Study of Adjunctive Ganaxolone Treatment in Children and Young Adults With CDKL5 Deficiency Disorder (Marigold)

A Double-blind, Randomized, Placebo-controlled Trial of Adjunctive Ganaxolone Treatment in Children and Young Adults With Cyclin-dependent Kinase-like 5 (CDKL5) Deficiency Disorder (CDD) Followed by Long-term Open-label Treatment

A clinical study to evaluate the efficacy, safety, and tolerability of adjunctive ganaxolone therapy compared to placebo for the treatment of seizures in children and young adults with genetically confirmed CDKL5 gene mutation.

Study Overview

• Status: Completed
• Conditions: CDKL5 Deficiency Disorder
• Intervention / Treatment: Drug: Placebo; Drug: ganaxolone

Detailed Description

The Marigold Study is a global, double-blind, placebo-controlled, Phase 3 clinical trial that will enroll approximately 70 patients between the ages of 2 and 21 with a confirmed disease-related CDKL5 gene variant. Patients will undergo a baseline period before being randomized to receive, in addition to their existing anti-seizure treatment, either ganaxolone or placebo for 17 weeks. Following the treatment period, all patients that meet certain eligibility requirements will have the opportunity to receive ganaxolone in the open label phase of the study. The study's primary efficacy endpoint is percent reduction in seizures. Secondary outcome measures will include non-seizure-related endpoints to capture certain behavioral and sleep disturbances that have been seen in previous clinical studies with ganaxolone.

• Study Type: Interventional
• Enrollment (Actual): 101
• Phase: Phase 3

Contacts and Locations

Study Locations

• Australia
  • Queensland
    • Brisbane, Queensland, Australia, 4101
      • Marinus Research Site
  • Victoria
    • Heidelberg, Victoria, Australia, 3084
      • Marinus Research Site
    • Melbourne, Victoria, Australia, 3168
      • Marinus Research Site
• France
  • Paris, France
    • Marinus Research Site
• Israel
  • Ramat Gan, Israel
    • Marinus Research Site
• Italy
  • Firenze, Italy
    • Marinus Research Site
  • Milano, Italy
    • Marinus Research Site
  • Pavia, Italy
    • Marinus Research Site
  • Roma, Italy
    • Marinus Research Site
  • Verona, Italy
    • Marinus Research Site
• Poland
  • Bydgoszcz, Poland
    • Marinus Research Site
  • Kraków, Poland
    • Marinus Research Site
• Russian Federation
  • Moscow, Russian Federation
    • Marinus Research Site
  • Nizhniy Novgorod, Russian Federation
    • Marinus Research Site
  • Novosibirsk, Russian Federation
    • Marinus Research Site
• United Kingdom
  • Birmingham, United Kingdom
    • Marinus Research Site
  • Bristol, United Kingdom
    • Marinus Research Site
  • Glasgow, United Kingdom
    • Marinus Research Facility
  • London, United Kingdom
    • Marinus Research Site
• United States
  • Arizona
    • Phoenix, Arizona, United States, 85016
      • Marinus Research Site
  • California
    • Los Angeles, California, United States, 90095-1742
      • Marinus Research Site
  • Colorado
    • Aurora, Colorado, United States, 80045
      • Marinus Research Site
  • Florida
    • Gulf Breeze, Florida, United States, 32561
      • Marinus Research Site
    • Orlando, Florida, United States, 32819
      • Marinus Research Site
  • Georgia
    • Norcross, Georgia, United States, 30093
      • Marinus Research Site
  • Illinois
    • Chicago, Illinois, United States, 60612-3852
      • Marinus Research Site
  • Iowa
    • Iowa City, Iowa, United States, 52242
      • Marinus Research Site
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Marinus Research Site
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Marinus Research Site
  • Missouri
    • Saint Louis, Missouri, United States, 63130
      • Marinus Research Site
  • New Jersey
    • Livingston, New Jersey, United States, 07039
      • Marinus Research Site
  • Ohio
    • Cleveland, Ohio, United States, 44195
      • Marinus Research Site
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104-4318
      • Marinus Research Site
    • Pittsburgh, Pennsylvania, United States, 15224
      • Marinus Research Site
  • Texas
    • Fort Worth, Texas, United States, 76104
      • Marinus Research Site
    • Houston, Texas, United States, 77030
      • Marinus Research Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 2 years to 21 years (Child, Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Genetically confirmed CDKL5 gene mutation, seizure onset by 1 year of age and lack of independent ambulation by 2 years of age
• Failure to control seizures despite 2 or more anti-seizure medications
• At least 16 seizures per 28 days of primary seizure types
• On a stable regimen of 0-4 anti-seizure medications (Vagus nerve stimulator, ketogenic diet, and modified Atkins diet do not count towards this limit)
• Additional Inclusion Criteria apply and can be discussed with study team

Exclusion Criteria:

