A Phase 3, Randomized, Double-Blind, Placebo-Controlled, Fixed-Dose, Multicenter Study To Examine The Efficacy And Safety Of ZX008 In Subjects With CDKL5 Deficiency Disorder Followed By An Open-Label Extension
概览
- 阶段
- 3 期
- 干预措施
- Fenfluramine
- 疾病 / 适应症
- CDKL5 Deficiency Disorder
- 发起方
- Zogenix, Inc.
- 入组人数
- 87
- 试验地点
- 90
- 主要终点
- The median percentage change from the Baseline Period (Baseline) in "monthly (28 days) countable motor seizure frequency
- 状态
- 进行中（未招募）
- 最后更新
- 3天前
概览
简要总结
This is a Phase 3 Study to examine the efficacy and safety of ZX008 in children and adults with cyclin-dependent kinase like-5 (CDKL5) deficiency disorder (CDD).
详细描述
This is an up to 3-part multicenter study: a double-blind, placebo-controlled part (Part 1) which includes Baseline Period (4 weeks), Titration Period (2 weeks), Maintenance Period (12 weeks) and Transition Period (2 weeks), followed by up to 2 open-label extension (OLE) parts: Part 2 of 54 weeks \[Treatment Period (52 weeks), Taper Period (2 weeks)\] and Part 3, i.e., OLE1 and OLE2, respectively, with the addition of the second OLE part (Part 3/OLE2) only for participants who will continue on fenfluramine and have no alternative treatment access from another source (e.g., a managed access program \[MAP\]). Participants can remain in Part 3 until MAP access or approval of fenfluramine (ZX008) has been obtained from regulatory authorities for CDD in the participant's country of residence, or until the investigational product development for CDD is stopped by the Sponsor, whichever comes first. Participants who discontinue early from Part 1, Part 2, or Part 3 will attend a Cardiac Follow-Up Visit 6 months after their last dose of study drug.
研究者
入排标准
入选标准
- •Subject has a confirmed pathogenic or likely pathogenic mutation in the CDKL5 gene and a clinical diagnosis of CDKL5 deficiency disorder (CDD) with epilepsy onset in the first year of life, plus motor and developmental delays.
- •Subject is male or female, aged 1 to 35 years, inclusive, as of the day of the Screening Visit.
- •Subject must have failed to achieve seizure control despite previous or current use of 2 or more antiepileptic treatments (AETs).
- •Subject is currently receiving at least 1 concomitant antiseizure treatment: antiseizure medication (ASM), vagus nerve stimulation (VNS), responsive neurostimulation (RNS), or ketogenic diet (KD).
- •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.
- •At the Screening Visit, parent/caregiver reports that subject has ≥ 4 countable motor seizures (CMS) per week.
排除标准
- •Subject has a known hypersensitivity to fenfluramine or any of the excipients in the study drug.
- •Subject has a diagnosis of pulmonary arterial hypertension.
- •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.
- •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).
- •Subject has current eating disorder that suggests anorexia nervosa or bulimia.
- •Subject has a current or past history of glaucoma.
- •Subject is taking \> 4 concomitant antiseizure medications (ASMs). Rescue medications are not included in the count.
- •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.
- •Subject has moderate to severe hepatic impairment.
- •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.
研究组 & 干预措施
Fenfluramine (hydrochloride) 0.8 mg/kg/day
Part 1: Fenfluramine (hydrochloride) 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.
干预措施: Fenfluramine
Fenfluramine (hydrochloride) Open-label
Part 2 and Part 3: Open-label fenfluramine (hydrochloride) will be administered using a flexible dosing regimen, up to fenfluramine 0.8 mg/kg/day; maximum dose: 30 mg/day (subjects taking concomitant stiripentol will receive 0.5 mg/kg/day, \[maximum of 20 mg/day\]). Fenfluramine (hydrochloride) will be administered twice a day (BID) in equally divided doses with or without food.
干预措施: Fenfluramine
Placebo
Part 1: Matching fenfluramine (hydrochloride) placebo will be administered twice a day (BID) in equally divided doses with or without food.
