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

• ClinicalTrials.gov Identifier: NCT00904826
• Recruitment Status: Completed
• First Posted: May 20, 2009
• Results First Posted: November 4, 2013
• Last Update Posted: November 4, 2013
• Sponsor: Mayo Clinic
• Collaborator: Alexion Pharmaceuticals
• Information provided by: Mayo Clinic

• Study Type: Interventional
• Study Design: Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Conditions: Neuromyelitis Optica; Devic's Disease
• Intervention: Drug: Eculizumab
• Enrollment: 14

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.
Pre-assignment Details

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 Number of Baseline Participants		14
Baseline Analysis Population Description		[Not Specified]
Age Continuous; Mean (Full Range); Unit of measure: Years
	Number Analyzed	14 participants
		41.1; (18.4 to 67.6)
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	14 participants
	Female	14 100.0%
	Male	0 0.0%
Region of Enrollment; Measure Type: Number; Unit of measure: Participants
United States	Number Analyzed	14 participants
		14
Ethnic origin; Measure Type: Number; Unit of measure: Participants	Number Analyzed	14 participants
African American		2
Hispanic		3
White		9
Diagnosis; Measure Type: Number; Unit of measure: Participants	Number Analyzed	14 participants
Neuromyelitis optica		8
Relapsing optic neuritis		2
Relapsing transverse myelitis		4
Coexisting autoimmune diseases; Measure Type: Number; Unit of measure: Participants	Number Analyzed	14 participants
Myasthenia gravis		2
Idiopathic thrombocytopenic purpura		2
Mixed connective tissue disease		2
No coexisting autoimmune disease		10
Type of previous attacks at enrollment; Measure Type: Number; Unit of measure: Attacks	Number Analyzed	14 participants
Optic neuritis		28
Transverse myelitis		52
Brainstem		1
Multifocal optic neuritis and transverse myelitis		3
Other multifocal		2
Number of previous attacks per subject; Mean (Full Range); Unit of measure: Attacks per subject
	Number Analyzed	14 participants
		5.5; (2.0 to 10.0)
Expanded Disability Status Scale (EDSS) Score [1]; Mean (Full Range); Unit of measure: Units on a scale
	Number Analyzed	14 participants
		4.8; (2.0 to 8.0)
		[1] Measure Description: The EDSS is an ordinal clinical rating scale ranging from 0 (normal neurologic examination) to 10 (death) in half-point increments.

Outcome Measures

1. Primary Outcome

Title	Median Number of Neuromyelitis Optica (NMO) Attacks Per Year
Description	[Not Specified]
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.
Overall Number of Participants Analyzed	14
Median (Full Range); Unit of Measure: attacks per year
Baseline	3; (2 to 4)
After 12 months of treatment	0; (0 to 1)

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	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	[Not Specified]
	Method	Wilcoxon (Mann-Whitney)
	Comments	[Not Specified]

2. Secondary Outcome

Title	Number Subjects Experiencing an NMO Attack in 12 Months of Eculizumab Treatment
Description	[Not Specified]
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.
Overall Number of Participants Analyzed	14
Measure Type: Number; Unit of Measure: participants
	2

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.
Overall Number of Participants Analyzed	14
Mean (95% Confidence Interval); Unit of Measure: units on a scale
	-0.7; (-1.2 to -0.2)

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	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0078
	Comments	[Not Specified]
	Method	Wilcoxon (Mann-Whitney)
	Comments	[Not Specified]

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.
Overall Number of Participants Analyzed	14
Measure Type: Number; Unit of Measure: participants
	5

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.
Overall Number of Participants Analyzed	14
Measure Type: Number; Unit of Measure: participants
	3

6. Secondary Outcome

Title	Mean Serum Concentration of Eculizumab
Description	[Not Specified]
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.
Overall Number of Participants Analyzed	14
Mean (Standard Deviation); Unit of Measure: micrograms/mL
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.
Overall Number of Participants Analyzed	14
Mean (Standard Deviation); Unit of Measure: percentage of hemolysis
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	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	[Not Specified]
	Method	Wilcoxon (Mann-Whitney)
	Comments	[Not Specified]

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	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	[Not Specified]
	Method	Wilcoxon (Mann-Whitney)
	Comments	[Not Specified]

