An Open Label Study of the Effects of Eculizumab in Neuromyelitis Optica

• Sponsor: Mayo Clinic (Other)
• Overall Status: Completed
• CT.gov ID: NCT00904826
• Collaborator: Alexion Pharmaceuticals (Industry)
• Enrollment: 14
• Locations: 2
• Arm: 1
• Duration (Months): 32
• Patients Per Site: 7
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

The purpose of this study is to determine if the drug eculizumab reduces the attack rate and improves outcome in patients with neuromyelitis optica.

Condition or Disease	Intervention/Treatment	Phase
Neuromyelitis Optica; Devic's Disease	Drug: Eculizumab	Phase 1/Phase 2

Detailed Description

It has been shown in some scientific studies that the the antibody marker specific for neuromyelitis optica (NMO), known as NMO-Immunoglobulin G (IgG), causes inflammation in brain tissues by activating a substance called complement. Complement can greatly increase the immune attack in the optic nerves (causing optic neuritis (ON)), spinal cords (causing transverse myelitis (TM)) and brains of patients with NMO. Eculizumab has already been shown to be effective in a rare blood disorder known as paroxysmal nocturnal hemoglobinuria (PNH). Attacks of PNH are also mediated through complement. Therefore, the investigators of this study are investigating whether by 'turning off' complement in NMO, further attacks of NMO can be prevented.

The primary (most important) objectives of this study are to determine:

Whether Eculizumab reduces relapse frequency in patients with relapsing NMO. The number of attacks during the one year treatment period will be compared to the number of attacks that occurred prior to initiation of eculizumab treatment. For patients with more than 2 year disease duration, the average number of attacks in the preceding 2 years will be calculated. For patients with less than 2 years disease duration the number of attacks in the preceding year will be used.

The safety profile of eculizumab in patients with NMO.

The secondary objectives are to determine:

Whether eculizumab maintains or improves walking, visual function and quality of life as measured by a variety of established disability scales. We will also assess the severity of an individual attack and the degree of recovery.

How the drug behaves in the patient's blood (called pharmacodynamics and pharmacokinetics).

Depending on our preliminary investigations we may evaluate patient cerebrospinal fluid in the laboratory to see how effective eculizumab is at getting into the cerebrospinal fluid from the blood stream, and to see if the drug reverses the biological effects of the NMO-IgG antibody.

Study Design

• Study Type: Interventional
• Actual Enrollment: 14 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: An Open Label Study of the Effects of Eculizumab in Neuromyelitis Optica
• Study Start Date: Apr 1, 2009
• Actual Primary Completion Date: Dec 1, 2011
• Actual Study Completion Date: Dec 1, 2011

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Eculizumab The patient will receive eculizumab at a dose of 600mg intravenously (an infusion given into the vein) each week for 4 weeks, then 900mg intravenously at the fifth week, then 900mg every 2 weeks for 48 weeks. Subjects will receive therapy for a total of 12 months.

Drug: Eculizumab; The patient will receive eculizumab at a dose of 600mg intravenously (an infusion given into the vein) each week for 4 weeks, then 900mg intravenously at the fifth week, then 900mg every 2 weeks for 48 weeks. The first infusion will be given at Mayo Clinic site; subsequent infusions will be administered in the subject's home by a company which will send a nurse to administer the infusion. Subjects will receive therapy for a total of 12 months.; Other Names: Soliris

Outcome Measures

Primary Outcome Measures

1. Median Number of Neuromyelitis Optica (NMO) Attacks Per Year [baseline, after 12 months of treatment]

Secondary Outcome Measures

1. Number Subjects Experiencing an NMO Attack in 12 Months of Eculizumab Treatment [12 months]

2. Change in Expanded Disability Status Scale (EDDS) Score [baseline, 12 months]

   The EDSS is an ordinal clinical rating scale ranging from 0 (normal neurologic examination) to 10 (death) in half-point increments.

3. Number of Subjects With Change in Visual Acuity in at Least One Eye by at Least One Point [12 months]

   Visual acuity was measured using the the Visual Acuity subscale of the Opticospinal Impairment Score (OSIS) for Exacerbations. This subscale ranges from 0 (normal) to 8 (no light perception).

