A Study to Examine the Efficacy and Safety of ZX008 in Subjects with CDKL5 Deficiency Disorder

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Zogenix International Limited

Participant type

Pediatric, Patients

Age range

0-17 years, 18-64 years

Gender

Male and Female

Therapeutic area

Diseases [C] - Nervous System Diseases [C10]

Trial duration

20 Jun 2023 → ongoing

Decision date (initial)

2024-08-12

Transition trial

Yes

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

External identifiers

EU CT number

2023-506269-78-00

EudraCT number

2021-003222-76

WHO UTN

U1111-1303-2043

ClinicalTrials.gov

NCT05064878

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Pharmacokinetic, Safety, Others, Efficacy, Therapy

- To demonstrate that the efficacy of fenfluramine (ZX008) 0.8 mg/kg/day is superior to placebo as an adjunctive therapy for pediatric and adult subjects with CDD (Part 1)

- To characterize the long-term safety and tolerability of fenfluramine (ZX008) in pediatric and adult subjects with CDD (Part 2 and Part 3)

Secondary objectives 1

1. - To characterize the safety and tolerability of fenfluramine (ZX008) in pediatric and adult subjects with CDD (Part 1) - To assess long-term effectiveness of fenfluramine (ZX008) as an adjunctive therapy for pediatric and adult subjects with CDD (Part 2)

Conditions and MedDRA coding

CDKL5 Deficiency disorder

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 8

1. Subject has a confirmed pathogenic or likely pathogenic mutation in the CDKL5 gene and a clinical diagnosis of CDD with epilepsy onset in the first year of life, plus motor and developmental delays.
2. Subject is male or female, aged 1 to 35 years, inclusive, as of the day of the Screening Visit. Subjects aged 1 to < 2 years will ONLY be permitted to enroll in the trial AFTER the DSMB has determined that it is appropriate to do so based on a planned unblinded interim safety review to be conducted after approximately 40 subjects aged ≥ 2 to 35 years have completed Visit 6.
3. Subject must have failed to achieve seizure control despite previous or current use of 2 or more AETs.
4. Subject is currently receiving at least 1 concomitant antiseizure treatment: antiseizure medication (ASM), vagus nerve stimulation (VNS), responsive neurostimulation (RNS), or ketogenic diet (KD). During the trial, rescue medications or interventions for rescue treatment of seizures will not be counted towards the total number of antiseizure treatments established at Baseline.
5. All medications or interventions for epilepsy (including VNS, RNS, and KD) must be stable prior to screening and are expected to remain stable throughout the study. In order to establish stability at BL, duration of treatment with medications or interventions for epilepsy prior to the Screening visit must be as follows: VNS and RNS: ≥ 6 months duration; ASMs or KD: ≥ 4 weeks duration.
6. At the Screening Visit, parent/caregiver reports that subject has ≥ 4 countable motor seizures (CMS) per week. CMS include distinct seizures of the generalized tonic-clonic [GTC], bilateral clonic, bilateral tonic, atonic (drop), bilateral tonic/atonic (drop), or focal to bilateral tonicclonic type lasting approximately 3 seconds or longer, to distinguish from short-clustered seizures, spasms, or jerks.
7. Subject (and/or subject's parent[s]/legal guardian[s]) has provided written informed consent (and assent if applicable).
8. Subject (and/or subject's parent/caregiver) is willing and able to comply with study requirements (including diary completion, visit schedule, and study drug accountability).

Exclusion criteria 17

1. Subject has a known hypersensitivity to fenfluramine or any of the excipients in the study drug.
2. Subject has moderate to severe renal impairment (estimated glomerular filtration rate < 50 mL/min/1.73 m2 calculated with the Isotope Dilution Mass Spectrometry [IDMS] Traceable Schwartz equation for children and the Chronic Kidney Disease Epidemiology Collaboration [CKD-EPI] equation for adults, using actual body weight).
3. Subject is receiving concomitant therapy with any of the following: centrally-acting anorectic agents; monoamine-oxidase inhibitors; any centrally-acting compound with clinically appreciable amount of serotonin agonist or antagonist properties, including serotonin reuptake inhibition; other centrally-acting noradrenergic agonists, including atomoxetine; or cyproheptadine. (Note: Short-term requirements for prohibited medications will be handled on a per case basis by the Medical Monitor.)
4. Subject is currently receiving another investigational product(s) or has received another investigational product within 30 days or within <5 times the half-lives of the investigational product, whichever is longer, prior to the Screening Visit.
5. Female subjects of childbearing potential must not be pregnant or breastfeeding. Female subjects of childbearing potential must have a negative urine or serum pregnancy test at Screening. Subjects of childbearing or child-fathering potential must be willing to use an approved method of highly effective contraception, which includes abstinence, while participating in this study and for 90 days after the last dose of study drug.
6. Subject is known to be human immunodeficiency virus positive.
7. Subject is known to have active viral hepatitis B or C.
8. Subject is institutionalized in a facility that does not provide skilled epilepsy care.
9. Subject has a diagnosis of pulmonary arterial hypertension.
10. Subject has a clinically significant medical condition, including chronic obstructive pulmonary disease, interstitial lung disease, or portal hypertension, or has had clinically relevant symptoms or a clinically significant illness currently or in the 4 weeks prior to the Screening Visit, other than epilepsy, that would negatively impact study participation, collection of study data, or pose a risk to the subject.
11. Subject has current or past history of cardiovascular or cerebrovascular disease, such as cardiac valvulopathy, myocardial infarction or stroke, severe ventricular arrhythmias, or clinically significant structural cardiac abnormality, including but not limited to mitral valve prolapse, atrial or ventricular septal defects, patent ductus arteriosus, and patent foramen ovale with reversal of shunt. (Note:Patent foramen ovale or a bicuspid aortic valve are not considered exclusionary.)
12. Subject has current eating disorder that suggests anorexia nervosa or bulimia.
13. Subject has a current or past history of glaucoma.
14. Subject is taking > 4 concomitant ASMs. Rescue medications are not included in the count.
15. Subject is receiving concomitant treatment with cannabidiol (CBD) other than Epidiolex/Epidyolex or is being actively treated with tetrahydrocannabinol (THC) or any marijuana product for any condition. Disallowed medications are subject to wash-out requirements.
16. Subject has moderate to severe hepatic impairment, assessed based on the Child-Pugh system.
17. Subject has previously been treated with Fintepla® (fenfluramine) prior to the Screening Visit.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 15