干预措施: Placebo
结局指标
主要结局
The median percentage change from the Baseline Period (Baseline) in "monthly (28 days) countable motor seizure frequency
时间窗: 14 Weeks
The median percentage change from the Baseline Period (Baseline) in "monthly (28 days) countable motor seizure frequency," or CMSF, during the combined Titration and Maintenance Periods (T+M) in the ZX008 0.8 mg/kg/day group compared with the placebo group
Percentage Change from Baseline in Countable Motor Seizure Frequency (CMSF) (Part 1)
时间窗: Baseline (28 days), Combined Titration and Maintenance (T+M) Periods (14 weeks)
The median percentage change from the Baseline in monthly (per 28 days) CMSF during the combined Titration and Maintenance Periods with the fenfluramine (ZX008) 0.8 mg/kg/day group compared with the placebo group will be reported.
Percentage of Participants with Pulmonary Arterial Hypertension (PASP > 35 mmHg) at any Time During Treatment on Repeat Testing (Part 2)
时间窗: OLE1 Treatment Period Day 1 to EoT/ET Visit 16 of OLE1 Treatment Period (up to 68 weeks)
Percentage of Participants With Treatment Emergent Adverse Events (TEAEs) (Part 2)
时间窗: Up to OLE1 Treatment Period Post-Dose Safety Follow-up Visit 17 (up to 70 weeks)
An adverse event (AE) is any untoward medical occurrence in a patient or clinical investigation participant administered a pharmaceutical product, which does not necessarily have a causal relationship with this treatment. Treatment Emergent Adverse Events (TEAEs) are defined as any AEs reported on or after the first dose of study medication.
Percentage of Participants With Abnormal Physical Examination Findings (Part 2)
时间窗: Up to End of Treatment (EoT)/Early Termination (ET) Visit 16 of OLE1 Treatment Period (up to 68 weeks)
Abnormal findings of physical exam that is considered clinically significant by Principal Investigator (PI).
Percentage of Participants With Abnormal Neurological Examination Findings (Part 2)
时间窗: Up to EoT/ET Visit 16 of OLE1 Treatment Period (up to 68 weeks)
Abnormal findings of neurological exam that is considered clinically significant by PI.
Percentage of Participants with Positive Response to Self-harm Question (Part 2)
时间窗: OLE1 Treatment Period Day 1 to OLE1 Treatment Period Post-Dose Safety Follow-up Visit 17 (up to 70 weeks)
Percentage of Participants with Increase in Valvular Regurgitation from Baseline (except absent to trace) (Part 2)
时间窗: Baseline (28 days), Cardiac Follow-up Visit 18 (up to 96 weeks)
Valvular regurgitation will be assessed using a 2-dimensional (2-D) Color Doppler Echocardiography (ECHO).
Change from Baseline in Laboratory Parameters (Hematology) (Part 2)
时间窗: Baseline (28 days), EoT/ET Visit 16 of OLE1 Treatment Period (up to 68 weeks)
Change from Baseline in Laboratory Parameters (Hormones) (Part 2)
时间窗: Baseline (28 days), EoT/ET Visit 16 of OLE1 Treatment Period (up to 68 weeks)
Change from Baseline in Laboratory parameters (Chemistry) (Part 2)
时间窗: Baseline (28 days), EoT/ET Visit 16 of OLE1 Treatment Period (up to 68 weeks)
Change from Baseline in Laboratory Parameters (Urinalysis) (Part 2)
时间窗: Baseline (28 days), EoT/ET Visit 16 of OLE1 Treatment Period (up to 68 weeks)
Change from Baseline in Vital Signs (Blood pressure) (Part 2)
时间窗: Baseline (28 days), EoT/ET Visit 16 of OLE1 Treatment Period (up to 68 weeks)
Change from Baseline in Vital Signs (Heart rate) (Part 2)
时间窗: Baseline (28 days), EoT/ET Visit 16 of OLE1 Treatment Period (up to 68 weeks)
Change from Baseline in Vital Signs (Temperature) (Part 2)
时间窗: Baseline (28 days), EoT/ET Visit 16 of OLE1 Treatment Period (up to 68 weeks)
Change from Baseline in Vital Signs (Respiratory rate) (Part 2)
时间窗: Baseline (28 days), EoT/ET Visit 16 of OLE1 Treatment Period (up to 68 weeks)
Change from Baseline in Body Weight (Part 2)
时间窗: Baseline (28 days), EoT/ET Visit 16 of OLE1 Treatment Period (up to 68 weeks)
Change from Baseline in Tanner Staging (Part 2)
时间窗: Baseline (28 days), EoT/ET Visit 16 of OLE1 Treatment Period (up to 68 weeks)
Percentage of Participants with TEAEs (Part 3)
时间窗: Up to OLE2 Period Post-Dose Safety Follow-up (up to 200 weeks)
An AE is any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product, which does not necessarily have a causal relationship with this treatment. Treatment Emergent Adverse Events are defined as any AEs reported on or after the first dose of study medication.