4. Number of Subjects With Change in Ambulation by at Least 1 Point [12 months]

   Ambulation was measured by the Hauser Ambulation Index, which ranges from 0 (asymptomatic; fully active) to 9 (restricted to wheelchair; unable to transfer self independently.)

5. Mean Serum Concentration of Eculizumab [6 weeks, 3 months, 6 months, 9 months, 12 months]

6. Percentage Hemolysis [baseline, 6 weeks, 3 months, 6 months, 9 months, 12 months]

   Percentage of hemolysis is a measure of complement activity. Less than 20% lysis is deemed to be complete complement inhibition.

7. Mean Eculizumab Concentration in Cerebrospinal Fluid (CSF) [3 months]

8. Mean Complement Protein 5 (C5) Concentration in CSF [baseline, 3 months]

Eligibility Criteria

Criteria

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

Inclusion Criteria:

1. Diagnosis of NMO, as defined by 2006 criteria OR NMO seropositive spectrum disorder (Recurrent ON or longitudinally extensive transverse myelitis (LETM)). All patients must be NMO-IgG seropositive.

2. Clinical evidence of at least 2 relapses in last 6 months or 3 relapses in the last 12 months (with at least 1 relapse occurring in the preceding 6 months).

3. Age ≥18 years

4. Corrected visual acuity 20/100 or better in at least one eye. If fails item # 4 then entry allowed but only if last attack was myelitis and only attacks of myelitis are considered as outcome measurement.

5. Ambulatory (with or without walker). If fails item # 5 then entry allowed but only if last attack was ON and only attacks of ON are considered as outcome measurement.

6. Provision of written informed consent (see attached) to participate in the study.

7. 1. meningitidis vaccination at least 14 days prior to receiving the first eculizumab infusion. If patient in midst of an acute relapse, then relapse will be treated with standard therapy and vaccination given only after a minimum of 4 weeks post attack onset.

Exclusion Criteria:

Candidates will be excluded from study entry if any of the following criteria are met at the time of randomization:

1. Progressive neurological deterioration unrelated to relapses of ON or myelitis.

2. Pregnant, breastfeeding, or intending to conceive during the course of the study

3. Patients will not participate in any other clinical therapeutic study or will not have participated in any other experimental treatment study within 30 days of screening

4. Patients with a history of splenectomy, because of a potential increased risk of developing meningococcal infection.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Mayo Clinic	Scottsdale	Arizona	United States	85259
2	Mayo Clinic	Rochester	Minnesota	United States	55905

Sponsors and Collaborators

• Mayo Clinic
• Alexion Pharmaceuticals

Investigators

• Principal Investigator: Sean J. Pittock, M.D., Mayo Clinic

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Mayo Clinic Clinical Trials

Publications

• Hinson SR, McKeon A, Fryer JP, Apiwattanakul M, Lennon VA, Pittock SJ. Prediction of neuromyelitis optica attack severity by quantitation of complement-mediated injury to aquaporin-4-expressing cells. Arch Neurol. 2009 Sep;66(9):1164-7. doi: 10.1001/archneurol.2009.188.
• Hinson SR, Pittock SJ, Lucchinetti CF, Roemer SF, Fryer JP, Kryzer TJ, Lennon VA. Pathogenic potential of IgG binding to water channel extracellular domain in neuromyelitis optica. Neurology. 2007 Dec 11;69(24):2221-31. Epub 2007 Oct 10.
• Lennon VA, Kryzer TJ, Pittock SJ, Verkman AS, Hinson SR. IgG marker of optic-spinal multiple sclerosis binds to the aquaporin-4 water channel. J Exp Med. 2005 Aug 15;202(4):473-7. Epub 2005 Aug 8.
• Lennon VA, Wingerchuk DM, Kryzer TJ, Pittock SJ, Lucchinetti CF, Fujihara K, Nakashima I, Weinshenker BG. A serum autoantibody marker of neuromyelitis optica: distinction from multiple sclerosis. Lancet. 2004 Dec 11-17;364(9451):2106-12.
• Rother RP, Rollins SA, Mojcik CF, Brodsky RA, Bell L. Discovery and development of the complement inhibitor eculizumab for the treatment of paroxysmal nocturnal hemoglobinuria. Nat Biotechnol. 2007 Nov;25(11):1256-64. Erratum in: Nat Biotechnol. 2007 Dec;25(12):1488.
• Wingerchuk DM, Lennon VA, Lucchinetti CF, Pittock SJ, Weinshenker BG. The spectrum of neuromyelitis optica. Lancet Neurol. 2007 Sep;6(9):805-15. Review.
• Wingerchuk DM, Lennon VA, Pittock SJ, Lucchinetti CF, Weinshenker BG. Revised diagnostic criteria for neuromyelitis optica. Neurology. 2006 May 23;66(10):1485-9.

