Intravenous Immunoglobulin Therapy in Optic Neuritis



Sponsors


Source

National Eye Institute (NEI)

Brief Summary

To determine whether high-dose intravenous immunoglobulin (IVIg) is more effective than
placebo in restoring lost visual function (visual acuity) in optic neuritis (ON).

To determine the time course of recovery following IVIg administration. If the reports of
IVIg-associated clinical improvement occurring within 3 to 6 months following treatment can
be confirmed, this would provide indirect evidence that IVIg may promote central nervous
system (CNS) remyelination in optic neuritis and multiple sclerosis (MS).

Detailed Description

Optic neuritis is the leading cause of transient, spontaneous, reversible visual loss in
young adults. Characteristically, patients present with central visual loss that peaks within
a few days and is often associated with eye pain. Visual loss may be complete. Spontaneous
recovery usually begins within 4 weeks, and marked recovery occurs within 1 to 3 months in
most patients. Although clinical improvement is the rule, not all patients recover fully, and
many are left with residual symptoms. Although there are limited pathological studies in
inflammatory ON, the pathological changes are thought to be virtually identical with those
seen in MS, with disruption of the blood-nerve (brain) barrier; primary demyelination with
axonal sparing; variable degrees of lymphocytic infiltration; an abundance of macrophages
around the inflammatory demyelination lesion; various degrees of remyelination; and, later,
oligodendrocyte loss, axonal loss, and gliosis.

Remyelination by oligodendrocytes occurs early in the MS lesion, as documented by myelin
sheaths that are abnormally thin relative to axon diameter. These thin myelin sheaths are
often seen prominently at the edge of demyelinated plaques. A recent series of studies has
shown that within weeks of the initial event, there is extensive oligodendrocyte regeneration
and remyelination. These immature oligodendrocytes express a series of developmentally
restricted antigens. This finding has been interpreted to suggest that the cells that
repopulate the acute plaque and that affect remyelination are newly generated and not
residual, mature oligodendrocytes. These observations support the possibility that factors
that promote remyelination could be used to improve clinical recovery in ON and MS.

Work at the Mayo Clinic, has shown that both immunoglobulin G (IgG) directed against spinal
cord antigens and purified polyclonal mouse IgG administered systemically promote extensive
remyelination in SJL mice chronically infected with Theiler's virus. In addition, tissue
culture studies suggest that IgG directed against CNS components may promote oligodendroglial
proliferation and differentiation. Thus, experimental evidence exists for the concept that
immunoglobulins may stimulate the proliferation and differentiation of oligodendrocytes. It
is possible that myelin components on the surface of oligodendrocytes could function as
receptors or components of receptors. Antibodies could mimic endogenous ligands, thereby
inducing the proliferation or differentiation of these cells.

In a preliminary, open-label pilot study of patients with chronic, steroid-unresponsive ON,
Drs. van Engelen, Hommes, and colleagues suggested that improvement in visual recovery could
be seen following IgG treatment in patients with chronic, stable ON. These encouraging but
preliminary basic and clinical studies have prompted us to design a double-blind and
placebo-controlled clinical trial of IVIg in patients with recently acquired but apparently
permanent muscle paralysis from MS (NS31506) and to develop this NEI-funded ON study
(U10EY1096301).

In this randomized, placebo-controlled, double-blind clinical trial, 60 patients were
assigned to receive either IVIg or a placebo over a period of 3 months. In order to be
eligible, patients who meet the inclusion criteria needed to have a stable loss of visual
function (unchanged between the pre-enrollment screening visit and the enrollment visit). All
patients wre re-examined at 3, 6, 9, and 12 months, with the primary outcome being the impact
of treatment on visual acuity at 6 months as determined by measurements on a retroilluminated
Early Treatment Diabetic Retinopathy Study chart at 4 meters.

One group of patients received 0.4 g/kg Gammimmune N intravenously daily for 5 days, and
thereafter once a month for 3 months (total: eight infusions). The other group of patients
received infusions of 0.1 percent human serum albumin in 10 percent maltose (placebo)
according to the identical protocol used for Gammimmune N.

