Trial Outcomes & Findings for Safety and Efficacy Study of Eculizumab in Patients With Refractory Generalized Myasthenia Gravis (NCT NCT00727194)

NCT ID: NCT00727194

Last Updated: 2019-09-24

Results Overview

Recruitment status

TERMINATED

Study phase

PHASE2

Target enrollment

14 participants

Primary outcome timeframe

16 weeks

Results posted on

2019-09-24

Participant Flow

There were 26 IRB/IEC-approved study sites. Patients were screened at 13 Institutional Review Board/Independent Ethics Committee approved study sites; and 14 patients were randomized at 8 sites.

Patients received standard of care during the Screening Period. Patients were randomized to a treatment sequence to receive eculizumab in Period 1 followed by placebo in Period 2 or placebo in Period 1 followed by eculizumab in Period 2. Patients were permitted to continue on background immunosuppressive therapy throughout the study.

Participant milestones

Participant milestones
Measure	Eculizumab to Placebo Sequence Eculizumab: eculizumab 600 mg IV weekly (4 doses) followed by 900 mg IV every other week (7 doses) Placebo: matching placebo IV weekly (4 doses) followed by IV every other week (7 doses) Period 1: patients received eculizumab for 16 weeks. Wash-out period for 5 weeks. Period 2 (cross-over treatment period): patients received placebo for 16 weeks.	Placebo to Eculizumab Sequence Placebo: matching placebo IV weekly (4 doses) followed by IV every other week (7 doses). Eculizumab: eculizumab 600 mg IV weekly (4 doses) followed by 900 mg IV every other week (7 doses). Period 1: patients received placebo for 16 weeks. Wash-out period for 5 weeks. Period 2 (cross-over treatment period): patients received eculizumab for 16 weeks.	Not Randomized/Screen Failures Not randomized; not treatment cohort
Screening Period STARTED	7	7	16
Screening Period COMPLETED	7	7	0
Screening Period NOT COMPLETED	0	0	16
Treatment Period 1 STARTED	7	7	0
Treatment Period 1 COMPLETED	7	7	0
Treatment Period 1 NOT COMPLETED	0	0	0
Washout Period STARTED	7	7	0
Washout Period COMPLETED	7	7	0
Washout Period NOT COMPLETED	0	0	0
Treatment Period 2 STARTED	6	6	0
Treatment Period 2 COMPLETED	6	5	0
Treatment Period 2 NOT COMPLETED	0	1	0

Reasons for withdrawal

Reasons for withdrawal
Measure	Placebo to Eculizumab Sequence Placebo: matching placebo IV weekly (4 doses) followed by IV every other week (7 doses). Eculizumab: eculizumab 600 mg IV weekly (4 doses) followed by 900 mg IV every other week (7 doses). Period 1: patients received placebo for 16 weeks. Wash-out period for 5 weeks. Period 2 (cross-over treatment period): patients received eculizumab for 16 weeks.	Not Randomized/Screen Failures Not randomized; not treatment cohort
Screening Period Low QMG scores	0	6
Screening Period Lacked AChR antibodies	0	5
Screening Period Not stable on concomitant MG therapy	0	2
Screening Period Severe infections	0	2
Screening Period History of thymoma	0	1
Treatment Period 2 Lack of Efficacy	1	0

Baseline Characteristics

Safety and Efficacy Study of Eculizumab in Patients With Refractory Generalized Myasthenia Gravis

