FENFLURAMINE HYDROCHLORIDE for CDKL5 deficiency disorder

Inclusion criteria

• {"criterion_text":"- 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.\n- 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.\n- Subject must have failed to achieve seizure control despite previous or current use of 2 or more AETs.\n- 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.\n- 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.\n- 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.\n- Subject (and/or subject's parent[s]/legal guardian[s]) has provided written informed consent (and assent if applicable).\n- 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

• {"criterion_text":"- Subject has a known hypersensitivity to fenfluramine or any of the excipients in the study drug.\n- 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.\n- 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.)\n- Subject has current eating disorder that suggests anorexia nervosa or bulimia.\n- Subject has a current or past history of glaucoma.\n- Subject is taking > 4 concomitant ASMs. Rescue medications are not included in the count.\n- 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.\n- Subject has moderate to severe hepatic impairment, assessed based on the Child-Pugh system.\n- Subject has previously been treated with Fintepla® (fenfluramine) prior to the Screening Visit.\n- 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).\n- 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.)\n- 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.\n- 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.\n- Subject is known to be human immunodeficiency virus positive.\n- Subject is known to have active viral hepatitis B or C.\n- Subject is institutionalized in a facility that does not provide skilled epilepsy care.\n- Subject has a diagnosis of pulmonary arterial hypertension."}

Primary endpoints

• {"endpoint_text":"- Percentage change from Baseline in CMSF during Titration and Maintenance Periods (T+M) (Part 1)","definition_or_measurement_approach":"Percent change from Baseline in countable motor seizure frequency (CMSF) during the Titration and Maintenance Periods (T+M)."}
• {"endpoint_text":"- Treatment-emergent adverse events (TEAEs) (Part 2)","definition_or_measurement_approach":"Treatment-emergent adverse events recorded during Part 2."}
• {"endpoint_text":"- Abnormal physical examination findings (Part 2)","definition_or_measurement_approach":"Abnormal findings on physical examination assessed in Part 2."}
• {"endpoint_text":"- Abnormal neurological examination findings (Part 2)","definition_or_measurement_approach":"Abnormal findings on neurological examination assessed in Part 2."}
• {"endpoint_text":"- Positive response to self-harm question (Part 2)","definition_or_measurement_approach":"Positive response to self-harm question during Part 2 assessments."}
• {"endpoint_text":"- Increase in valvular regurgitation from baseline (except absent to trace) (Part 2)","definition_or_measurement_approach":"Increase in degree of valvular regurgitation from baseline (excluding absent to trace) assessed in Part 2."}
• {"endpoint_text":"- Pulmonary arterial hypertension (PASP > 35 mmHg) at any time during treatment on repeat testing (Part 2)","definition_or_measurement_approach":"Occurrence of pulmonary arterial hypertension defined as PASP > 35 mmHg on repeat testing during treatment in Part 2."}
• {"endpoint_text":"- Change from Baseline at end of OLE1 Period in Laboratory parameters (hematology, hormones, chemistry, urinalysis) (Part 2)","definition_or_measurement_approach":"Change from baseline in laboratory parameters (hematology, hormones, clinical chemistry, urinalysis) at end of OLE1 (Part 2)."}
• {"endpoint_text":"- Change from Baseline at end of OLE1 Period in Vital signs (blood pressure, heart rate, temperature, and respiratory rate) (Part 2)","definition_or_measurement_approach":"Change from baseline in vital signs (BP, HR, temperature, respiratory rate) at end of OLE1 (Part 2)."}
• {"endpoint_text":"- Change from Baseline at end of OLE1 Period in Body weight (Part 2)","definition_or_measurement_approach":"Change from baseline in body weight at end of OLE1 (Part 2)."}
• {"endpoint_text":"- Change from Baseline at end of OLE1 Period in Tanner Staging (Part 2)","definition_or_measurement_approach":"Change from baseline in Tanner staging at end of OLE1 (Part 2)."}
• {"endpoint_text":"- Treatment-emergent adverse events (TEAEs) (Part 3)","definition_or_measurement_approach":"Treatment-emergent adverse events recorded during Part 3."}
• {"endpoint_text":"- Change from Baseline at end of OLE2 Period in height and/or body weight (Part 3)","definition_or_measurement_approach":"Change from baseline in height and/or body weight at end of OLE2 (Part 3)."}
• {"endpoint_text":"- Increase in valvular regurgitation from baseline (except absent to trace) (Part 3)","definition_or_measurement_approach":"Increase in valvular regurgitation from baseline (excluding absent to trace) assessed in Part 3."}
• {"endpoint_text":"- Pulmonary arterial hypertension (PASP > 35 mmHg) at any time during treatment on repeat testing (Part 3)","definition_or_measurement_approach":"Occurrence of pulmonary arterial hypertension (PASP > 35 mmHg) on repeat testing during treatment in Part 3."}

