Guillain-Barre Syndrome
Conditions
Keywords
Eculizumab, Soliris, Alexion, C5 Inhibition Therapy
Brief summary
This is a Phase 3, prospective, multicenter, placebo controlled, double blind, randomized study to investigate the efficacy and safety of eculizumab in participants with severe GBS, defined using the Hughes Functional Grade (FG) scale as progressively deteriorating FG3 or FG4/FG5 within 2 weeks from onset of weakness due to GBS. This study will be conducted only at sites in Japan.
Detailed description
Eligible participants will be randomized to receive intravenous (IV) infusion of eculizumab or placebo at a 2:1 ratio. All participants will be on concomitant IV immunoglobulin G (Ig) therapy as per standard of care.
Interventions
BIOLOGICALEculizumab
Eculizumab will be administered via IV infusion once a week for 4 weeks.
DRUGPlacebo
Placebo will be administered via IV infusion once a week for 4 weeks.
Sponsors
Alexion Pharmaceuticals, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Participants who meet the GBS criteria. * Participants who were able to run prior to onset of GBS symptoms. * Participants with onset of weakness due to GBS \< 2 weeks before screening. * Participants unable to walk unaided for ≥ 5 meters (progressively deteriorating FG3 or FG4 to FG5). * Participants who are already on IVIg or deemed eligible for and who will start IVIg. * Participants who can start their first dose of study drug before the end of the IVIg treatment period.
Exclusion criteria
* Participants who have previously received or are currently receiving treatment with complement modulators. * Participants who have been administered another investigational product within 30 days or 5 half-lives (whichever is longer) prior to providing consent or are currently participating in another interventional study. * Participants who have received rituximab within 12 weeks prior to screening. * Participants who are being considered for or are already on plasmapheresis. * Participants who have received immunosuppressive treatment during the 4 weeks prior to providing consent.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Time to First Reaching a Hughes Functional Grade (FG) Score <=1 | Up to Week 24 | The mobility of the participants was evaluated on a 7 point disability functional grade scale and described as Hughes FG score of 0 (Healthy, no signs or symptoms of Guillain-Barré syndrome); 1 (Minor signs or symptoms and able to run); 2 (Able to walk 5 metre (m) across an open space without assistance); 3 (Able to walk 5 m across an open space with the help of one person and waist-level walking-frame, stick, or sticks); 4 (Chairbound/bedbound: unable to walk as in 3); 5 (Requiring assisted ventilation \[for at least part of day or night\]) and 6 (Dead), where higher numbers indicate more severe impairment. The Kaplan-Meier estimate of time to event of FG\<=1 is reported. Time (days) to first event=Date of first event-Date of first dose+1. Participants who discontinued early without achieving FG \<= 1 were censored at the date of discontinuation. Participants who completed the study without achieving FG\<=1 were censored at the date of study completion. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With A Hughes Functional Grade (FG) Score <=1 | Week 8, Week 24 | The mobility of the participants was evaluated on a 7 point disability FG scale and described as Hughes FG score of 0 (Healthy, no signs or symptoms of Guillain-Barré syndrome); 1 (Minor signs or symptoms and able to run); 2 (Able to walk 5 m across an open space without assistance); 3 (Able to walk 5 m across an open space with the help of one person and waist-level walking-frame, stick, or sticks); 4 (Chairbound/bedbound: unable to walk as in 3); 5 (Requiring assisted ventilation \[for at least part of day or night\]) and 6 (Dead), where higher numbers indicate more severe impairment. If a participant had an FG score \<= 1 prior to or at Week 8 and Week 24, respectively, then the participant is considered a responder. Otherwise, participants discontinued prior to Week 8 and Week 24 or with an FG score \> 1 at Week 8 and Week 24 are nonresponders, respectively. |
| Number of Participants With A Hughes Functional Grade Score Improvement of >=3 | Week 24 | The mobility of the participants was evaluated on a 7 point disability FG scale and described as Hughes FG score of 0 (Healthy, no signs or symptoms of Guillain-Barré syndrome); 1 (Minor signs or symptoms and able to run); 2 (Able to walk 5 m across an open space without assistance); 3 (Able to walk 5 m across an open space with the help of one person and waist-level walking-frame, stick, or sticks); 4 (Chairbound/bedbound: unable to walk as in 3); 5 (Requiring assisted ventilation \[for at least part of day or night\]) and 6 (Dead), where higher numbers indicate more severe impairment. Participants with a change from baseline in FG score (value at Week 24 - baseline value) \<= -3 were considered a responder. Participants with change from baseline \> -3 and participants who discontinued prior to Week 24 were considered non-responders. |
| Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Day 1 up to Week 24 | TEAEs were defined as an adverse event (AE) with onset on or after the first dose of the study drug. An AE is any untoward medical occurrence in a participant, temporally associated with the use of study drug, whether or not considered related to the study drug. A summary of all Serious Adverse Events and Other Adverse Events (nonserious) regardless of causality is located in the 'Reported Adverse Events' Section. |
| Free Complement Component 5 in Serum | Week 24 | — |
| Hemolytic Complement Activity in Serum | Week 24 | — |
| Length of Stay in the Hospital | Up to Week 24 | For participants with multiple hospitalizations, the total duration of all hospitalizations was summarized. |
| Number of Participants Who Required Mechanical Ventilator Support | Up to Week 24 | For participants with more than 1 episode of the same support, the total duration across all episodes was summarized. |
| Concentration of Eculizumab in Serum | Up to Week 24 | — |
| Number of Participants With Positive Antidrug Antibodies | Up to Week 12 | — |
Countries
Japan
Participant flow
Pre-assignment details
All participants were on concomitant intravenous immunoglobulin (IVIg) therapy as per standard of care.
