Growth and Development
Conditions
Keywords
TSC-associated SEGA,, height,, weight,, Tanner Stage,, growth development,, everolimus,, RAD001
Brief summary
The primary objective of CRAD001M2305 was to report the long-term effects of everolimus treatment on height, weight and sexual development (using Tanner Stages) in children and adolescents with Tuberous Sclerosis Complex (TSC)-associated with Subependymal Giant Cell Astrocytoma (SEGA). The study monitored the growth and development of pediatric patients with TSC-associated SEGA, previously enrolled in CRAD001M2301 (NCT00789828) until they reach Tanner Stage V, or until age 16 for females or 17 for males whichever occurred first.
Detailed description
CRAD001M2305 was a prospective, multi-center phase IIIb/IV study. This study investigated if the physical and sexual development of pediatric patients was affected by previous or ongoing treatment with everolimus. The study monitored the growth and development of pediatric patients with TSC-associated SEGA, previously enrolled in CRAD001M2301(NCT00789828) until they reached Tanner Stage V, or until age 16 for females or 17 for males whichever occurred first. Continued treatment with everolimus was at investigator discretion and was not required for participation in CRAD001M2305. Growth (height, weight), and sexual development (Tanner Stages, sex hormone levels, age at menarche, thelarche (females) and adrenarche (males)), and brain development (assessed by TAND Checklist, dates of brain MRI) of patients participating in this long-term follow-up study was followed at annual visits to the site until patients achieve Tanner Stage V or age 16 (females), age 17 (males) whichever occurred first. Adverse events, concomitant medication, appearance of menarche, were monitored and data collected every 3 months (3-monthly). Unless clinically indicated these 3-monthly visits were performed per telephone.
Interventions
DRUGEverolimus
At the discretion of the investigator, pediatric patients could be treated with commercially available everolimus, as per local product information / standard of care. Treatment duration and dose modifications were at the investigator's discretion, as per the local product information.
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
OTHER
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
0 Years to 17 Years
Healthy volunteers
No
Inclusion criteria
* Pediatric female patients who were on study treatment in study \[CRAD001M2301\] within the past 6 months and have not reached Tanner Stage V or age 16 at the time of completion of \[CRAD001M2301\] or * Pediatric male patients who were on study treatment in study \[CRAD001M2301\] within the past 6 months and have not reached Tanner Stage V or age 17 at the time of completion of \[CRAD001M2301\] * Written informed consent according to local guidelines
Exclusion criteria
* Pediatric female patients who were on study treatment in CRAD001M2301 and have not reached Tanner Stage V but are within 3 month of turning age 16 or * Pediatric male patients who were on study treatment in CRAD001M2301 and have not reached Tanner Stage V but are within 3 months of turning age 17 * Any patient who was pregnant prior to start of CRAD001M2305
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Who Achieved Tanner Stage V at or Before Age 16 (Females) or 17 (Males) | Annually, up to 14 years from the first visit in parent study CRAD001M2301 (including up to 9 years of follow-up in study CRAD001M2305) | Tanner Staging, also known as Sexual Maturity Rating (SMR), is an objective classification system that providers use to document and track the development and sequence of secondary sex characteristics of children during puberty. Tanner Stage included two components for boys (testis and pubic hair) and two components for girls (breast development and pubic hair). Tanner Stage V: Males and females: Terminal hair that extends beyond the inguinal crease onto the thigh. Female Breast Development Scale: Areolar mound recedes into single breast contour with areolar hyperpigmentation, papillae development, and nipple protrusion. Male External Genitalia Scale: \> 20 ml (or \> 4.5 cm long) |