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Overall Study n=14 Participants Eculizumab: Eculizumab \[600 mg IV weekly (4 doses) followed by 900 mg IV every other week (7 doses)\]. Period 1: patients received eculizumab for 16 weeks; Period 2: wash-out period for 5 weeks (the cross-over treatment period). Patients then received placebo for 16 weeks. Placebo: Matching placebo \[IV weekly (4 doses) followed by IV every other week (7 doses)\] Period 1: patients received placebo for 16 weeks; Period 2: wash-out period for 5 weeks (the cross-over treatment period). Patients then received eculizumab for 16 weeks.
Age, Continuous	49 years STANDARD_DEVIATION 14 • n=5 Participants
Sex: Female, Male Female	8 Participants n=5 Participants
Sex: Female, Male Male	6 Participants n=5 Participants
Race/Ethnicity, Customized Caucasian	11 participants n=5 Participants
Race/Ethnicity, Customized Hispanic	2 participants n=5 Participants
Race/Ethnicity, Customized Black	1 participants n=5 Participants
Region of Enrollment United States	13 participants n=5 Participants
Region of Enrollment United Kingdom	1 participants n=5 Participants
Myasthenia Gravis Foundation of America (MGFA) classification at Screening IIa	2 participants n=5 Participants
Myasthenia Gravis Foundation of America (MGFA) classification at Screening IIb	2 participants n=5 Participants
Myasthenia Gravis Foundation of America (MGFA) classification at Screening IIIa	8 participants n=5 Participants
Myasthenia Gravis Foundation of America (MGFA) classification at Screening IVa	2 participants n=5 Participants
Number of MG crisis/exacerbation prior to Screening	5 Events STANDARD_DEVIATION 6 • n=5 Participants
Prednisone use at Screening Prednisone use	7 participants n=5 Participants
Prednisone use at Screening No prednisone use	7 participants n=5 Participants
Immunosuppression therapy other than prednisone at Screening Yes	7 participants n=5 Participants
Immunosuppression therapy other than prednisone at Screening No	7 participants n=5 Participants
Cholinesterase inhibitor use at Screening Yes	12 participants n=5 Participants
Cholinesterase inhibitor use at Screening No	2 participants n=5 Participants
Quantitative Myasthenia Gravis (QMG) at Screening	19 QMG score STANDARD_DEVIATION 6 • n=5 Participants
Myasthenia Gravis-Activity of Daily Living (MG-ADL)	8.2 units on a scale n=5 Participants

PRIMARY outcome

Timeframe: 16 weeks

Outcome measures

Outcome measures
Measure	Eculizumab Period 1 n=7 Participants eculizumab eculizumab: eculizumab 600 mg IV weekly for 4 doses followed by eculizumab 900 mg IV every two weeks for 7 doses	Placebo Period 1 n=7 Participants Placebo Placebo: Placebo IV weekly for 4 doses then every two weeks for 7 doses	Eculizumab Both Periods eculizumab eculizumab: eculizumab 600 mg IV weekly for 4 doses followed by eculizumab 900 mg IV every two weeks for 7 doses	Placebo Both Periods Placebo Placebo: Placebo IV weekly for 4 doses then every two weeks for 7 doses
Quantitative Myasthenia Gravis (QMG): The Primary Efficacy Endpoint in This Study Was the Percentage of Patients With a 3-point Reduction From Baseline in the QMG Total Score for Disease Severity.	86 percentage of patients	57 percentage of patients	—	—

SECONDARY outcome

Timeframe: 16 weeks

The QMG scoring system is considered to be an objective evaluation of muscle strength based on quantitative testing of sentinel muscle groups. The Myasthenia Gravis Foundation of America task force has recommended that the QMG score be used in prospective studies of therapy for MG. The QMG scoring system consists of 13 items. Each item is graded 0 to 3, with 3 being the most severe. The range of total QMG score is 0-39.

Outcome measures

Outcome measures
Measure	Eculizumab Period 1 n=7 Participants eculizumab eculizumab: eculizumab 600 mg IV weekly for 4 doses followed by eculizumab 900 mg IV every two weeks for 7 doses	Placebo Period 1 n=7 Participants Placebo Placebo: Placebo IV weekly for 4 doses then every two weeks for 7 doses	Eculizumab Both Periods n=12 Participants eculizumab eculizumab: eculizumab 600 mg IV weekly for 4 doses followed by eculizumab 900 mg IV every two weeks for 7 doses	Placebo Both Periods n=12 Participants Placebo Placebo: Placebo IV weekly for 4 doses then every two weeks for 7 doses
Mean Change From Baseline in QMG Total Score	-7.43 units on a scale Standard Deviation 5.563	-2.71 units on a scale Standard Deviation 4.855	-7.92 units on a scale Standard Deviation 5.054	-3.67 units on a scale Standard Deviation 4.008

