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

• ClinicalTrials.gov Identifier: NCT03572933
• Recruitment Status: Completed
• First Posted: June 28, 2018
• Results First Posted: July 26, 2022
• Last Update Posted: July 26, 2022
• Sponsor: Marinus Pharmaceuticals
• Information provided by (Responsible Party): Marinus Pharmaceuticals

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
CDKL5 Deficiency Disorder	Drug: ganaxolone; Drug: Placebo	Phase 3

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 Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 101 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Intervention Model Description: The double-blind phase will randomize subjects to adjunctive ganaxolone or placebo at a 1:1 ratio to standard of care
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: 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
• Actual Study Start Date: June 30, 2018
• Actual Primary Completion Date: July 31, 2020
• Actual Study Completion Date: May 28, 2021

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures :

1. Summary of 28-day Seizure Frequency for Major Motor Seizure Types [ Time Frame: End of the double-blind 17 week treatment period ]

   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.

Secondary Outcome Measures :

1. Caregiver Global Impression of Change in Attention [ Time Frame: End of the double-blind 17 week treatment period ]
   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
2. Caregiver Global Impression of Change in Target Behavior [ Time Frame: End of the double-blind 17 week treatment period ]
   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.
3. Clinical Global Impression of Improvement - Parent/Caregiver [ Time Frame: End of the double-blind 17 week treatment period ]
   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.
4. Clinical Global Impression of Improvement - Clinician [ Time Frame: [Time Frame: End of the double-blind 17 week treatment period] ]
   Clinical global impression of improvement during the double-blind treatment period of ganaxolone compared to placebo
5. Percentage of Seizure-free Days for Major Motor Seizure Types [ Time Frame: End of the double-blind 17 week treatment period ]
   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.
6. Arithmetic Change in Longest Seizure Free Interval, Based on Primary Seizure Types [ Time Frame: End of the double-blind 17 week treatment period ]
   Arithmetic change in longest seizure free interval, based on primary seizure types during the double-blind treatment period of ganaxolone compared to placebo
7. Caregiver Global Impression of Change in Seizure Intensity and Duration [ Time Frame: End of the double-blind 17 week treatment period ]
   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.

Eligibility Criteria

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

Criteria

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

Contacts and Locations

Locations

United States, Arizona

Marinus Research Site

Phoenix, Arizona, United States, 85016

United States, California

Marinus Research Site

Los Angeles, California, United States, 90095-1742

United States, Colorado

Marinus Research Site

Aurora, Colorado, United States, 80045

United States, Florida

Marinus Research Site

Gulf Breeze, Florida, United States, 32561

Marinus Research Site

Orlando, Florida, United States, 32819

United States, Georgia

Marinus Research Site

Norcross, Georgia, United States, 30093

United States, Illinois

Marinus Research Site

Chicago, Illinois, United States, 60612-3852

United States, Iowa

Marinus Research Site

Iowa City, Iowa, United States, 52242

United States, Massachusetts

Marinus Research Site

Boston, Massachusetts, United States, 02115

United States, Minnesota

Marinus Research Site

Rochester, Minnesota, United States, 55905

United States, Missouri

Marinus Research Site

Saint Louis, Missouri, United States, 63130

United States, New Jersey

Marinus Research Site

Livingston, New Jersey, United States, 07039

United States, Ohio

Marinus Research Site

Cleveland, Ohio, United States, 44195

United States, Pennsylvania

Marinus Research Site

Philadelphia, Pennsylvania, United States, 19104-4318

Marinus Research Site

Pittsburgh, Pennsylvania, United States, 15224

United States, Texas

Marinus Research Site

Fort Worth, Texas, United States, 76104

Marinus Research Site

Houston, Texas, United States, 77030

Australia, Queensland

Marinus Research Site

Brisbane, Queensland, Australia, 4101

Australia, Victoria

Marinus Research Site

Heidelberg, Victoria, Australia, 3084

Marinus Research Site

Melbourne, Victoria, Australia, 3168

France

Marinus Research Site

Paris, France

Israel

Marinus Research Site

Ramat Gan, Israel

Italy

Marinus Research Site

Firenze, Italy

Marinus Research Site

Milano, Italy

Marinus Research Site

Pavia, Italy

Marinus Research Site

Roma, Italy

Marinus Research Site

Verona, Italy

Poland

Marinus Research Site

Bydgoszcz, Poland

Marinus Research Site

Kraków, Poland

Russian Federation

Marinus Research Site

Moscow, Russian Federation

Marinus Research Site

Nizhniy Novgorod, Russian Federation

Marinus Research Site

Novosibirsk, Russian Federation

United Kingdom

Marinus Research Site

Birmingham, United Kingdom

Marinus Research Site

Bristol, United Kingdom

Marinus Research Facility

Glasgow, United Kingdom

Marinus Research Site

London, United Kingdom

Sponsors and Collaborators

Marinus Pharmaceuticals

Investigators

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

  Study Documents (Full-Text)

Documents provided by Marinus Pharmaceuticals:

Study Protocol  [PDF] May 27, 2020

Statistical Analysis Plan  [PDF] August 22, 2019

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

• Responsible Party: Marinus Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT03572933
• Other Study ID Numbers: 1042-CDD-3001; 2018-001180-23 ( EudraCT Number )
• First Posted: June 28, 2018
• Results First Posted: July 26, 2022
• Last Update Posted: July 26, 2022
• Last Verified: May 2022

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Marinus Pharmaceuticals:

refractory seizures; genetic pediatric encephalopathies; epilepsy in children; seizure disorder

Additional relevant MeSH terms:

Disease; Pathologic Processes; Pregnanolone; Ganaxolone; Neurosteroids; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Physiological Effects of Drugs; GABA Modulators; GABA Agents; Anesthetics; Central Nervous System Depressants