| Number of Participants With Notably Low and Notably High Height and Body Mass Index (BMI) Standard Deviation Score (SDS) | Baseline, annually up to Year 10 of treatment since the start of everolimus in parent study CRAD001M2301 (including a median of 5 years of exposure to everolimus in study CRAD001M2305) | Height and body weight (with minimal clothing, without shoes) were measured annually. The height standard deviation score (SDS) and BMI SDS were calculated based on height/BMI data collected during the study and published reference height/BMI information (De Onis M, et al. Development of a WHO growth reference for school-aged children and adolescents. Bull World Health Organ. 2007 Sep;85(9):660-7). The number of participants with height and BMI SDS values lower than the 5th percentile (notably low) or higher than the 95th percentile (notably high) are reported. The baseline corresponds to the last available assessment on or before the start of everolimus in the parent study CRAD001M2301. The assessment is performed up to age of 12 years. |
| Endocrine Laboratory Values LH and FSH in Male Participants | Annually, starting at 10-year age until 16-year age (in both studies CRAD001M2301 and CRAD001M2305) | Luteinizing hormone (LH) is a glycoprotein hormone that is co-secreted along with follicle-stimulating hormone by the gonadotrophin cells in the adenohypophysis (anterior pituitary). Untreated LH deficiency results in infertility, and if it occurs before puberty, the patient fails to develop puberty and secondary sexual characteristics. Follicle-stimulating hormone (FSH) is a hormone produced by the anterior pituitary in response to gonadotropin-releasing hormone (GnRH) from the hypothalamus. FSH plays a role in sexual development and reproduction in both males and females. |
| Endocrine Laboratory Values LH and FSH in Female Participants | Annually, starting at 10-year age until 16-year age (in both studies CRAD001M2301 and CRAD001M2305) | Luteinizing hormone (LH) is a glycoprotein hormone that is co-secreted along with follicle-stimulating hormone by the gonadotrophin cells in the adenohypophysis (anterior pituitary). Untreated LH deficiency results in infertility, and if it occurs before puberty, the patient fails to develop puberty and secondary sexual characteristics. Follicle-stimulating hormone (FSH) is a hormone produced by the anterior pituitary in response to gonadotropin-releasing hormone (GnRH) from the hypothalamus. FSH plays a role in sexual development and reproduction in both males and females. |
| Endocrine Laboratory Values of Testosterone in Male Participants | Annually, starting at 10-year age until 16-year age (in both studies CRAD001M2301 and CRAD001M2305) | Testosterone is the primary male hormone responsible for regulating sex differentiation, producing male sex characteristics, spermatogenesis, and fertility. |
| Endocrine Laboratory Values of Estrogen in Female Participants | Annually, starting at 10-year age until 16-year age (in both studies CRAD001M2301 and CRAD001M2305) | Estrogen is a steroid hormone associated with the female reproductive organs and is responsible for developing female sexual characteristics. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| TAND Checklist - Number of Participants With Scholastic Issues | From enrollment in study CRAD001M2305 until end of study, up to approximately 9 years. | Tuberous Sclerosis Complex (TSC) is associated with a range of neuropsychiatric disorders which refers to as TAND (TSC-Associated-Neuropsychiatric-Disorders). A specific TAND Checklist has been developed to assess Behavioral, Psychiatric, Intellectual, Academic, Neuropsychological and Psychosocial areas. At academic level, it is described the specific learning disorders associated with school performance, such as reading, writing, mathematics, and spelling. Baseline is defined as the first available assessment on or after the enrollment date of the CRAD001M2305 study. Overall consists of all responses including baseline. |
