A Phase IV Trial of Neuroprotection With ACTH in Acute Optic Neuritis

Study ID
06APR2012

Cancer Related
No

Healthy Volunteers
No

Study Sites

  • UT Southwestern Ambulatory Services

Contact
Jenny Wheeler
214/645-0560
jenny.wheeler@utsouthwestern.edu

Principal Investigator
Elliot Frohman, M.D., Ph.D.

Official Title

A Phase IV Trial of Neuroprotection With ACTH in Acute Optic Neuritis

Brief Overview


We hypothesize that the novel melanocortin-mediated anti-inflammatory effects of
Adrenocorticotropic hormone (ACTH) will reduce axonal loss following ON by limiting
inflammatory optic nerve injury. We will compare the effect of ACTH and intravenous
methylprednisolone therapy on axonal injury following ON using ocular coherence tomography
(OCT), a sensitive, reproducible and noninvasive tool to measure retinal nerve fiber layer
(RNFL) thickness.

The primary outcome will be the average RNFL thickness at 6 months. Additional pre-specified
statistical analyses will compare the difference in the mean RNFL thickness at 6 months in
the affected eye between the IV methylprednisolone- and Acthar-treated groups, and the mean
6-month affected eye RNFL thicknesses adjusted for the baseline unaffected eye RNFL. The
secondary outcome measure will examine the frequency of optic nerves with RNFL swelling
between the IV methylprednisolone- and Acthar-treated groups at 1 and 3 months. The tertiary
outcome will be changes in mfVEP amplitude and latency, ONHP detection, and pupillary
diameter (UTSW only). A predefined exploratory outcome will compare the ganglion cell plus
inner plexiform layer (GC+IPL) thickness at 6 months between treatment groups

Summary


Patients with their first episode of unilateral acute optic neuritis (ON) will be treated
with either 3 days of IV methylprednisolone followed by 11 days of oral prednisone or 15
days of intramuscular (IM) or sub-cutaneous corticotropin (SQ) Acthar, adrenocorticotropic
hormone (ACTH).

This is a single blind, parallel active group, randomized controlled trial in which 60
people with clinically unilateral acute optic neuritis (≤ 2 weeks of vision loss; with or
without a previous diagnosis of relapsing remitting multiple sclerosis (MS) will be treated
with either ACTH or IV methylprednisolone/prednisone (IVMP) for 2 weeks. The primary,
secondary, and tertiary outcomes will be as noted above. The assessing physicians will be
blinded to treatment to minimize bias. We intend to recruit a target number of 3
participants per month and to complete recruitment within 10 months. This rate of
recruitment is estimated on the incidence of optic neuritis among the visits to the Rocky
Mountain MS Center and the University of Texas Southwestern (tertiary care MS centers with >
6,000 patient visits/year). Participants will be assessed for inclusion/exclusion criteria
by their treating neurologist at the Rocky Mountain MS Center (PI- Dr. Jeffrey Bennett) or
University of Texas Southwestern (PI - Dr. Elliot Frohman), and following informed consent,
will be randomized with gender, prior diagnosis of MS, disease modifying treatment (DMT)
usage (interferons vs. Glatiramer Acetate vs. Tysabri/Gilenya/Aubagio/Tecfidera vs. no
treatment), and time to randomization as binary minimization data. We expect to enroll 30
subjects per institution.

Following informed consent and randomization, participants will receive treatment either
high dose methylprednisolone (1000 mg IV daily for 3 days followed by 60 mg oral prednisone
daily for 11 days) or Acthar (80 U IM or SQ daily for 5 days followed by 40 U IM or SQ daily
for 10 days). Clinical follow-up by the treating physician is planned at months 0, 1, 3, and
6. During each visit, Early Treatment Diabetic Retinopathy Study (ETDRS) chart, low contrast
acuity (2.5%), and color vision (Farnsworth D-15) will be assessed. OCT evaluations (ONH and
macular cube) will be performed at months 0, 1, 3 and 6 months using spectral domain OCT
(Cirrus OCT; Carl Zeiss Meditec, Dublin, California, USA). Automated visual fields (Humphrey
30-2 SITA) will be performed at baseline and month 6. MfVEP, multifocal electroretinography
(mfERG), fundus photography (to assess for pallor) and pupillometry will be performed at
baseline, month 3 and month 6 in the cohort of patients recruited at the University of Texas
Southwestern. The patient's treating neurologist will perform blood tests and magnetic
resonance imaging (MRI) evaluations to exclude other causes of optic neuropathy at the
initial study visit as part of their routine care.

RNFL edema will be defined as either average RNFL thickness greater than the 95th percentile
of the age matched normal database or a ratio of RNFL thickness (affected/fellow eye)
greater than 1.1 in any quadrant.11 The study sites will collect and report data on adverse
events (AEs) and serious adverse events (SAEs) per standard practice.

