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A Study to Examine the Efficacy and Safety of Pozelimab and Cemdisiran Combination Therapy in Adult Patients With Symptomatic Generalized Myasthenia Gravis (NIMBLE)

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ClinicalTrials.gov Identifier: NCT05070858
Recruitment Status : Recruiting
First Posted : October 7, 2021
Last Update Posted : October 31, 2023
Sponsor:
Information provided by (Responsible Party):
Regeneron Pharmaceuticals

Study Description
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Brief Summary:

The primary objective is:

To evaluate the effect of pozelimab + cemdisiran on daily functioning that is impacted by signs and symptoms in patients with symptomatic generalized myasthenia gravis (gMG)

The secondary objectives of the study are:

  • To evaluate the effect of pozelimab + cemdisiran (ie, combination) and cemdisiran monotherapy on:

    • Clinician-assessed signs of myasthenia gravis (MG) and muscle strength
    • Daily functioning that is impacted by signs and symptoms in patients with symptomatic gMG (cemdisiran monotherapy only).
    • Proportion of patients with improvements in daily function that is impacted by signs and symptoms of MG
    • Proportion of patients that have improvements in clinician-assessed signs of MG and muscle strength
    • Health related quality of life
    • Proportion of patients with minimal MG symptoms
    • Patient- and clinician-reported signs and symptoms of MG
  • To evaluate the safety and tolerability of pozelimab + cemdisiran and cemdisiran monotherapy
  • To assess the concentration of total pozelimab in serum
  • To assess the concentrations of cemdisiran and its metabolites in plasma
  • To assess the immunogenicity of pozelimab
  • To assess the concentration of total C5 in plasma
  • To assess the immunogenicity of cemdisiran
  • To study the effect of pozelimab + cemdisiran and cemdisiran monotherapy on complement activation

Condition or disease Intervention/treatment Phase
Generalized Myasthenia Gravis Drug: Pozelimab + Cemdisiran Drug: Cemdisiran Other: Placebo Drug: Pozelimab Phase 3

Detailed Description:
DBTP- Double blind treatment plan (24 weeks) ETP - Extension treatment plan (28 weeks) OLTP- Open label treatment plan (68 weeks) Off-treatment follow up period (52 weeks)
Study Design
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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 235 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Efficacy and Safety of Pozelimab and Cemdisiran Combination Therapy in Patients With Symptomatic Generalized Myasthenia Gravis
Actual Study Start Date : December 14, 2021
Estimated Primary Completion Date : August 14, 2024
Estimated Study Completion Date : May 1, 2027

Resource links provided by the National Library of Medicine


Arms and Interventions
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Arm Intervention/treatment
Experimental: Group 1
Placebo in DBTP; Re-randomized to Combination or Cemdisiran in ETP and OLTP
 Drug: Pozelimab + Cemdisiran
Subcutaneous administration as described in the protocol

Drug: Cemdisiran
SC administration as described in the protocol
Other Name: ALN-CC5

Other: Placebo
SC administration as described in the protocol
Experimental: Group 2
Combination regimen throughout the study
 Drug: Pozelimab + Cemdisiran
Subcutaneous administration as described in the protocol
Experimental: Group 3
Cemdisiran throughout the study
 Drug: Cemdisiran
SC administration as described in the protocol
Other Name: ALN-CC5
Experimental: Group 4
Pozelimab monotherapy in DBTP followed by combination in ETP and OLTP
 Drug: Pozelimab
SC administration as described in the protocol
Other Name: REGN3918


Outcome Measures
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Primary Outcome Measures :
  1. Change in Myasthenia Gravis-Activities of Daily Living (MG-ADL) total score [ Time Frame: From baseline to week 24 ]
    The total MG-ADL score ranges from 0 to 24 points, with higher scores indicating greater functional impairment and disability


Secondary Outcome Measures :
  1. Change from baseline in Quantitative Myasthenia Gravis (QMG) score [ Time Frame: Week 24 ]
    QMG total scores range from 0 to 39, with higher scores representing greater impairment

  2. Proportion of patients responding on the MG-ADL [ Time Frame: From baseline to week 24 ]
    ≥3-point improvement

  3. Proportion of patients responding on the QMG [ Time Frame: From baseline to week 24 ]
    ≥5-point improvement

  4. Proportion of patients with consistent response on the MG-ADL [ Time Frame: From baseline to week 24 ]
    At least a 2-point MG-ADL improvement on 2 or more consecutive assessments spanning 4 or more weeks during the DBTP

  5. Proportion of patients with minimal symptom expression (MSE) [ Time Frame: Week 24 ]
    Score of 0 to 1 on the MG-ADL

  6. Change from baseline in the Myasthenia Gravis Composite (MGC) total score [ Time Frame: Week 24 ]
    MGC score ranges from 0 to 50, with higher score indicating higher impairment

  7. Change from baseline in Myasthenia Gravis Quality of Life (MG QOL15r) total score [ Time Frame: Week 24 ]
    Total score ranges from 0 to 30 points; a higher score represents greater impairment

  8. Proportion of patients with improvement point thresholds on MG-ADL [ Time Frame: From baseline to week 24 ]
    ≥2, 4, 5, 6, 7, 8, 9, or 10

  9. Proportion of patients with improvement point thresholds on QMG [ Time Frame: From baseline to week 24 ]
    ≥3, 4, 6, 7, 8, 9, or 10