• ClinicalTrials.gov Identifier: NCT00904826
• Other Study ID Numbers: 09-001240
• First Posted: May 20, 2009
• Last Update Posted: Nov 3, 2013
• Last Verified: Aug 1, 2013

• Keywords provided by , ,: NMO; Devic's disease; Neuromyelitis optica; NMO-IgG; Aquaporin-4 antibody; Eculizumab; Complement
• Additional relevant MeSH terms: Neuromyelitis Optica; Eculizumab

Study Results

Participant Flow

Recruitment Details	Between October 2009 and November 2010, subjects were directly recruited at the Mayo Clinics in Rochester, Minnesota and Scottsdale, Arizona, or identified through the Mayo Clinic study-specific repository or clinicoserological database.

Arm/Group Title	Eculizumab
Arm/Group Description	The patient will receive eculizumab at a dose of 600mg intravenously (an infusion given into the vein) each week for 4 weeks, then 900mg intravenously at the fifth week, then 900mg every 2 weeks for 48 weeks. Subjects will receive therapy for a total of 12 months.
Period Title: Overall Study
STARTED	14
COMPLETED	14
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	Eculizumab
Arm/Group Description	The patient will receive eculizumab at a dose of 600mg intravenously (an infusion given into the vein) each week for 4 weeks, then 900mg intravenously at the fifth week, then 900mg every 2 weeks for 48 weeks. Subjects will receive therapy for a total of 12 months.
Overall Participants	14
Age (years) [Mean (Full Range) ]
Mean (Full Range) [years]	41.1
Sex: Female, Male (Count of Participants)
Female	14 100%
Male	0 0%
Region of Enrollment (participants) [Number]
United States	14 100%
Ethnic origin (participants) [Number]
African American	2 14.3%
Hispanic	3 21.4%
White	9 64.3%
Diagnosis (participants) [Number]
Neuromyelitis optica	8 57.1%
Relapsing optic neuritis	2 14.3%
Relapsing transverse myelitis	4 28.6%
Coexisting autoimmune diseases (participants) [Number]
Myasthenia gravis	2 14.3%
Idiopathic thrombocytopenic purpura	2 14.3%
Mixed connective tissue disease	2 14.3%
No coexisting autoimmune disease	10 71.4%
Type of previous attacks at enrollment (attacks) [Number]
Optic neuritis	28
Transverse myelitis	52
Brainstem	1
Multifocal optic neuritis and transverse myelitis	3
Other multifocal	2
Number of previous attacks per subject (attacks per subject) [Mean (Full Range) ]
Mean (Full Range) [attacks per subject]	5.5
Expanded Disability Status Scale (EDSS) Score (units on a scale) [Mean (Full Range) ]
Mean (Full Range) [units on a scale]	4.8

Outcome Measures

1. Primary Outcome

Title	Median Number of Neuromyelitis Optica (NMO) Attacks Per Year
Time Frame	baseline, after 12 months of treatment

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Eculizumab
Arm/Group Description	The patient will receive eculizumab at a dose of 600mg intravenously (an infusion given into the vein) each week for 4 weeks, then 900mg intravenously at the fifth week, then 900mg every 2 weeks for 48 weeks. Subjects will receive therapy for a total of 12 months.
Measure Participants	14
Baseline	3
After 12 months of treatment	0