A representative at UTSW will determine patient randomization accounting for the variables
noted above.

Detailed Patient Schedule of Assessments

Month 0, within 2 weeks of onset of vision loss (approximately 7 hours):

- Consent and Discussion of Study Expectations

- Eligibility Checklist

- Review of Medical History & Demographics

- Record list of Con Meds, Comorbidities, and Symptoms at time of Diagnosis

- Obtain Randomization Number

- Eye Testing (OCT - [Optic Disc Cube 200x200 and Macular Cube 200x200], VEP, Visual
Acuity [High Contrast ETDRS], Low-contrast Letter Acuity [Sloan 2.5% and 1.25%
letters], Color Vision [Farnsworth D15], mfVEP, mfERG, Humphrey's visual fields (HVF),
fundus photography, and Pupillometry)

- Administer Study Medication (either IM or SQ Acthar Gel OR IV Methylprednisolone with
oral taper)

- Labs and MRI, per standard of care

Month 1, +/- 3 days (approximately 5 hours):

- Review of AEs and Con Meds

- Eye Testing (OCT - [Optic Disc Cube 200x200 and Macular Cube 200x200], VEP (at UTSW),
Visual Acuity [High Contrast ETDRS], Low-contrast Letter Acuity [Sloan 2.5% and 1.25%
letters], Color Vision [Farnsworth D15], Humphrey's visual fields (HVF) at UTSW, fundus
photography at UTSW)

Month 3, +/- 3 days (approximately 5 hours):

- Review of AEs and Con Meds

- Eye Testing (OCT - [Optic Disc Cube 200x200 and Macular Cube 200x200], VEP, Visual
Acuity [High Contrast ETDRS], Low-contrast Letter Acuity [Sloan 2.5% and 1.25%
letters], Color Vision [Farnsworth D15], mfVEP, mfERG, Humphrey's visual fields (HVF)
at UTSW, fundus photography (at UTSW), and Pupillometry at UTSW)

Month 6, +/- 3 days (approximately 5 hours):

- Review of AEs and Con Meds

- Eye Testing (OCT - [Optic Disc Cube 200x200 and Macular Cube 200x200], VEP, Visual
Acuity [High Contrast ETDRS], Low-contrast Letter Acuity [Sloan 2.5% and 1.25%
letters], Color Vision [Farnsworth D15], mfVEP, mfERG, Humphrey's visual fields (HVF),
fundus photography, and Pupillometry)

Participant Eligibility


Inclusion Criteria:

1. Written informed consent must be obtained before any assessment is performed.

2. Male and female patients aged between 18 and 55 years, inclusive.

3. Diagnosis of clinically unilateral acute demyelinating optic neuritis (ADON)

4. Clinical signs and symptoms of ADON starting within the 14 day prior to intended
randomization (loss of vision, pain on movement, impairment of color vision).

5. The qualifying episode of optic neuritis must be the first clinical episode of optic
neuritis in the affected eye.

6. Able to undergo treatment with intravenous methylprednisolone or Acthar gel.

Exclusion Criteria:

1. Functionally or clinically relevant comorbidity of the affected eye (e.g., glaucoma,
amblyopia, optic nerve hypoplasia, macular hole, macular edema, vitreomacular
traction, uveitis, diabetes, optic neuritis, or other diseases of the optic nerve or
a history thereof).

2. Bilateral optic neuritis.

3. Concurrent functionally or clinically relevant disturbances of the eye not affected
by ADON.

4. High clinical likelihood of a form of optic neuritis other than ADON (e.g., no pain
on movement, no light perception, severe optic disk edema, atrophic optic disk,
retinal exudates, or hemorrhages).

5. Non-assessable OCT at screening.

6. Refractive error greater than ±5 diopters or (pre-surgical value to be used for
patients having undergone refractive surgery).

7. Patients with an immune system disorder other than MS or ADON (e.g. rheumatoid
arthritis, scleroderma, Sjogren's syndrome, Crohn's disease, ulcerative colitis,
etc.) or with a known immunodeficiency syndrome (AIDS, hereditary immune deficiency,
drug-induced immune deficiency). Diagnosis of neuromyelitis optica will not exclude a
patient from the study but will be accounted for in the data analysis.

8. Prior treatment with IV methylprednisolone (IVMP) or Acthar gel within the past 30
days.

9. Treatment with rituximab, mitoxantrone, cyclophosphamide, mycophenolate,
azathioprine, alemtuzumab, ocrelizumab, or other non-approved agents for the
treatment of relapsing forms of MS.

10. Concurrent use of 4-aminopyridine.