Clinical Trial Results:
A Phase 3, Multicenter, Randomized, Double Blind, Placebo-Controlled Study to Confirm the Safety, Tolerability, and Efficacy of Zilucoplan in Subjects with Generalized Myasthenia Gravis
Summary
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EudraCT number |
2019-001564-30 |
Trial protocol |
DE NO GB ES IT |
Global end of trial date |
30 Dec 2021
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Results information
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Results version number |
v1(current) |
This version publication date |
04 Jan 2023
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First version publication date |
04 Jan 2023
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Other versions |
Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
RA101495-02.301
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT04115293 | ||
WHO universal trial number (UTN) |
- | ||
Sponsors
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Sponsor organisation name |
Ra Pharmaceuticals, Inc.
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Sponsor organisation address |
87 Cambridge Park Drive, Cambridge, Massachusetts, United States, 02140
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Public contact |
Clin Trial Reg & Results Disclosure, UCB BIOSCIENCES GmbH, clinicaltrials@ucb.com
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Scientific contact |
Clin Trial Reg & Results Disclosure, UCB BIOSCIENCES GmbH, clinicaltrials@ucb.com
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
18 Jan 2022
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Is this the analysis of the primary completion data? |
No
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Global end of trial reached? |
Yes
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Global end of trial date |
30 Dec 2021
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Was the trial ended prematurely? |
No
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General information about the trial
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Main objective of the trial |
To confirm the efficacy, safety and tolerability of zilucoplan in subjects with gMG.
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Protection of trial subjects |
During the conduct of the study all participants were closely monitored.
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Background therapy |
Background therapy as permitted in the protocol. | ||
Evidence for comparator |
Not applicable | ||
Actual start date of recruitment |
17 Sep 2019
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
No
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
Canada: 3
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Country: Number of subjects enrolled |
France: 7
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Country: Number of subjects enrolled |
Germany: 3
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Country: Number of subjects enrolled |
Italy: 4
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Country: Number of subjects enrolled |
Japan: 16
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Country: Number of subjects enrolled |
Norway: 6
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Country: Number of subjects enrolled |
Poland: 23
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Country: Number of subjects enrolled |
Spain: 5
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Country: Number of subjects enrolled |
United Kingdom: 19
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Country: Number of subjects enrolled |
United States: 88
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Worldwide total number of subjects |
174
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EEA total number of subjects |
48
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
126
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From 65 to 84 years |
48
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85 years and over |
0
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Recruitment
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Recruitment details |
The study started to enroll participants in September 2019 and concluded in December 2021. | ||||||||||||||||||||||||
Pre-assignment
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Screening details |
The Participant flow refers to the Randomized Set. | ||||||||||||||||||||||||
Period 1
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Period 1 title |
Overall Study (overall period)
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Is this the baseline period? |
Yes | ||||||||||||||||||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Double blind | ||||||||||||||||||||||||
Roles blinded |
Subject, Investigator, Carer, Assessor | ||||||||||||||||||||||||
Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Placebo | ||||||||||||||||||||||||
Arm description |
Participants self-administered zilucoplan (RA101495) matching placebo as subcutaneous (SC) injection during 12-week Treatment Period. | ||||||||||||||||||||||||
Arm type |
Placebo | ||||||||||||||||||||||||
Investigational medicinal product name |
Placebo
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Solution for injection in pre-filled syringe
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Routes of administration |
Subcutaneous use
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Dosage and administration details |
Participants self-administered zilucoplan matching placebo as SC injection during 12-week Treatment Period or at pre-specified timepoints.
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Arm title
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Zilucoplan 0.3 mg/kg | ||||||||||||||||||||||||
Arm description |
Participants self-administered zilucoplan (RA101495) 0.3 milligrams/kilogram/day (mg/kg/day) SC injection during 12-week Treatment Period. | ||||||||||||||||||||||||
Arm type |
Active comparator | ||||||||||||||||||||||||
Investigational medicinal product name |
Zilucoplan
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Investigational medicinal product code |
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Other name |
RA101495
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Pharmaceutical forms |
Solution for injection in pre-filled syringe
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Routes of administration |
Subcutaneous use
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Dosage and administration details |
Participants self-administered zilucoplan 0.3 mg/kg SC injection during 12-week Treatment Period or at pre-specified timepoints.
