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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).
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Stage 1 Open Label | Experimental | 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. |
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| TAVT-18 (sirolimus) | Drug | 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. |
| Measure | Description | Time Frame |
|---|---|---|
| Safety - Adverse Events | Percentage of subjects reporting severe (CTCAE v5.0 grade >= 3) adverse event (AE) or serious adverse event (SAE) | 12 months of age |
| Efficacy - Time to Seizure Onset | Time from treatment initiation to seizure onset | 12 months of age |
| Measure | Description | Time Frame |
|---|---|---|
| Treatment Discontinuance Due to Adverse Events | Percentage of subjects that reduce or discontinue treatment due to an AE or SAE (any grade) | 12 months of age |
| Treatment Disruption Due to Adverse Events |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Darcy Krueger, MD, PhD | Children's Hospital Medical Center, Cincinnati | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Cincinnati Children's Hospital | Cincinnati | Ohio | 45229 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 39331837 | Derived | Masuda S, Lemaitre F, Barten MJ, Bergan S, Shipkova M, van Gelder T, Vinks S, Wieland E, Bornemann-Kolatzki K, Brunet M, de Winter B, Dieterlen MT, Elens L, Ito T, Johnson-Davis K, Kunicki PK, Lawson R, Lloberas N, Marquet P, Millan O, Mizuno T, Moes DJAR, Noceti O, Oellerich M, Pattanaik S, Pawinski T, Seger C, van Schaik R, Venkataramanan R, Walson P, Woillard JB, Langman LJ. Everolimus Personalized Therapy: Second Consensus Report by the International Association of Therapeutic Drug Monitoring and Clinical Toxicology. Ther Drug Monit. 2025 Feb 1;47(1):4-31. doi: 10.1097/FTD.0000000000001250. Epub 2024 Sep 25. |
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Five participants were screened; all five were eligible for enrollment.
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| ID | Title | Description |
|---|---|---|
| FG000 | 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. |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
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| ID | Title | Description |
|---|---|---|
| BG000 | 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. |
| Units | Counts |
|---|---|
| Participants |
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| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | ||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Safety - Adverse Events | Percentage of subjects reporting severe (CTCAE v5.0 grade >= 3) adverse event (AE) or serious adverse event (SAE) | Posted | Number | percentage of participants | 12 months of age |
|
12 months of Age
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | 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. |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Constipation | Gastrointestinal disorders | CTCAE 5.0 | Systematic Assessment | Total Reported: 4; Grade 1: 4; Relatedness: Unrelated 100% |
Primary endpoints and universal treatment by study design continued through 12 months. Between 12-24 months, ongoing treatment with sirolimus was optional. In this study, 4/5 participants elected to continue sirolimus treatment through the secondary 24 month timepoint.
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Darcy A. Krueger, MD., PhD | Cincinnati Children's Hospital Medical Center | 513-636-4222 | krueger_darcy@cchmc.org |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | May 11, 2022 | Jan 27, 2024 | Prot_SAP_000.pdf |
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| ID | Term |
|---|---|
| D014402 | Tuberous Sclerosis |
| D004827 | Epilepsy |
| ID | Term |
|---|---|
| D006222 | Hamartoma |
| D009369 | Neoplasms |
| D009378 | Neoplasms, Multiple Primary |
| D009386 | Neoplastic Syndromes, Hereditary |
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| ID | Term |
|---|---|
| D020123 | Sirolimus |
| ID | Term |
|---|---|
| D018942 | Macrolides |
| D007783 | Lactones |
| D009930 | Organic Chemicals |
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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).
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Number of days treatment is withheld due to an AE or SAE (any grade).