SECONDARY outcome

Timeframe: 16 weeks

The MGFA PIS is designed to assess the clinical state of MG patients at any time after treatment of MG is initiated. Change in status categories of Improved, Unchanged, Worse, Exacerbation, and Died of MG was to be assessed and recorded at every visit from Visits 3 to 24 (Weeks 1 to 16). Minimal manifestations were to be assessed at these visits.

Outcome measures

Outcome measures
Measure	Eculizumab Period 1 n=7 Participants eculizumab eculizumab: eculizumab 600 mg IV weekly for 4 doses followed by eculizumab 900 mg IV every two weeks for 7 doses	Placebo Period 1 n=7 Participants Placebo Placebo: Placebo IV weekly for 4 doses then every two weeks for 7 doses	Eculizumab Both Periods n=6 Participants eculizumab eculizumab: eculizumab 600 mg IV weekly for 4 doses followed by eculizumab 900 mg IV every two weeks for 7 doses	Placebo Both Periods n=6 Participants Placebo Placebo: Placebo IV weekly for 4 doses then every two weeks for 7 doses
Change From Baseline in the MGFA Post-Intervention Status (PIS) Improved	5 participants	6 participants	6 participants	2 participants
Change From Baseline in the MGFA Post-Intervention Status (PIS) Unchanged	2 participants	1 participants	0 participants	4 participants
Change From Baseline in the MGFA Post-Intervention Status (PIS) Worse	0 participants	0 participants	0 participants	0 participants
Change From Baseline in the MGFA Post-Intervention Status (PIS) Exacerbation	0 participants	0 participants	0 participants	0 participants
Change From Baseline in the MGFA Post-Intervention Status (PIS) Died of MG	0 participants	0 participants	0 participants	0 participants

SECONDARY outcome

Timeframe: 16 weeks

Population: Comparison of MG Activities of Daily Living (Total score) at the Last Visit Between Eculizumab and Placebo Cohorts.

The MG-ADL is an 8-point questionnaire that focuses on relevant symptoms and functional performance of activities of daily living (ADL) in MG patients. The 8 items of the MG-ADL were derived from symptom-based components of the original 13-item QMG to assess disability secondary to ocular (2 items), bulbar (3 items), respiratory (1 item), and gross motor or limb (2 items) impairment related to effects from MG. In this functional status instrument, each response is graded 0 (normal) to 3 (most severe). The range of total MG-ADL score is 0 - 24. MG-ADL was to be performed at every study visit. The recall period for MG-ADL was since the preceding study visit (1 or 2 weeks).

Outcome measures

Outcome measures
Measure	Eculizumab Period 1 n=7 Participants eculizumab eculizumab: eculizumab 600 mg IV weekly for 4 doses followed by eculizumab 900 mg IV every two weeks for 7 doses	Placebo Period 1 n=7 Participants Placebo Placebo: Placebo IV weekly for 4 doses then every two weeks for 7 doses	Eculizumab Both Periods n=12 Participants eculizumab eculizumab: eculizumab 600 mg IV weekly for 4 doses followed by eculizumab 900 mg IV every two weeks for 7 doses	Placebo Both Periods n=12 Participants Placebo Placebo: Placebo IV weekly for 4 doses then every two weeks for 7 doses
Change From Baseline in the MG-Activity of Daily Living Profile (MG-ADL)	4.29 units on a scale Standard Deviation 1.799	7.86 units on a scale Standard Deviation 3.716	5.42 units on a scale Standard Deviation 3.315	7.00 units on a scale Standard Deviation 3.464

SECONDARY outcome

Timeframe: 16 weeks

Population: Comparison of SF-36 at the Last Visit Between Eculizumab and Placebo Cohorts.