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Eculizumab
	Comments	Comparison between before treatment and one year after treatment.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

2. Secondary Outcome

Title	Number Subjects Experiencing an NMO Attack in 12 Months of Eculizumab Treatment
Time Frame	12 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Eculizumab
Arm/Group Description	The patient will receive eculizumab at a dose of 600mg intravenously (an infusion given into the vein) each week for 4 weeks, then 900mg intravenously at the fifth week, then 900mg every 2 weeks for 48 weeks. Subjects will receive therapy for a total of 12 months.
Measure Participants	14
Number [participants]	2 14.3%

3. Secondary Outcome

Title	Change in Expanded Disability Status Scale (EDDS) Score
Description	The EDSS is an ordinal clinical rating scale ranging from 0 (normal neurologic examination) to 10 (death) in half-point increments.
Time Frame	baseline, 12 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Eculizumab
Arm/Group Description	The patient will receive eculizumab at a dose of 600mg intravenously (an infusion given into the vein) each week for 4 weeks, then 900mg intravenously at the fifth week, then 900mg every 2 weeks for 48 weeks. Subjects will receive therapy for a total of 12 months.
Measure Participants	14
Mean (95% Confidence Interval) [units on a scale]	-0.7

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Eculizumab
	Comments	Comparison was made between baseline and after 12 months of treatment.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0078
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

4. Secondary Outcome

Title	Number of Subjects With Change in Visual Acuity in at Least One Eye by at Least One Point
Description	Visual acuity was measured using the the Visual Acuity subscale of the Opticospinal Impairment Score (OSIS) for Exacerbations. This subscale ranges from 0 (normal) to 8 (no light perception).
Time Frame	12 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Eculizumab
Arm/Group Description	The patient will receive eculizumab at a dose of 600mg intravenously (an infusion given into the vein) each week for 4 weeks, then 900mg intravenously at the fifth week, then 900mg every 2 weeks for 48 weeks. Subjects will receive therapy for a total of 12 months.
Measure Participants	14
Number [participants]	5 35.7%

5. Secondary Outcome

Title	Number of Subjects With Change in Ambulation by at Least 1 Point
Description	Ambulation was measured by the Hauser Ambulation Index, which ranges from 0 (asymptomatic; fully active) to 9 (restricted to wheelchair; unable to transfer self independently.)
Time Frame	12 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Eculizumab
Arm/Group Description	The patient will receive eculizumab at a dose of 600mg intravenously (an infusion given into the vein) each week for 4 weeks, then 900mg intravenously at the fifth week, then 900mg every 2 weeks for 48 weeks. Subjects will receive therapy for a total of 12 months.
Measure Participants	14
Number [participants]	3 21.4%

6. Secondary Outcome

Title	Mean Serum Concentration of Eculizumab
Time Frame	6 weeks, 3 months, 6 months, 9 months, 12 months

Outcome Measure Data

Analysis Population Description

Patient 13 was excluded from the 3 months measurement because she had temporarily discontinued treatment.

Arm/Group Title	Eculizumab
Arm/Group Description	The patient will receive eculizumab at a dose of 600mg intravenously (an infusion given into the vein) each week for 4 weeks, then 900mg intravenously at the fifth week, then 900mg every 2 weeks for 48 weeks. Subjects will receive therapy for a total of 12 months.
Measure Participants	14
6 weeks	206 (77)
3 months	187 (91.2)
9 months	230 (85.3)
12 months	246 (102)

7. Secondary Outcome

Title	Percentage Hemolysis
Description	Percentage of hemolysis is a measure of complement activity. Less than 20% lysis is deemed to be complete complement inhibition.
Time Frame	baseline, 6 weeks, 3 months, 6 months, 9 months, 12 months

Outcome Measure Data

Analysis Population Description

Subject 13 was excluded at 3 months visit because she had temporarily discontinued treatment.