| 12 months of age |
| Precision Dosing Accuracy | Blood trough concentration of sirolimus (ng/ml) | 12 months of age |
| Age at Seizure Onset | Patient age in months at time of seizure onset | 12 and 24 months of age |
| Seizure Type | Percentage of subjects reporting infantile spasms, focal seizures, or other seizure types | 12 and 24 months of age |
| Seizure Frequency | Number of seizures in past 30 days | 12 and 24 months of age |
| 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 | 12 and 24 months of age |
| 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 | 12 and 24 months of age |
| 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 | 12 and 24 months of age |
| Participants |
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| Age, Continuous | Median | Full Range | months |
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| Sex: Female, Male | Count of Participants | Participants |
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| Ethnicity (NIH/OMB) | Count of Participants | Participants |
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| Race (NIH/OMB) | Count of Participants | Participants |
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| Region of Enrollment | Number | participants |
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| Units | Counts |
|---|---|
| Participants |
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| Primary | Efficacy - Time to Seizure Onset | Time from treatment initiation to seizure onset | Posted | Median | Full Range | days | 12 months of age |
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| Secondary | Treatment Discontinuance Due to Adverse Events | Percentage of subjects that reduce or discontinue treatment due to an AE or SAE (any grade) | Posted | Number | percentage of participants | 12 months of age |
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| Secondary | Treatment Disruption Due to Adverse Events | Number of days treatment is withheld due to an AE or SAE (any grade). | Posted | Median | Full Range | days | 12 months of age |
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| Secondary | Precision Dosing Accuracy | Blood trough concentration of sirolimus (ng/ml) | Posted | Median | Full Range | ng/mL | 12 months of age |
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| Secondary | Age at Seizure Onset | Patient age in months at time of seizure onset | Posted | Median | Full Range | months | 12 and 24 months of age |
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| Secondary | Seizure Type | Percentage of subjects reporting infantile spasms, focal seizures, or other seizure types | Five participants were enrolled in the study. Only three of the enrolled participants developed seizures during the course of the study. | Posted | Number | percentage of participants | 12 and 24 months of age |
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| Secondary | Seizure Frequency | Number of seizures in past 30 days | Five participants were enrolled in the study. Only three of the enrolled participants developed seizures during the course of the study. | Posted | Number | seizures | 12 and 24 months of age |
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| 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 | All participants completed the assessment at 12 months of age. One participant was unable to complete the assessment at the 24 month timepoint. | Posted | Median | Full Range | units on a scale (0 - 10) | 12 and 24 months of age |
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| 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 | Posted | Median | Full Range | composite score | 12 and 24 months of age |
|
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| 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 | 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. | Posted | Median | Full Range | composite score | 12 and 24 months of age |
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| 0 |
| 5 |
| 0 |
| 5 |
| 5 |
| 5 |
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| Excessive Flatulence | Gastrointestinal disorders | CTCAE 5.0 | Systematic Assessment | Total Reported: 4; Grade 1: 1; Grade 2: 3; Relatedness: Unrelated 100% |
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| Emesis (vomiting) | Gastrointestinal disorders | CTCAE 5.0 | Systematic Assessment | Total Reported: 5; Grade 1: 5; Relatedness: Unrelated 100% |
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| Hematochezia (Bloody stool) | Gastrointestinal disorders | CTCAE 5.0 | Systematic Assessment | Total Reported: 1; Grade 2: 1; Relatedness: Possibly related 100% |
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| Diarrhea | Gastrointestinal disorders | CTCAE 5.0 | Systematic Assessment | Total Reported: 1; Grade 2: 1; Relatedness: Possibly related 100% |
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| Stomatitis (mouth sores/ulcers) | Gastrointestinal disorders | CTCAE 5.0 | Systematic Assessment | Total Reported: 5; Grade 1: 2; Grade 2: 3; Relatedness: Probable 60%, Definite 40% |
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| Pyrexia (fever) | General disorders | CTCAE 5.0 | Systematic Assessment | Total Reported: 8; Grade 2: 8; Relatedness: Unrelated 100% |
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| Fussiness | General disorders | CTCAE 5.0 | Systematic Assessment | Total Reported: 13; Grade 1: 1, Grade 2: 12; Relatedness: Unrelated 100% |