The SF-36 is a multi-purpose, short-form health survey with 36 questions. It yields an 8-scale profile of functional health and well-being scores (physical functioning, role-physical, bodily pain, general health, mental health, role-emotional, social functioning and vitality) as well as psychometrically-based physical and mental health summary measures. It is a generic measure, as opposed to one that targets a specific age, disease or treatment group. The lower the score the more disability; the higher the score the less disability. Norm-based scoring involving a linear T-score transformation method was used so that scores for each of the health domain scales and component summary measures have a mean of 50 and a standard deviation of 10 based on the 1998 US general population. Thus, scores above and below 50 are above and below the average, respectively, in the 1998 US general.

Outcome measures

Outcome measures
Measure	Eculizumab Period 1 n=7 Participants eculizumab eculizumab: eculizumab 600 mg IV weekly for 4 doses followed by eculizumab 900 mg IV every two weeks for 7 doses	Placebo Period 1 n=7 Participants Placebo Placebo: Placebo IV weekly for 4 doses then every two weeks for 7 doses	Eculizumab Both Periods n=12 Participants eculizumab eculizumab: eculizumab 600 mg IV weekly for 4 doses followed by eculizumab 900 mg IV every two weeks for 7 doses	Placebo Both Periods n=12 Participants Placebo Placebo: Placebo IV weekly for 4 doses then every two weeks for 7 doses
Change From Baseline in the QoL Instrument, SF-36. Physical Functioning (Last Visit)	56.43 units on a scale Standard Deviation 29.255	64.29 units on a scale Standard Deviation 24.054	57.92 units on a scale Standard Deviation 26.921	57.08 units on a scale Standard Deviation 27.507
Change From Baseline in the QoL Instrument, SF-36. Vitality (Last Visit)	50.00 units on a scale Standard Deviation 23.936	52.68 units on a scale Standard Deviation 15.670	53.13 units on a scale Standard Deviation 19.310	48.96 units on a scale Standard Deviation 18.238
Change From Baseline in the QoL Instrument, SF-36. Social Functioning (Last Visit)	66.07 units on a scale Standard Deviation 25.733	82.14 units on a scale Standard Deviation 17.466	66.67 units on a scale Standard Deviation 24.034	78.13 units on a scale Standard Deviation 17.778
Change From Baseline in the QoL Instrument, SF-36. Role Emotional (Last Visit)	77.38 units on a scale Standard Deviation 36.233	71.43 units on a scale Standard Deviation 29.603	70.83 units on a scale Standard Deviation 34.542	82.64 units on a scale Standard Deviation 25.981
Change From Baseline in the QoL Instrument, SF-36. Physical Component Score (Last Visit)	38.73 units on a scale Standard Deviation 10.235	44.97 units on a scale Standard Deviation 7.721	41.40 units on a scale Standard Deviation 8.591	40.32 units on a scale Standard Deviation 10.025
Change From Baseline in the QoL Instrument, SF-36. Mental Component Score (Last Visit)	49.50 units on a scale Standard Deviation 12.066	43.95 units on a scale Standard Deviation 12.530	46.11 units on a scale Standard Deviation 12.596	49.03 units on a scale Standard Deviation 11.476
Change From Baseline in the QoL Instrument, SF-36. Role Physical (Last Visit)	61.61 units on a scale Standard Deviation 38.600	68.75 units on a scale Standard Deviation 25.769	64.06 units on a scale Standard Deviation 31.771	60.94 units on a scale Standard Deviation 27.324
Change From Baseline in the QoL Instrument, SF-36. Bodily Pain (Last Visit)	60.00 units on a scale Standard Deviation 24.235	74.86 units on a scale Standard Deviation 20.651	66.75 units on a scale Standard Deviation 22.511	76.17 units on a scale Standard Deviation 15.689
Change From Baseline in the QoL Instrument, SF-36. General Health (Last Visit)	47.86 units on a scale Standard Deviation 16.994	40.43 units on a scale Standard Deviation 23.201	44.67 units on a scale Standard Deviation 16.267	37.50 units on a scale Standard Deviation 19.365
Change From Baseline in the QoL Instrument, SF-36. Mental Health (Last Visit)	76.43 units on a scale Standard Deviation 17.728	58.57 units on a scale Standard Deviation 25.284	69.17 units on a scale Standard Deviation 20.542	68.75 units on a scale Standard Deviation 23.270

SECONDARY outcome

Timeframe: 16 weeks

Population: Comparison of FVC at the Last Visit Between Eculizumab and Placebo Cohorts.

