Traumatic Optic Neuropathy Treatment Trial (TONTT)

Study Overview
=================
Brief Summary
-----------------
The pathophysiology of Traumatic Optic Neuropathy (TON) is thought to be multifactorial, and some researchers have also postulated a primary and secondary mechanism of injury.TON is categorized as direct or indirect.In indirect TON cases, the injury to the axons is thought to be induced by shearing forces that are transmitted to the fibers or to the vascular supply of the nerve. Studies have shown that forces applied to the frontal bone and malar eminences are transferred and concentrated in the area near the optic canal. The tight adherence of the optic nerve's dural sheath to the periosteum within the optic canal is also thought to contribute to this segment of the nerve being extremely susceptible to the deformative stresses of the skull bones. Such injury leads to ischemic injury to the axons of the retinal ganglion cells within the optic canal. At present, no studies validate a particular approach to the management of TON. There are three management lines for these patients that include 1)observation only;2)medical treatment with high or megadoses of methylprednisolone; and 3)surgical intervention. Generally no line precedes the others and additionally, medical or surgical interventions may result in serious side effects or complications. In 2005, the results of the Corticosteroid Randomization after Significant Head Injury (CRASH) trial raised concerns regarding the use of mega dose steroids in traumatic brain injury. This study was the largest randomized study that evaluated steroids in patients with traumatic brain injury and was stopped early due to the significantly increased risk of death in patients that received mega dose steroids at their 6-month follow-up when compared with the placebo group (25.7% vs 22.3%; Relative Risk 1.15 Confidence Interval 1.07 to 1.24; p=0.0001). Although the etiology of the increased risk of death was not determined, the findings of this study should be taken into consideration when managing cases of TON with concurrent traumatic brain injury. Very recently it has been shown the cytokine hormone erythropoietin (EPO) that had been long known and used as a valuable agent to promote hematopoiesis has been protective in experimental models of mechanical trauma, neuroinflammation, cerebral and retinal ischemia, and even in a human stroke trial, and most notably in optic nerve transection. A double blind placebo-controlled multicenter trial on EPO add-on treatment in chronic schizophrenic men was performed. Treatment over 12 weeks with high-dose weekly (40,000 IU intravenously) EPO led to significant improvement of cognitive performance compared to placebo controls. Different studies have been performed on the effect of EPO on neuropathy in different studies. The investigators recently published our results on treating patients with TON with EPO and found it safe and effective. Patients were compared with a historical control group of patients who received no treatment for TON. A better visual recovery was found. The aim of this study is to determine the effectiveness of EPO on TON in a Multi- center clinical trial using a semi-experimental design.

Official Title
-----------------
Study of Visual Recovery After Erythropoietin (EPO) Injection, in Patients With Traumatic Optic Neuropathy (TON)

Conditions
-----------------
Traumatic Optic Neuropathy

Intervention / Treatment
-----------------
* Drug: Recombinant human erythropoietin (EPO)
* Other: Observation
* Drug: Methyl prednisolone


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Having indirect traumatic optic neuropathy, not more than 3 weeks between trauma and treatment, normal fundoscopy Exclusion Criteria: Having other injuries that effect on visual function, direct optic neuropathy, glaucoma, diabetic retinopathy, uncontrolled hypertension, polycythemia, creatinin more than 3 mg/dl, sensitivity to EPO, hyperkalemia, women who use contraceptive pill, pregnant and breast feeding women, history of stroke and cardiovascular diseases, having malignancy

Ages Eligible for Study
-----------------
Minimum Age: 5 Years
Maximum Age: 90 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Recombinant human erythropoietin (EPO)<br>Intravenous EPO 10,000 IU for 5-13 years of age and 20,000 IU for >13 years/ day for 3 days | Drug: Recombinant human erythropoietin (EPO)<br>* 4000 units per vial<br>* Other names: EPO (Pooyesh darou Co., Tehran);|
| Active Comparator: Methylprednisolone<br>Just Intravenous Methyl prednisolone 250 mg every 6 hours for 3 days. | Drug: Methyl prednisolone<br>* 250 mg every 6 hours for 3 days.<br>* Other names: Depo-Medrol;|
| Other: Observation<br>Observation | Other: Observation<br>* Just observation<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Change/Improvement Visual Acuity From the Beseline | Best corrected visual acuity will measure at 1,2,3 days, 1 week, 2 weeks and 1 month and at least 3 months after treatment. Improvement is defined based on 1) mean logMAR[12], 2) 0.3 change in logMAR (improvement, deterioration, and no change) [12,16] , 3) mean improvement percentage which is calculated as: improvement%= (logMar ( of VA after treatment)-logMar ( of initial VA))/(logMar(20/13)˟-logMar ( of initial VA) 4) percentage of patients at different ordinal categorization of the BCVA as no light perception (NLP), light perception (LP)and hand motion (HM), count fingers (CF), and ≥ 20/200. | Change from baseline at least 3 months after treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Relative Afferent Papillary Defect (RAPD) Grade +4 | A positive RAPD means there are differences between the two eyes in the afferent pathway due to retinal or optic nerve disease. Graded from +1 to +4. The higher one is a better grade | Change from baseline at least 3 months after treatment | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Erythropoietin, Traumatic Optic Neuropathy, Visual function