A Phase III Study to Investigate Efficacy, Safety and Tolerability of Iptacopan Compared With Placebo in Participants Aged 18 to 85 Years With gMG.

Official title

A Randomized, Double-blind, Placebo-controlled Phase III Study to Evaluate the Efficacy, Safety, and Tolerability of Iptacopan in Patients With Generalized Myasthenia Gravis, Followed by an Open-label Extension Phase

Overview

The study is a randomized, double-blind, placebo-controlled, multicenter, Phase III study, to evaluate efficacy, safety and tolerability of iptacopan in patients with AChR+ gMG who are on stable SOC treatment. Participants who meet the eligibility criteria will be randomized in a ratio of 1:1, to receive either iptacopan or matching placebo, for 6 months (180 days) while continuing on a stable SOC treatment. The randomization will be stratified based on region.

Detailed description

The study consists of a 6-month double-blind treatment period for the primary efficacy and safety analysis followed by a maximum duration of 60 month open label extension period. A safety follow up assessment will be performed, one 7 days after the last administration of study treatment and one 30 days after the last administration of study treatment for all participants.

Interventions

• Drug Iptacopan
  Hard gelatin capsule
• Other Matching Placebo
  Hard gelatin capsule

Primary outcome measures

• Change from baseline to Month 6 in Myasthenia Gravis Activity of Daily Living (MG-ADL) total score [Time frame: Baseline to Month 6]

Secondary outcome measures (12)

• Change from baseline to Month 6 in Quantitative MG (QMG) total score [Time frame: Baseline to Month 6]
• Proportion of participants with ≥ 5 points reduction from baseline to Month 6 of QMG total score without rescue medication and/or strongly confounding prohibited medication [Time frame: Baseline to Month 6]
• Proportion of participants with ≥ 3 points reduction from baseline to Month 6 of MG-ADL total score without rescue medication and/or strongly confounding prohibited medication [Time frame: Baseline to Month 6]
• Proportion of participants achieving MSE at Month 6, defined as MG-ADL score of 0 or 1 at Month 6 without rescue therapy and/or strongly confounding prohibited medication [Time frame: Baseline to Month 6]
• Change from baseline to Month 6 in Myasthenia Gravis Composite (MGC) total score [Time frame: Baseline to Month 6]
• Change from baseline to Month 6 in revised MG Quality of Life Questionnaire (MG-QOL15r) survey score [Time frame: Baseline to Month 6]
• Incidence of adverse events [Time frame: Baseline to Month 6]
• Proportion of time during which participants showed a reduction of ≥ 2 points in MG-ADL total score that was maintained up to Month 6 [Time frame: Baseline to Month 6]
• Proportion of early MG-ADL responders during treatment (early responders with first MG-ADL improvement from baseline of ≥ 2 points occurring by week 4） [Time frame: Baseline to Month 6]
• Change from baseline to Month 6 in EuroQol-5 Dimensions-5 Level (EQ-5D-5L) [Time frame: Baseline to Month 6]
• Proportion of participants with a reduction of ≥ 3 points from baseline to Month 6 in MGC total score [Time frame: Baseline to month 6]
• Change from baseline in MG-ADL total score [Time frame: Baseline to Month 66 (end of extension phase)]

Eligibility criteria

Inclusion criteria

• Adult patients with generalized Myasthenia Gravis (age 18-85 years) at screening
• Positive serology testing for AChR+ antibody at screening
• Myasthenia Gravis Foundation of America (MGFA) Class II-IV gMG at screening and likely not in need of a respirator for the duration of the study, as judged by the Investigator.
• The confirmation of the diagnosis of gMG should be documented and supported by ≥1 of the following 3 tests:
• History of abnormal neuromuscular transmission demonstrated by single-fiber electromyography or repetitive nerve stimulation.
• History of positive test with short-acting acetylcholinesterase inhibitors (e.g. neostigmine or edrophonium chloride)
• Patient has demonstrated improvement in MG signs on oral acetylcholinesterase inhibitors as assessed by the treating physician.
• Baseline MG-ADL score ≥6, with ≥50% of the total score due to non-ocular symptoms
• Participants receiving at least one of the following treatments for gMG for ≥ 6 months prior to baseline;
• One or more NSISTs or
• plasmapheresis, plasma exchange, or intravenous immunoglobulin (at least quarterly) to control symptoms despite treatment with steroids and NSISTs; or
• an approved FcRN antagonist approved for gMG; or
• rituximab or
• other approved gMG disease modifying therapies excluding complement inhibitors.
• Vaccination against Neisseria meningitidis and Streptococcus pneumoniae infection is required prior to the start of study treatment. If the participant has not been previously vaccinated, or if a booster was required, the vaccine should be given according to local guidelines at least 2 weeks prior to first study drug administration. If study treatment has to start earlier than 2 weeks post-vaccination, prophylactic antibiotic treatment should be initiated at the start of study treatment and continued until at least 2 weeks after vaccination or booster was completed.

Note: For US sites participating in Study CLNP023Q12301, the completion of the meningococcal vaccination or booster is required for patients with gMG prior to initiating study treatment, irrespective of prophylactic antibiotic use.

