Safety, Tolerability, and Efficacy of Zilucoplan in Subjects With Generalized Myasthenia Gravis (RAISE)

• ClinicalTrials.gov Identifier: NCT04115293
• Recruitment Status: Completed
• First Posted: October 4, 2019
• Results First Posted: January 17, 2023
• Last Update Posted: May 2, 2024
• Sponsor: Ra Pharmaceuticals, Inc.
• Information provided by (Responsible Party): UCB Pharma ( Ra Pharmaceuticals, Inc. )

Tracking Information

• First Submitted Date: October 2, 2019
• First Posted Date: October 4, 2019
• Results First Submitted Date: December 19, 2022
• Results First Posted Date: January 17, 2023
• Last Update Posted Date: May 2, 2024
• Actual Study Start Date: September 17, 2019
• Actual Primary Completion Date: December 30, 2021 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: December 19, 2022)

Change From Baseline (CFB) to Week 12 in Myasthenia Gravis-Activities of Daily Living (MG-ADL) Total Score [ Time Frame: From Baseline to End of Treatment (Week 12) ]

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.

Original Primary Outcome Measures (submitted: October 2, 2019)

Change from Baseline (CFB) in the MG-ADL Score [ Time Frame: 12 Weeks ]

The MG-ADL profile provides an assessment of MG symptom severity and measures 8 items on a 0-3 scale, with 0 being the least severe. The total sum of the 13 items represents the ADL score.

Current Secondary Outcome Measures (submitted: December 19, 2022)

• Change From Baseline to Week 12 in the Quantitative Myasthenia Gravis (QMG) Total Score [ Time Frame: From Baseline to End of Treatment (Week 12) ]
  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.
• Change From Baseline to Week 12 in the Myasthenia Gravis Composite (MGC) Scale Total Score [ Time Frame: From Baseline to End of Treatment (Week 12) ]
  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.
• Change From Baseline to Week 12 in the Myasthenia Gravis - Quality of Life Revised (MG-QoL15r) Scale Total Score [ Time Frame: From Baseline to End of Treatment (Week 12) ]
  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.
• Time to First Receipt of Rescue Therapy Over the 12-week Treatment Period [ Time Frame: From Baseline to End of Treatment (Week 12) ]
  Time 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.
• Percentage of Participants Achieving Minimal Symptom Expression (MSE) at Week 12 Without Rescue Therapy [ Time Frame: End of Treatment (Week 12) ]
  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.
• Percentage of Participants Achieving a ≥ 3-point Reduction in MG-ADL Score at Week 12 Without Rescue Therapy [ Time Frame: End of Treatment (Week 12) ]
  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.
• Percentage of Participants Achieving a ≥5-point Reduction in QMG Score Without Rescue Therapy at Week 12 [ Time Frame: End of Treatment (Week 12) ]
  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.
• Percentage of Participants With Treatment-emergent Adverse Events (TEAEs) [ Time Frame: From Baseline (Day 1) to Safety Follow-up visit (19 Weeks [12 weeks Treatment Period plus up to 7 weeks Follow-up]) ]
  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.

Original Secondary Outcome Measures (submitted: October 2, 2019)

Change from Baseline (CFB) in the QMG Score [ Time Frame: 12 Weeks ]

The QMG test is a standardized quantitative strength scoring system and measures 13 items on a 0-3 scale, with 0 being the least severe. The total sum of the 13 items represents the QMG score.

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Safety, Tolerability, and Efficacy of Zilucoplan in Subjects With Generalized Myasthenia Gravis
• Official Title: 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
• Brief Summary: The RAISE study is a multicenter, randomized, double-blind, placebo controlled study to confirm the efficacy, safety, and tolerability of zilucoplan in subjects with generalized Myasthenia Gravis. Subjects will be randomized in a 1:1 ratio to receive daily SC doses of 0.3 mg/kg zilucoplan or placebo for 12 weeks.
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment
• Condition: Myasthenia Gravis, Generalized

Intervention

• Drug: zilucoplan (RA101495)
  Daily subcutaneous (SC) injection
• Drug: Placebo
  Daily subcutaneous (SC) injection

Study Arms

• Experimental: 0.3 mg/kg zilucoplan (RA101495)
  Intervention: Drug: zilucoplan (RA101495)
• Placebo Comparator: Placebo
  Intervention: Drug: Placebo

