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NCT03572933: Marigold

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

Completed Phase 3 Results posted Last updated 14 April 2023
What this trial tests

Phase 3 trial testing ganaxolone in CDKL5 Deficiency Disorder in 101 participants. Completed in 28 May 2021.

Timeline
30 June 2018
Primary endpoint
31 July 2020
28 May 2021

Quick facts

Lead sponsorMarinus Pharmaceuticals
PhasePhase 3
StatusCompleted
Study typeINTERVENTIONAL
Allocationrandomized
Designparallel
Maskingquadruple
Primary purposetreatment
Enrollment101
Start date30 June 2018
Primary completion31 July 2020
Estimated completion28 May 2021
Sites36 locations across France, Italy, Russia, United Kingdom, Israel, Poland, Australia, United States

Drugs / interventions tested

Conditions studied

Sponsor

Marinus Pharmaceuticals — full company profile →

Who can join

Adults 2 to 21, any sex, with CDKL5 Deficiency Disorder. Patients with the condition only — healthy volunteers not accepted.

Results — posted to ClinicalTrials.gov

Per-arm endpoint measurements with 95% confidence intervals where reported. Source: trial results section.

Summary of 28-day Seizure Frequency for Major Motor Seizure Types Primary · 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.

Baseline (Median)
GroupValue95% CI
Placebo49.1732.20 – 60.67
Ganaxolone54.0038.24 – 106.67
17 week-post baseline phase (Median)
GroupValue95% CI
Placebo55.5035.75 – 80.14
Ganaxolone45.0331.83 – 76.03
Caregiver Global Impression of Change in Attention Secondary · 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

Very Much Improved - Visit 5 (End of Week 17)
GroupValue95% CI
Placebo1
Ganaxolone1
Much Improved - Visit 5 (End of Week 17)
GroupValue95% CI
Placebo7
Ganaxolone2
Minimally Improved - Visit 5 (End of Week 17)
GroupValue95% CI
Placebo14
Ganaxolone21
No Change - Visit 5 (End of Week 17)
GroupValue95% CI
Placebo23
Ganaxolone18
Minimally Worse - Visit 5 (End of Week 17)
GroupValue95% CI
Placebo1
Ganaxolone1
Much Worse - Visit 5 (End of Week 17)
GroupValue95% CI
Placebo1
Ganaxolone1
Very Much Worse - Visit 5 (End of Week 17)
GroupValue95% CI
Placebo0
Ganaxolone1
Caregiver Global Impression of Change in Target Behavior Secondary · 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.

Very Much Improved - Visit 5 (End of Week 17)
GroupValue95% CI
Placebo0
Ganaxolone0
Much Improved - Visit 5 (End of Week 17)
GroupValue95% CI
Placebo6
Ganaxolone4
Minimally Improved - Visit 5 (End of Week 17)
GroupValue95% CI
Placebo14
Ganaxolone20
No Change - Visit 5 (End of Week 17)
GroupValue95% CI
Placebo22
Ganaxolone19
Minimally Worse - Visit 5 (End of Week 17)
GroupValue95% CI
Placebo1
Ganaxolone2
Much Worse - Visit 5 (End of Week 17)
GroupValue95% CI
Placebo2
Ganaxolone0
Very Much Worse - Visit 5 (End of Week 17)
GroupValue95% CI
Placebo1
Ganaxolone0
Clinical Global Impression of Improvement - Parent/Caregiver Secondary · 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.

Very Much Improved - Visit 5 (End of Week 17) - Parent/Caregiver
GroupValue95% CI
Placebo1
Ganaxolone0
Much Improved - Visit 5 (End of Week 17) - Parent/Caregiver
GroupValue95% CI
Placebo7
Ganaxolone13
Minimally Improved - Visit 5 (End of Week 17) - Parent/Caregiver
GroupValue95% CI
Placebo13
Ganaxolone17
No Change - Visit 5 (End of Week 17) - Parent/Caregiver
GroupValue95% CI
Placebo22
Ganaxolone14
Minimally Worse - Visit 5 (End of Week 17) - Parent/Caregiver
GroupValue95% CI
Placebo4
Ganaxolone2
Much Worse - Visit 5 (End of Week 17) - Parent/Caregiver
GroupValue95% CI
Placebo1
Ganaxolone2
Very Much Worse - Visit 5 (End of Week 17) - Parent/Caregiver
GroupValue95% CI
Placebo0
Ganaxolone0
Clinical Global Impression of Improvement - Clinician Secondary · [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

