Efficacy and Safety of a New Formulation of Oral Cladribine Compared With Placebo in Participants With Generalized Myasthenia Gravis (MyClad)

Official title

A Phase 3, Randomized, Double-Blind, Placebo-Controlled, 3-Arm, 3-Period Study to Assess the Efficacy and Safety of a New Formulation of Oral Cladribine Compared With Placebo in Participants With Generalized Myasthenia Gravis (MyClad)

Overview

The purpose of this clinical study is to determine the efficacy and safety of a new oral cladribine formulation in participants with Generalized Myasthenia Gravis (gMG) in comparison to placebo. It will also investigate the sustained efficacy, the need for retreatment, and the long-term safety of oral cladribine in gMG. An additional component is included to characterize the Pharmacokinetics (PK) of the new cladribine formulation in gMG participants. This study is divided into 3 periods: the double-blind placebo control (DBPC) pivotal period, and 2 extensions, the blinded extension (BE) and the retreatment (RT) period. Furthermore, in trial interviews will be conducted as a sub-study to MyClad with a sub-set of participants to gain an in depth understanding of the participant cladribine treatment and study experience.

Interventions

• Other Placebo
  Participants will receive placebo matched to cladribine in two courses separated by 4 weeks.
• Drug Cladribine Low Dose
  Participants will receive cladribine low dose in two courses separated by 4 weeks.
• Drug Cladribine High Dose
  Participants will receive cladribine high dose in two courses separated by 4 weeks.

Primary outcome measures

• Change from Baseline in Myasthenia Gravis - Activities of Daily Living (MG-ADL) Scale Score at Week 24 During the Double-Blind Placebo Controlled (DBPC) Period [Time frame: Baseline, Week 24]

Secondary outcome measures (11)

• Change from Baseline in Quantitative Myasthenia Gravis (QMG) Scale Score at Week 24 During the Double-Blind Placebo Controlled (DBPC) Period [Time frame: Baseline, Week 24]
• Percentage of MG-ADL Responders at Week 24 During the Double-Blind Placebo Controlled (DBPC) Period [Time frame: At Week 24]
• Change from Baseline in Myasthenia Gravis Composite (MGC) Scale Score at Week 24 During the Double-Blind Placebo Controlled (DBPC) Period [Time frame: Baseline, Week 24]
• Percentage of Quantitative Myasthenia Gravis (QMG) Scale Responders at Week 24 During the Double-Blind Placebo Controlled (DBPC) Period [Time frame: At Week 24]
• Time From Initial Cladribine Full Dose Treatment to First Retreatment or Rescue Treatment up to end of Study [Time frame: Up to End of Study (Week 144)]
• Number of Participants With Adverse Events (AEs) and Adverse Events of Special Interest (AESIs) [Time frame: Up to End of Study (Week 144)]
• Number of participants with Adverse Events (AEs) by Severity as per National Cancer Institute Common Terminology Criteria for Adverse Events, version 5.0 [Time frame: Up to End of Study (Week 144)]
• Number of Participants with Abnormal Laboratory Variables including Absolute Lymphocyte Count and Vital Signs [Time frame: Up to End of Study (Week 144)]
• Pharmacokinetic (PK) Plasma Concentration of Cladribine [Time frame: Pre-dose, 0.25, 1, 2, 3, 4, 6, 8 and 24 hours post-dose]
• Change from Baseline in the Revised Myasthenia Gravis Quality of Life - 15 Scale (MG-Qol15r) Score at Week 24 During the Double-Blind Placebo Controlled (DBPC) Period [Time frame: Baseline, Week 24]
• Number of Participants with Abnormal ECG parameters [Time frame: Up to End of Study (Week 144)]

Eligibility criteria

Inclusion criteria

• Adults of ≥ 18 years of age at the time of signing the informed consent.
• Diagnosis of Myasthenia Gravis with generalized muscle weakness, meeting clinical criteria for Myasthenia Gravis Foundation of America Class II to IVa classification.

• In participants positive for Acetylcholine receptor antibody (anti-AChR) or muscle-specific kinase antibody(anti-MuSK)
• In participants that are autoantibody seronegative i.e. not positive for anti-AChR and anti-MuSK antibodies and participants who are positive for anti-low-density lipoprotein receptor-related protein 4 antibodies (anti-LRP4)
• Has a Screening and Baseline MG-ADL score more than or equal to (>=) 6 with >= 50 percentage (%) of the total score due to non-ocular symptoms. Screening and Baseline MG-ADL scores must be stable. The difference between the Screening and Baseline scores should not be more than 2 and there should be no reported MG exacerbation during the Screening period
• If treated with oral corticosteroids: should be on a stable daily dose for at least 3 months prior to and during screening. In such case, the daily dose of oral steroids should not exceed 20 milligrams(mg)/day for prednisone/ prednisolone, 16 mg/day for methylprednisolone, 3 mg/day for dexamethasone, or 80 mg for hydrocortisone or equivalent doses for other corticosteroids.
• If treated with acetylcholinesterase inhibitor should be on a stable daily dose (pyridostigmine dose ≤ 480 mg/day or neostigmine ≤ 300 mg/day) for at least 3 months prior to and during screening
• Have a body weight >= 40 kilograms
• Other protocol defined inclusion criteria could apply