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Baseline characteristics reporting groups
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Reporting group title |
Placebo
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Reporting group description |
Participants self-administered zilucoplan (RA101495) matching placebo as subcutaneous (SC) injection during 12-week Treatment Period. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Zilucoplan 0.3 mg/kg
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Reporting group description |
Participants self-administered zilucoplan (RA101495) 0.3 milligrams/kilogram/day (mg/kg/day) SC injection during 12-week Treatment Period. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Placebo
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Reporting group description |
Participants self-administered zilucoplan (RA101495) matching placebo as subcutaneous (SC) injection during 12-week Treatment Period. | ||
Reporting group title |
Zilucoplan 0.3 mg/kg
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Reporting group description |
Participants self-administered zilucoplan (RA101495) 0.3 milligrams/kilogram/day (mg/kg/day) SC injection during 12-week Treatment Period. |
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End point title |
Change from Baseline (CFB) to Week 12 in Myasthenia Gravis-Activities of Daily Living (MG-ADL) Total Score | ||||||||||||
End point description |
The MG-ADL is an 8-item patient-reported outcome measure assessing MG symptoms and their effects on daily activities. Each item in the scale scored 0 to 3 (0=None, 3=severe disease) point scale. The total score was the sum of all individual item scores and ranged from 0 to 24. Higher scores indicated more severe disability due to MG. A decrease from Baseline score indicated improvement. The modified Intention-to-Treat (mITT) population included all randomized participants who received at least 1 dose of study drug and had at least 1 post-dosing MG-ADL score.
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End point type |
Primary
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End point timeframe |
From Baseline to End of Treatment (Week 12)
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Statistical analysis title |
RA101495 0.3 mg/kg vs Placebo | ||||||||||||
Comparison groups |
Placebo v Zilucoplan 0.3 mg/kg
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Number of subjects included in analysis |
174
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
P-value |
< 0.001 | ||||||||||||
Method |
MMRM ANCOVA | ||||||||||||
Parameter type |
LS Mean Difference | ||||||||||||
Point estimate |
-2.09
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
-3.24 | ||||||||||||
upper limit |
-0.95 |
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End point title |
Change from Baseline to Week 12 in the Quantitative Myasthenia Gravis (QMG) Total Score | ||||||||||||
End point description |
The QMG is a standardized and validated quantitative strength scoring system that was developed specifically for MG. The scale consisted of 13 items. Each item in the scale scored on a 0 to 3-point scale, ranging from 0 (no weakness) to 3 (severe weakness), summing up to the overall score range from 0 to 39. Higher scores indicated more severe impairment. A decrease from Baseline score indicated improvement. The modified Intention-to-Treat (mITT) population included all randomized participants who received at least 1 dose of study drug and had at least 1 post-dosing MG-ADL score.
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End point type |
Secondary
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End point timeframe |
From Baseline to End of Treatment (Week 12)
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Statistical analysis title |
RA101495 0.3 mg/kg vs Placebo | ||||||||||||
Comparison groups |
Placebo v Zilucoplan 0.3 mg/kg
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Number of subjects included in analysis |
174
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
P-value |
< 0.001 | ||||||||||||
Method |
MMRM ANCOVA | ||||||||||||
Parameter type |
LS Mean Difference | ||||||||||||
Point estimate |
-2.94
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
-4.39 | ||||||||||||
upper limit |
-1.49 |
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End point title |
Change from Baseline to Week 12 in the Myasthenia Gravis Composite (MGC) Scale Total Score | ||||||||||||
End point description |
The total MGC score was sum of responses to 10 individual items : 1. Ptosis upward gaze (0 to 3), 2. Double vision on lateral gaze, left or right (0, to 4), 3. Eye closure (0 to 2), 4. Talking (0 to 6), 5. Chewing (0 to 6), 6. Swallowing [0 to 6], 7. Breathing (0 to 9), 8. Neck flexion or extension (0 to 4), 9. Shoulder abduction (0 to 5), 10. Hip flexion (0 to 5). The higher score for each item indicated severity. The total score ranged 0 to 50 with higher score indicative of severe disease activity). A decrease from Baseline score showed improvement. The modified Intention-to-Treat (mITT) population included all randomized participants who received at least 1 dose of study drug and had at least 1 post-dosing MG-ADL score.
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End point type |
Secondary
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End point timeframe |
From Baseline to End of Treatment (Week 12)
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Statistical analysis title |
RA101495 0.3 mg/kg vs Placebo | ||||||||||||
Comparison groups |
Placebo v Zilucoplan 0.3 mg/kg
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Number of subjects included in analysis |
174
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
P-value |
= 0.0023 | ||||||||||||
Method |
MMRM ANCOVA | ||||||||||||
Parameter type |
LS Mean Difference | ||||||||||||
Point estimate |
-3.2
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
-5.24 | ||||||||||||
upper limit |
-1.16 |
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End point title |
Change from Baseline to Week 12 in the Myasthenia Gravis - Quality of Life revised (MG-QoL15r) Scale Total Score | ||||||||||||
End point description |
The MG-QoL15r is a 15-item patient-reported outcome measure designed to assess quality of life in patients with MG. Each item in the scale scored on a 0 to 2-point scale (0=Not much at all, 1=Somewhat, 2=Very much). The total score was the sum of the 15 individual item scores, ranging from 0 to 30. Higher scores indicated more severe impact of the disease on aspects of the patient’s life. A decrease from Baseline score indicated improvement. The modified Intention-to-Treat (mITT) population included all randomized participants who received at least 1 dose of study drug and had at least 1 post-dosing MG-ADL score.