Very Much Improved - Visit 5 (End of Week 17) - Clinician
GroupValue95% CI
Placebo0
Ganaxolone0
Much Improved - Visit 5 (End of Week 17) - Clinician
GroupValue95% CI
Placebo7
Ganaxolone7
Minimally Improved - Visit 5 (End of Week 17) - Clinician
GroupValue95% CI
Placebo13
Ganaxolone19
No Change - Visit 5 (End of Week 17) - Clinician
GroupValue95% CI
Placebo19
Ganaxolone16
Minimally Worse - Visit 5 (End of Week 17) - Clinician
GroupValue95% CI
Placebo9
Ganaxolone2
Much Worse - Visit 5 (End of Week 17) - Clinician
GroupValue95% CI
Placebo0
Ganaxolone3
Very Much Worse - Visit 5 (End of Week 17) - Clinician
GroupValue95% CI
Placebo0
Ganaxolone1
Percentage of Seizure-free Days for Major Motor Seizure Types Secondary · 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.

Baseline
GroupValue95% CI
Placebo30.32± 27.070
Ganaxolone22.57± 25.761
17-week-Post-Baseline Phase
GroupValue95% CI
Placebo36.17± 30.932
Ganaxolone32.29± 30.615
Arithmetic Change from Baseline
GroupValue95% CI
Placebo5.86± 15.350
Ganaxolone9.62± 21.364
Arithmetic Change in Longest Seizure Free Interval, Based on Primary Seizure Types Secondary · 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

GroupValue95% CI
Placebo-4.63± 14.867
Ganaxolone-0.02± 9.376
Caregiver Global Impression of Change in Seizure Intensity and Duration Secondary · 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.

Very Much Improved - Visit 5 (End of Week 17)
GroupValue95% CI
Placebo1
Ganaxolone2
Much Improved - Visit 5 (End of Week 17)
GroupValue95% CI
Placebo5
Ganaxolone15
Minimally Improved - Visit 5 (End of Week 17)
GroupValue95% CI
Placebo11
Ganaxolone11
No Change - Visit 5 (End of Week 17)
GroupValue95% CI
Placebo21
Ganaxolone10
4Minimally Worse - Visit 5 (End of Week 17)
GroupValue95% CI
Placebo5
Ganaxolone3
Much Worse - Visit 5 (End of Week 17)
GroupValue95% CI
Placebo4
Ganaxolone2
Very Much Worse - Visit 5 (End of Week 17)
GroupValue95% CI
Placebo0
Ganaxolone2

Adverse events — posted to ClinicalTrials.gov

Time frame: Screening through 17-week Double-blind Phase. Reporting threshold: 3%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

Placebo
Serious: 5/51 (10%)
Deaths: 0/51
Ganaxolone
Serious: 6/50 (12%)
Deaths: 0/50

Serious adverse events (14 terms)

ReactionSystemPlaceboGanaxolone
BronchitisInfections and infestations
Rhinovirus InfectionInfections and infestations
Urinary Tract InfectionInfections and infestations
Pneumonia MycoplasmalInfections and infestations
Pneumonia ViralInfections and infestations
Respiratory Syncytial Virus BronchiolitisInfections and infestations
Oxygen Saturation DecreasedInvestigations
Food RefusalMetabolism and nutrition disorders
Pneumonia AspirationRespiratory, thoracic and mediastinal disorders
HypoxiaRespiratory, thoracic and mediastinal disorders
FaecalomaGastrointestinal disorders
HypotoniaNervous system disorders
SeizureNervous system disorders
Unresponsive to StimuliNervous system disorders
Other adverse events (33 terms — click to expand)