Change from Baseline in Height (Part 3)
时间窗: Baseline (28 days), OLE2 Period EoT/ET Visit 23 (up to 198 weeks)
Change from Baseline in Body Weight (Part 3)
时间窗: Baseline (28 days), OLE2 Period EoT/ET Visit 23 (up to 198 weeks)
Percentage of Participants with Increase in Valvular Regurgitation from Baseline (except absent to trace) (Part 3)
时间窗: Baseline (28 days), Cardiac Follow-up Visit (up to 295 weeks)
Valvular regurgitation will be assessed using a 2 D Color Doppler ECHO.
Percentage of Participants with Pulmonary Arterial Hypertension (PASP > 35 mmHg) at any Time During Treatment on Repeat Testing (Part 3)
时间窗: OLE2 Period Day 1 to EoT/ET Visit 23 of OLE2 Period (up to 198 weeks)
次要结局
- The percentage of subjects who achieve a ≥ 50% reduction from Baseline in CMSF(14 Weeks)
- The percentage of subjects who achieve improvement in the Clinical Global Impression-Improvement (CGI-I) rating as assessed by the Investigator(14 Weeks)
- The median percentage change from Baseline in monthly Generalized Tonic-Clonic (GTC) seizure frequency(14 Weeks)
- Percentage of Participants Who Achieve a ≥ 50% Reduction from Baseline in CMSF (Part 1)(Baseline (28 days), Combined T+M Periods (14 weeks))
- Percentage of Participants with a Clinical Global Impression-Improvement (CGI-I) Rating of 'Much Improved' or 'Very Much Improved' as Assessed by Investigator (Part 1)(At the end of the combined T+M Periods (14 weeks))
- Percentage Change From Baseline in Monthly Generalized Tonic-Clonic (GTC) Seizure Frequency (Part 1)(Baseline (28 days), Combined Titration and Maintenance (T+M) Periods (14 weeks))
- Categorized Percentage Change in Seizures from Baseline in CMSF (Part 1)(Baseline (28 days), Combined Titration and Maintenance (T+M) Periods (14 weeks))
- Percentage of Participants who Achieve "Near Seizure Freedom" (Part 1)(Combined T+M Periods (14 weeks))
- Percentage of Participants with a CGI-I Rating of 'Much Improved' or 'Very Much Improved' as Assessed by the Parent/Caregiver (Part 1)(At the end of the combined T+M Periods (14 weeks))
- Percentage of Participants with Improvement (Minimal, Much or Very Much Improved) on the CGI-I Rating as Assessed, Independently, by the Investigator (Part 1)(At the end of the combined T+M Periods (14 weeks))
- Percentage of Participants with Improvement (Minimal, Much or Very Much Improved) on the CGI-I Rating as Assessed, Independently, by the Parent/Caregiver (Part 1)(At the end of the combined T+M Periods (14 weeks))
- Percentage Change from Baseline in the Monthly Frequency of all Seizures (Part 1)(Baseline (28 days), Combined Titration and Maintenance (T+M) Periods (14 weeks))
- Change from Baseline in the Monthly Frequency of Countable Motor Seizure (CMS)-free Days (Part 1)(Baseline (28 days), Combined Titration and Maintenance (T+M) Periods (14 weeks))
- Percentage of Participants with TEAEs (Part 1)(From Day of first dose to the End of the Maintenance Periods (up to 14 weeks))
- Percentage of Participants With Abnormal Physical Examination Findings (Part 1)(Baseline, Visit 6 (Day 43), Visit 7 (Day 71), Visit 8 (Day 99))
- Percentage of Participants With Abnormal Neurological Examination Findings (Part 1)(Baseline, Visit 6 (Day 43), Visit 8 (Day 99))
- Percentage of Participants with Positive Response to Self-harm question (Part 1)(Baseline, Visit 5 (Day 15), Visit 6 (Day 43), Visit 7 (Day 71), Visit 8 (Day 99))