Exclusion criteria

• Immunologic disorder other than MG or any other condition requiring chronic oral, intravenous, intramuscular, or intraarticular corticosteroid therapy. Well-controlled thyroid disease, as per the Treating Investigator or the participants regular treating physician recorded in the source documents, is not exclusionary
• Molecularly characterized or suspected congenital myasthenic syndrome, Lambert-Eaton myasthenic syndrome, inherited myopathy, muscular dystrophy, acquired myopathy or any other neurologic or systematic disease that mimics MG muscular weakness
• Active, clinically significant viral, bacterial, or fungal infection, including brain MRI or chest X-ray findings consistent with signs of infection such as PML or TB, or any major episode of infection requiring hospitalization or treatment with parenteral anti-infectives within 8 weeks prior or during Screening, or completion of oral anti-infectives within 8 weeks prior or during Screening. Vaginal candidiasis, onychomycosis, and genital or oral herpes simplex virus considered by the Investigator to be sufficiently controlled would not be exclusionary
• Has a history of or current diagnosis of active tuberculosis (TB) or is currently undergoing treatment for latent TB infection or has an untreated latent TB infection as determined by documented results within 3 months of the Screening Visit of a positive TB skin test .
• Active malignancy, or history of cancer or signs of malignancy in any Screening assessment
• Treatment with nonsteroidal immunosuppressants, used in gMG, such as azathioprine, mycophenolate mofetil, methotrexate, cyclosporine, cyclophosphamide, tacrolimus within 4 weeks prior to randomization
• Treatment with FcRn or complement inhibitors (such as eculizumab, rozanolixizumab efgartigimod, ravulizumab, zilucoplan or nipocalimab) within 8 weeks prior to randomization
• History of thymectomy within 6 months prior to Screening.
• History of generalized seizures (except for history of febrile seizures during the participant's childhood).
• Negative or indeterminate for Varicella Zoster Virus antibodies at screening
• History of myasthenic crisis in the last 12 months prior to and during screening
• History of recurrent infections (that is 3 or more infections per year documented in available source data) within the last 2 years
• Discontinuation of treatment with any non-steroidal immunosuppressants used in gMG, such as azathioprine, mycophenolate mofetil, methotrexate, cyclosporine, cyclophosphamide, tacrolimus within the last 6 months prior to Screening
• If treated with non-steroidal immunosuppressants for gMG, the dose at Screening higher than 50 mg/day for azathioprine, 500 mg/day for mycophenolate mofetil, 1 mg/day for tacrolimus, 50 mg/day for cyclosporine, 25 mg/day for cyclophosphamide, or 7.5 mg/week for methotrexate
• Participation in clinical study of any investigational drug within 6 months, or 5 half-lives of the investigational drug used in the previous clinical study prior to randomization, whichever is longer. However, participants with any prior exposure to cladribine may not enter the study regardless of timing of exposure
• Other protocol defined exclusion criteria could apply

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Sequential

Masking

Quadruple blind

Primary purpose

Treatment

Study locations

United States · 21 centers

• Arizona Neuroscience Research, LLC — Phoenix
• Advanced Neurosciences Research LLC — Longmont
• University of Connecticut Health Center - Department of Medicine — Farmington
• The George Washington University Medical Faculty Associates Foggy Bottom South Pavilion — Washington D.C.
• Neurology of Central Florida Research Center, LLC — Altamonte Springs
• SFM Clinical Research, LLC — Boca Raton
• University of Florida Health Science Center - 300120311 — Jacksonville
• Neurology Associates, P. A. — Maitland
• … and 13 more centers

China · 15 centers

• The First Affiliated Hospital of Bengbu Medical College — Anhui Sheng
• Xuanwu Hospital Capital Medical University — Beijing
• Peking Union Medical College Hospital — Beijing
• The First Affiliated Hospital of Guangzhou University of Chinese Medicine - 300164595 — Guangzhou
• Affiliated Hospital of Zunyi Medical University — Zunyi
• Shijiazhuang People's Hospital — Shijiazhuang
• Henan Provincial People's Hospital — Zhengzhou
• Xiangya Hospital, Central South University — Changsha
• … and 7 more centers

Japan · 12 centers

Center list to be confirmed — check the primary protocol.

