Fenfluramine for CDKL5 Deficiency Disorder

Recruiting at 63 trial locations

Overseen By UCB Cares

Age: < 65

Sex: Any

Trial Phase: Phase 3

Sponsor: Zogenix, Inc.

Must be taking: Antiseizure treatments

Must not be taking: Cannabidiol, THC

Disqualifiers: Pulmonary hypertension, Cardiovascular disease, others

Stay on Your Current Meds You can continue your current medications while participating

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 1

87 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a medication called ZX008, or fenfluramine, to determine if it reduces seizures in people with CDKL5 deficiency disorder (CDD), a condition causing seizures and developmental delays. Researchers aim to assess the treatment's effectiveness and safety when combined with other epilepsy treatments. The trial has two parts: one group receives a placebo (a non-active substance), and another receives varying doses of ZX008. Ideal participants have uncontrolled seizures despite trying at least two other seizure treatments and experience at least four motor seizures per week. As a Phase 3 trial, this study represents the final step before FDA approval, offering participants a chance to contribute to potentially groundbreaking treatment advancements.

Do I need to stop my current medications for the trial?

No, you don't need to stop your current medications. In fact, you must continue your current antiseizure treatments, and they should remain stable throughout the study.

Will I have to stop taking my current medications?

No, you won't have to stop your current medications. The trial requires that all epilepsy treatments, including medications, remain stable throughout the study.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

A previous study tested fenfluramine hydrochloride (also called ZX008) in people with CDKL5 Deficiency Disorder (CDD) and showed positive results. The research found that most patients tolerated it without major issues. Some common side effects included reduced appetite and fatigue, but these were not severe for most participants.

Fenfluramine is already approved in the U.S. for treating seizures in conditions like Dravet syndrome. This approval indicates it is generally safe for managing seizures. Ongoing studies continue to assess its safety for CDD, but current evidence supports its use in similar conditions. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about ZX008 (Fenfluramine Hydrochloride) for CDKL5 Deficiency Disorder because it offers a unique approach by using fenfluramine, which has a different mechanism of action compared to existing treatments like antiepileptic drugs. Unlike standard therapies that primarily focus on controlling seizures, ZX008 acts on serotonin pathways, which could potentially offer broader neurological benefits. Additionally, ZX008's flexible dosing regimen allows it to be tailored to individual needs, which might improve its effectiveness and tolerability for patients. This innovative approach gives hope for more comprehensive management of CDKL5 Deficiency Disorder symptoms.

What evidence suggests that ZX008 could be an effective treatment for CDKL5 deficiency disorder?

Research has shown that fenfluramine, also known as ZX008, may help treat CDKL5 deficiency disorder (CDD), a condition that causes seizures. Studies have found that it can significantly reduce the number of seizures in people with CDD. In this trial, participants will receive either ZX008 or a matching placebo. Previous trials successfully met their primary and important secondary goals, proving its effectiveness. Early results suggest that ZX008 could be a valuable option for managing seizures related to CDD. Fenfluramine has undergone thorough study and has shown positive results in reducing seizures. ^{1 4 5 6 7}

Who Is on the Research Team?

UCB Cares

Principal Investigator

001 844 599 2273

Are You a Good Fit for This Trial?

This trial is for children and adults aged 1 to 35 with CDKL5 Deficiency Disorder (CDD) who have seizures starting in the first year of life, along with motor and developmental delays. They must have tried at least two seizure treatments without success and be on a stable epilepsy treatment plan.

Inclusion Criteria

I have a CDKL5 mutation and was diagnosed with CDD, having seizures in my first year along with motor and developmental delays.

I am between 1 and 35 years old.

I still have seizures despite trying 2 or more epilepsy treatments.

Exclusion Criteria

You have an eating disorder like anorexia nervosa or bulimia.

I have a history of serious heart or stroke issues, but not a simple hole in my heart or a two-flap aortic valve.

I have or had glaucoma.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

4 weeks

1 visit (in-person)

Baseline

Baseline observation period including the Screening Visit

4 weeks

Titration

Participants undergo a titration period to adjust to the study medication

2 weeks

Maintenance

Participants receive a fixed dose of ZX008 or placebo

12 weeks

Transition

Transition period to the open-label starting dose

2 weeks

Open-Label Extension

Participants receive open-label ZX008 with a flexible dosing regimen

52 weeks

Taper

Taper period to gradually reduce the dose

2 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Matching ZX008 Placebo
• ZX008 (Fenfluramine Hydrochloride)

Trial Overview The study tests ZX008 (Fenfluramine Hydrochloride) as an additional therapy against a placebo for reducing uncontrolled seizures in CDD patients. It's double-blind, meaning neither participants nor researchers know who gets the real drug or placebo.

