Long-term neuropsychologic outcome of pre-emptive mTOR inhibitor treatment in children with tuberous sclerosis complex (TSC) under 4 months of age (PROTECT)

The primary objective of this study is to evaluate the **neuropsychologic outcome** at 24 months of age in children with **tuberous sclerosis complex (TSC)**. This will be assessed through rater-blinded neuropsychologic testing using the cognitive scale on the Bayley Scales of Infant and Toddler Development III (BSID-III), comparing pre-emptive mTOR inhibitor treatment with standard care alone. This objective is clinically relevant as it aims to determine the efficacy of early intervention in improving cognitive outcomes in TSC, a condition known for its neurodevelopmental challenges.

Secondary objectives include: - Neuropsychologic outcome at 12 months of age using the BSID-III cognitive scale. - Assessment of adaptive behavior with the Vineland Adaptive Behaviour Scales (VABS-3) at 12 and 24 months. - Evaluation for autism spectrum disorder using the Autism Diagnostic Observation Schedule (ADOS-2) and the Modified Checklist for Autism in Toddlers revised (M-CHAT-R/F). - Assessment of TSC-associated Neuropsychiatric Disorders (TAND) severity with the TAND-L Checklist. - Monitoring of seizure frequency and infantile spasms through seizure diaries, caregiver questionnaires, and EEG recordings. - Evaluation of cardiac rhabdomyoma and arrhythmia, and cerebral tumor size and number via imaging. - Documentation of adverse events using the Common Terminology Criteria of Adverse Events (CTCAE). - Assessment of safety laboratory data, vital signs, and EEG recordings for hypsarrhythmia and epileptiform discharges. - Renal changes assessment through abdominal sonography.

The clinical trial involves a study population diagnosed with **Tuberous sclerosis complex (TSC)**, focusing on infants under 4 months of age at the time of enrollment. The trial includes both male and female participants, and the population is considered vulnerable due to the young age of the subjects. The sponsor has not provided information regarding the total number of participants. Participants were selected based on a definite diagnosis of TSC according to the 2021 Updated International Tuberous Sclerosis Complex Diagnostic Criteria. The trial does not specify any particular lifestyle considerations such as diet or physical activity. The study aims to assess the neuropsychologic outcome at 24 months of age using the Bayley Scales of Infant and Toddler Development III, compared with Standard of Care alone.

The clinical trial is designed to evaluate the **neuropsychologic** outcomes of pre-emptive mTOR inhibitor treatment in children diagnosed with **tuberous sclerosis complex** (TSC) under the age of four months. This study is a randomized, double-blind, controlled trial, with a primary objective to assess neuropsychologic outcomes at 24 months of age using the Bayley Scales of Infant and Toddler Development III (BSID-III). The trial is expected to run until December 2028, with recruitment starting in August 2023. Participants will be involved in the study for a maximum of 24 months, with the treatment period varying depending on the specific medication administered.

Study visits are structured to ensure comprehensive data collection and participant safety. The inclusion visit, or screening, will confirm eligibility based on criteria such as a definite diagnosis of TSC and age under four months at enrollment. Follow-up visits will occur at regular intervals to monitor neuropsychologic development, adaptive behavior, and potential adverse events. The end-of-study visit will finalize data collection and assess long-term outcomes. Participants may be withdrawn from the study early if they experience significant adverse events or if the legal guardian withdraws consent.

The trial involves multiple medicinal products, including **sirolimus** as the primary investigational product, administered as an oral solution. Other medications, such as **tetracosactide**, **diazepam**, and **propranolol hydrochloride**, serve as auxiliary treatments. The maximum treatment period for these medications ranges from 14 to 24 months, with specific dosing regimens tailored to each product. The study aims to provide insights into the efficacy and safety of early mTOR inhibitor intervention in managing TSC-related neurodevelopmental challenges.

The clinical trial involves the administration of several experimental and non-experimental medications. **Tetracosactide** is utilized as a **suspension for injection** and is administered via **intramuscular injection**. The maximum daily dose is 40 IU, with a total maximum dose of 280 IU over a treatment period of 14 days. This synthetic peptide is not a pediatric formulation and is not classified as an orphan drug.

**Diazepam** is provided in the form of a **rectal solution** and is administered through **rectal use**. The maximum daily dose is 30 mg, with a total maximum dose of 21,600 mg over a 24-day period. Diazepam is categorized as a benzodiazepine and is not formulated for pediatric use.

