Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Randomized Controlled Trial
. 2024 Jan;65(1):37-45.
doi: 10.1111/epi.17826. Epub 2023 Nov 29.

Long-term treatment with ganaxolone for seizures associated with cyclin-dependent kinase-like 5 deficiency disorder: Two-year open-label extension follow-up

Heather E Olson  1 , Sam Amin  2 , Nadia Bahi-Buisson  3 , Orrin Devinsky  4 , Eric D Marsh  5 , Elia Pestana-Knight  6 , Rajsekar R Rajaraman  7 , Alex A Aimetti  8 , Eva Rybak  8 , Fanhui Kong  8 , Ian Miller  8 , Joseph Hulihan  8 , Scott Demarest  9
Affiliations
Randomized Controlled Trial

Long-term treatment with ganaxolone for seizures associated with cyclin-dependent kinase-like 5 deficiency disorder: Two-year open-label extension follow-up

Heather E Olson et al. Epilepsia. 2024 Jan.

Abstract

Objective: In the placebo-controlled, double-blind phase of the Marigold study (NCT03572933), ganaxolone significantly reduced major motor seizure frequency (MMSF) in patients with cyclin-dependent kinase-like 5 deficiency disorder (CDD). We report 2-year safety and clinical outcomes data from the open-label extension (OLE) phase of Marigold.

Methods: Patients with CDD who completed the double-blind phase were eligible to continue in the OLE. Efficacy assessments included MMSF reduction from prerandomization baseline, responder rates, and Clinical Global Impression-Improvement scores, including assessment of seizure intensity and duration (CGI-CSID). Safety assessments included treatment-emergent adverse events (TEAEs) and TEAEs leading to discontinuation.

Results: Of 101 patients who enrolled in Marigold, 88 (87.1%) entered the OLE (median age = 5 years, 79.5% female). Median 28-day MMSF at baseline was 50.6. At 2 years in the OLE (months 22-24), MMSF was reduced by a median of 48.2% (n = 50); when missing data were imputed, median reduction in MMSF was 43.8% using a mixed effects model and 27.4% using a last observation carried forward model. During months 22-24, 23 of 50 (46.0%) patients experienced reductions in MMSF of ≥50%; 12 of 50 (24.0%) patients experienced MMSF reductions of ≥75%. During months 22-24, 40 of 49 (81.6%) patients were rated by caregivers as having improvement in seizure-related outcomes based on CGI-CSID scores. Thirty-seven patients discontinued ganaxolone due to lack of efficacy (n = 13), withdrawal by caregiver (n = 12), adverse event (n = 10), physician decision (n = 1), or death (n = 1; unrelated to study drug). The most common treatment-related TEAEs were somnolence (17.0%), seizure (11.4%), and decreased appetite (5.7%). Patients reported serious TEAEs (n = 28, 31.8%); those reported in ≥3% of patients were seizure (n = 6), pneumonia (n = 5), acute respiratory failure (n = 3), aspiration pneumonia (n = 3), and dehydration (n = 3).

Significance: Sustained reductions in MMSF at 2 years in the OLE support the efficacy of ganaxolone in seizures associated with CDD. Safety findings in the OLE were consistent with the double-blind phase.

Keywords: Clinical Global Impression-Improvement; open-label extension; phase 3.

PubMed Disclaimer

References

REFERENCES

    1. Siri B, Varesio C, Freri E, Darra F, Gana S, Mei D, et al. CDKL5 deficiency disorder in males: five new variants and review of the literature. Eur J Paediatr Neurol. 2021;33:9-20.
    1. Symonds JD, Zuberi SM, Stewart K, McLellan A, O'Regan M, MacLeod S, et al. Incidence and phenotypes of childhood-onset genetic epilepsies: a prospective population-based national cohort. Brain. 2019;142(8):2303-2318.
    1. Olson HE, Demarest ST, Pestana-Knight EM, Swanson LC, Iqbal S, Lal D, et al. Cyclin-dependent kinase-like 5 (CDKL5) deficiency disorder: clinical review. Pediatr Neurol. 2019;97:18-25.
    1. Zhu Y, Xiong Z. Molecular and synaptic bases of CDKL5 disorder. Dev Neurobiol. 2019;79(1):8-19.
    1. Leonard H, Downs J, Benke TA, Swanson L, Olson H, Demarest S. CDKL5 deficiency disorder: clinical features, diagnosis, and management. Lancet Neurol. 2022;21(6):563-576.

Publication types

Supplementary concepts

LinkOut - more resources