits in the judgment of the investigator; 11. Subjects who have severe liver disease (Child-Pugh Class C hepatic insufficiency), or subject with SGPT and/or SGOT >5 X ULN (upper limit of normal); 12. Subjects with any other condition, which, in the investigators judgment might decrease the chance of obtaining satisfactory data to achieve the objectives of the study. |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary endpoint for this study is optic nerve toxicity. Other endpoints will be peripheral neuropathy and lactic acidosis. |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | No |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | Yes |
E.6.13.1 | Other scope of the trial description |
Characterize optic side effect associated with long term linezolid theraphy |
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E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | Information not present in EudraCT |
E.8.2.2 | Placebo | Information not present in EudraCT |
E.8.2.3 | Other | Information not present in EudraCT |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 3 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
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E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 2 |
E.8.9.1 | In the Member State concerned months | 10 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 10 |