| TAND Checklist: Number of Participants With Difficulty in Specific Brain Skills | From enrollment in study CRAD001M2305 until end of study, up to approximately 9 years. | Tuberous Sclerosis Complex (TSC) is associated with a range of neuropsychiatric disorders which refers to as TAND (TSC-Associated-Neuropsychiatric-Disorders). A specific TAND Checklist has been developed to assess Behavioral, Psychiatric, Intellectual, Academic, Neuropsychological and Psychosocial areas. Neuropsychological evaluations are used to describe the strengths and weaknesses of brain referenced systems used for learning, thinking, and behavior regulation. Baseline is defined as the first available assessment on or after the enrollment date of the CRAD001M2305 study. Overall consists of all responses including baseline. |
| TAND Checklist - Number of Participants With Psychological Issues | From enrollment in study CRAD001M2305 until end of study, up to approximately 9 years. | Tuberous Sclerosis Complex (TSC) is associated with a range of neuropsychiatric disorders which refers to as TAND (TSC-Associated-Neuropsychiatric-Disorders). A specific TAND Checklist has been developed to assess Behavioral, Psychiatric, Intellectual, Academic, Neuropsychological and Psychosocial areas. At psychosocial level it is considered important determinants of quality of life, such as self-esteem, family functioning, parental stress, and relationship difficulties. All these are markers of resilience and burden of care, and all the psychosocial factors may be amenable to intervention and support. Baseline is defined as the first available assessment on or after the enrollment date of the CRAD001M2305 study. Overall consists of all responses including baseline. |
| TAND Checklist - Number of Participants With Varied Levels of Language Skills | From enrollment in study CRAD001M2305 until end of study, up to approximately 9 years. | Tuberous Sclerosis Complex (TSC) is associated with a range of neuropsychiatric disorders which refers to as TAND (TSC-Associated-Neuropsychiatric-Disorders). A specific TAND Checklist has been developed to assess Behavioral, Psychiatric, Intellectual, Academic, Neuropsychological and Psychosocial areas. Neuropsychological evaluations are used to describe the strengths and weaknesses of brain referenced systems used for learning, thinking, and behavior regulation. These include language skills (including non-verbal, simple language, fluence of language). All the responses are categorical in nature from the TAND Checklist. The frequency of (baseline and) worst-post baseline is summarized. |
| Number of Participants With Treatment Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) | From enrollment in study CRAD001M2305 until end of study, up to approximately 9 years. | Number of participants with treatment emergent AEs (any AE regardless of seriousness), AEs led to study treatment discontinuation, SAEs and SAEs led to study treatment discontinuation. |
| TAND Checklist: Number of Participants With Different Levels of Mobility | From enrollment in study CRAD001M2305 until end of study, up to approximately 9 years. | Tuberous Sclerosis Complex (TSC) is associated with a range of neuropsychiatric disorders which refers to as TAND (TSC-Associated-Neuropsychiatric-Disorders). A specific TAND Checklist has been developed to assess Behavioral, Psychiatric, Intellectual, Academic, Neuropsychological and Psychosocial areas. This outcome measure assesses the TAND checklist part about mobility. All the responses are categorical in nature from the TAND Checklist. The frequency of (baseline and) worst-post baseline is summarized. |
| TAND Checklist: Number of Participants With Different Levels of Intelligence Quotient | From enrollment in study CRAD001M2305 until end of study, up to approximately 9 years. | Tuberous Sclerosis Complex (TSC) is associated with a range of neuropsychiatric disorders which refers to as TAND (TSC-Associated-Neuropsychiatric-Disorders). A specific TAND Checklist has been developed to assess Behavioral, Psychiatric, Intellectual, Academic, Neuropsychological and Psychosocial areas. At intellectual level, it is described the intellectual developmental abilities of an individual in comparison with others of the same chronological age. All the responses are categorical in nature from the TAND Checklist. The frequency of (baseline and) worst-post baseline is summarized. |
