| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Drug-Resistant Epilepsy with Partial-Onset Seizures |
|
| E.1.1.1 | Medical condition in easily understood language |
| Epilepsy with Seizures which are partial and are Resistant to therapy |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Nervous System Diseases [C10] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 19.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10015037 |
| E.1.2 | Term | Epilepsy |
| E.1.2 | System Organ Class | 10029205 - Nervous system disorders |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
To evaluate efficacy of ganaxolone compared to placebo as adjunctive therapy in adults with partial-onset seizures (POS), with or without secondary
generalizations. |
|
| E.2.2 | Secondary objectives of the trial |
Secondary Objectives:
• To evaluate the safety and tolerability of ganaxolone compared to placebo as adjunctive therapy in adults with POS.
• To evaluate serum levels of ganaxolone at 1200 mg/d and 1800 mg/d after chronic dosing
• To evaluate the safety and tolerability of ganaxolone when administered |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Written consent.
2. Willing to participate for the full term of 9 or 14-week double blind phase and willing to enter into the open-label phase.
3. Male/Female outpatients >18 years of age.
4. Confident diagnosis of drug-resistant epilepsy with POS with or without secondary generalization (classified according to International League Against Epilepsy Guidelines [Guy, 1981] and as determined by secondary review by the Epilepsy Consortium) for ≥2 years and is having POS despite having been treated in the past with ≥2 approved anti-epilepsy drugs (AEDs) either alone or in combination at adequate doses for a sufficient length of time in the opinion of the investigator. Diagnosis should have been established by clinical history, electroencephalogram (EEG) or video EEG with results consistent with partialonset epilepsy, and computerized tomography (CT) or magnetic resonance imaging (MRI) of the brain to rule out progressive structural lesions within the last 10 years.
5. Based on documented history of POS, the investigator judges that the subject is likely to have 3 or more POS* during any 4-week period prior to study treatment, i.e., rarely falls below that threshold with usual fluctuations. Further, the pattern of seizures makes it unlikely the subject will have 21 seizure-free days in any 4-week period prior to study treatment.
* POS includes complex partial seizures [CPS], and simple partial seizures [SPS] with motor expression. Partial seizures may be seizures secondarily generalized [SGTC]. Subjects who only have simple partial seizures without any observable motor component will NOT be eligible to participate in this study.
6. Currently being treated and maintained with a stable regimen of 1, 2, or 3 AEDs for ≥1 month prior to the screening visit, without a foreseeable change in dosing for the duration of the double-blind phase of the study (AEDs may be adjusted during the open-label phase of the study).
a. Barbituates: If the subject is taking barbiturates (e.g., phenobarbital), the dose of the barbiturate must have been stable for ≥3 months prior to the
screening visit.
b. Vagus Nerve Stimulator (VNS): VNS will not be counted towards the number of concomitant AEDs. Subjects with surgically implanted VNS
will be allowed to enter the study provided that all of the following conditions are met:
i. The VNS has been in place for ≥1 year prior to the screening visit
ii. The settings must have remained constant for ≥3 months prior to the screening visit and remain constant throughout the study
iii. The battery is expected to last for the duration of DB Phase I (9 or 14 weeks) of the study
c. Benzodiazepines: The chronic use of a benzodiazepine as a concurrent AED is permitted as long as the dose has been stable for ≥1 month prior to the screening visit and remains constant throughout the study. See Section9.4.10 for use of benzodiazepines for seizure rescue or for other
indications.
d. Felbamate: The use of felbamate is allowed provided that the subject has been maintained on a stable dose of felbamate for >18 months, and has had stable liver function (AST/ALT) and hematology during the course of treatment, and is expected to remain constant throughout the study.
e. Perampanel: The use of perampanel is allowed provided that the subject has been maintained on a stable dose of perampanel for >3 months and has not experienced any serious psychiatric and behavioral reactions such as hostility- and aggression- related adverse reactions.
7. Able and willing to maintain an accurate and complete daily written seizure calendar or has a caregiver who is able and willing to maintain an accurate and complete daily written seizure calendar.
8. Able and willing to take drug with food twice daily. Ganaxolone must be administered with food.
9. Sexually active women of childbearing potential (WCBP) must be using a medically acceptable method of birth control and have a negative qualitative serum β-human chorionic growth hormone (β-HCG) pregnancy test from a blood sample collected at the screening visit and negative urine pregnancy tests at baseline line and subsequent visits. A woman of childbearing potential is defined as a female who is biologically capable of becoming pregnant. A medically acceptable method of birth control includes intrauterine devices in place for at least 3 months, surgical sterilization, or adequate barrier methods (e.g., diaphragm and foam). An oral contraceptive alone is not considered adequate for the purpose of this study. Use of oral contraceptives in combination with another method (e.g., a spermicidal cream) is acceptable. In subjects who are not sexually active, abstinence is an acceptable form of birth control and β-HCG will be tested per protocol. Birth control should be continued for a minimum of 3 days after the last dose of study drug. |
|
| E.4 | Principal exclusion criteria |
1. Have had previous exposure to ganaxolone.
2. Known sensitivity or allergy to any component in the study drug, progesterone, or other related steroid compounds.
3. Exposure to any investigational drug or device <30 days prior to screening, or plans to take another investigational drug at any time during the study.