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| Discomfort/Pain due to Teething | General disorders | CTCAE 5.0 | Systematic Assessment | Total Reported: 3; Grade 2: 3; Relatedness: Unrelated 100% |
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| Fatigue | General disorders | CTCAE 5.0 | Systematic Assessment | Total Reported: 1; Grade 1: 1; Relatedness: Unrelated 100% |
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| Rash (Allergic reaction) | Immune system disorders | CTCAE 5.0 | Systematic Assessment | Total Reported: 1; Grade 2: 1; Relatedness: Unrelated 100% |
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| Rhinitis | Infections and infestations | CTCAE 5.0 | Systematic Assessment | Total Reported: 4; Grade 1: 4; Relatedness: Unrelated 50%, Possible 50% |
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| Otitis Media | Infections and infestations | CTCAE 5.0 | Systematic Assessment | Total Reported: 3; Grade 2: 3; Relatedness: Possible 66.7%, Probable 33.3% |
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| Rhinosinusitis (Sinus infection) | Infections and infestations | CTCAE 5.0 | Systematic Assessment | Total Reported: 1; Grade 2: 1; Relatedness: Probable 100% |
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| Abscess w/Infection | Infections and infestations | CTCAE 5.0 | Systematic Assessment | Total Reported: 1; Grade 2: 1; Relatedness: Unlikely 100% |
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| Croup w/Stridor | Infections and infestations | CTCAE 5.0 | Systematic Assessment | Total Reported: 1; Grade 2: 1; Relatedness: Possible 100% |
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| Respiratory Syncytial Virus (RSV) | Infections and infestations | CTCAE 5.0 | Systematic Assessment | Total Reported: 1; Grade 2: 1; Relatedness: Possible 100% |
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| Hand-Foot-Mouth Disease | Infections and infestations | CTCAE 5.0 | Systematic Assessment | Total Reported: 1; Grade 2; Relatedness: Possible 100% |
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| Hypertriglyceridemia | Metabolism and nutrition disorders | CTCAE 5.0 | Systematic Assessment | Total Reported: 4; Grade 1: 2, Grade 3: 2; Relatedness: Definite 100% |
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| Hypercholesterolemia | Metabolism and nutrition disorders | CTCAE 5.0 | Systematic Assessment | Total Reported: 4; Grade 1: 4; Relatedness: Definite 100% |
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| Insomnia | Psychiatric disorders | CTCAE 5.0 | Systematic Assessment | Total Reported: 2; Grade 1: 1, Grade 2: 1; Relatedness: Unrelated 100% |
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| Tussis (cough) | Respiratory, thoracic and mediastinal disorders | CTCAE 5.0 | Systematic Assessment | Total Reported: 3; Grade 1: 2, Grade 2: 1; Relatedness: Unrelated: 66.7%, Possible: 33.3% |
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| Rhinorrhea (Congestion) | Respiratory, thoracic and mediastinal disorders | CTCAE 5.0 | Systematic Assessment | Total Reported: 8; Grade 1: 4, Grade 2: 4; Relatedness: Unrelated 50%, Possible 50% |
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| Lip Lesion | Skin and subcutaneous tissue disorders | CTCAE 5.0 | Systematic Assessment | Total Reported: 4; Grade 2: 4; Relatedness: Possible 100% |
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| Dermatitis | Skin and subcutaneous tissue disorders | CTCAE 5.0 | Systematic Assessment | Total Reported: 5; Grade 1: 4, Grade 2: 1; Relatedness: Unrelated 80%, Possible 20% |
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| Eczema | Skin and subcutaneous tissue disorders | CTCAE 5.0 | Systematic Assessment | Total Reported: 2; Grade 1: 2; Relatedness: Unrelated 100% |
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| Hypertension | Vascular disorders | CTCAE 5.0 | Systematic Assessment | Total Reported: 1; Grade 2: 1; Relatedness: Unrelated 100% |
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| D065703 |
| Malformations of Cortical Development, Group I |
| D054220 | Malformations of Cortical Development |
| D009421 | Nervous System Malformations |
| D009422 | Nervous System Diseases |
| D020752 | Neurocutaneous Syndromes |
| D020271 | Heredodegenerative Disorders, Nervous System |
| D019636 | Neurodegenerative Diseases |
| D000013 | Congenital Abnormalities |
| D009358 | Congenital, Hereditary, and Neonatal Diseases and Abnormalities |
| D030342 | Genetic Diseases, Inborn |
| D001927 | Brain Diseases |
| D002493 | Central Nervous System Diseases |
| Title | Measurements |
|---|---|
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| 24 months of Age -- Focal Seizures |
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| 24 months of Age -- Parent Rating |
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| 24 months of Age -- Clinician Rating |
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| 12 months of Age -- Motor Domain |
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| 24 months of Age -- Cognitive Domain |
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| 24 months of Age -- Language Domain |
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| 24 months of Age -- Motor Domain |
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