Tuberous Sclerosis Complex
Conditions
Keywords
Tuberous Sclerosis Complex-Related Epilepsy, Ganaxolone, Adjunctive
Brief summary
This is a Phase 3, global, open-label extension (OLE) study of adjunctive GNX treatment in children and adults with TSC who previously participated in either Study 1042-TSC-3001 or Study 1042-TSC-2001
Interventions
DRUGGanaxolone
GNX will be administered.
Sponsors
Marinus Pharmaceuticals
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Masking description
This is an open-label, single arm study with no blinding as all participants will receive adjunctive GNX
Eligibility
Sex/Gender
ALL
Age
1 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
1. Completion of Study 1042-TSC-3001 or participants who continue to meet study requirements in Study 1042-TSC-2001. 2. Participant/parent(s)/LAR(s) willing and able to give written informed consent/assent, after being properly informed of the nature and risks of the study and prior to engaging in any study-related procedures. If the participant is not qualified or able to provide written informed consent based on age, developmental stage, intellectual capacity, or other factors, parent(s)/LAR(s) must provide assent for study participation, if appropriate. 3. Parent(s)/caregiver(s) is (are) willing and able to maintain an accurate and complete daily seizure diary for the duration of the study. 4. Willing and able to take Investigational product (IP) (suspension) as directed with food TID. 5. Women of childbearing potential (WOCBP) must be using a medically acceptable method of birth control and have a negative quantitative serum beta-human chorionic growth hormone (β-HCG) test collected at the initial visit. Childbearing potential is defined as a female who is biologically capable of becoming pregnant. Medically acceptable methods of birth control include intrauterine devices (that have been in place for at least 1 month prior to the screening visit), hormonal contraceptives (eg, combined oral contraceptives, patch, vaginal ring, injectables, and implants), and surgical sterilization (such as oophorectomy or tubal ligation). When used consistently and correctly, double-barrier methods of contraception can be used as an effective alternative to highly effective contraception methods. Contraceptive measures such as Plan B™, sold for emergency use after unprotected sex, are not acceptable methods for routine use 6. Male participants must agree to use highly effective contraceptive methods during the study and for 30 days after the last dose of IP. Highly effective methods of contraception include surgical sterilization (such as a vasectomy) and adequate double-barrier methods.
Exclusion criteria
1. Pregnant or breastfeeding. 2. An active Central nervous system (CNS) infection, demyelinating disease, or degenerative neurological disease. 3. History of psychogenic nonepileptic seizures. 4. Any disease or condition (other than TSC) at the initial visit that could compromise the hematologic, cardiovascular (including any cardiac conduction defect), pulmonary, renal, gastrointestinal, or hepatic systems; or other conditions that might interfere with the absorption, distribution, metabolism, or excretion of the IP, or would place the participant at increased risk or interfere with the assessment of safety/efficacy. This may include any illness in the past 4 weeks which in the opinion of the investigator may affect seizure frequency. 5. Unwillingness to avoid excessive alcohol use or cannabis use throughout the study. 6. Have active suicidal plan/intent or have had active suicidal thoughts in the past 6 months or a suicide attempt in the past 6 months. 7. Known sensitivity or allergy to any component in the IP(s), progesterone, or other related steroid compounds. 8. Exposed to any other investigational drug (except for GNX in Study 1042-TSC-2001 or Study 1042-TSC-3001) or investigational device within 30 days or fewer than 5 half-lives prior to Visit 1 (first visit of the OLE). For therapies in which half-life cannot be readily established, the Sponsor's medical monitor should be consulted.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants (Age Greater Than 17 Years) With Abnormal Columbia-Suicide Severity Rating Scale (C-SSRS) | Up to Week 52 | The C-SSRS is a clinician administered assessment tool that evaluates suicidal ideation and behavior. Number of participants that have an affirmative response to the 5 items for suicidal ideation (1. Wish to be dead, 2. Non-specific active suicidal thoughts, 3. Active suicidal ideation with any methods (not plan) without intent to act, 4. Active suicidal ideation with some intent to act, without specific plan, 5. Active suicidal ideation with specific plan and intent) and/or to the 5 items for suicidal behavior (1. Preparatory acts or behavior, 2. Aborted attempt, 3. Interrupted attempt, 4. Actual attempt, 5. Completed suicide) will be reported. The score ranges from 1 to 5 and higher scores indicate worse symptoms. |