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End point type |
Secondary
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End point timeframe |
From Baseline to End of Treatment (Week 12)
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Statistical analysis title |
RA101495 0.3 mg/kg vs Placebo | ||||||||||||
Comparison groups |
Placebo v Zilucoplan 0.3 mg/kg
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Number of subjects included in analysis |
174
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
P-value |
= 0.0128 | ||||||||||||
Method |
MMRM ANCOVA | ||||||||||||
Parameter type |
LS Mean Difference | ||||||||||||
Point estimate |
-2.49
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
-4.45 | ||||||||||||
upper limit |
-0.54 |
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End point title |
Time to first receipt of rescue therapy over the 12-week Treatment Period | ||||||||||||
End point description |
Time to to first receipt of rescue therapy over the 12-week treatment period (in days) was defined as the date of first rescue therapy use minus date of first Investigational Medicinal Product (IMP) + 1. The modified Intention-to-Treat (mITT) population included all randomized participants who received at least 1 dose of study drug and had at least 1 post-dosing MG-ADL score.
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End point type |
Secondary
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End point timeframe |
From Baseline to End of Treatment (Week 12)
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Notes [1] - 99999: Time to first receipt of rescue therapy was not estimated due to less number of events. [2] - 99999: Time to first receipt of rescue therapy was not estimated due to less number of events. |
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No statistical analyses for this end point |
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End point title |
Percentage of participants achieving Minimal Symptom Expression (MSE) at Week 12 without rescue therapy | ||||||||||||
End point description |
Percentage of Participants achieving MSE was defined as achieving a MG-ADL value of a 0 (No MG symptoms) or 1 (Mild MG symptoms) at Week 12 and not having taken rescue therapy. Any participant with an event of death, myasthenic crisis or rescue therapy was considered as non-responders. Any other missing data was imputed using the Missing at Random (MAR) assumption. The modified Intention-to-Treat (mITT) population included all randomized participants who received at least 1 dose of study drug and had at least 1 post-dosing MG-ADL score.
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End point type |
Secondary
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End point timeframe |
End of Treatment (Week 12)
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Statistical analysis title |
Zilucoplan 0.3 mg/kg vs Placebo | ||||||||||||
Comparison groups |
Placebo v Zilucoplan 0.3 mg/kg
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Number of subjects included in analysis |
174
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
P-value |
= 0.0885 | ||||||||||||
Method |
Regression, Logistic | ||||||||||||
Parameter type |
Odds ratio (OR) | ||||||||||||
Point estimate |
2.608
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
0.866 | ||||||||||||
upper limit |
7.86 |
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End point title |
Percentage of participants achieving a ≥ 3-point reduction in MG-ADL Score at Week 12 without rescue therapy | ||||||||||||
End point description |
Percentage of participants achieving a ≥ 3-point reduction in MG-ADL Score at Week 12 without rescue therapy were reported. The MG-ADL is an 8-item patient-reported outcome measure assessing MG symptoms and their effects on daily activities. Each item in the scale scored on a 0 to 3 (0=None, 3=severe disease) point scale. The total score was the sum of all individual item scores and ranged from 0 to 24. Higher scores indicated more severe disability due to MG. Any participant with an event of death, myasthenic crisis or rescue therapy was considered as non-responders. Any other missing data was imputed using the MAR assumption. The modified Intention-to-Treat (mITT) population included all randomized participants who received at least 1 dose of study drug and had at least 1 post-dosing MG-ADL score.
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End point type |
Secondary
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End point timeframe |
End of Treatment (Week 12)
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Statistical analysis title |
Zilucoplan 0.3 mg/kg vs Placebo | ||||||||||||
Comparison groups |
Placebo v Zilucoplan 0.3 mg/kg
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Number of subjects included in analysis |
174
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
P-value |
< 0.001 | ||||||||||||
Method |
Regression, Logistic | ||||||||||||
Parameter type |
Odds ratio (OR) | ||||||||||||
Point estimate |
3.184
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
1.662 | ||||||||||||
upper limit |
6.101 |
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End point title |
Percentage of participants achieving a ≥5-point reduction in QMG Score without rescue therapy at Week 12 | ||||||||||||
End point description |
Percentage of participants achieving a ≥5-point reduction in QMG Score without rescue therapy at Week 12 were reported. The QMG is a standardized and validated quantitative strength scoring system that was developed specifically for MG. The scale consisted of 13 items. Each item in the scale scored on a 0 to 3-point scale, ranging from 0 (no weakness) to 3 (severe weakness), summing up to the overall score range from 0 to 39. Higher scores indicated more severe impairment. Any participant with an event of death, myasthenic crisis or rescue therapy was considered as non-responders. Any other missing data was imputed using the MAR assumption. The modified Intention-to-Treat (mITT) population included all randomized participants who received at least 1 dose of study drug and had at least 1 post-dosing MG-ADL score.