Participants by arm
| Arm | Count |
|---|---|
| Eculizumab Participants received eculizumab IV infusion on Days 1, 8, 15, and 22. | 37 |
| Placebo Participants received placebo matched to eculizumab via IV infusion on Days 1, 8, 15, and 22. | 20 |
| Total | 57 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 1 | 0 |
| Overall Study | Death | 1 | 0 |
| Overall Study | Physician Decision | 1 | 1 |
| Overall Study | Protocol Violation | 0 | 1 |
| Overall Study | Withdrawal by Subject | 2 | 0 |
Baseline characteristics
| Characteristic | Placebo | Total | Eculizumab |
|---|---|---|---|
| Age, Continuous | 56.2 years STANDARD_DEVIATION 18.34 | 56.4 years STANDARD_DEVIATION 19.01 | 56.6 years STANDARD_DEVIATION 19.61 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 20 Participants | 57 Participants | 37 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 20 Participants | 57 Participants | 37 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Female | 5 Participants | 24 Participants | 19 Participants |
| Sex: Female, Male Male | 15 Participants | 33 Participants | 18 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 1 / 37 | 0 / 20 |
| other Total, other adverse events | 34 / 37 | 18 / 20 |
| serious Total, serious adverse events | 4 / 37 | 1 / 20 |
Outcome results
Primary
Time to First Reaching a Hughes Functional Grade (FG) Score <=1
The mobility of the participants was evaluated on a 7 point disability functional grade scale and described as Hughes FG score of 0 (Healthy, no signs or symptoms of Guillain-Barré syndrome); 1 (Minor signs or symptoms and able to run); 2 (Able to walk 5 metre (m) across an open space without assistance); 3 (Able to walk 5 m across an open space with the help of one person and waist-level walking-frame, stick, or sticks); 4 (Chairbound/bedbound: unable to walk as in 3); 5 (Requiring assisted ventilation \[for at least part of day or night\]) and 6 (Dead), where higher numbers indicate more severe impairment. The Kaplan-Meier estimate of time to event of FG\<=1 is reported. Time (days) to first event=Date of first event-Date of first dose+1. Participants who discontinued early without achieving FG \<= 1 were censored at the date of discontinuation. Participants who completed the study without achieving FG\<=1 were censored at the date of study completion.
Time frame: Up to Week 24
Population: Full analysis set included all randomized participants who received at least 1 dose of study drug and had a baseline FG score and at least 1 postbaseline FG score. Here, Number of Participants analyzed signifies those who were evaluable for this outcome measure.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Eculizumab | Time to First Reaching a Hughes Functional Grade (FG) Score <=1 | 112.0 Days |
| Placebo | Time to First Reaching a Hughes Functional Grade (FG) Score <=1 | 168.0 Days |
p-value: 0.893895% CI: [0.45, 1.97]Log Rank
Secondary
Concentration of Eculizumab in Serum
Time frame: Up to Week 24
Population: Pharmacokinetic analysis set (PKAS) included all participants who received at least 1 dose of study drug and who had at least 1 postdose PK sample. Here, Number of Participants analyzed signifies those who were evaluable for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Eculizumab | Concentration of Eculizumab in Serum | 4.690 micrograms/milliliters | Standard Deviation 0 |
Secondary
Free Complement Component 5 in Serum
Time frame: Week 24
Population: Pharmacodynamic (PD) analysis set included all participants who received at least 1 dose of study drug and who have at least 1 postdose PD sample. Here, Number of Participants analyzed signifies those who were evaluable for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Eculizumab | Free Complement Component 5 in Serum | 131.0438 micrograms/milliliters | Standard Deviation 29.40068 |
| Placebo | Free Complement Component 5 in Serum | 147.8833 micrograms/milliliters | Standard Deviation 36.70182 |
Secondary
Hemolytic Complement Activity in Serum
Time frame: Week 24
Population: Pharmacodynamic analysis set included all participants who received at least 1 dose of study drug and who have at least 1 postdose PD sample. Here, Number of Participants analyzed signifies those who were evaluable for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Eculizumab | Hemolytic Complement Activity in Serum | 91.79 percentage of hemolysis | Standard Deviation 11.077 |
| Placebo | Hemolytic Complement Activity in Serum | 91.83 percentage of hemolysis | Standard Deviation 11.767 |
Secondary
Length of Stay in the Hospital
For participants with multiple hospitalizations, the total duration of all hospitalizations was summarized.