| Number of Participants Reporting Treatment Emergent Adverse Events (TEAEs), Serious TEAEs and Withdrawals and Dose-Reductions Due to AEs | Up to 150 Weeks | An adverse event (AE) was any untoward medical occurrence in a clinical study patient, temporally associated with the use of study drug, whether or not considered related to the study drug. A serious adverse event was any untoward medical occurrence that, at any dose, results in death, is life threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect, or any other event that requires scientific judgment. |
| Number of Participants With Clinically Significant Changes in Vital Parameters | Up to 150 Weeks | Vital parameters including heart rate, respiration rate, blood pressure, and body temperature were measured in seated position for at least 5 minutes. |
| Number of Participants With Clinically Significant Changes in Physical Examinations | Up to 150 Weeks | Physical examinations included a full physical evaluation of body systems including: General appearance, head (eyes, ears, nose, and throat), cardiovascular, respiratory, gastrointestinal, genitourinary, musculoskeletal, endocrine/metabolic, hematologic/lymphatic, skin, and other systems as appropriate. |
| Number of Participants With Clinically Significant Changes in Neurological Examinations | Up to 150 Weeks | Neurological examinations included an evaluation of: Cranial nerves, motor exam, sensory exam, reflexes, coordination/cerebellar |
| Number of Participants With Clinically Significant Changes in Hematology Parameters | Week 1 through Week 150 | Blood samples were collected for the analysis of hematology parameters: hemoglobin, hematocrit, erythrocytes, thrombocytes (platelet count). Differential blood counts, including basophils, eosinophils, neutrophils, lymphocytes, and monocytes |
| Number of Participants With Clinically Significant Changes in Developmental Examinations | Up to 150 Weeks | Developmental examinations (applicable only to pediatric participants 1 to 17 years of age, inclusive) included an evaluation of speech/language, motor skills, and social skills |
| Number of Participants With Clinically Significant 12-lead Electrocardiogram (ECG) Findings | Up to 150 Weeks | Twelve-lead ECGs were performed by the physician using an ECG machine that automatically calculates the heart rate and measure PR, QRS, QT and QTc intervals. |
| Number of Participants With Clinically Significant Changes in Chemistry Parameters | Up to 150 Weeks | Blood samples were collected for the analysis of chemistry parameters: blood urea nitrogen (BUN), potassium, alanine aminotransferase (ALT), alkaline phosphatase (ALP)/serum glutamic pyruvic transaminase (SGPT), total bilirubin, creatinine, sodium, aspartate aminotransferase (AST)/serum glutamic oxaloacetic (SGOT), total protein, fasting blood glucose, calcium, carbon dioxide, estimated glomerular filtration rate (eGFR), and chloride |
| Number of Participants With Clinically Significant Changes in Urinalysis | Up to 150 Weeks | Urine samples were collected for the analysis of urinalysis parameters: Specific gravity, color, clarity, pH, glucose, protein, blood, nitrite, protein, ketones, bilirubin, urobilinogen, nitrite, leukocyte esterase by dipstick, and microscopic examination (if blood or protein was abnormal) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percent Change From Baseline in 28-day Seizure Frequency During Open Label Extension | Baseline (Day 1), Week 52 | Seizure frequency will be calculated as the total number of seizures divided by the number of days with seizure data, multiplied by 28. Percent change from baseline in 28-day frequency was calculated for each participant by subtracting Baseline 28-day seizure frequency from post-Baseline 28-day seizure frequency, whole divided by Baseline 28-day seizure frequency and multiplied by 100. |
Countries
Australia, Canada, China, France, Germany, Israel, Italy, Spain, United Kingdom, United States
Participant flow
Recruitment details
A total 117 participants entered the OLE phase and had received at least 1 dose of Ganaxolone (GNX). Of these 8 were previously in Study 1042-TCS-2001 and 109 were previously in Study 1042-TCS-3001 and met eligibility criteria for continued treatment.