ReactionSystemPlaceboGanaxolone
SomnolenceNervous system disorders
VomitingGastrointestinal disorders
SeizureNervous system disorders
PyrexiaGeneral disorders
Upper Respiratory Tract InfectionInfections and infestations
NasopharyngitisInfections and infestations
RhinitisInfections and infestations
DiarrhoeaGastrointestinal disorders
RashSkin and subcutaneous tissue disorders
SedationNervous system disorders
Ear InfectionInfections and infestations
Respiratory Tract Infection ViralInfections and infestations
Urinary Tract InfectionInfections and infestations
ConstipationGastrointestinal disorders
Salivary HypersecretionGastrointestinal disorders
Gastrooesophageal Reflux DiseaseGastrointestinal disorders
CoughRespiratory, thoracic and mediastinal disorders
Seasonal AllergyImmune system disorders
HypersomniaNervous system disorders
LethargyNervous system disorders
HyperaesthesiaNervous system disorders
BronchitisInfections and infestations
InfluenzaInfections and infestations
SinusitisInfections and infestations
VaricellaInfections and infestations
Abdominal PainGastrointestinal disorders
Gait DisturbanceGeneral disorders
Nasal CongestionRespiratory, thoracic and mediastinal disorders
RhinorrhoeaRespiratory, thoracic and mediastinal disorders
InsomniaRespiratory, thoracic and mediastinal disorders
IrritabilityPsychiatric disorders
Body Temperature IncreasedInvestigations
AlopeciaSkin and subcutaneous tissue disorders

Most-reported serious reactions: Bronchitis, Rhinovirus Infection, Urinary Tract Infection, Pneumonia Mycoplasmal, Pneumonia Viral, Respiratory Syncytial Virus Bronchiolitis, Oxygen Saturation Decreased, Food Refusal.

Data from ClinicalTrials.gov NCT03572933 adverse events section.

Sponsor's own description

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.

Publications & conference data

8 peer-reviewed publications reference this trial (live from Europe PMC):

  1. Cyclin-Dependent Kinase-Like 5 Deficiency Disorder: Clinical Review.
    Olson HE, Demarest ST, Pestana-Knight EM, Swanson LC, et al · · 2019 · cited 182× · PMID 30928302 · DOI 10.1016/j.pediatrneurol.2019.02.015
  2. 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.
    Knight EMP, Amin S, Bahi-Buisson N, Benke TA, et al · · 2022 · cited 120× · PMID 35429480 · DOI 10.1016/s1474-4422(22)00077-1
  3. CDKL5 deficiency disorder: clinical features, diagnosis, and management.
    Leonard H, Downs J, Benke TA, Swanson L, et al · · 2022 · cited 106× · PMID 35483386 · DOI 10.1016/s1474-4422(22)00035-7
  4. Realising the therapeutic potential of neuroactive steroid modulators of the GABA<sub>A</sub> receptor.
    Belelli D, Hogenkamp D, Gee KW, Lambert JJ. · · 2020 · cited 48× · PMID 32435660 · DOI 10.1016/j.ynstr.2019.100207
  5. Epileptogenesis in tuberous sclerosis complex-related developmental and epileptic encephalopathy.
    Aronica E, Specchio N, Luinenburg MJ, Curatolo P. · · 2023 · cited 45× · PMID 36806388 · DOI 10.1093/brain/awad048
  6. Current neurologic treatment and emerging therapies in CDKL5 deficiency disorder.
    Olson HE, Daniels CI, Haviland I, Swanson LC, et al · · 2021 · cited 38× · PMID 34530725 · DOI 10.1186/s11689-021-09384-z
  7. CDKL5 Deficiency Disorder-Related Epilepsy: A Review of Current and Emerging Treatment.
    Hong W, Haviland I, Pestana-Knight E, Weisenberg JL, et al · · 2022 · cited 31× · PMID 35633486 · DOI 10.1007/s40263-022-00921-5
  8. International Consensus Recommendations for the Assessment and Management of Individuals With CDKL5 Deficiency Disorder.
    Amin S, Monaghan M, Aledo-Serrano A, Bahi-Buisson N, et al · · 2022 · cited 23× · PMID 35795799 · DOI 10.3389/fneur.2022.874695

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Primary sources · FDA · ClinicalTrials.gov · EMA · SEC EDGAR · ChEMBL · Wikidata · full sourcing