How Is the Trial Designed?

Group I: ZX008 0.8 mg/kg/day Experimental Treatment 1 Intervention

Part 1: ZX008 0.8 mg/kg/day will be administered twice a day (BID) in equally divided doses; maximum of 30 mg/day, (subjects taking concomitant stiripentol will receive 0.5 mg/kg/day, \[maximum of 20 mg/day\]) with or without food.

Group II: ZX008 Experimental Treatment 1 Intervention

Part 2: Open-label ZX008 will be administered using a flexible dosing regimen, up to ZX008 0.8 mg/kg/day; maximum dose: 30 mg/day (subjects taking concomitant stiripentol will receive 0.5 mg/kg/day, \[maximum of 20 mg/day\]). ZX008 will be administered twice a day (BID) in equally divided doses with or without food.

Group III: Placebo Placebo Group 1 Intervention

Part 1: Matching ZX008 placebo will be administered twice a day (BID) in equally divided doses with or without food.

Who Is Running the Clinical Trial?

Zogenix, Inc.

Lead Sponsor

Trials

25

Recruited

2,600+

Published Research Related to This Trial

In a study involving 10 healthy male volunteers, a 30 mg dose of D-fenfluramine did not produce significant effects on hormone levels (cortisol and prolactin) or subjective measures of mood, stress, and alertness.

The lack of observed effects raises questions about the efficacy of this dose in men and suggests that previous studies using D-fenfluramine may need to be re-evaluated, particularly regarding the drug's dose-response relationship and its absorption after food.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Oral D-fenfluramine and neuroendocrine challenge: problems with the 30 mg dose in men. Goodwin, GM., Murray, CL., Bancroft, J.[2019]

In a clinical trial involving 119 patients with Dravet syndrome, fenfluramine at a dose of 0.7 mg/kg per day resulted in a significant 74.9% reduction in convulsive seizure frequency compared to a 19.2% reduction in the placebo group, demonstrating its efficacy as a treatment option.

Fenfluramine was generally well tolerated, with no evidence of serious heart issues like valvular heart disease or pulmonary arterial hypertension, indicating a favorable safety profile for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Fenfluramine hydrochloride for the treatment of seizures in Dravet syndrome: a randomised, double-blind, placebo-controlled trial. Lagae, L., Sullivan, J., Knupp, K., et al.[2022]

In a study involving nine children with infantile autism, fenfluramine treatment showed some improvement in autistic behavior for three patients, although objective psychometric tests did not show significant changes.

Fenfluramine treatment was associated with a significant reduction in elevated beta-endorphin levels in the cerebrospinal fluid of autistic patients, suggesting a potential mechanism of action related to beta-endorphin in autism.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Reduction of elevated CSF beta-endorphin by fenfluramine in infantile autism. Ross, DL., Klykylo, WM., Hitzemann, R.[2019]

In a retrospective study of three patients with SCN8A-related epilepsy, fenfluramine treatment led to a significant reduction in seizures, with a decrease of 60%-90% over 3, 6, and 12 months, despite patients having previously failed multiple antiseizure medications.

Patients also showed clinically meaningful improvements in non-seizure related symptoms, such as ambulation and attention, with minimal side effects reported, suggesting fenfluramine could be a promising treatment option for SCN8A-related disorders.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of fenfluramine on seizures and comorbidities in SCN8A-developmental and epileptic encephalopathy: A case series. Aledo-Serrano, Á., Cabal-Paz, B., Gardella, E., et al.[2022]

Fenfluramine and its active metabolite, norfenfluramine, significantly reduce both locomotor and investigatory activity in rats, indicating a strong behavioral effect.

The reduction in activity caused by fenfluramine and norfenfluramine is not linked to serotonin (5-HT) release, as shown by the lack of effect from drugs that inhibit 5-HT uptake or synthesis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Suppression of behavioral activity by norfenfluramine and related drugs in rats is not mediated by serotonin release. Callaway, CW., Wing, LL., Nichols, DE., et al.[2019]

In a study involving 232 pediatric patients with Dravet syndrome, low-dose fenfluramine (up to 0.7 mg/kg/day) was found to have a low risk of causing cardiac valvulopathy or pulmonary artery hypertension, with no cases reported during the treatment period.

The average treatment duration was 256 days, and the findings suggest that fenfluramine can be safely used to reduce seizure frequency in children without significant cardiovascular risks.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cardiovascular safety of fenfluramine in the treatment of Dravet syndrome: Analysis of an ongoing long-term open-label safety extension study. Lai, WW., Galer, BS., Wong, PC., et al.[2022]

In a 12-month double-blind study involving 42 obese patients, those treated with d-fenfluramine (30 mg daily) experienced significantly greater weight loss compared to the placebo group on a low-calorie diet.