Pre-assignment details
Participants who completed Study 1042-TCS-2001 and 1042-TCS-3001 were enrolled in the Open-Label Extension (OLE) phase and the study was terminated prematurely due to Sponsor decision.
Participants by arm
| Arm | Count |
|---|---|
| Ganaxolone (GNX) Oral Suspension, 3 Times a Day (TID) Participants received 50 mg/mL oral suspension containing 110 mL Ganaxolone (GNX), 3 times a day (TID) with food. | 117 |
| Total | 117 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 6 |
| Overall Study | Early study termination by sponsor | 77 |
| Overall Study | Lack of Efficacy | 5 |
| Overall Study | Lost to Follow-up | 6 |
| Overall Study | Other | 6 |
| Overall Study | Physician Decision | 6 |
| Overall Study | Withdrawal by Subject | 11 |
Baseline characteristics
| Characteristic | Ganaxolone (GNX) Oral Suspension, 3 Times a Day (TID) |
|---|---|
| Age, Continuous | 16.4 years STANDARD_DEVIATION 11.2 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 16 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 100 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants |
| Race (NIH/OMB) Asian | 24 Participants |
| Race (NIH/OMB) Black or African American | 8 Participants |
| Race (NIH/OMB) More than one race | 2 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 82 Participants |
| Sex: Female, Male Female | 62 Participants |
| Sex: Female, Male Male | 55 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 1 / 117 |
| other Total, other adverse events | 79 / 117 |
| serious Total, serious adverse events | 21 / 117 |
Outcome results
Primary
Number of Participants (Age Greater Than 17 Years) With Abnormal Columbia-Suicide Severity Rating Scale (C-SSRS)
The C-SSRS is a clinician administered assessment tool that evaluates suicidal ideation and behavior. Number of participants that have an affirmative response to the 5 items for suicidal ideation (1. Wish to be dead, 2. Non-specific active suicidal thoughts, 3. Active suicidal ideation with any methods (not plan) without intent to act, 4. Active suicidal ideation with some intent to act, without specific plan, 5. Active suicidal ideation with specific plan and intent) and/or to the 5 items for suicidal behavior (1. Preparatory acts or behavior, 2. Aborted attempt, 3. Interrupted attempt, 4. Actual attempt, 5. Completed suicide) will be reported. The score ranges from 1 to 5 and higher scores indicate worse symptoms.
Time frame: Up to Week 52
Population: Safety Analysis Set. Only those participants with data available at specified timepoints have been analyzed
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Ganaxolone (GNX) Oral Suspension, 3 Times a Day (TID) | Number of Participants (Age Greater Than 17 Years) With Abnormal Columbia-Suicide Severity Rating Scale (C-SSRS) | Suicidal Behavior: Aborted attempt | 0 Participants |
| Ganaxolone (GNX) Oral Suspension, 3 Times a Day (TID) | Number of Participants (Age Greater Than 17 Years) With Abnormal Columbia-Suicide Severity Rating Scale (C-SSRS) | Suicidal Behavior: Interrupted attempt | 0 Participants |
| Ganaxolone (GNX) Oral Suspension, 3 Times a Day (TID) | Number of Participants (Age Greater Than 17 Years) With Abnormal Columbia-Suicide Severity Rating Scale (C-SSRS) | Suicidal Behavior: Completed suicide | 0 Participants |
| Ganaxolone (GNX) Oral Suspension, 3 Times a Day (TID) | Number of Participants (Age Greater Than 17 Years) With Abnormal Columbia-Suicide Severity Rating Scale (C-SSRS) | Suicidal Ideation: Non-specific Active thoughts | 0 Participants |
