Epilepsy, Tuberous Sclerosis Complex
Conditions
Brief summary
This phase I/II clinical trial is an open-label clinical trial design to verify safety and dosing for TAVT-18 (sirolimus) powder for oral solution in TSC infants (N=5).
Detailed description
Tuberous Sclerosis Complex (TSC) is caused by genetic mutation in TSC1 or TSC2, resulting in dysregulation of the mechanistic target of rapamycin (mTOR) signaling pathway. Age at time of seizure onset in TSC infants has been linked to long-term neurodevelopmental outcome in this high-risk population. TAVT-18 is a novel formulation of sirolimus, an mTOR inhibitor. This study evaluates TAVT-18 as a targeted, disease-modifying drug therapy for preventing or delaying seizure onset in TSC using a rational, mechanism-based therapeutic approach.
Interventions
DRUGTAVT-18 (sirolimus)
The investigational drug product to be used in this study is TAVT-18, a proprietary formulation of sirolimus in clinical development, by Tavanta Therapeutics, Inc. It is provided in a powder formulation in pre-measured vials.
Sponsors
Children's Hospital Medical Center, Cincinnati
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
PREVENTION
Masking
NONE
Intervention model description
This trial is a single stage, phase I/II clinical trial design. Treatment is open-label to verify safety and dosing for TAVT-18 in TSC infants. Note that this clinical trial originally planned for a follow-up second stage employing a randomized, double-blind, placebo-controlled multisite design. In October 2021, the second stage of this study was replaced by the TSC-STEPS clinical trial (clinicaltrials.gov NCT05104983).
Eligibility
Sex/Gender
ALL
Age
1 Days to 6 Months
Healthy volunteers
No
Inclusion criteria
* 0-6 months of age at the time of enrollment (randomization and treatment initiation must occur before 7 months of age and infants born prematurely must have a corrected age of at least 39 weeks, calculated by subtracting the number of weeks born before 40 weeks gestation from the actual chronological age, in weeks) * Has a confirmed diagnosis of TSC based on established clinical or genetic criteria
Exclusion criteria
* Prior history of seizures (clinical or electrographic) at the time of enrollment or identified on baseline EEG * Has been treated in the past or is currently being treated at the time of enrollment with conventional anticonvulsant medications (AEDs), systemic (oral) mTOR inhibitors (such as rapamycin, sirolimus, or everolimus), ketogenic-related special diet, or another anti-seizure therapeutic agent, device, or procedure * Has taken any other investigational drug as part of another research study, within 30 days prior to the baseline screening visit * Has a significant illness or active infection at the time of the baseline screening visit * Has a history of significant prematurity, defined as gestational age \<30 weeks at the time of delivery, or other significant medical complications at birth or during the neonatal period that other than TSC would convey additional risk of seizures or neurodevelopmental delay (i.e. HIE, severe neonatal infection, major surgery, prolonged ventilatory or other life-saving supportive care or procedures) * Abnormal laboratory values at baseline (i.e., renal function, liver function, or bone marrow production) that are in the opinion of the investigator clinically significant and may jeopardize the safety of the study subject * Prior, planned or anticipated neurosurgery within 3 months of the baseline visit * Has a TSC-associated condition for which mTOR treatment is clinically indicated (i.e. SEGA or AML) * Subjects who are, in the opinion of the investigator, unable to comply with the requirements of the study
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Safety - Adverse Events | 12 months of age | Percentage of subjects reporting severe (CTCAE v5.0 grade \>= 3) adverse event (AE) or serious adverse event (SAE) |
| Efficacy - Time to Seizure Onset | 12 months of age | Time from treatment initiation to seizure onset |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Precision Dosing Accuracy | 12 months of age | Blood trough concentration of sirolimus (ng/ml) |
| Age at Seizure Onset | 12 and 24 months of age | Patient age in months at time of seizure onset |
| Seizure Type | 12 and 24 months of age | Percentage of subjects reporting infantile spasms, focal seizures, or other seizure types |
| Treatment Discontinuance Due to Adverse Events | 12 months of age | Percentage of subjects that reduce or discontinue treatment due to an AE or SAE (any grade) |
| TAND Severity Assessed by the TAND-L Checklist | 12 and 24 months of age | Overall severity rating on the TSC-associated Neuropsychiatric Disorders-Lifetime Version (TAND-L) Checklist. The TAND-L Checklist severity rating ranges from 0-10, with higher values indicating greater concern. Parent Rating: Considering all of the issues reported today how much have these bothered, troubled, or distressed you/your child/family?; Min = 0 Max = 10; higher values indicate greater concern. Clinician Rating: Interviewer's judgement of impact/burden on the individual/child/family.; Min = 0 Max = 10; higher values indicate greater concern |