Time frame: Up to Week 24
Population: Full analysis set included all randomized participants who received at least 1 dose of study drug and had a baseline FG score and at least 1 postbaseline FG score.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Eculizumab | Length of Stay in the Hospital | 49.5 days | Standard Deviation 27.15 |
| Placebo | Length of Stay in the Hospital | 39.8 days | Standard Deviation 12.97 |
Secondary
Number of Participants Who Required Mechanical Ventilator Support
For participants with more than 1 episode of the same support, the total duration across all episodes was summarized.
Time frame: Up to Week 24
Population: Full analysis set included all randomized participants who received at least 1 dose of study drug and had a baseline FG score and at least 1 postbaseline FG score.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Eculizumab | Number of Participants Who Required Mechanical Ventilator Support | 8 Participants |
| Placebo | Number of Participants Who Required Mechanical Ventilator Support | 1 Participants |
Secondary
Number of Participants With A Hughes Functional Grade (FG) Score <=1
The mobility of the participants was evaluated on a 7 point disability FG scale and described as Hughes FG score of 0 (Healthy, no signs or symptoms of Guillain-Barré syndrome); 1 (Minor signs or symptoms and able to run); 2 (Able to walk 5 m across an open space without assistance); 3 (Able to walk 5 m across an open space with the help of one person and waist-level walking-frame, stick, or sticks); 4 (Chairbound/bedbound: unable to walk as in 3); 5 (Requiring assisted ventilation \[for at least part of day or night\]) and 6 (Dead), where higher numbers indicate more severe impairment. If a participant had an FG score \<= 1 prior to or at Week 8 and Week 24, respectively, then the participant is considered a responder. Otherwise, participants discontinued prior to Week 8 and Week 24 or with an FG score \> 1 at Week 8 and Week 24 are nonresponders, respectively.
Time frame: Week 8, Week 24
Population: Full analysis set included all randomized participants who received at least 1 dose of study drug and had a baseline FG score and at least 1 postbaseline FG score.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Eculizumab | Number of Participants With A Hughes Functional Grade (FG) Score <=1 | Week 8 | 12 Participants |
| Eculizumab | Number of Participants With A Hughes Functional Grade (FG) Score <=1 | Week 24 | 20 Participants |
| Placebo | Number of Participants With A Hughes Functional Grade (FG) Score <=1 | Week 8 | 7 Participants |
| Placebo | Number of Participants With A Hughes Functional Grade (FG) Score <=1 | Week 24 | 13 Participants |
Comparison: Week 8p-value: 0.898795% CI: [0.27, 3.17]Regression, Logistic
Comparison: Week 24p-value: 0.408395% CI: [0.18, 2.02]Regression, Logistic
Secondary
Number of Participants With A Hughes Functional Grade Score Improvement of >=3
The mobility of the participants was evaluated on a 7 point disability FG scale and described as Hughes FG score of 0 (Healthy, no signs or symptoms of Guillain-Barré syndrome); 1 (Minor signs or symptoms and able to run); 2 (Able to walk 5 m across an open space without assistance); 3 (Able to walk 5 m across an open space with the help of one person and waist-level walking-frame, stick, or sticks); 4 (Chairbound/bedbound: unable to walk as in 3); 5 (Requiring assisted ventilation \[for at least part of day or night\]) and 6 (Dead), where higher numbers indicate more severe impairment. Participants with a change from baseline in FG score (value at Week 24 - baseline value) \<= -3 were considered a responder. Participants with change from baseline \> -3 and participants who discontinued prior to Week 24 were considered non-responders.
Time frame: Week 24
Population: Full analysis set included all randomized participants who received at least 1 dose of study drug and had a baseline FG score and at least 1 postbaseline FG score.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Eculizumab | Number of Participants With A Hughes Functional Grade Score Improvement of >=3 | 16 Participants |
| Placebo | Number of Participants With A Hughes Functional Grade Score Improvement of >=3 | 10 Participants |
p-value: 0.673995% CI: [0.24, 2.54]Regression, Logistic
Secondary
Number of Participants With Positive Antidrug Antibodies
Time frame: Up to Week 12
Population: Safety set included all participants who received at least 1 dose of study drug.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Eculizumab | Number of Participants With Positive Antidrug Antibodies | 0 Participants |
| Placebo | Number of Participants With Positive Antidrug Antibodies | 0 Participants |
Secondary
Number of Participants With Treatment-emergent Adverse Events (TEAEs)
TEAEs were defined as an adverse event (AE) with onset on or after the first dose of the study drug. An AE is any untoward medical occurrence in a participant, temporally associated with the use of study drug, whether or not considered related to the study drug. A summary of all Serious Adverse Events and Other Adverse Events (nonserious) regardless of causality is located in the 'Reported Adverse Events' Section.
Time frame: Day 1 up to Week 24
Population: Safety set included all participants who received at least 1 dose of study drug.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Eculizumab | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | 34 Participants |
| Placebo | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | 19 Participants |