• Previous exposure to ganaxolone
• West Syndrome with hypsarrhythmia pattern on EEG or seizures predominantly of Infantile Spasms type
• Use of adrenocorticotropic hormone (ACTH), prednisone or other glucocorticoid or use of moderate or strong inducers or inhibitors of CYP3A4/5/7 are prohibited
• Use of tetrahydrocannabinol (THC) or cannabidiol (CBD) is prohibited during the double-blind phase, unless patient has a prescription of Epidiolex®
• Exposure to any other investigational drug within 30 days or fewer than 5 half-lives prior to screening
• Plasma allopregnanolone-sulfate (Allo-S) levels greater than or equal to 6.0 ng/ml at screening visit
• Additional Exclusion Criteria apply and can be discussed with study team

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo; placebo suspension 3x's /day for 17 weeks	Drug: Placebo; inactive; Other Names: Placebo (for ganaxolone)
Experimental: Ganaxolone; ganaxolone suspension (50 mg/ml) 3x's /day for 17 weeks	Drug: ganaxolone; active drug

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Summary of 28-day Seizure Frequency for Major Motor Seizure Types	Summary of 28-day seizure frequency for Major Motor Seizure Types during the double-blind treatment period relative to the 6-week prospective baseline period Note: Summaries are based on the sum of the individual seizures, the countable seizures, and the clusters with uncountable seizures (each cluster with uncountable seizures counts as 1 seizure). Within the baseline and post baseline intervals, 28-day seizure frequency was calculated as the total number of seizures in the interval divided by the number of days with available seizure data in the interval, multiplied by 28.	End of the double-blind 17 week treatment period

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Caregiver Global Impression of Change in Attention	Caregiver global impression of change in attention during the double-blind treatment period of ganaxolone compared to placebo. Investigators and caregivers reported improvements in attention, mood, behavior and sleep via investigator narratives	End of the double-blind 17 week treatment period
Caregiver Global Impression of Change in Target Behavior	Caregiver global impression of change in target behavior during the double-blind treatment period of ganaxolone compared to placebo. Investigators and caregivers reported improvements in attention, mood, behavior and sleep via investigator narratives.	End of the double-blind 17 week treatment period
Clinical Global Impression of Improvement - Parent/Caregiver	Clinical global impression of improvement during the double-blind treatment period of ganaxolone compared to placebo. The CGI is rated on a 7-point scale, with the severity of illness scale using a range of responses.	End of the double-blind 17 week treatment period
Clinical Global Impression of Improvement - Clinician	Clinical global impression of improvement during the double-blind treatment period of ganaxolone compared to placebo	[Time Frame: End of the double-blind 17 week treatment period]
Percentage of Seizure-free Days for Major Motor Seizure Types	Percentage of Seizure-free Days for Major Motor Seizure types during the double-blind treatment period of ganaxolone compared to placebo. The major motor seizure types include bilateral tonic (sustained motor activity = 3 seconds), generalized tonic-clonic, atonic/drop, bilateral clonic, and focal to bilateral tonic-clonic.	End of the double-blind 17 week treatment period
Arithmetic Change in Longest Seizure Free Interval, Based on Primary Seizure Types	Arithmetic change in longest seizure free interval, based on primary seizure types during the double-blind treatment period of ganaxolone compared to placebo	End of the double-blind 17 week treatment period
Caregiver Global Impression of Change in Seizure Intensity and Duration	Caregiver global impression of change in seizure intensity and duration during the double-blind treatment period of ganaxolone compared to placebo. CGI-C is a 7 point scale that requires the clinician to assess how much the patient's illness has improved or worsened relative to a baseline state at the beginning of the intervention.	End of the double-blind 17 week treatment period

Collaborators and Investigators

• Sponsor: Marinus Pharmaceuticals
• Investigators: Study Director: Joseph Hulihan, MD, Marinus Pharmaceuticals, Inc.

Publications and helpful links

General Publications

• Knight EMP, Amin S, Bahi-Buisson N, Benke TA, Cross JH, Demarest ST, Olson HE, Specchio N, Fleming TR, Aimetti AA, Gasior M, Devinsky O; Marigold Trial Group. Safety and efficacy of ganaxolone in patients with CDKL5 deficiency disorder: results from the double-blind phase of a randomised, placebo-controlled, phase 3 trial. Lancet Neurol. 2022 May;21(5):417-427. doi: 10.1016/S1474-4422(22)00077-1. Erratum In: Lancet Neurol. 2022 Jul;21(7):e7.

Study record dates

Study Major Dates

• Study Start (Actual): June 30, 2018
• Primary Completion (Actual): July 31, 2020
• Study Completion (Actual): May 28, 2021

Study Registration Dates

• First Submitted: June 19, 2018
• First Submitted That Met QC Criteria: June 19, 2018
• First Posted (Actual): June 28, 2018

Study Record Updates

• Last Update Posted (Actual): April 14, 2023
• Last Update Submitted That Met QC Criteria: April 12, 2023
• Last Verified: April 1, 2023

More Information

Terms related to this study

• Keywords: seizure disorder; refractory seizures; epilepsy in children; genetic pediatric encephalopathies
• Additional Relevant MeSH Terms: Pathologic Processes; Disease; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Anesthetics; GABA Modulators; GABA Agents; Neurosteroids; Ganaxolone; Pregnanolone
• Other Study ID Numbers: 1042-CDD-3001; 2018-001180-23 (EudraCT Number)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No