Change from Baseline in Forced Vital Capacity

Outcome measures

Outcome measures
Measure	Eculizumab Period 1 n=7 Participants eculizumab eculizumab: eculizumab 600 mg IV weekly for 4 doses followed by eculizumab 900 mg IV every two weeks for 7 doses	Placebo Period 1 n=7 Participants Placebo Placebo: Placebo IV weekly for 4 doses then every two weeks for 7 doses	Eculizumab Both Periods n=12 Participants eculizumab eculizumab: eculizumab 600 mg IV weekly for 4 doses followed by eculizumab 900 mg IV every two weeks for 7 doses	Placebo Both Periods n=12 Participants Placebo Placebo: Placebo IV weekly for 4 doses then every two weeks for 7 doses
Change From Baseline in Respiratory Function Tests to Characterize the Degree of Involvement of Respiratory Muscles.	76.43 percentage of predicted Standard Deviation 15.328	87.00 percentage of predicted Standard Deviation 23.544	80.00 percentage of predicted Standard Deviation 14.894	76.75 percentage of predicted Standard Deviation 23.152

SECONDARY outcome

Timeframe: 16 weeks

Population: Comparison of NIF at the Last Visit Between Eculizumab and Placebo Cohorts.

Change from Baseline in Negative Inspiratory Force. NIF is a measurement of respiratory muscle strength and ventilator reserve. NIF is represented by centimeters of water pressure (cmH2O). A normal NIF measurement is negative 60 cmH2O, or as 100% predicted value.

Outcome measures

Outcome measures
Measure	Eculizumab Period 1 n=7 Participants eculizumab eculizumab: eculizumab 600 mg IV weekly for 4 doses followed by eculizumab 900 mg IV every two weeks for 7 doses	Placebo Period 1 n=7 Participants Placebo Placebo: Placebo IV weekly for 4 doses then every two weeks for 7 doses	Eculizumab Both Periods n=12 Participants eculizumab eculizumab: eculizumab 600 mg IV weekly for 4 doses followed by eculizumab 900 mg IV every two weeks for 7 doses	Placebo Both Periods n=12 Participants Placebo Placebo: Placebo IV weekly for 4 doses then every two weeks for 7 doses
Change From Baseline in Respiratory Function Tests to Characterize the Degree of Involvement of Respiratory Muscles.	92.43 percentage of predicted Standard Deviation 13.464	99.00 percentage of predicted Standard Deviation 2.646	93.50 percentage of predicted Standard Deviation 12.087	93.50 percentage of predicted Standard Deviation 12.042

SECONDARY outcome

Timeframe: 16 weeks

Population: The Investigators selected the 2 most affected items (double vision, ptosis) out of the 13 items in the QMG scoring system for each of their patients based on their clinical evaluation at Baseline. The count is provided when the item was selected as the most affected by the Investigator, for participants who were treated in the respective sequence.

The QMG scoring system is considered to be an objective evaluation of muscle strength based on quantitative testing of sentinel muscle groups. The MGFA task force has recommended that the QMG score be used in prospective studies of therapy for MG. All individual QMG items are scored 0 to 3, with 3 being the most severe. Negative values imply an improvement in QMG Item Score.