Germany · 9 centers

• Universitaetsklinikum Ulm - Klinik fuer Neurologie — Ulm
• Universitaetsmedizin Goettingen - Abteilung fuer Nephrologie und Rheumatologie — Göttingen
• Medizinische Hochschule Hannover - Klinik fur Neurologie mit Klinischer Neurophysiol — Hanover
• St. Joseph Hospital - St. Joseph Hospital Haan — Bochum
• Universitaetsklinikum Duesseldorf AoeR - Klinik fuer Neurologie — Düsseldorf
• Universitaetsklinikum Carl Gustav Carus TU Dresden - Medizinische Klinik I — Dresden
• Universitaetsklinikum Leipzig AoeR - Klinik und Poliklinik fuer Neurologie — Leipzig
• Universitaetsklinikum Schleswig-Holstein - Campus Luebeck - Neurologie — Lübeck
• … and 1 more center

Argentina · 8 centers

• Expertia S.A- Mautalen Salud e Investigación — Ciudad Autonoma Buenos Aires
• Instituto de Investigaciones Neurologicas Raul Carrea, FLENI - de Investigaciones Clinicas — Ciudad Autonoma Buenos Aires
• Instituto de Investigaciones Metabolicas (IDIM) — Ciudad Autonoma Buenos Aires
• Hospital Cordoba — Córdoba
• Fundacion Rosarina de Neurorehabilitacion — Rosario
• INECO Neurociencias Oroño — Rosario
• CER San Juan Centro Polivalente de Asistencia e Inv. Clinica — San Juan
• Centro de Investigaciones Medicas Tucuman — San Miguel de Tucumán

France · 8 centers

• CHU Nice - Hôpital Pasteur - Cardiology — Nice
• CHU Strasbourg - Hopital Hautepierre - Service Anesthesie-Reanimation&Medecine Peri-Opera — Strasbourg
• CHU de Grenoble - Hôpital Albert Michallon - Centre de Références des Maladies Neuromuscul — La Tronche
• Fondation Ophtalmologique Adolphe de Rothschild - Service de neurologie — Paris
• CHU Clermont Ferrand - Hopital Gabriel Montpied - service de neurologie B — Clermont-Ferrand
• Hopital Neurologique Pierre Wertheimer - Pathologies neuro-musculaires. Electromyographie — Bron
• Hôpital Henri Mondor - Service de Neurologie — Créteil
• Groupe Hospitalier Pitie-Salpetriere - Centre Référent Maladies Rares SLA - Neurologie — Paris

Italy · 8 centers

Center list to be confirmed — check the primary protocol.

India · 7 centers

Center list to be confirmed — check the primary protocol.

South Korea · 7 centers

Center list to be confirmed — check the primary protocol.

Australia · 6 centers

• Brain and Mind Research Institute — Camperdown
• Sunshine Coast University Hospital — Birtinya
• Princess Alexandra Hospital - PARENT — South Brisbane
• John Hunter Hospital - PARENT — City of Burnside
• Box Hill Hospital - PARENT — Box Hill
• Gold Coast University Hospital - PARENT — Southport

Bulgaria · 5 centers

• Medical Center Hera - branch Montana — Montana
• UMHAT 'Dr. Georgi Stranski', EAD — Pleven
• UMHAT "Sv. Georgi", EAD — Plovdiv
• MHATNP "Sv.Naum", EAD - Third Neurology Clinic — Sofia
• UMHATEM 'N.I. Pirogov', EAD — Sofia

Poland · 5 centers

Center list to be confirmed — check the primary protocol.

Spain · 5 centers

Center list to be confirmed — check the primary protocol.

Turkey (Türkiye) · 5 centers

Center list to be confirmed — check the primary protocol.

Romania · 4 centers

Center list to be confirmed — check the primary protocol.

Taiwan · 4 centers

Center list to be confirmed — check the primary protocol.

Georgia · 3 centers

• Ltd. Pineo Medical Ecosystem — Tbilisi
• New Hospitals LLC — Tbilisi
• Aversi Clinic Ltd — Tbilisi

Greece · 3 centers

• University General Hospital of Larissa - Rheumatology Clinic — Larissa
• University Hospital of Patra — Pátrai
• … and 1 more center

Sweden · 3 centers

Center list to be confirmed — check the primary protocol.

Belgium · 2 centers

• UZ Leuven — Leuven
• C. H. R. de la Citadelle - Account 1 — Liège

United Kingdom · 2 centers

Center list to be confirmed — check the primary protocol.

Canada · 1 center

• Burnaby Hospital - Fraser Health Multiple Sclerosis Clinic — Burnaby

Hungary · 1 center

Center list to be confirmed — check the primary protocol.

Switzerland · 1 center

Center list to be confirmed — check the primary protocol.

Identifiers

NCT: NCT06463587 · MS700568_0183 · 2023-507746-83-00 · CTR20243857 · jRCT2031240175 · SNCTP000006603

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)
• NMPA/CDE CTR20243857 (chinadrugtrials.org.cn platform)

View this study on ClinicalTrials.gov ↗