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End point type |
Secondary
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End point timeframe |
End of Treatment (Week 12)
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Statistical analysis title |
Zilucoplan 0.3 mg/kg vs Placebo | ||||||||||||
Comparison groups |
Placebo v Zilucoplan 0.3 mg/kg
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Number of subjects included in analysis |
174
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
P-value |
= 0.0012 | ||||||||||||
Method |
Regression, Logistic | ||||||||||||
Parameter type |
Odds ratio (OR) | ||||||||||||
Point estimate |
2.865
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
1.518 | ||||||||||||
upper limit |
5.409 |
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End point title |
Percentage of participants with treatment-emergent adverse events (TEAEs) | ||||||||||||
End point description |
A TEAE is defined as an AE starting on or after the time of first administration of IMP and up to and including 40 days after the final dose (or last contact depending on which occurs first). Adverse events starting before the date of the first administration of IMP were not considered TEAEs. The Safety Set (SS) included all participants who received at least 1 dose of study drug based on the actual study treatment received.
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End point type |
Secondary
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End point timeframe |
From Baseline (Day 1) to Safety Follow-up visit (19 Weeks [12 weeks Treatment Period plus up to 7 weeks Follow-up])
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No statistical analyses for this end point |
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Adverse events information
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Timeframe for reporting adverse events |
From Baseline (Day 1) to Safety Follow-up visit (19 Weeks [12 weeks Treatment Period plus up to 7 weeks Follow-up])
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Adverse event reporting additional description |
A TEAE is defined as an AE starting on or after the time of first administration of IMP and up to and including 40 days after the final dose (or last contact depending on which occurs first). Adverse events starting before the date of the first administration of IMP were not considered TEAEs.
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Assessment type |
Non-systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
24
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Reporting groups
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Reporting group title |
Placebo
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Reporting group description |
Participants self-administered zilucoplan (RA101495) matching placebo as subcutaneous (SC) injection during 12-week Treatment Period. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
RA101495 0.3 mg/kg
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Reporting group description |
Participants self-administered zilucoplan (RA101495) 0.3 mg/kg/day SC injection during 12-week Treatment Period. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Frequency threshold for reporting non-serious adverse events: 5% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
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18 Dec 2020 |
Protocol Amendment Version 2.0 was dated 18 Dec 2020 and had incorporated all the country-specific amendments into single protocol amendment:
• The total sample size was increased from 130 study participants (65 study participants per treatment group) to 156 study participants (78 study participants per treatment group). This increase was made to account for higher variability in the primary endpoint than originally assumed, and to maintain the power of the study.
• An unblinded interim analysis was added to be performed after the final study participant had completed the Week 12 Visit, or after the final study participant had prematurely discontinued prior to reaching Week 12. The purpose of this interim analysis was to perform a comprehensive evaluation of all available double-blind data to prepare regulatory submissions for approval of the gMG target indication.
• Changes made in earlier country-specific protocol amendments (France, Germany, Italy, Japan, Norway, United Kingdom) were consolidated into a single global protocol.
• The objectives and endpoints were revised to reflect current UCB practices for the categorization and description of study objectives, estimands, and endpoints. |
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18 Dec 2020 |
Protocol amendment version 2.0 Continued:
• The following provisions for the coronavirus disease 2019; disease caused by severe acute respiratory syndrome coronavirus 2 (COVID-19) pandemic were included: − In situations when the study participant could not return to the study site, the Investigator assessed the study participant’s safety by telephone/video contact. If the study participant was suitable for IMP continuation, the Investigator or designee assessed if the study participant agreed to provide name, address, telephone number, and email to the appointed courier. If the shipment was agreed, the Investigator or designee clearly explained to the study participant everything needed regarding the handling (in case of inconsistencies at delivery) and administration of the IMP and how to return all unused IMP to the study site at the next on-site visit. Additional details regarding the shipment of IMP and deviations to data collection are provided in the protocol.
− Ad hoc study participant contact may have been warranted to understand the current health status of the study participants, to follow up on AEs, and to inform them of any protective measures taken by the clinical site as a result of the COVID-19 pandemic.
− If a study participant needed to be discontinued from the study and could not come into the clinic, a visit was scheduled to perform final safety assessments as soon as possible.
− If a study participant visited another facility for a medical issue, the Investigator was to request contact with the physician providing care to provide a detailed explanation of the study participant’s condition and his/her participation in the clinical study. Study participants and/or caregivers were reminded to completely collect and keep records of this visit.
• Administrative updates. |
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Interruptions (globally) |
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Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
None reported |