| TAND Checklist: Number of Participants With Different Levels of Intellectual Ability | From enrollment in study CRAD001M2305 until end of study, up to approximately 9 years. | Tuberous Sclerosis Complex (TSC) is associated with a range of neuropsychiatric disorders which refers to as TAND (TSC-Associated-Neuropsychiatric-Disorders). A specific TAND Checklist has been developed to assess Behavioral, Psychiatric, Intellectual, Academic, Neuropsychological and Psychosocial areas. At intellectual level, it is described the intellectual developmental abilities of an individual to identify their overall functional and adaptive behaviors in comparison with others of the same chronological age. This level is the combination of formal measures of intellectual ability (such as IQ-type tests) and evaluation of adaptive behaviors (such as self-care, daily living skills, communication, and social abilities in daily life). All the responses are categorical in nature from the TAND Checklist. The frequency of (baseline and) worst-post baseline is summarized. |
| TAND Checklist - Number of Participants With Different Levels of Physical Dependency | From enrollment in study CRAD001M2305 until end of study, up to approximately 9 years. | Tuberous Sclerosis Complex (TSC) is associated with a range of neuropsychiatric disorders which refers to as TAND (TSC-Associated-Neuropsychiatric-Disorders). A specific TAND Checklist has been developed to assess Behavioral, Psychiatric, Intellectual, Academic, Neuropsychological and Psychosocial areas. This outcome measure assesses the TAND checklist part about physical dependency. All the responses are categorical in nature from the TAND Checklist. The frequency of (baseline and) worst-post baseline is summarized. |
| Participants Age at Menarche/Thelarche (Females) or Adrenarche (Males) | Up to approximately 14.4 years from the first dose of everolimus in parent study CRAD001M2301 (including up to 9 years of follow-up in study CRAD001M2305) | Menarche is defined as the first menstrual period in a female adolescent. Menarche typically occurs between the ages of 10 and 16, with the average age of onset being 12.4 years. Thelarche is the beginning of adult breast development, marks the onset of puberty in the majority of women and occurs at a mean age of 10 years. Adrenarche refers to the time during puberty when the adrenal glands increase their production and secretion of adrenal androgens. Potential delayed puberty in girls is defined as failure to attain Tanner Stage II (for both breast development and pubic hair) by age 13, or absence of menarche by age 15 or within 5 years of attainment of Tanner Stage II. Potential delayed puberty in boys is defined as failure to attain Tanner Stage II (for both testis and pubic hair) by age 14. |
| Participants Age at Tanner Stage II, III, IV, V | Up to approximately 14.4 years from the first dose of everolimus in parent study CRAD001M2301 (including up to 9 years of follow-up in study CRAD001M2305) | Tanner Staging, also known as Sexual Maturity Rating (SMR), is an objective classification system that providers use to document and track the development and sequence of secondary sex characteristics of children during puberty. Pubic Hair Scale Stages: II-Downy hair III-Scant terminal hair IV-Terminal hair that fills the entire triangle overlying the pubic region V-Terminal hair that extends beyond the inguinal crease onto the thigh Female Breast Development Scale Stages: II-Breast bud palpable under the areola (1st pubertal sign in females) III-Breast tissue palpable outside areola; no areolar development IV-Areola elevated above the contour of the breast, forming a double scoop appearance V-Areolar mound recedes into single breast contour with areolar hyperpigmentation, papillae development, and nipple protrusion Male External Genitalia Scale Stages: II- 2.5 to 3.3 cm long, 1st pubertal sign in males III- 3.4 to 4.0 cm long IV- 4.1 to 4.5 cm long V- or \> 4.5 cm long |