**Propranolol Hydrochloride** is available as a **solution for injection** and is administered via injection. The dosing is calculated at 4 mg/kg per day, with a total maximum dose of 2,880 mg/kg over 24 days. It is classified as a betablocker and is not a pediatric formulation.

**Propranolol** is also administered in the form of a **film-coated tablet** for **oral use**. The dosing regimen is similar to propranolol hydrochloride, with a maximum daily dose of 4 mg/kg and a total maximum dose of 2,880 mg/kg over 24 days. It is also classified as a betablocker.

**Phenobarbital** is provided as a **tablet** for **oral administration**. The maximum daily dose is 5 mg/kg, with a total maximum dose of 3,600 mg/kg over a 24-day period. Phenobarbital is a barbiturate and is not formulated for pediatric use.

**Valproic Acid** is administered as a **capsule, prolonged release, hard** for **oral use**. The dosing is set at 4 mg/kg per day, with a total maximum dose of 2,880 mg/kg over 24 days. It is classified as an anti-epileptic medicine.

**Rapamune 1 mg/mL oral solution**, containing **sirolimus**, is administered as an **oral solution**. The maximum daily dose is 0.9 mg/m², with a total maximum dose of 657 mg/m² over 24 days. This formulation is not pediatric and is not an orphan drug.

**Prednisolone** is provided in **tablet** form for **oral administration**. The maximum daily dose is 40 mg/kg, with a total maximum dose of 560 mg/kg over a 2-day period. It is not a pediatric formulation.

**Vigabatrin** is administered as **granules for oral solution**. The maximum daily dose is 150 mg/kg, with a total maximum dose of 108,000 mg/kg over 24 days. It is classified as an anti-epileptic.

**Midazolam Hydrochloride** is provided as an **oromucosal solution** for **buccal use**. The maximum daily dose is 20 mg, with a total maximum dose of 14,400 mg over 24 days. It is categorized as a benzodiazepine.

**Verapamil** is administered as a **film-coated tablet** for **oral use**. The maximum daily dose is 80 mg, with a total maximum dose of 28,800 mg over 24 days. It is classified as a calcium antagonist.

**Carbamazepine** is provided as an **oral suspension**. The maximum daily dose is 35 mg/kg, with a total maximum dose of 25,200 mg/kg over 24 days. It is classified as an anti-epileptic.

**Oxcarbazepine** is also administered as an **oral suspension**. The dosing regimen is similar to carbamazepine, with a maximum daily dose of 35 mg/kg and a total maximum dose of 25,200 mg/kg over 24 days. It is classified as an anti-epileptic.

**Sodium Valproate** is provided as an **oral solution**. The maximum daily dose is 30 mg/kg, with a total maximum dose of 21,600 mg/kg over 24 days. It is classified as an anti-epileptic medicine.

Efficacy in this clinical trial will be assessed through a series of primary and secondary endpoints. The primary endpoint is the neuropsychologic outcome at 24 months of age, evaluated using rater-blinded neuropsychologic testing measured by the cognitive scale on the Bayley Scales of Infant and Toddler Development III (BSID-III). This will be compared with the Standard of Care (SOC) alone. Secondary endpoints include neuropsychologic outcomes at 12 months, adaptive behavior assessed by the Vineland Adaptive Behaviour Scales (VABS-3), and evidence for autism spectrum disorder measured by the Autism Diagnostic Observation Schedule (ADOS-2) and the Modified Checklist for Autism in Toddlers revised (M-CHAT-R/F). Additionally, TSC-associated Neuropsychiatric Disorders (TAND) severity will be assessed using the TAND-L Checklist, and seizure frequency and severity of infantile spasms will be monitored through seizure diaries, caregiver questionnaires, and electroencephalogram (EEG) recordings.

Further secondary endpoints involve the reduction in the number and size of cardiac rhabdomyoma and arrhythmia, as well as cerebral tumor size on cranial magnetic resonance imaging (cMRI). Adverse events will be assessed using the Common Terminology Criteria of Adverse Events (CTCAE, Version 5.0). Laboratory data, vital signs, and EEG recordings for hypsarrhythmia and epileptiform discharges will also be evaluated. Renal changes will be monitored through abdominal sonography, focusing on the volume and size of angiomyolipomas, kidney size, renal pelvis dilation, and echogenicity. These assessments will be conducted at specified intervals, including at 12 and 24 months, to ensure comprehensive evaluation of the treatment's efficacy.