4. Time of onset of epilepsy treatment <2 years prior to enrollment
5. Have generalized epilepsy, such as Lennox-Gastaut syndrome, juvenile myoclonic epilepsy, absence epilepsy, or non-epileptic seizures within the last 12- month period prior to study entry.
6. Have less than 3 POS seizures in a 28-day period or more than 21 consecutive seizure-free days during the 8-week baseline period.
7. Have only simple partial seizures without any observable motor component.
8. Have innumerable seizures or status epilepticus within the last 12-months prior to screening.
9. Have more than 100 POS total (complex partial seizures [CPS] only + simple partial seizures [SPS] with motor (both types with or without secondary generalized tonic-clonic seizures [SGTC]) per each 4-week baseline period.
10. Seizures secondary to illicit drug or alcohol use, infection, neoplasm, demyelinating disease, degenerative neurological disease, or central nervous system (CNS) disease deemed progressive, metabolic illness, or progressive degenerative disease.
11. Current use of vigabatrin is not permitted, as well as prior use of vigabatrin without stable visual fields tested prior to screening. If used during the last 12 months two visual field tests are required.
12. Current use of ezogabine (retigabine; Potiga; Trobalt) is not permitted. Subjects who may have used this agent in the past should have been off this medication for at least 3 months prior to screening and should have had a documented normal fundoscopic exam by an ophthalmologist.
13. Are planning surgery, or to be evaluated for surgery, during the 9 or 14-week double blind phase to control seizures including those subjects who are considering implantation of a VNS device.
14. Are suffering from acute or progressive neurological disease, moderate or severe psychiatric disease, or severe mental abnormalities that are likely to require changes in pharmacotherapy during the 9 or 14-week double blind portion of the study or interfere with the objectives of the study or the ability to adhere to the protocol requirements.
15. Have active suicidal plan/intent, or have had active suicidal thoughts in the past 6 months.
16. Have a history of an actual suicide attempt in the last 5 years or more than 1 lifetime actual suicide attempt as classified by the Columbia-Suicide Severity Rating Scale (C-SSRS).
17. Have a positive urine drug screen at Screening or meet criteria for current or historical Substance Use Disorder (DSM-V criteria) within the past 5 years. As with other AEDs, the use of alcohol is not advised.
18. Have any medical condition that, in the investigator's judgment, is considered to be clinically significant and could potentially affect subject safety or study outcome, including but not limited to: clinically significant cardiac, renal, pulmonary, gastrointestinal, hematologic or hepatic conditions; or a condition that affects the absorption, distribution, metabolism or excretion of drugs.
19. Have Alanine transferase (ALT; SGPT) or Aspartate transferase (AST; SGOT) levels >3 times upper limits of normal (ULN), or total bilirubin >1.5 time ULN at the screening and baseline visits.
20. Have a history of malignancy within the past 2 years, with the exception of basal cell carcinoma.
21. Are currently following or planning to follow a ketogenic diet.
22. Use of dietary supplements or herbal preparations are not permitted if subject has been using them consistently for less than 6 months prior to screening, or does not plan on remaining on stable doses for the duration of the double blind phase. Use of St. John’s Wort is not permitted (See Section 9.4.11: Excluded, Prior, and Concomitant Medications).
23. Females who are pregnant, currently breastfeeding or planning to become pregnant during the duration of the study.
24. A history of chronic noncompliance with drug regimens.
25. Inability to withhold grapefruit and grapefruit juice from diet during the entire clinical trial (See Section 9.4.11: Excluded, Prior, and Concomitant Medications). |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Criteria for Efficacy Evaluation:
The primary efficacy endpoint for US Food and Drug Administration
registration is the percent change in the 28-day seizure frequency
(POS with or without secondary generalization) from baseline to the DB
phase for Cohort 2.
The primary endpoint analysis will consist of rank analysis of covariance
(ANCOVA) conducted on the percent change data, with treatment and
pooled countries as factors and the rank baseline seizure frequency per
28 days as a covariate.