Outcome measures

Outcome measures
Measure	Eculizumab Period 1 n=7 Participants eculizumab eculizumab: eculizumab 600 mg IV weekly for 4 doses followed by eculizumab 900 mg IV every two weeks for 7 doses	Placebo Period 1 n=7 Participants Placebo Placebo: Placebo IV weekly for 4 doses then every two weeks for 7 doses	Eculizumab Both Periods eculizumab eculizumab: eculizumab 600 mg IV weekly for 4 doses followed by eculizumab 900 mg IV every two weeks for 7 doses	Placebo Both Periods Placebo Placebo: Placebo IV weekly for 4 doses then every two weeks for 7 doses
Change From Baseline to the End of Treatment (16 Weeks) in the Two Most Affected QMG Items for Disease Severity (Individual Test Item: Double Vision)	-0.71 units on a scale Standard Deviation 1.113	-0.29 units on a scale Standard Deviation 0.488	—	—

SECONDARY outcome

Timeframe: 16 weeks

Outcome measures

Outcome measures
Measure	Eculizumab Period 1 n=4 Participants eculizumab eculizumab: eculizumab 600 mg IV weekly for 4 doses followed by eculizumab 900 mg IV every two weeks for 7 doses	Placebo Period 1 n=4 Participants Placebo Placebo: Placebo IV weekly for 4 doses then every two weeks for 7 doses	Eculizumab Both Periods eculizumab eculizumab: eculizumab 600 mg IV weekly for 4 doses followed by eculizumab 900 mg IV every two weeks for 7 doses	Placebo Both Periods Placebo Placebo: Placebo IV weekly for 4 doses then every two weeks for 7 doses
Change From Baseline to the End of Treatment (16 Weeks) in the Two Most Affected QMG Items for Disease Severity (Individual Test Item: Ptosis)	-1.00 units on a scale Standard Deviation 1.155	-0.5 units on a scale Standard Deviation 1.000	—	—

Adverse Events

Placebo

Serious events: 1 serious events

Other events: 11 other events

Deaths: 0 deaths

Eculizumab

Serious events: 1 serious events

Other events: 13 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	Placebo n=13 participants at risk Placebo Placebo: Placebo IV weekly for 4 doses then every two weeks for 7 doses Events that occurred during the Washout Period were attributed to treatment assignment during Treatment Period 1.	Eculizumab n=13 participants at risk Eculizumab Eculizumab: eculizumab 600 mg IV weekly for 4 doses followed by eculizumab 900 mg IV every two weeks for 7 doses Events that occurred during the Washout Period were attributed to treatment assignment during Treatment Period 1.
Nervous system disorders Myasthenia Gravis	0.00% 0/13 • 46 weeks (Screening Period [up to 4 weeks], Treatment Period 1 [16 weeks], Washout Period [5 weeks], Treatment Period 2 [16 weeks], Follow-up Period [5 weeks]) for adverse events (AEs); 42 weeks for treatment emergent AEs (TEAEs). TEAEs were collected at every visit and follow-up	7.7% 1/13 • Number of events 1 • 46 weeks (Screening Period [up to 4 weeks], Treatment Period 1 [16 weeks], Washout Period [5 weeks], Treatment Period 2 [16 weeks], Follow-up Period [5 weeks]) for adverse events (AEs); 42 weeks for treatment emergent AEs (TEAEs). TEAEs were collected at every visit and follow-up
Nervous system disorders Myasthenia Gravis Crisis	7.7% 1/13 • Number of events 1 • 46 weeks (Screening Period [up to 4 weeks], Treatment Period 1 [16 weeks], Washout Period [5 weeks], Treatment Period 2 [16 weeks], Follow-up Period [5 weeks]) for adverse events (AEs); 42 weeks for treatment emergent AEs (TEAEs). TEAEs were collected at every visit and follow-up	0.00% 0/13 • 46 weeks (Screening Period [up to 4 weeks], Treatment Period 1 [16 weeks], Washout Period [5 weeks], Treatment Period 2 [16 weeks], Follow-up Period [5 weeks]) for adverse events (AEs); 42 weeks for treatment emergent AEs (TEAEs). TEAEs were collected at every visit and follow-up

Other adverse events

Additional Information

Alexion Pharmaceuticals

Phone: 855-752-2356

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place