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	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0001
	Comments	[Not Specified]
	Method	Wilcoxon (Mann-Whitney)
	Comments	[Not Specified]

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	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0001
	Comments	[Not Specified]
	Method	Wilcoxon (Mann-Whitney)
	Comments	[Not Specified]

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	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	[Not Specified]
	Method	Wilcoxon (Mann-Whitney)
	Comments	[Not Specified]

8. Secondary Outcome

Title	Mean Eculizumab Concentration in Cerebrospinal Fluid (CSF)
Description	[Not Specified]
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.
Overall Number of Participants Analyzed	11
Mean (Standard Deviation); Unit of Measure: ng/mL
	34.7 (18.7)

9. Secondary Outcome

Title	Mean Complement Protein 5 (C5) Concentration in CSF
Description	[Not Specified]
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.
Overall Number of Participants Analyzed	14
Mean (Standard Deviation); Unit of Measure: ng/mL
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	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0019
	Comments	[Not Specified]
	Method	Wilcoxon (Mann-Whitney)
	Comments	[Not Specified]

Adverse Events

Time Frame	[Not Specified]
Adverse Event Reporting 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.
All-Cause Mortality
	Eculizumab
	Affected / at Risk (%)
Total	--/--
Serious Adverse Events
	Eculizumab
	Affected / at Risk (%)	# Events
Total	1/14 (7.14%)
Infections and infestations
Meningococcal infection †	1/14 (7.14%)	1
† Indicates events were collected by systematic assessment
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	Eculizumab
	Affected / at Risk (%)	# Events
Total	9/14 (64.29%)
Blood and lymphatic system disorders
Swelling or ankle swelling †	2/14 (14.29%)	2
Gastrointestinal disorders
Nausea †	6/14 (42.86%)	18
Diarrhea †	6/14 (42.86%)	7
General disorders
Headache †	9/14 (64.29%)	23
Dizziness †	6/14 (42.86%)	13
Abdominal Pain †	4/14 (28.57%)	5
Flu like symptoms †	2/14 (14.29%)	3
Fatigue †	2/14 (14.29%)	3
Nasal congestion or watery eyes †	2/14 (14.29%)	3
Infections and infestations
Urinary tract infection †	2/14 (14.29%)	6
Musculoskeletal and connective tissue disorders
Muscle cramps †	2/14 (14.29%)	9
Respiratory, thoracic and mediastinal disorders
Coughing †	5/14 (35.71%)	6
Skin and subcutaneous tissue disorders
Rash †	3/14 (21.43%)	3
† Indicates events were collected by systematic assessment

Limitations and Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

Results Point of Contact

• Name/Title: Dr. Sean J. Pittock
• Organization: Mayo Clinic
• Phone: 507-284-4741
• EMail: pittock.sean@mayo.edu

Publications of Results:

Pittock SJ, Lennon VA, McKeon A, Mandrekar J, Weinshenker BG, Lucchinetti CF, O'Toole O, Wingerchuk DM. Eculizumab in AQP4-IgG-positive relapsing neuromyelitis optica spectrum disorders: an open-label pilot study. Lancet Neurol. 2013 Jun;12(6):554-62. doi: 10.1016/S1474-4422(13)70076-0. Epub 2013 Apr 26.

Other Publications:

Wingerchuk DM, Lennon VA, Lucchinetti CF, Pittock SJ, Weinshenker BG. The spectrum of neuromyelitis optica. Lancet Neurol. 2007 Sep;6(9):805-15. Review.

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.

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.

Wingerchuk DM, Lennon VA, Pittock SJ, Lucchinetti CF, Weinshenker BG. Revised diagnostic criteria for neuromyelitis optica. Neurology. 2006 May 23;66(10):1485-9.

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.

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.

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.

• Responsible Party: Sean J. Pittock, M.D., Mayo Clinic
• ClinicalTrials.gov Identifier: NCT00904826 History of Changes
• Other Study ID Numbers: 09-001240
• First Submitted: May 18, 2009
• First Posted: May 20, 2009
• Results First Submitted: August 30, 2013
• Results First Posted: November 4, 2013
• Last Update Posted: November 4, 2013