Secondary endpoints

• {"endpoint_text":"- Achievement of a ≥ 50% reduction from Baseline in CMSF during T+M (Part 1)","definition_or_measurement_approach":"Proportion achieving ≥50% reduction from baseline in CMSF during T+M (Part 1)."}
• {"endpoint_text":"- 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)","definition_or_measurement_approach":"Clinician Global Impression - Improvement (CGI-I) rating by investigator at end of T+M (Part 1)."}
• {"endpoint_text":"- Percentage change from Baseline in monthly GTC seizure frequency during T+M (Part 1)","definition_or_measurement_approach":"Percent change from baseline in monthly generalized tonic-clonic seizure frequency during T+M (Part 1)."}
• {"endpoint_text":"- Achievement of Categorized Percentage change in seizures from Baseline in CMSF during T+M Periods (no reduction or worsening, ≥ 25%, ≥ 75%, or 100% reduction)","definition_or_measurement_approach":"Categorized percent change in CMSF from baseline during T+M (no reduction/worsening, ≥25%, ≥75%, or 100%)."}
• {"endpoint_text":"- Achievement of “near seizure freedom” (0 or 1 seizures) during T+M (Part 1)","definition_or_measurement_approach":"Proportion of subjects with 0 or 1 seizures during T+M (Part 1)."}
• {"endpoint_text":"- 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)","definition_or_measurement_approach":"CGI-I rating by parent/caregiver at end of T+M (Part 1)."}
• {"endpoint_text":"- 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)","definition_or_measurement_approach":"Independent investigator assessment of CGI-I categories at end of T+M (Part 1)."}
• {"endpoint_text":"- 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)","definition_or_measurement_approach":"Independent parent/caregiver assessment of CGI-I categories at end of T+M (Part 1)."}
• {"endpoint_text":"- Percentage change from Baseline in the monthly frequency of all seizures during T+M (Part 1)","definition_or_measurement_approach":"Percent change from baseline in monthly frequency of all seizures during T+M (Part 1)."}
• {"endpoint_text":"- Change from Baseline in the monthly frequency of CMS-free days during T+M (Part 1)","definition_or_measurement_approach":"Change from baseline in monthly frequency of CMS-free days during T+M (Part 1)."}
• {"endpoint_text":"- Treatment-emergent adverse events (TEAEs) (Part 1)","definition_or_measurement_approach":"Treatment-emergent adverse events recorded during Part 1."}
• {"endpoint_text":"- Abnormal physical examination findings (Part 1)","definition_or_measurement_approach":"Abnormal physical examination findings detected in Part 1."}
• {"endpoint_text":"- Abnormal neurological examination findings (Part 1)","definition_or_measurement_approach":"Abnormal neurological examination findings detected in Part 1."}
• {"endpoint_text":"- Positive response to self-harm question (Part 1)","definition_or_measurement_approach":"Positive response to self-harm question during Part 1 assessments."}
• {"endpoint_text":"- Increase in valvular regurgitation from baseline (except absent to trace) (Part 1)","definition_or_measurement_approach":"Increase in valvular regurgitation from baseline (excluding absent to trace) in Part 1."}
• {"endpoint_text":"- Pulmonary arterial hypertension (PASP > 35 mmHg) at any time during treatment on repeat testing (Part 1)","definition_or_measurement_approach":"Occurrence of PASP > 35 mmHg on repeat testing during treatment in Part 1."}