1. Percentage change from Baseline in CMSF during Titration and Maintenance Periods (T+M) (Part 1)
2. Treatment-emergent adverse events (TEAEs) (Part 2)
3. Abnormal physical examination findings (Part 2)
4. Abnormal neurological examination findings (Part 2)
5. Positive response to self-harm question (Part 2)
6. Increase in valvular regurgitation from baseline (except absent to trace) (Part 2)
7. Pulmonary arterial hypertension (PASP > 35 mmHg) at any time during treatment on repeat testing (Part 2)
8. Change from Baseline at end of OLE1 Period in Laboratory parameters (hematology, hormones, chemistry, urinalysis) (Part 2)
9. Change from Baseline at end of OLE1 Period in Vital signs (blood pressure, heart rate, temperature, and respiratory rate) (Part 2)
10. Change from Baseline at end of OLE1 Period in Body weight (Part 2)
11. Change from Baseline at end of OLE1 Period in Tanner Staging (Part 2)
12. Treatment-emergent adverse events (TEAEs) (Part 3)
13. Change from Baseline at end of OLE2 Period in height and/or body weight (Part 3)
14. Increase in valvular regurgitation from baseline (except absent to trace) (Part 3)
15. Pulmonary arterial hypertension (PASP > 35 mmHg) at any time during treatment on repeat testing (Part 3)

Secondary endpoints 28

1. Achievement of a ≥ 50% reduction from Baseline in CMSF during T+M (Part 1)
2. Achievement of a CGI-I rating of much or very much improved as assessed by the Investigator at the end of T+M (Part 1)
3. Percentage change from Baseline in monthly GTC seizure frequency during T+M (Part 1)
4. Achievement of Categorized Percentage change in seizures from Baseline in CMSF during T+M Periods (no reduction or worsening, ≥ 25%, ≥ 75%, or 100% reduction)
5. Achievement of “near seizure freedom” (0 or 1 seizures) during T+M (Part 1)
6. Achievement of a CGI-I rating of much or very much improved as assessed by the parent/caregiver at the end of T+M (Part 1)
7. Achievement of improvement (minimal, much, or very much improved) in the CGI-I rating as assessed, independently, by the Investigator at the end of T+M (Part 1)
8. Achievement of improvement (minimal, much, or very much improved) in the CGI-I rating as assessed, independently, by the parent/caregiver at the end of T+M (Part 1)
9. Percentage change from Baseline in the monthly frequency of all seizures during T+M (Part 1)
10. Change from Baseline in the monthly frequency of CMS-free days during T+M (Part 1)
11. Treatment-emergent adverse events (TEAEs) (Part 1)
12. Abnormal physical examination findings (Part 1)
13. Abnormal neurological examination findings (Part 1)
14. Positive response to self-harm question (Part 1)
15. Increase in valvular regurgitation from baseline (except absent to trace) (Part 1)
16. Pulmonary arterial hypertension (PASP > 35 mmHg) at any time during treatment on repeat testing (Part 1)
17. Change from Baseline in Laboratory parameters (hematology, hormones, chemistry, urinalysis) (Part 1)
18. Change from Baseline in Vital signs (blood pressure, heart rate, temperature, and respiratory rate) (Part 1)
19. Change from Baseline in Body weight Part 1)
20. Change from Baseline in Tanner Staging (Part 1)
21. Percentage change from Baseline in CMSF during the OLE1 Treatment Period (Part 2)
22. Achievement of Categorized Percentage change in seizures from Baseline in CMSF during OLE1 Treatment Period (no reduction or worsening, ≥ 25%, ≥ 50%, ≥ 75%, or 100% reduction) (Part 2)
23. Achievement of “near seizure freedom” (0 or 1 seizures) during T+M (Part 2)
24. Achievement of a CGI-I rating of much or very much improved as assessed by the Investigator and by the parent/caregiver at the end of the OLE1 Treatment Period (Part 2)
25. Achievement of improvement (minimal, much, or very much improved) in the CGI-I rating as assessed by the Investigator at the end of the OLE1 Treatment Period (Part 2)
26. Achievement of improvement (minimal, much, or very much improved) in the CGI-I rating as assessed by the Parent/Caregiver at the end of the OLE1 Treatment Period (Part 2)
27. Percentage change from Baseline in monthly GTC seizure frequency during the OLE1 Treatment Period (Part 2)
28. Change from Baseline in the monthly frequency of CMS-free days during the OLE1 Treatment Period (Part 2)

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 3

Placebo 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Zogenix International Limited

Sponsor organisation

Zogenix International Limited

Address

Windlesham Campus, Sunninghill Road Sunninghill Road

City

Windlesham

Postcode

GU20 6PP

Country

United Kingdom

Scientific contact point

Organisation

Zogenix International Limited

Contact name

UCB Cares

Public contact point

Organisation

Zogenix International Limited

Contact name

UCB Cares

Third parties 15

Locations

8 EU/EEA countries · 21 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 203 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

7 submissions — initial application plus substantial / non-substantial modifications