The primary outcome measure was improvement in Logmar visual acuity by an average of 0.2 at 6
months. The secondary outcome measures included change in visual acuity at 3, 9, and 12
months, as determined on a retroilluminated ETDRS chart at 4 meters; change in visual fields
at 6 and 12 months; change in visual evoked responses at 3, 6, and 12 months; and change in
neurological examination (EDSS, FS, AI) at 3, 6, 9, and 12 months.

Overall Status

Completed

Start Date

1995-08-01

Completion Date

1997-12-01

Primary Completion Date

N/A

Phase

Phase 3

Study Type

Interventional


Condition


Intervention

Intervention Type

Drug

Intervention Name



Eligibility

Criteria

To be eligible, patients must have a history of one or more episodes of previous
demyelinating optic neuritis occurring in the setting of classic, adult-onset definite MS
(clinically definite or laboratory-supported definite MS, or cranial MRI changes consistent
with MS). In most cases, onset of MS will have occurred between the ages of 18 and 45.
Patients must be younger than 50 years and must have apparently irreversible loss of visual
acuity that meets the following criteria:

Visual acuity must be worse than 20/40 for at least 6 months. Patients must be able to read
at least one letter on the 1-meter eye chart. Patients with no light perception or hand
movement vision only are not eligible.

The above level of visual dysfunction must be observed on at least two serial examinations
(separated by at least 1 month) in the Department of Ophthalmology at the Mayo Clinic.

Optic disc pallor must be present.

Patients must have impairment in the affected eye(s) on perimetry consistent with optic
nerve dysfunction and must have a visual field mean deviation of less than -4.00.

Patients must not have received ACTH or corticosteroids within the preceding 2 months.

Gender

All

Minimum Age

N/A

Maximum Age

50 Years


Location

Facility

Mayo Clinic, Department of Neurology
Rochester Minnesota United States
Mayo Clinic
Rochester Minnesota United States

Location Countries

Country

United States


Verification Date

2009-09-01

Lastchanged Date

N/A

Firstreceived Date

N/A

Has Expanded Access

No

Condition Browse


Intervention Browse

Mesh Term

Immunoglobulins

Antibodies

Immunoglobulins, Intravenous

gamma-Globulins

Rho(D) Immune Globulin



Firstreceived Results Date

N/A

Firstreceived Results Disposition Date

N/A

Study Design Info

Allocation

Randomized

Primary Purpose

Treatment

Masking

Double


Study First Submitted

September 23, 1999

Study First Submitted Qc

September 23, 1999

Study First Posted

September 24, 1999

Last Update Submitted

September 16, 2009

Last Update Submitted Qc

September 16, 2009

Last Update Posted

September 17, 2009


ClinicalTrials.gov processed this data on August 24, 2018

Conditions

Conditions usually refer to a disease, disorder, syndrome, illness, or injury. In ClinicalTrials.gov, conditions include any health issue worth studying, such as lifespan, quality of life, health risks, etc.
Interventions

Interventions refer to the drug, vaccine, procedure, device, or other potential treatment being studied. Interventions can also include less intrusive possibilities such as surveys, education, and interviews.
Study Phase

Most clinical trials are designated as phase 1, 2, 3, or 4, based on the type of questions that study is seeking to answer:

In Phase 1 (Phase I) clinical trials, researchers test a new drug or treatment in a small group of people (20-80) for the first time to evaluate its safety, determine a safe dosage range, and identify side effects.

In Phase 2 (Phase II) clinical trials, the study drug or treatment is given to a larger group of people (100-300) to see if it is effective and to further evaluate its safety.

In Phase 3 (Phase III) clinical trials, the study drug or treatment is given to large groups of people (1,000-3,000) to confirm its effectiveness, monitor side effects, compare it to commonly used treatments, and collect information that will allow the drug or treatment to be used safely.

In Phase 4 (Phase IV) clinical trials, post marketing studies delineate additional information including the drug's risks, benefits, and optimal use.

These phases are defined by the Food and Drug Administration in the Code of Federal Regulations.



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