• {"endpoint_text":"- Change from Baseline in Laboratory parameters (hematology, hormones, chemistry, urinalysis) (Part 1)","definition_or_measurement_approach":"Change from baseline in laboratory parameters (hematology, hormones, clinical chemistry, urinalysis) in Part 1."}
• {"endpoint_text":"- Change from Baseline in Vital signs (blood pressure, heart rate, temperature, and respiratory rate) (Part 1)","definition_or_measurement_approach":"Change from baseline in vital signs (BP, HR, temperature, respiratory rate) in Part 1."}
• {"endpoint_text":"- Change from Baseline in Body weight Part 1)","definition_or_measurement_approach":"Change from baseline in body weight in Part 1."}
• {"endpoint_text":"- Change from Baseline in Tanner Staging (Part 1)","definition_or_measurement_approach":"Change from baseline in Tanner staging in Part 1."}
• {"endpoint_text":"- Percentage change from Baseline in CMSF during the OLE1 Treatment Period (Part 2)","definition_or_measurement_approach":"Percent change from baseline in CMSF during the OLE1 treatment period (Part 2)."}
• {"endpoint_text":"- 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)","definition_or_measurement_approach":"Categorized percent change in CMSF from baseline during OLE1 (Part 2)."}
• {"endpoint_text":"- Achievement of “near seizure freedom” (0 or 1 seizures) during T+M (Part 2)","definition_or_measurement_approach":"Proportion achieving 0 or 1 seizures during T+M (Part 2)."}
• {"endpoint_text":"- 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)","definition_or_measurement_approach":"CGI-I ratings by investigator and parent/caregiver at end of OLE1 (Part 2)."}
• {"endpoint_text":"- 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)","definition_or_measurement_approach":"Investigator-assessed CGI-I improvement categories at end of OLE1 (Part 2)."}
• {"endpoint_text":"- 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)","definition_or_measurement_approach":"Parent/caregiver-assessed CGI-I improvement categories at end of OLE1 (Part 2)."}
• {"endpoint_text":"- Percentage change from Baseline in monthly GTC seizure frequency during the OLE1 Treatment Period (Part 2)","definition_or_measurement_approach":"Percent change from baseline in monthly GTC seizure frequency during OLE1 (Part 2)."}
• {"endpoint_text":"- Change from Baseline in the monthly frequency of CMS-free days during the OLE1 Treatment Period (Part 2)","definition_or_measurement_approach":"Change from baseline in monthly frequency of CMS-free days during OLE1 (Part 2)."}

Methods

• Advocacy factsheets distributed to patient groups and caregivers (country-specific factsheets available, e.g., BE/IE/DE/AT/IT/PT/ES/NL).
• Social media awareness messages and campaigns to raise study awareness (materials prepared per country/language).
• Study brochures and study-specific informational brochures for potential participants and caregivers.
• Digital registration pack / information on website (digital registry information pages) for interested participants.
• Recruitment procedure descriptions (K1 documents) and local recruitment arrangements published for each country.
• Use of patient organisation/advocacy partnerships and targeted outreach to epilepsy/CDKL5 communities.