| Adaptive Behavior Assessed by the the VABS | 12 and 24 months of age | Composite score on the Vineland Adaptive Behavior Scales (VABS). The VABS composite score is normed to 100 = average or 50% percentile in normal populations, with lower values indicative of greater concern. Adaptive Scale: Minimum = 20, Maximum = 140, Standard deviation is +/- 15 |
| Global Neurodevelopment Assessed by the Bayley Scales of Infant Development | 12 and 24 months of age | Composite score on the Bayley Scales of Infant Development. The Bayley Scales of Infant Development is normed to 100 = average or 50% percentile in normal populations, with lower values indicative of greater concern. Cognitive Domain: Minimum = 40, Maximum = 160, Standard Deviation is +/- 15 Language Domain: Minimum = 40, Maximum = 160, Standard Deviation is +/- 15 Motor Doman: Minimum = 40, Maximum = 160, Standard Deviation is +/- 15 |
| Seizure Frequency | 12 and 24 months of age | Number of seizures in past 30 days |
| Treatment Disruption Due to Adverse Events | 12 months of age | Number of days treatment is withheld due to an AE or SAE (any grade). |
Countries
United States
Participant flow
Recruitment details
Five participants were screened; all five were eligible for enrollment.
Participants by arm
| Arm | Count |
|---|---|
| Stage 1 Open Label Phase I/II, open-label PK and initial safety analysis. TAVT-18 administered orally twice/daily to achieve precision dosing target of 10 ng/ml. Whole blood sirolimus levels are assessed at defined intervals on days 1, 7, and 14. After day 14, participants can elect to continue open-label treatment with TAVT-18 until 12 months of age. Final developmental outcomes are assessed at 24 months of age.
TAVT-18 (sirolimus): The investigational drug product to be used in this study is TAVT-18, a proprietary formulation of sirolimus in clinical development, by Tavanta Therapeutics, Inc. It is provided in a powder formulation in pre-measured vials. | 5 |
| Total | 5 |
Baseline characteristics
| Characteristic | Stage 1 Open Label |
|---|---|
| Age, Categorical <=18 years | 5 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants |
| Age, Continuous | 2.0 months |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 4 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 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 | 5 Participants |
| Region of Enrollment United States | 5 participants |
| Sex: Female, Male Female | 4 Participants |
| Sex: Female, Male Male | 1 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 5 |
| other Total, other adverse events | 5 / 5 |
| serious Total, serious adverse events | 0 / 5 |
Outcome results
Primary
Efficacy - Time to Seizure Onset
Time from treatment initiation to seizure onset
Time frame: 12 months of age
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Stage 1 Open Label | Efficacy - Time to Seizure Onset | 102 days |
Primary
Safety - Adverse Events
Percentage of subjects reporting severe (CTCAE v5.0 grade \>= 3) adverse event (AE) or serious adverse event (SAE)
Time frame: 12 months of age
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Stage 1 Open Label | Safety - Adverse Events | 40 percentage of participants |
Secondary
Adaptive Behavior Assessed by the the VABS
Composite score on the Vineland Adaptive Behavior Scales (VABS). The VABS composite score is normed to 100 = average or 50% percentile in normal populations, with lower values indicative of greater concern. Adaptive Scale: Minimum = 20, Maximum = 140, Standard deviation is +/- 15
Time frame: 12 and 24 months of age
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Stage 1 Open Label | Adaptive Behavior Assessed by the the VABS | 12 months of Age -- Adaptive Behavior Composite Score | 91 composite score |
| Stage 1 Open Label | Adaptive Behavior Assessed by the the VABS | 24 months of age -- Adaptive Behavior Composite Score | 88 composite score |
Secondary
Age at Seizure Onset
Patient age in months at time of seizure onset
Time frame: 12 and 24 months of age
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Stage 1 Open Label | Age at Seizure Onset | 10.6 months |
Secondary
Global Neurodevelopment Assessed by the Bayley Scales of Infant Development
Composite score on the Bayley Scales of Infant Development. The Bayley Scales of Infant Development is normed to 100 = average or 50% percentile in normal populations, with lower values indicative of greater concern. Cognitive Domain: Minimum = 40, Maximum = 160, Standard Deviation is +/- 15 Language Domain: Minimum = 40, Maximum = 160, Standard Deviation is +/- 15 Motor Doman: Minimum = 40, Maximum = 160, Standard Deviation is +/- 15
