Fenfluramine for CDKL5 Deficiency Disorder

Recruiting at 59 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

Trial Summary

What is the purpose of this trial?

This trial tests ZX008, a medication added to current treatments, in children and adults with CDD who have uncontrolled seizures. The goal is to see if ZX008 can help better control their seizures.

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.

What data supports the idea that the drug Fenfluramine for CDKL5 Deficiency Disorder is an effective treatment?

The available research does not provide specific data on the effectiveness of Fenfluramine for CDKL5 Deficiency Disorder. However, studies on other conditions, like obesity and autism, show some positive effects. For instance, in a study on obesity, patients taking Fenfluramine lost more weight than those on a placebo. In autism, some parents noticed improvements in their children, although these were not confirmed by tests. This suggests Fenfluramine might have potential benefits, but more research is needed for CDKL5 Deficiency Disorder specifically. ^{1 2 3 4 5}

What data supports the effectiveness of the drug fenfluramine for CDKL5 Deficiency Disorder?

While there is no direct evidence for fenfluramine's effectiveness in CDKL5 Deficiency Disorder, studies have shown that fenfluramine can reduce motor activity in rats and has been used to treat conditions like obesity and autism, suggesting it may have potential benefits in managing symptoms related to neurological disorders. ^{1 2 3 4 5}

What safety data is available for fenfluramine treatment?

Fenfluramine has been evaluated for safety in various contexts. In a study on SCN8A epilepsy, fenfluramine showed no treatment-related adverse events, including no reports of valvular heart disease or pulmonary arterial hypertension. Another study focused on its cardiovascular safety in Dravet syndrome, noting its previous withdrawal due to cardiac valvulopathy concerns. A Phase I study assessed its safety in combination with other antiepileptic drugs. Overall, fenfluramine has been studied for safety in different conditions, with some concerns addressed in specific populations. ^{1 4 6 7 8}

Is fenfluramine generally safe for humans?

Fenfluramine has been studied for safety in various conditions, including epilepsy and weight loss. In recent studies, it showed no significant adverse effects like heart valve issues or high blood pressure in the lungs when used at low doses for epilepsy. However, it was previously withdrawn as a weight loss drug due to heart-related side effects. ^{1 4 6 7 8}

Is fenfluramine a promising drug for CDKL5 deficiency disorder?

Yes, fenfluramine is a promising drug for CDKL5 deficiency disorder. In a study with six patients, it significantly reduced the frequency of seizures, with a median reduction of 90% for tonic-clonic seizures. This suggests that fenfluramine could be an effective treatment for managing seizures in people with this disorder. ^{4 6 7 9 10}

How does the drug fenfluramine differ from other treatments for CDKL5 deficiency disorder?

Fenfluramine is unique for CDKL5 deficiency disorder because it has shown a significant reduction in seizure frequency, with a median 90% reduction in tonic-clonic seizures, which is notable given the condition's resistance to other antiseizure medications. It is repurposed from its use in Dravet syndrome and is administered as an oral solution, making it a novel option for this specific disorder. ^{4 6 7 9 10}

Research Team

UCB Cares

Principal Investigator

001 844 599 2273

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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 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 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]

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 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]

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 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 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 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]

References

1. Germany pubmed.ncbi.nlm.nih.gov

Suppression of behavioral activity by norfenfluramine and related drugs in rats is not mediated by serotonin release. [2019]

2. Italy pubmed.ncbi.nlm.nih.gov

[Clinical observations on the treatment of obese patients with dexfenfluramine]. [2013]

3. United States pubmed.ncbi.nlm.nih.gov

Fenfluramine treatment of autism: relationship of treatment response to blood levels of fenfluramine and norfenfluramine. [2019]

4. Germany 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 . [2020]

5. United States pubmed.ncbi.nlm.nih.gov

Reduction of elevated CSF beta-endorphin by fenfluramine in infantile autism. [2019]

6. United States pubmed.ncbi.nlm.nih.gov

Effect of fenfluramine on seizures and comorbidities in SCN8A-developmental and epileptic encephalopathy: A case series. [2022]

7. Netherlands pubmed.ncbi.nlm.nih.gov

Oral D-fenfluramine and neuroendocrine challenge: problems with the 30 mg dose in men. [2019]

8. United States 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. [2022]

9. United States pubmed.ncbi.nlm.nih.gov

Effect of fenfluramine on convulsive seizures in CDKL5 deficiency disorder. [2021]

10. England pubmed.ncbi.nlm.nih.gov

Fenfluramine hydrochloride for the treatment of seizures in Dravet syndrome: a randomised, double-blind, placebo-controlled trial. [2022]