Publications *

• Howard JF Jr, Bresch S, Genge A, Hewamadduma C, Hinton J, Hussain Y, Juntas-Morales R, Kaminski HJ, Maniaol A, Mantegazza R, Masuda M, Sivakumar K, Smilowski M, Utsugisawa K, Vu T, Weiss MD, Zajda M, Boroojerdi B, Brock M, de la Borderie G, Duda PW, Lowcock R, Vanderkelen M, Leite MI; RAISE Study Team. Safety and efficacy of zilucoplan in patients with generalised myasthenia gravis (RAISE): a randomised, double-blind, placebo-controlled, phase 3 study. Lancet Neurol. 2023 May;22(5):395-406. doi: 10.1016/S1474-4422(23)00080-7.
• Weiss MD, Freimer M, Leite MI, Maniaol A, Utsugisawa K, Bloemers J, Boroojerdi B, Howard E, Savic N, Howard JF Jr. Improvement of fatigue in generalised myasthenia gravis with zilucoplan. J Neurol. 2024 May;271(5):2758-2767. doi: 10.1007/s00415-024-12209-3. Epub 2024 Feb 24.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: October 11, 2021): 174
• Original Estimated Enrollment (submitted: October 2, 2019): 130
• Actual Study Completion Date: December 30, 2021
• Actual Primary Completion Date: December 30, 2021 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Diagnosis of gMG [Myasthenia Gravis Foundation of America (MGFA) Class II-IV] at Screening
• Positive serology for acetylcholine receptor (AChR) autoantibodies
• MG-ADL Score of ≥ 6 at Screening and Baseline
• QMG score ≥ 12 at Screening and Baseline
• No change in corticosteroid dose for at least 30 days prior to Baseline or anticipated to occur during the 12-week Treatment Period
• No change in immunosuppressive therapy, including dose, for at least 30 days prior to Baseline or anticipated to occur during the 12-week Treatment Period

Exclusion Criteria:

• Thymectomy within 12 months prior to Baseline or scheduled to occur during the 12 week Treatment Period
• History of meningococcal disease
• Current or recent systemic infection within 2 weeks prior to Baseline or injection requiring intravenous (IV) antibiotics within 4 weeks prior to Baseline

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 74 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Canada, France, Germany, Italy, Japan, Norway, Poland, Spain, United Kingdom, United States

Administrative Information

• NCT Number: NCT04115293
• Other Study ID Numbers: RA101495-02.301
• Has Data Monitoring Committee: Not Provided

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: Yes
• Plan Description: Data from this trial may be requested by qualified researchers six months after product approval in the US and/or Europe, or global development is discontinued, and 18 months after trial completion. Investigators may request access to anonymized individual patient-level data and redacted trial documents which may include: analysis-ready datasets, study protocol, annotated case report form, statistical analysis plan, dataset specifications, and clinical study report. Prior to use of the data, proposals need to be approved by an independent review panel at www.Vivli.org and a signed data sharing agreement will need to be executed. All documents are available in English only, for a prespecified time, typically 12 months, on a password protected portal. This plan may change if the risk of re-identifying trial participants is determined to be too high after the trial is completed;in this case and to protect participants, individual patient-level data would not be made available.
• Supporting Materials: Study Protocol
• Supporting Materials: Statistical Analysis Plan (SAP)
• Supporting Materials: Clinical Study Report (CSR)
• Time Frame: Data from this trial may be requested by qualified researchers six months after product approval in the US and/or Europe or global development is discontinued, and 18 months after trial completion.
• Access Criteria: Qualified researchers may request access to anonymized IPD and redacted study documents which may include: raw datasets, analysis-ready datasets, study protocol, blank case report form, annotated case report form, statistical analysis plan, dataset specifications, and clinical study report. Prior to use of the data, proposals need to be approved by an independent review panel at www.Vivli.org and a signed data sharing agreement will need to be executed. All documents are available in English only, for a pre-specified time, typically 12 months, on a password protected portal.
• URL: http://www.Vivli.org

• Current Responsible Party: UCB Pharma ( Ra Pharmaceuticals, Inc. )
• Original Responsible Party: Ra Pharmaceuticals
• Current Study Sponsor: Ra Pharmaceuticals, Inc.
• Original Study Sponsor: Ra Pharmaceuticals
• Collaborators: Not Provided

Investigators

• Study Director: UCB Cares; 0018445992273 (UCB)

• PRS Account: UCB Pharma
• Verification Date: April 2024