  10. Incidence and severity of treatment-related adverse events (TEAEs) in patients treated with pozelimab + cemdisiran or placebo [ Time Frame: Through week 24 ]
  11. Incidence and severity of serious adverse events (SAEs) in patients treated with pozelimab + cemdisiran or placebo [ Time Frame: Through week 24 ]
  12. Incidence and severity of adverse events of special interest (AESIs) in patients treated with pozelimab + cemdisiran or placebo [ Time Frame: Through week 24 ]
  13. Concentrations of total pozelimab in serum [ Time Frame: Through study duration, approximate 172 weeks ]
  14. Concentrations of cemdisiran and its metabolites in plasma [ Time Frame: Through study duration, approximate 172 weeks ]
  15. Incidence of treatment-emergent anti-drug antibodies (ADAs) to pozelimab over time [ Time Frame: Through study duration, approximately 172 weeks ]
  16. Incidence of treatment-emergent ADAs to cemdisiran over time [ Time Frame: Through study duration, approximate 172 weeks ]
  17. Change in CH50 over time [ Time Frame: Through study duration, approximately 172 weeks ]
  18. Percent change in CH50 over time [ Time Frame: Through study duration, approximately 172 weeks ]

Eligibility Criteria
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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Key Inclusion Criteria:

  1. Male or female patients ≥18 years of age at screening (or ≥ legal age of adulthood based on local regulations, whichever is older)
  2. Patient with documented diagnosis of myasthenia gravis (MG) based on medical history and supported by previous evaluations as described in the protocol
  3. Documented prior history of positive serologic test or a positive result during screening of anti-acetylcholine receptor (AChR) antibodies or anti-LRP4 antibodies.
  4. Myasthenia Gravis Foundation of America (MGFA) Clinical Classification Class II to IVa at screening
  5. Myasthenia Gravis-Activities of Daily Living (MG-ADL) score ≥6 at screening. Ocular items should not contribute more than 50% of MG-ADL total score
  6. Currently receiving an acetylcholinesterase inhibitor or documented reason for not using acetylcholinesterase inhibitor therapy per investigator 7. Currently receiving an immunosuppressive therapy (IST) for MG, or documented reason why the patient is not taking an IST per investigator

8. If currently receiving an IST, not anticipated to have IST dosage changed before randomization or during double-blind treatment period (DBTP).

Key Exclusion Criteria:

  1. Patients with antibody profile that is only positive for muscle specific tyrosine kinase (MuSK) (MuSK positivity is based on a documented prior history of positive serologic test for antibodies to MuSK or a positive result during screening
  2. History of thymectomy within 12 months prior to screening or planned during the study
  3. History of malignant thymoma (patients with stage 1 may be enrolled), or history of cancer within the past 5 years, except for adequately treated basal cell skin cancer, squamous cell skin cancer, or in situ cervical cancer
  4. Myasthenic crisis or Myasthenia Gravis Foundation of America (MGFA) Class V within 1 month of screening
  5. No documented meningococcal vaccination within 5 years prior to screening visit unless vaccination will be administered during the screening period and prior to initiation of study treatment
  6. Known contraindication to meningococcal vaccines (group ACWY conjugate and group B vaccines) as described in the protocol
  7. Patients who require antibiotics for meningococcal prophylaxis and have a contraindication, warning, or precaution precluding the use of penicillin class and penicillin-alternative antibiotics planned to be used for prophylaxis, or a history of intolerance leading to the discontinuation of these antibiotics
  8. Positive hepatitis B surface antigen or hepatitis C virus ribonucleic acid (RNA) during screening. NOTE: Cases with unclear interpretation should be discussed with the medical monitor
  9. History of HIV infection or a positive test at screening per local requirements

NOTE: Other protocol-defined Inclusion/ Exclusion Criteria apply

Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT05070858


Contacts
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Contact: Clinical Trials Administrator 844-734-6643 clinicaltrials@regeneron.com

Locations
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Sponsors and Collaborators
Regeneron Pharmaceuticals
Investigators
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Study Director: Clinical Trial Management Regeneron Pharmaceuticals
More Information
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Responsible Party: Regeneron Pharmaceuticals
ClinicalTrials.gov Identifier: NCT05070858    
Other Study ID Numbers: R3918-MG-2018
2020-003272-41 ( EudraCT Number )
First Posted: October 7, 2021    Key Record Dates
Last Update Posted: October 31, 2023
Last Verified: March 2023
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: All Individual Patient Data (IPD) that underlie publicly available results will be considered for sharing
Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
Informed Consent Form (ICF)
Clinical Study Report (CSR)
Analytic Code
Time Frame: When Regeneron has received marketing authorization from major health authorities (e.g., FDA, European Medicines Agency (EMA), Pharmaceuticals and Medical Devices Agency (PMDA), etc.) for the product and indication, has made the study results publicly available (e.g., scientific publication, scientific conference, clinical trial registry), has the legal authority to share the data, and has ensured the ability to protect participant privacy.
Access Criteria: Qualified researchers can submit a proposal for access to individual patient or aggregate level data from a Regeneron-sponsored clinical trial through Vivli. Regeneron's Independent Research Request Evaluation Criteria can be found at: https://www.regeneron.com/sites/default/files/Regeneron-External-Data-Sharing-Policy-and-Independent-Research-Request-Evaluation-Criteria.pdf
URL: https://vivli.org/

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Myasthenia Gravis
Muscle Weakness
Muscular Diseases
Musculoskeletal Diseases
Neuromuscular Manifestations
Neurologic Manifestations
Nervous System Diseases
Pathologic Processes
Paraneoplastic Syndromes, Nervous System
Nervous System Neoplasms
 Neoplasms by Site
Neoplasms
Paraneoplastic Syndromes
Autoimmune Diseases of the Nervous System
Neurodegenerative Diseases
Neuromuscular Junction Diseases
Neuromuscular Diseases
Autoimmune Diseases
Immune System Diseases