| Ganaxolone (GNX) Oral Suspension, 3 Times a Day (TID) | Number of Participants (Age Greater Than 17 Years) With Abnormal Columbia-Suicide Severity Rating Scale (C-SSRS) | Suicidal Behavior: Preparatory acts or behavior | 0 Participants |
| Ganaxolone (GNX) Oral Suspension, 3 Times a Day (TID) | Number of Participants (Age Greater Than 17 Years) With Abnormal Columbia-Suicide Severity Rating Scale (C-SSRS) | Suicidal Behavior: Actual attempt | 0 Participants |
| Ganaxolone (GNX) Oral Suspension, 3 Times a Day (TID) | Number of Participants (Age Greater Than 17 Years) With Abnormal Columbia-Suicide Severity Rating Scale (C-SSRS) | Suicidal Ideation: Wish to be dead | 0 Participants |
| Ganaxolone (GNX) Oral Suspension, 3 Times a Day (TID) | Number of Participants (Age Greater Than 17 Years) With Abnormal Columbia-Suicide Severity Rating Scale (C-SSRS) | Suicidal Ideation: Active ideation without intention to act | 0 Participants |
| Ganaxolone (GNX) Oral Suspension, 3 Times a Day (TID) | Number of Participants (Age Greater Than 17 Years) With Abnormal Columbia-Suicide Severity Rating Scale (C-SSRS) | Suicidal Ideation: Active ideation with some intent to act without a plan | 0 Participants |
| Ganaxolone (GNX) Oral Suspension, 3 Times a Day (TID) | Number of Participants (Age Greater Than 17 Years) With Abnormal Columbia-Suicide Severity Rating Scale (C-SSRS) | Suicidal Ideation: Active ideation with a specific plan and intent | 0 Participants |
| Ganaxolone (GNX) Oral Suspension, 3 Times a Day (TID) | Number of Participants (Age Greater Than 17 Years) With Abnormal Columbia-Suicide Severity Rating Scale (C-SSRS) | Non-suicidal Self-Injurious Behavior | 1 Participants |
Primary
Number of Participants Reporting Treatment Emergent Adverse Events (TEAEs), Serious TEAEs and Withdrawals and Dose-Reductions Due to AEs
An adverse event (AE) was any untoward medical occurrence in a clinical study patient, temporally associated with the use of study drug, whether or not considered related to the study drug. A serious adverse event was any untoward medical occurrence that, at any dose, results in death, is life threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect, or any other event that requires scientific judgment.
Time frame: Up to 150 Weeks
Population: Safety Analysis Set
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Ganaxolone (GNX) Oral Suspension, 3 Times a Day (TID) | Number of Participants Reporting Treatment Emergent Adverse Events (TEAEs), Serious TEAEs and Withdrawals and Dose-Reductions Due to AEs | Withdrawals Due to AEs | 6 Participants |
| Ganaxolone (GNX) Oral Suspension, 3 Times a Day (TID) | Number of Participants Reporting Treatment Emergent Adverse Events (TEAEs), Serious TEAEs and Withdrawals and Dose-Reductions Due to AEs | Dose-Reduction Due to AEs | 16 Participants |
| Ganaxolone (GNX) Oral Suspension, 3 Times a Day (TID) | Number of Participants Reporting Treatment Emergent Adverse Events (TEAEs), Serious TEAEs and Withdrawals and Dose-Reductions Due to AEs | Any serious TEAE | 21 Participants |
| Ganaxolone (GNX) Oral Suspension, 3 Times a Day (TID) | Number of Participants Reporting Treatment Emergent Adverse Events (TEAEs), Serious TEAEs and Withdrawals and Dose-Reductions Due to AEs | Any TEAE | 79 Participants |
Primary
Number of Participants With Clinically Significant 12-lead Electrocardiogram (ECG) Findings
Twelve-lead ECGs were performed by the physician using an ECG machine that automatically calculates the heart rate and measure PR, QRS, QT and QTc intervals.