The study found that 30 mg daily of d-fenfluramine was effective and well tolerated, indicating a favorable long-term balance between effectiveness and acceptability for weight management.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Clinical observations on the treatment of obese patients with dexfenfluramine]. Cairella, M., Pisculli, M., Petraroli, AR., et al.[2013]

In a Phase I study involving 26 healthy adults, ZX008 (a liquid formulation of fenfluramine) did not significantly affect the pharmacokinetics of the combined antiepileptic drug regimen (stiripentol, valproate, and clobazam), suggesting it can be safely administered alongside these medications.

The combined antiepileptic regimen moderately increased the levels of fenfluramine while decreasing its major metabolite, indicating that while ZX008 is safe to use with these drugs, a dose adjustment may be necessary to optimize treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase I, randomized, open-label, single-dose, 3-period crossover study to evaluate the drug-drug interaction between ZX008 (fenfluramine HCl oral solution) and a regimen of stiripentol, clobazam, and valproate in healthy subjects . Boyd, B., Smith, S., Gammaitoni, A., et al.[2020]

In a small study of six patients with CDKL5 deficiency disorder, fenfluramine (FFA) led to a significant median reduction of 90% in tonic-clonic seizure frequency, indicating its potential efficacy as an antiseizure medication for this condition.

Despite some adverse events like lethargy and decreased appetite, no serious side effects such as valvular heart disease were reported, suggesting that FFA may be a safe option for patients with CDD who have not responded to other treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of fenfluramine on convulsive seizures in CDKL5 deficiency disorder. Devinsky, O., King, L., Schwartz, D., et al.[2021]

In a double-blind crossover trial involving nine children with infantile autism, treatment with fenfluramine hydrochloride did not show significant improvements on standardized rating instruments, suggesting limited efficacy.

Despite the lack of measurable improvement, parents of two children with the highest fenfluramine blood levels expressed a desire for continued treatment, indicating a potential link between blood levels of the drug and perceived treatment response.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Fenfluramine treatment of autism: relationship of treatment response to blood levels of fenfluramine and norfenfluramine. Beeghly, JH., Kuperman, S., Perry, PJ., et al.[2019]

Citations

1. ucb.com ucb.com/newsroom/press-releases/article/ucb-announces-positive-results-from-gemz-phase-3-study-of-fenfluramine-in-cdkl5-deficiency-disorder

UCB announces positive results from GEMZ phase 3 study ... The phase 3 study investigating the safety and efficacy of adjunctive fenfluramine in CDKL5 Deficiency Disorder (CDD) met its primary and key secondary ...

2. clinicaltrials.gov clinicaltrials.gov/study/NCT05064878

NCT05064878 | A Study to Investigate the Efficacy and ... The primary study analysis to evaluate the efficacy and safety of ZX008 in children and adults with CDD will be based on Part 1 data in all randomized subjects.

3. ucb-usa.com ucb-usa.com/stories-media/UCB-U-S-News/detail/article/ucb-announces-positive-results-gemz-phase-3-study

UCB announces positive results from GEMZ Phase 3 study ... UCB announces positive results from GEMZ Phase 3 study of fenfluramine in CDKL5 deficiency disorder. Phase 3 study met primary and most key ...

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC8360137/

Effect of fenfluramine on convulsive seizures in CDKL5 ... Our preliminary results suggest that FFA may be a promising ASM for CDD. Randomized clinical trials are warranted. Keywords: CDKL5 deficiency ...

5. cdkl5.com cdkl5.com/wp-content/uploads/2023/08/ZX008-2103_EP0216_Advocacy-Factsheet_V1-0_US-Eng_08MAY2023.pdf

CDKL5 deficiency disorder? Fenfluramine hydrochloride is taken daily by mouth (orally). The GEMZ Study is a 2-part trial that lasts up to 98 weeks (approx. 2 years) and.

6. ucb.com ucb.com/innovation/clinical-studies/clinical-studies-index/Fenfluramine%20%20%28Fintepla%29

Fenfluramine (Fintepla) Dravet Syndrome, A Study to Evaluate Safety, Tolerability, and Pharmacokinetics of Fenfluramine (Hydrochloride) in Infants 1 Year to Less Than 2 Years of Age ...

7. clinicaltrials.gov clinicaltrials.gov/study/NCT03936777

NCT03936777 | A Study to Investigate the Long-Term ... A Study to Investigate the Long-Term Safety of ZX008 (Fenfluramine Hydrochloride) Oral Solution in Children and Adults With Epileptic Encephalopathy ...