The primary efficacy endpoint for European registration is 50%
responder rate during the maintenance treatment phase of the doubleblind
phase for Cohort 2. A 50%
responder is an individual who experiences at least a 50% decrease in
seizure frequency compared to baseline. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
The PRIMARY and secondary efficacy outcome measures will be
assessed for each of the time periods listed below in Cohort 1 DB phase
([a-e] below) and Cohort 1 + Cohort 2
OL if below:
a) Ganaxolone Titration + Maintenance 1200 mg/day + Maintenance
1800 mg/day vs Placebo (Cohort 1: Weeks 1-9).
b) Ganaxolone Maintenance 1200 mg/day + Maintenance 1800 mg/day
vs Placebo (Cohort 1: Weeks 2-9).
c) Ganaxolone Titration + Maintenance 1200 mg/d vs placebo (Cohort 1:
Weeks 1-5).
d) Ganaxolone Maintenance 1800 mg/d vs placebo (Cohort 1: Weeks 6-
9).
e) Ganaxolone maintenance 1200 mg/d vs placebo (Cohort 1: Weeks 2-
5).
f) OL (Cohort 1: Weeks 10-61; Cohort 2: Weeks 16-66). |
|
| E.5.2 | Secondary end point(s) |
Key secondary end-points
The three key secondary endpoints will be tested using a fixed sequence
procedure to protect the familywise error rate at 0.05. If the primary outcome measure is statistically significant, the p-values of the
secondary measures will be examined in the order listed below. The
process stops at the first p-value above 0.05.
# Responder rate (experiencing a ≥ 50% reduction) during the titration
+ maintenance treatment periods of the DB phase for Cohort 2
# Change in the number of seizure free days per 28-day period from
baseline during the titration + maintenance treatment periods of the DB
phase for Cohort 2
# Clinical Global Impression of Change – Improvement (CGI-I;
Investigator) at Week 14 of the double blind treatment phase relative to
the baseline for Cohort 2
All remaining secondary efficacy endpoints listed in the protocol will be
tested at alpha = .05 so all p-values are nominal.
Secondary efficacy outcome measures are listed below.
a) Percent change in the 28-day seizure frequency from baseline to the
DB phase during the maintenance treatment period for Cohort 2
b) Change from baseline in 28-day seizure frequency during the DB
phase for Cohort 2 (titration + maintenance and maintenance only).
c) Change in the number of seizure free days per 28-day period from
baseline during the maintenance treatment period of the DB phase for
Cohort 2
d) Proportion of responders experiencing a ≥R% reduction from baseline
to the end of treatment period in 28-day seizure frequency (titration +
maintenance and
maintenance only) for Cohort 2. R% will be 20%, 40%, 60%, and 80%
e) Proportion of subjects who completed the DB portion of the study
(Cohort 2) and did not experience any seizures during the maintenance
phase of the study
f) Proportion of subjects who experienced at least one 28-day seizure
free period during the DB phase of the study (titration + maintenance)
for Cohort 2
g) Longest period of time seizure free (%) (longest period of seizure
free days divided by number of days with available seizure data) during
the double blind
phase (titration + maintenance) for Cohort 2
h) Change from baseline in 28-day seizure frequency for different
subtypes of seizures during the DB portion of the study (titration +
maintenance) for Cohort
2 (SPS, SPS-motor, CPS, SGTC)
i) Patient Global Impression of Change – Improvement (PGI-I;
Patient/Caregiver) at each assessment visit
j) Clinical Global Impression of Change – Improvement (CGI-I;
Investigator) at each assessment visit. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
The primary and SECONDARY efficacy outcome measures will be
assessed for each of the time periods listed below in Cohort 1 DB phase
([a-e] below) and Cohort 1 + Cohort 2
OL if below:
a) Ganaxolone Titration + Maintenance 1200 mg/day + Maintenance
1800 mg/day vs Placebo (Cohort 1: Weeks 1-9).
b) Ganaxolone Maintenance 1200 mg/day + Maintenance 1800 mg/day
vs Placebo (Cohort 1: Weeks 2-9).
c) Ganaxolone Titration + Maintenance 1200 mg/d vs placebo (Cohort 1:
Weeks 1-5).
d) Ganaxolone Maintenance 1800 mg/d vs placebo (Cohort 1: Weeks 6-
9).
e) Ganaxolone maintenance 1200 mg/d vs placebo (Cohort 1: Weeks 2-
5).
f) OL (Cohort 1: Weeks 10-61; Cohort 2: Weeks 16-66). |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
| A double blind treatment phase is followed by an open label phase. |
|
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 7 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 20 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Australia |
| Bulgaria |
| Germany |
| Poland |
| Russian Federation |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
| LVLS (Last Visit of Last Subject). |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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