Table:

Therapeutic interventions in clinical trials for patients with CDD

	Study design	Participants	Intervention	Comparator	Outcomes		Results
					Primary	Secondary
Highly purified cannabidiol
Devinsky et al (2018)3	Open-label, non-randomised, uncontrolled trial with a single group assignment	55 participants aged 1–30 years with various epileptic encephalopathies, including 20 patients with CDD	Highly purified cannabidiol (oral sesame oil-based solution) at an initial dose of 5 mg/kg per day, which was titrated every 2 weeks by increments of 2–10 mg/kg per day until intolerance or a maximum dose of 25 mg/kg per day*	No placebo group; participants were compared with their own 4-week baseline	Change in monthly frequency of convulsive seizures	Change in monthly frequency of all seizure types and subtypes	Median monthly convulsive seizure frequency in the CDD group decreased from 66 (IQR 26–212) at baseline to 36 (9–142) at week 12 (p=0·032) and remained stable (26, 7–75) at week 48; 4 participants withdrew due to adverse effects
Ganaxolone
Specchio et al (2021; NCT02358538)74	Phase 2, openlabel, nonrandomised, uncontrolled, proof-of-concept trial with single group assignment	30 participants aged 2–18 years with various epileptic encephalopathies, including seven patients with CDD	Ganaxolone (oral suspension or capsules) at a maximum dose of 1800 mg/day (patients weighing >28 kg) or 63 mg/kg per day (patients weighing ≤28 kg)	No placebo group; participants were compared with their own baseline	Change in 28-day seizure frequency	Clinician-assessed and caregiver-assessed Global Impression of Change scores; safety and tolerability of ganaxolone	Only preliminary results are available;74 patients with CDD on ganaxolone had a 44·4% median reduction in 28-day seizure frequency versus baseline; 4 patients progressed to the open-label extension phase and continued to have reduced seizure frequency until 18 months (study end)
Pestana Knight et al (2022; NCT03572933)75	Phase 3, doubleblind, randomised, placebo-controlled trial	101 participants with CDD aged 2–21 years	Enteral ganaxolone (maximum dose 63 mg/kg per day for patients weighing ≤28 kg or 1800 mg/day for patients weighing >28 kg) for 17 weeks	Matching enteral placebo for 17 weeks	Change in median 28-day major motor seizure frequency	Proportion with seizure frequency reduction of at least 50%; Clinical Global Impression of Improvement score; change in percentage of seizure-free days; Caregiver Global Impression of Change in Seizure Intensity/ Duration score; Caregiver Global Impression of Change in Attention score; Caregiver Global Impression of Change score in a target behaviour	28-day major motor seizure frequency reduced by 30·7% in the ganaxolone group compared with 6·9% in the placebo group (p=0·0036); the discontinuation rate was 4% in the ganaxolone group and 8% in the placebo group
Ataluren
Devinsky et al (2021; NCT02758626)76	Phase 2, doubleblind, randomised, placebocontrolled, crossover trial	16 participants aged 2–12 years with CDD or Dravet syndrome, with the number of participants with CDD unclear	Participants were randomly assigned to oral ataluren (10 mg/kg in the morning and midday and 20 mg/kg in the evening; treatment period 1; 12 weeks) followed by a 4-week washout and then placebo (treatment period 2; 12 weeks) or placebo (treatment period 1; 12 weeks) followed by a 4-week washout and then oral ataluren (same dose and schedule; treatment period 2; 12 weeks)	Participants were randomly assigned to oral ataluren (10 mg/kg in the morning and midday and 20 mg/kg in the evening; treatment period 1; 12 weeks) followed by a 4-week washout and then placebo (treatment period 2; 12 weeks) or placebo (treatment period 1; 12 weeks) followed by a 4-week washout and then oral ataluren (same dose and schedule; treatment period 2; 12 weeks)	Number of adverse events and serious adverse events	Change in seizure frequency; quality of life (as assessed by the Quality of Life of Childhood Epilepsy scale); and change in cognitive behaviour (as assessed by the Behavior Assessment System for Children)	During the blinded phase, seven of eight patients with CDD had adverse events while on ataluren (two patients had adverse events leading to study withdrawal [one due to gastrointestinal symptoms of moderate severity possibly related to the study drug and one due to increased seizures of mild severity not likely to be related to the study drug]); no efficacy was shown
Soticlestat
Demarest et al (2021; NCT03694275)77	Phase 2, openlabel, nonrandomised, uncontrolled, pilot trial with single group assignment	20 participants aged 2–55 years with CDD (n=12) or 15q duplication syndrome	Soticlestat tablets or mini-tablets; 8-week dose optimisation and then a 12-week maintenance period	No placebo group; participants were compared with their own baseline	Change in motor seizure frequency during the maintenance period (weeks 9–20)	Percentage of participants classified as treatment responders; change in motor seizure frequency during the treatment period (weeks 0–20); change from baseline in Clinician’s Global Impression of Severity Responses of Investigator; proportion of participants with Clinical Global Impression of Change responses as per the investigator-reported impression; correlation between plasma 24S-hydroxycholesterol concentrations and motor seizure frequency; and proportion of participants with Care Clinical Global Impression of Change responses assessed by parent or family	Participants with CDD showed a mean reduction in motor seizure frequency of 24% after the 12-week maintenance period
Fenfluramine
Devinsky et al (2018; NCT03861871)78	Phase 2, openlabel, nonrandomised, uncontrolled trial with single group assignment	6 participants aged 2–26 years with CDD	Oral fenfluramine titrated to 0·8 mg/kg per day or a maximum dose of 30 mg/day for 14 days	No placebo group; participants were compared with their own baseline	Median monthly convulsive seizure frequency	Caregiver Global Impression of Change; Quality of Life of Childhood Epilepsy scale; and Pediatric Quality of Life Inventory	90% reduction in seizure frequency in 5 participants with tonic-clonic seizures and 50–60% reduction in seizure frequency in 2 participants with tonic seizures (preliminary results)

CDD=CDKL5 deficiency disorder. FDA=Food and Drug Administration.

^*Some sites included patients who received up to a maximum dose of 50 mg/kg per day.