Arm/Group Title	Eculizumab
Arm/Group Description	The patient will receive eculizumab at a dose of 600mg intravenously (an infusion given into the vein) each week for 4 weeks, then 900mg intravenously at the fifth week, then 900mg every 2 weeks for 48 weeks. Subjects will receive therapy for a total of 12 months.
Measure Participants	14
Baseline	88.5 (13.2)
6 weeks	0.4 (0.8)
3 months	0 (0)
6 months	0.2 (0.6)
9 months	0.4 (0.9)
12 months	0.9 (1.5)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Eculizumab
	Comments	Comparison is between 6 weeks and baseline.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Eculizumab
	Comments	Comparison is between 3 months and baseline.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Eculizumab
	Comments	Comparison is between 6 months and baseline
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0001
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Eculizumab
	Comments	Comparison is between 9 months and baseline.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0001
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Eculizumab
	Comments	Comparison is between 12 months and baseline.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

8. Secondary Outcome

Title	Mean Eculizumab Concentration in Cerebrospinal Fluid (CSF)
Time Frame	3 months

Outcome Measure Data

Analysis Population Description

12 subjects including subject 13 agreed to have CSF draw at the 3 month visit, but subject 13 was excluded because she had temporarily discontinued treatment.

Arm/Group Title	Eculizumab
Arm/Group Description	The patient will receive eculizumab at a dose of 600mg intravenously (an infusion given into the vein) each week for 4 weeks, then 900mg intravenously at the fifth week, then 900mg every 2 weeks for 48 weeks. Subjects will receive therapy for a total of 12 months.
Measure Participants	11
Mean (Standard Deviation) [ng/mL]	34.7 (18.7)

9. Secondary Outcome

Title	Mean Complement Protein 5 (C5) Concentration in CSF
Time Frame	baseline, 3 months

Outcome Measure Data

Analysis Population Description

At 3 months, C5 was undetectable in 6 subjects; patient 13 was excluded because she had temporarily discontinued treatment.

Arm/Group Title	Eculizumab
Arm/Group Description	The patient will receive eculizumab at a dose of 600mg intravenously (an infusion given into the vein) each week for 4 weeks, then 900mg intravenously at the fifth week, then 900mg every 2 weeks for 48 weeks. Subjects will receive therapy for a total of 12 months.
Measure Participants	14
Baseline	144 (75.5)
3 months	60.8 (23.3)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Eculizumab
	Comments	Comparison was between 3 months and baseline.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0019
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Adverse Events

Arm/Group Title	Eculizumab
Arm/Group Description	The patient will receive eculizumab at a dose of 600mg intravenously (an infusion given into the vein) each week for 4 weeks, then 900mg intravenously at the fifth week, then 900mg every 2 weeks for 48 weeks. Subjects will receive therapy for a total of 12 months.
All Cause Mortality
	Eculizumab
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Eculizumab
	Affected / at Risk (%)	# Events
Total	1/14 (7.1%)
Infections and infestations
Meningococcal infection	1/14 (7.1%)	1
Other (Not Including Serious) Adverse Events
	Eculizumab
	Affected / at Risk (%)	# Events
Total	9/14 (64.3%)
Blood and lymphatic system disorders
Swelling or ankle swelling	2/14 (14.3%)	2
Gastrointestinal disorders
Nausea	6/14 (42.9%)	18
Diarrhea	6/14 (42.9%)	7
General disorders
Headache	9/14 (64.3%)	23
Dizziness	6/14 (42.9%)	13
Abdominal Pain	4/14 (28.6%)	5
Flu like symptoms	2/14 (14.3%)	3
Fatigue	2/14 (14.3%)	3
Nasal congestion or watery eyes	2/14 (14.3%)	3
Infections and infestations
Urinary tract infection	2/14 (14.3%)	6
Musculoskeletal and connective tissue disorders
Muscle cramps	2/14 (14.3%)	9
Respiratory, thoracic and mediastinal disorders
Coughing	5/14 (35.7%)	6
Skin and subcutaneous tissue disorders
Rash	3/14 (21.4%)	3

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE 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.