| TAND Checklist: Number of Participants Achieved Basic Developmental Milestones and the Age at Which Participants Achieved the Basic Developmental Milestones | From enrollment in study CRAD001M2305 until end of study, up to approximately 9 years. | Tuberous Sclerosis Complex (TSC) is associated with a range of neuropsychiatric disorders which refers to as TAND (TSC-Associated-Neuropsychiatric-Disorders). A specific TAND Checklist has been developed to assess Behavioral, Psychiatric, Intellectual, Academic, Neuropsychological and Psychosocial areas. This outcome measure assesses the TAND checklist part about basic development skills. Baseline is defined as the first available assessment on or after the enrollment date of the CRAD001M2305 study. Overall consists of all responses including baseline. |
| TAND Checklist: Number of Participants With Behavioral Disorders | From enrollment in study CRAD001M2305 until end of study, up to approximately 9 years. | Tuberous Sclerosis Complex (TSC) is associated with a range of neuropsychiatric disorders which refers to as TAND (TSC-Associated-Neuropsychiatric-Disorders). A specific TAND Checklist has been developed to assess Behavioral, Psychiatric, Intellectual, Academic, Neuropsychological and Psychosocial areas. Behavioral level- This level refers to any observed behaviors that may cause concern to the individual. Behavioral presentations include anxiety, depressed mood, aggressive behaviors, temper tantrums, attention-related behaviors (such as difficulty concentrating, hyperactivity, impulsivity), social, and communication-related behaviors (such as speech and language delays, poor eye contact, difficulties in relationships with peers, repetitive behaviors), self-injurious behaviors, and eating or sleep difficulties. Baseline is defined as the first available assessment on or after the enrollment date of the CRAD001M2305 study. Overall consists of all responses including baseline. |
| TAND Checklist - Number of Participants With Psychiatric Disorders | From enrollment in study CRAD001M2305 until end of study, up to approximately 9 years. | Tuberous Sclerosis Complex (TSC) is associated with a range of neuropsychiatric disorders which refers to as TAND (TSC-Associated-Neuropsychiatric-Disorders). A specific TAND Checklist has been developed to assess Behavioral, Psychiatric, Intellectual, Academic, Neuropsychological and Psychosocial areas. For psychiatric disorders some behaviors of concern are examined and evaluated in the context of the individual's overall developmental level and in terms of their biological, psychological, and social profile. Baseline is defined as the first available assessment on or after the enrollment date of the CRAD001M2305 study. Overall consists of all responses including baseline. |
Countries
Belgium, Russia, United States
Participant flow
Recruitment details
Participants took part in 6 investigative sites in 3 countries.
Pre-assignment details
All the pediatric patients enrolled into the current study had been treated with everolimus in the parent study CRAD001M2301.
Participants by arm
| Arm | Count |
|---|---|
| Everolimus Participants were treated with everolimus as part of CRAD001M2301. Continued treatment with everolimus is allowed but not required for participation in this study. | 15 |
| Total | 15 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Death | 1 |
| Overall Study | Physician Decision | 1 |
Baseline characteristics
| Characteristic | Everolimus |
|---|---|
| Age, Continuous | 6.390 years STANDARD_DEVIATION 3.5647 |
| Race/Ethnicity, Customized Black | 1 Participants |
| Race/Ethnicity, Customized Caucasian | 14 Participants |
| Sex: Female, Male Female | 8 Participants |
| Sex: Female, Male Male | 7 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 1 / 14 |
| other Total, other adverse events | 12 / 14 |
| serious Total, serious adverse events | 6 / 14 |
Outcome results
Primary
Endocrine Laboratory Values LH and FSH in Female Participants
Luteinizing hormone (LH) is a glycoprotein hormone that is co-secreted along with follicle-stimulating hormone by the gonadotrophin cells in the adenohypophysis (anterior pituitary). Untreated LH deficiency results in infertility, and if it occurs before puberty, the patient fails to develop puberty and secondary sexual characteristics. Follicle-stimulating hormone (FSH) is a hormone produced by the anterior pituitary in response to gonadotropin-releasing hormone (GnRH) from the hypothalamus. FSH plays a role in sexual development and reproduction in both males and females.