Time frame: Up to 150 Weeks
Population: Safety Analysis Set
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Ganaxolone (GNX) Oral Suspension, 3 Times a Day (TID) | Number of Participants With Clinically Significant 12-lead Electrocardiogram (ECG) Findings | 0 Participants |
Primary
Number of Participants With Clinically Significant Changes in Chemistry Parameters
Blood samples were collected for the analysis of chemistry parameters: blood urea nitrogen (BUN), potassium, alanine aminotransferase (ALT), alkaline phosphatase (ALP)/serum glutamic pyruvic transaminase (SGPT), total bilirubin, creatinine, sodium, aspartate aminotransferase (AST)/serum glutamic oxaloacetic (SGOT), total protein, fasting blood glucose, calcium, carbon dioxide, estimated glomerular filtration rate (eGFR), and chloride
Time frame: Up to 150 Weeks
Population: Safety Analysis Set
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Ganaxolone (GNX) Oral Suspension, 3 Times a Day (TID) | Number of Participants With Clinically Significant Changes in Chemistry Parameters | 0 Participants |
Primary
Number of Participants With Clinically Significant Changes in Developmental Examinations
Developmental examinations (applicable only to pediatric participants 1 to 17 years of age, inclusive) included an evaluation of speech/language, motor skills, and social skills
Time frame: Up to 150 Weeks
Population: Safety Analysis Set. Only pediatric participants of 1 to 17 years of age were analyzed.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Ganaxolone (GNX) Oral Suspension, 3 Times a Day (TID) | Number of Participants With Clinically Significant Changes in Developmental Examinations | 0 Participants |
Primary
Number of Participants With Clinically Significant Changes in Hematology Parameters
Blood samples were collected for the analysis of hematology parameters: hemoglobin, hematocrit, erythrocytes, thrombocytes (platelet count). Differential blood counts, including basophils, eosinophils, neutrophils, lymphocytes, and monocytes
Time frame: Week 1 through Week 150
Population: Safety Analysis Set
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Ganaxolone (GNX) Oral Suspension, 3 Times a Day (TID) | Number of Participants With Clinically Significant Changes in Hematology Parameters | 0 Participants |
Primary
Number of Participants With Clinically Significant Changes in Neurological Examinations
Neurological examinations included an evaluation of: Cranial nerves, motor exam, sensory exam, reflexes, coordination/cerebellar
Time frame: Up to 150 Weeks
Population: Safety Analysis Set
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Ganaxolone (GNX) Oral Suspension, 3 Times a Day (TID) | Number of Participants With Clinically Significant Changes in Neurological Examinations | 0 Participants |
Primary
Number of Participants With Clinically Significant Changes in Physical Examinations
Physical examinations included a full physical evaluation of body systems including: General appearance, head (eyes, ears, nose, and throat), cardiovascular, respiratory, gastrointestinal, genitourinary, musculoskeletal, endocrine/metabolic, hematologic/lymphatic, skin, and other systems as appropriate.
Time frame: Up to 150 Weeks
Population: Safety Analysis Set
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Ganaxolone (GNX) Oral Suspension, 3 Times a Day (TID) | Number of Participants With Clinically Significant Changes in Physical Examinations | 0 Participants |
Primary
Number of Participants With Clinically Significant Changes in Urinalysis
Urine samples were collected for the analysis of urinalysis parameters: Specific gravity, color, clarity, pH, glucose, protein, blood, nitrite, protein, ketones, bilirubin, urobilinogen, nitrite, leukocyte esterase by dipstick, and microscopic examination (if blood or protein was abnormal)
Time frame: Up to 150 Weeks
Population: Safety Analysis Set
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Ganaxolone (GNX) Oral Suspension, 3 Times a Day (TID) | Number of Participants With Clinically Significant Changes in Urinalysis | 0 Participants |
Primary
Number of Participants With Clinically Significant Changes in Vital Parameters
Vital parameters including heart rate, respiration rate, blood pressure, and body temperature were measured in seated position for at least 5 minutes.
Time frame: Up to 150 Weeks
Population: Safety Analysis Set
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Ganaxolone (GNX) Oral Suspension, 3 Times a Day (TID) | Number of Participants With Clinically Significant Changes in Vital Parameters | 0 Participants |
Secondary
Percent Change From Baseline in 28-day Seizure Frequency During Open Label Extension
Seizure frequency will be calculated as the total number of seizures divided by the number of days with seizure data, multiplied by 28. Percent change from baseline in 28-day frequency was calculated for each participant by subtracting Baseline 28-day seizure frequency from post-Baseline 28-day seizure frequency, whole divided by Baseline 28-day seizure frequency and multiplied by 100.
Time frame: Baseline (Day 1), Week 52
Population: Intent to Treat comprised all participants who received at least 1 dose of the IP. Only those participants with data available at specified timepoints have been analyzed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ganaxolone (GNX) Oral Suspension, 3 Times a Day (TID) | Percent Change From Baseline in 28-day Seizure Frequency During Open Label Extension | -31.59 percent change | Standard Deviation 113.997 |