Time frame: 12 and 24 months of age
Population: 24 months of Age: Cognitive Domain only four of five participants completed this assessment as one participant became ill during visit. Language and Motor Domains only three of five participants completed these assessments as one became ill during visit and one participant became non-compliant during testing.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Stage 1 Open Label | Global Neurodevelopment Assessed by the Bayley Scales of Infant Development | 12 months of Age -- Cognitive Domain | 90 composite score |
| Stage 1 Open Label | Global Neurodevelopment Assessed by the Bayley Scales of Infant Development | 12 months of Age -- Language Domain | 89 composite score |
| Stage 1 Open Label | Global Neurodevelopment Assessed by the Bayley Scales of Infant Development | 12 months of Age -- Motor Domain | 87 composite score |
| Stage 1 Open Label | Global Neurodevelopment Assessed by the Bayley Scales of Infant Development | 24 months of Age -- Cognitive Domain | 95 composite score |
| Stage 1 Open Label | Global Neurodevelopment Assessed by the Bayley Scales of Infant Development | 24 months of Age -- Language Domain | 77 composite score |
| Stage 1 Open Label | Global Neurodevelopment Assessed by the Bayley Scales of Infant Development | 24 months of Age -- Motor Domain | 74 composite score |
Secondary
Precision Dosing Accuracy
Blood trough concentration of sirolimus (ng/ml)
Time frame: 12 months of age
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Stage 1 Open Label | Precision Dosing Accuracy | 6.6 ng/mL |
Secondary
Seizure Frequency
Number of seizures in past 30 days
Time frame: 12 and 24 months of age
Population: Five participants were enrolled in the study. Only three of the enrolled participants developed seizures during the course of the study.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Stage 1 Open Label | Seizure Frequency | 12 months of Age | 0 seizures |
| Stage 1 Open Label | Seizure Frequency | 24 months of Age | 0 seizures |
Secondary
Seizure Type
Percentage of subjects reporting infantile spasms, focal seizures, or other seizure types
Time frame: 12 and 24 months of age
Population: Five participants were enrolled in the study. Only three of the enrolled participants developed seizures during the course of the study.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Stage 1 Open Label | Seizure Type | 12 months of Age -- Infantile Spasms | 40 percentage of participants |
| Stage 1 Open Label | Seizure Type | 12 months of Age -- Focal Seizures | 20 percentage of participants |
| Stage 1 Open Label | Seizure Type | 24 months of Age -- Infantile Spasms | 40 percentage of participants |
| Stage 1 Open Label | Seizure Type | 24 months of Age -- Focal Seizures | 60 percentage of participants |
Secondary
TAND Severity Assessed by the TAND-L Checklist
Overall severity rating on the TSC-associated Neuropsychiatric Disorders-Lifetime Version (TAND-L) Checklist. The TAND-L Checklist severity rating ranges from 0-10, with higher values indicating greater concern. Parent Rating: Considering all of the issues reported today how much have these bothered, troubled, or distressed you/your child/family?; Min = 0 Max = 10; higher values indicate greater concern. Clinician Rating: Interviewer's judgement of impact/burden on the individual/child/family.; Min = 0 Max = 10; higher values indicate greater concern
Time frame: 12 and 24 months of age
Population: All participants completed the assessment at 12 months of age. One participant was unable to complete the assessment at the 24 month timepoint.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Stage 1 Open Label | TAND Severity Assessed by the TAND-L Checklist | 12 months of Age -- Parent Rating | 2 units on a scale (0 - 10) |
| Stage 1 Open Label | TAND Severity Assessed by the TAND-L Checklist | 12 months of Age -- Clinician Rating | 2 units on a scale (0 - 10) |
| Stage 1 Open Label | TAND Severity Assessed by the TAND-L Checklist | 24 months of Age -- Parent Rating | 1 units on a scale (0 - 10) |
| Stage 1 Open Label | TAND Severity Assessed by the TAND-L Checklist | 24 months of Age -- Clinician Rating | 3.5 units on a scale (0 - 10) |
Secondary
Treatment Discontinuance Due to Adverse Events
Percentage of subjects that reduce or discontinue treatment due to an AE or SAE (any grade)
Time frame: 12 months of age
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Stage 1 Open Label | Treatment Discontinuance Due to Adverse Events | 20 percentage of participants |
Secondary
Treatment Disruption Due to Adverse Events
Number of days treatment is withheld due to an AE or SAE (any grade).
Time frame: 12 months of age
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Stage 1 Open Label | Treatment Disruption Due to Adverse Events | 19.5 days |