Exclusion criteria

• Have been treated with intravenous immunoglobulin (IVIG)/plasma exchange (PLEX) in the past month, with rituximab in the past 6 months, eculizumab in the past 2 months, ravulizumab or other complement inhibitors in the past 3 months, efgartigimod or other anti- FcRn therapies in the past 3 months, or had a thymectomy in the past 6 months or a planned thymectomy during the trial period.
• Participants with clinically significant active or chronic uncontrolled bacterial, viral, or fungal infection at screening, including patients who test positive for an active viral infection at screening with: Active Hepatitis B Virus (HBV); Active Hepatitis C Virus (HCV);

• Human Immunodeficiency Virus (HIV) positive serology associated with an Acquired Immune Deficiency Syndrome (AIDS)-defining condition or with a cluster of differentiation 4 (CD4) count

• 200 cells/mm3
• Female participants who are pregnant or lactating, or are intending to become pregnant.
• Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant from menarche until becoming post-menopausal, unless they are using effective methods of contraception during dosing of study treatment and an additional one week following cessation of study treatment. Women are considered post-menopausal if they have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g., hormonal profile confirming menopause and/or age-appropriate history of vasomotor symptoms).
• Active systemic bacterial, viral (including COVID-19) or fungal infection or any major episode of infection that required hospitalization or injectable antimicrobial therapy within 14 days prior to study drug administration.
• History of recurrent invasive infections caused by encapsulated organisms, e.g., N. meningitidis and S. pneumoniae.
• Presence of fever ≥ 38 °C (100.4 °F) within 7 days prior to study drug administration

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

Parallel assignment

Masking

Quadruple blind

Primary purpose

Treatment

Study locations

United States · 21 centers

• Honor Health Research Institute — Scottsdale
• Fullerton Neuro and Headache Ctr — Fullerton
• SC3 Research Pasadena — Pasadena
• California Pacific Medical Center — Sacramento
• Neurology Offices Of South Florida — Boca Raton
• Superior Associates in Research LLC — Hialeah
• Augusta University Georgia — Augusta
• Hawaii Pacific Neuroscience LLC — Honolulu
• … and 13 more centers

China · 14 centers

• Novartis Investigative Site — Hefei
• Novartis Investigative Site — Guangzhou
• Novartis Investigative Site — Shenzhen
• Novartis Investigative Site — Shijiazhuang
• Novartis Investigative Site — Changsha
• Novartis Investigative Site — Suzhou
• Novartis Investigative Site — Nanchang
• Novartis Investigative Site — Xi'an
• … and 6 more centers

Japan · 12 centers

• Novartis Investigative Site — Chiba
• Novartis Investigative Site — Narita
• Novartis Investigative Site — Sapporo
• Novartis Investigative Site — Nishinomiya
• … and 8 more centers

Italy · 11 centers

• Novartis Investigative Site — Bologna
• Novartis Investigative Site — Florence
• Novartis Investigative Site — Genova
• Novartis Investigative Site — Milan
• Novartis Investigative Site — Palermo
• Novartis Investigative Site — Palermo
• Novartis Investigative Site — Roma
• Novartis Investigative Site — Roma
• … and 3 more centers

Poland · 11 centers

Center list to be confirmed — check the primary protocol.

Spain · 8 centers

Center list to be confirmed — check the primary protocol.

United Kingdom · 8 centers

Center list to be confirmed — check the primary protocol.

Germany · 7 centers

• Novartis Investigative Site — Munich
• Novartis Investigative Site — Regensburg
• Novartis Investigative Site — Würzburg
• Novartis Investigative Site — Frankfurt am Main
• Novartis Investigative Site — Bochum
• Novartis Investigative Site — Bochum
• Novartis Investigative Site — Essen

Brazil · 5 centers

• Novartis Investigative Site — Porto Alegre
• Novartis Investigative Site — Porto Alegre
• Novartis Investigative Site — Joinville
• Novartis Investigative Site — Bahia
• Novartis Investigative Site — São Paulo

France · 5 centers

• Novartis Investigative Site — Limoges
• Novartis Investigative Site — Garches
• Novartis Investigative Site — Nice
• Novartis Investigative Site — Paris
• Novartis Investigative Site — Paris

Greece · 5 centers

• Novartis Investigative Site — Athens
• Novartis Investigative Site — Chaïdári
• Novartis Investigative Site — Larissa
• Novartis Investigative Site — Pátrai
• Novartis Investigative Site — Thessaloniki

Argentina · 4 centers

• Novartis Investigative Site — CABA
• Novartis Investigative Site — Córdoba
• Novartis Investigative Site — Buenos Aires
• Novartis Investigative Site — Córdoba

Portugal · 4 centers

Center list to be confirmed — check the primary protocol.

South Korea · 4 centers

Center list to be confirmed — check the primary protocol.

Israel · 2 centers

• Novartis Investigative Site — Haifa
• Novartis Investigative Site — Jerusalem

Serbia · 2 centers

Center list to be confirmed — check the primary protocol.

Australia · 1 center

• Novartis Investigative Site — Camperdown

Denmark · 1 center

• Novartis Investigative Site — Copenhagen

Identifiers

NCT: NCT06517758 · CLNP023Q12301 · 2023-507064-39-00

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