- Percentage of Participants with Increase in Valvular Regurgitation from Baseline (except absent to trace) (Part 1)(From Day of first dose to the End of the Maintenance Period (up to 14 weeks))
- Percentage of Participants with Pulmonary Arterial Hypertension (PASP > 35 mmHg) at any Time During Treatment on Repeat Testing (Part 1)(From Day of first dose to the End of the Maintenance Period (up to 14 weeks))
- Change from Baseline in Laboratory parameters (Hematology) (Part 1)(Baseline (28 days), end of the combined Titration and Maintenance (T+M) Periods (Day 99))
- Change from Baseline in Laboratory parameters (Hormones) (Part 1)(Baseline (28 days), end of the combined Titration and Maintenance (T+M) Periods (Day 99))
- Change from Baseline in Laboratory parameters (Chemistry) (Part 1)(Baseline (28 days), end of the combined Titration and Maintenance (T+M) Periods (Day 99))
- Change from Baseline in Laboratory Parameters (Urinalysis) (Part 1)(Baseline (28 days), end of the combined Titration and Maintenance (T+M) Periods (Day 99))
- Change from Baseline in Vital signs (Blood pressure) (Part 1)(Baseline (28 days), end of the combined Titration and Maintenance (T+M) Periods (Day 99))
- Change from Baseline in Vital signs (Heart rate) (Part 1)(Baseline (28 days), end of the combined Titration and Maintenance (T+M) Periods (Day 99))
- Change from Baseline in Vital signs (Temperature) (Part 1)(Baseline (28 days), end of the combined Titration and Maintenance (T+M) Periods (Day 99))
- Change from Baseline in Vital signs (Respiratory rate) (Part 1)(Baseline (28 days), end of the combined Titration and Maintenance (T+M) Periods (Day 99))
- Change from Baseline in Body Weight (Part 1)(Baseline (28 days), end of the combined Titration and Maintenance (T+M) Periods (Day 99))
- Change from Baseline in Tanner Staging (Part 1)(Baseline (28 days), end of the combined Titration and Maintenance (T+M) Periods (Day 99))
- Percentage Change from Baseline in CMSF (Part 2)(Baseline (28 days), OLE1 Treatment Period (up to 52 weeks))
- Categorized Percentage Change in Seizures from Baseline in CMSF (Part 2)(Baseline (28 days), OLE1 Treatment Period (up to 52 weeks))
- Percentage of Participants who Achieve "Near Seizure Freedom" (Part 2)(OLE1 Treatment Period (up to 52 weeks))
- Percentage of Participants with a CGI-I Rating of 'Much or Very Much Improved' as Assessed by the Investigator (Part 2)(At the End of the OLE1 Treatment Period (up to 52 weeks))
- Percentage of Participants with a CGI-I Rating of 'Much or Very Much Improved' as Assessed by the Parent/Caregiver (Part 2)(At the End of the OLE1 Treatment Period (up to 52 weeks))
- Percentage of Participants with Improvement (Minimal, Much or Very Much Improved) on the CGI-I Rating as Assessed, Independently, by the Investigator (Part 2)(At the End of the OLE1 Treatment Period (up to 52 weeks))
- Percentage of Participants with Improvement (Minimal, Much or Very Much Improved) on the CGI-I Rating as Assessed by the Parent/Caregiver (Part 2)(At the End of the OLE1 Treatment Period (up to 52 weeks))
- Percentage Change from Baseline in Monthly GTC Seizure Frequency (Part 2)(Baseline (28 days), OLE1 Treatment Period (up to 52 weeks))
- Change from Baseline in the Monthly Frequency of CMS-free Days (Part 2)(Baseline (28 days), OLE1 Treatment Period (up to 52 weeks))