Ireland

Earliest CTIS Part Ii Submission Date

24-07-2024

Latest Decision Or Authorization Date

08-01-2025

Processing Time Days

168

Number Of Sites

2

Number Of Participants

2

Germany

Earliest CTIS Part Ii Submission Date

24-07-2024

Latest Decision Or Authorization Date

15-12-2025

Processing Time Days

509

Number Of Sites

4

Number Of Participants

9

Austria

Earliest CTIS Part Ii Submission Date

24-07-2024

Latest Decision Or Authorization Date

15-12-2025

Processing Time Days

509

Number Of Sites

1

Number Of Participants

3

Netherlands

Earliest CTIS Part Ii Submission Date

24-07-2024

Latest Decision Or Authorization Date

16-12-2025

Processing Time Days

510

Number Of Sites

1

Number Of Participants

4

Portugal

Earliest CTIS Part Ii Submission Date

24-07-2024

Latest Decision Or Authorization Date

12-12-2025

Processing Time Days

506

Number Of Sites

2

Number Of Participants

3

Italy

Earliest CTIS Part Ii Submission Date

24-07-2024

Latest Decision Or Authorization Date

12-12-2025

Processing Time Days

506

Number Of Sites

6

Number Of Participants

18

Belgium

Earliest CTIS Part Ii Submission Date

24-07-2024

Latest Decision Or Authorization Date

16-12-2025

Processing Time Days

510

Number Of Sites

2

Number Of Participants

5

Spain

Earliest CTIS Part Ii Submission Date

24-07-2024

Latest Decision Or Authorization Date

25-04-2026

Processing Time Days

640

Number Of Sites

3

Number Of Participants

18

Primary sponsor

Full Name

Zogenix International Limited

Organisation Type

Pharmaceutical company

Country Of Registered Address

United Kingdom

Contract research organisations

Name

Icon Clinical Research Limited

Responsibilities

Project Management, Clinical Operations, Data Management, Medical Monitoring, Regulatory, Clinical Logistics, safety reporting, Clinical Site Agreements, Vendor Management

Name

Parexel International (IRL) Limited

Responsibilities

Safety - SUSAR reporting

Third parties

• {"country":"Ireland","full_name":"Icon Clinical Research Limited","duties_or_roles":"Project Management, Clinical Operations, Data Management, Medical Monitoring, Regulatory, Clinical Logistics, safety reporting, Clinical Site Agreements, Vendor Management","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Bioclinica Inc.","duties_or_roles":"ECG and Echo collection","organisation_type":"Laboratory/Research/Testing facility"}
• {"country":"United States","full_name":"Kcas LLC","duties_or_roles":"","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Sitero LLC","duties_or_roles":"","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Elligo Health Research Inc.","duties_or_roles":"Patient Travel and Patient reimbursement","organisation_type":"Laboratory/Research/Testing facility"}
• {"country":"Ireland","full_name":"Signant Health Global Solutions Limited","duties_or_roles":"eCOA collection","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"RWS Life Sciences Inc.","duties_or_roles":"Scales & Linguistic validation services","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Center For Information And Study On Clinical Research Participation Inc.","duties_or_roles":"","organisation_type":"Patient organisation/association"}
• {"country":"France","full_name":"Quipment","duties_or_roles":"Clinical Supplies","organisation_type":"Non-Pharmaceutical company"}
• {"country":"Ireland","full_name":"Parexel International (IRL) Limited","duties_or_roles":"Safety - SUSAR reporting","organisation_type":"Pharmaceutical company"}
• {"country":"Canada","full_name":"Altasciences Compagnie Inc.","duties_or_roles":"","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Epilepsy Study Consortium Inc.","duties_or_roles":"Seizure Identification and Diagnostic Review (SIF/DRF)","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Eurofins Central Laboratory LLC","duties_or_roles":"","organisation_type":"Laboratory/Research/Testing facility"}
• {"country":"United States","full_name":"ICPD: Institute for Clinical Pharmcodynamics","duties_or_roles":"","organisation_type":"Health care"}
• {"country":"United States","full_name":"National Medical Services Inc.","duties_or_roles":"","organisation_type":"Laboratory/Research/Testing facility"}