Time frame: Annually, starting at 10-year age until 16-year age (in both studies CRAD001M2301 and CRAD001M2305)
Population: Female participants in the FAS with at least one available value of the outcome measure. In each row, the number of participants with an available value at the specified timepoint is reported.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Everolimus | Endocrine Laboratory Values LH and FSH in Female Participants | 16 years age-LH | 3.7 IU/L | Standard Deviation 2.69 |
| Everolimus | Endocrine Laboratory Values LH and FSH in Female Participants | 16 years age-FSH | 2.8 IU/L | Standard Deviation 2.05 |
| Everolimus | Endocrine Laboratory Values LH and FSH in Female Participants | 10 years age-LH | 5.1 IU/L | Standard Deviation 3.89 |
| Everolimus | Endocrine Laboratory Values LH and FSH in Female Participants | 10 years age-FSH | 3.4 IU/L | Standard Deviation 2.68 |
| Everolimus | Endocrine Laboratory Values LH and FSH in Female Participants | 11 years age-LH | 3.2 IU/L | Standard Deviation 2.47 |
| Everolimus | Endocrine Laboratory Values LH and FSH in Female Participants | 11 years age-FSH | 3.5 IU/L | Standard Deviation 1.61 |
| Everolimus | Endocrine Laboratory Values LH and FSH in Female Participants | 12 years age-LH | 7.8 IU/L | Standard Deviation 6.73 |
| Everolimus | Endocrine Laboratory Values LH and FSH in Female Participants | 12 years age-FSH | 5.6 IU/L | Standard Deviation 2.43 |
| Everolimus | Endocrine Laboratory Values LH and FSH in Female Participants | 13 years age-LH | 4.4 IU/L | Standard Deviation 3.08 |
| Everolimus | Endocrine Laboratory Values LH and FSH in Female Participants | 13 years age-FSH | 5.0 IU/L | Standard Deviation 0.8 |
| Everolimus | Endocrine Laboratory Values LH and FSH in Female Participants | 14 years age-LH | 5.3 IU/L | Standard Deviation 6.97 |
| Everolimus | Endocrine Laboratory Values LH and FSH in Female Participants | 14 years age-FSH | 2.6 IU/L | Standard Deviation 2.05 |
| Everolimus | Endocrine Laboratory Values LH and FSH in Female Participants | 15 years age-LH | 7.5 IU/L | Standard Deviation 10.96 |
| Everolimus | Endocrine Laboratory Values LH and FSH in Female Participants | 15 years age-FSH | 2.5 IU/L | Standard Deviation 2.28 |
Primary
Endocrine Laboratory Values LH and FSH in Male Participants
Luteinizing hormone (LH) is a glycoprotein hormone that is co-secreted along with follicle-stimulating hormone by the gonadotrophin cells in the adenohypophysis (anterior pituitary). Untreated LH deficiency results in infertility, and if it occurs before puberty, the patient fails to develop puberty and secondary sexual characteristics. Follicle-stimulating hormone (FSH) is a hormone produced by the anterior pituitary in response to gonadotropin-releasing hormone (GnRH) from the hypothalamus. FSH plays a role in sexual development and reproduction in both males and females.
Time frame: Annually, starting at 10-year age until 16-year age (in both studies CRAD001M2301 and CRAD001M2305)
Population: Male participants in the FAS with at least one available value of the outcome measure. In each row, the number of participants with an available value at the specified timepoint is reported.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Everolimus | Endocrine Laboratory Values LH and FSH in Male Participants | 10 years age-LH | 1.0 IU/L | Standard Deviation 1.47 |
| Everolimus | Endocrine Laboratory Values LH and FSH in Male Participants | 10 years age-FSH | 1.5 IU/L | Standard Deviation 1.34 |
| Everolimus | Endocrine Laboratory Values LH and FSH in Male Participants | 11 years age-LH | 1.0 IU/L | Standard Deviation 0.77 |
| Everolimus | Endocrine Laboratory Values LH and FSH in Male Participants | 11 years age-FSH | 1.7 IU/L | Standard Deviation 1.11 |
| Everolimus | Endocrine Laboratory Values LH and FSH in Male Participants | 12 years age-LH | 1.8 IU/L | Standard Deviation 1.22 |
| Everolimus | Endocrine Laboratory Values LH and FSH in Male Participants | 12 years age-FSH | 2.1 IU/L | Standard Deviation 0.67 |
| Everolimus | Endocrine Laboratory Values LH and FSH in Male Participants | 13 years age-LH | 2.4 IU/L | Standard Deviation 2.26 |
| Everolimus | Endocrine Laboratory Values LH and FSH in Male Participants | 13 years age-FSH | 2.9 IU/L | Standard Deviation 1.81 |
| Everolimus | Endocrine Laboratory Values LH and FSH in Male Participants | 14 years age-LH | 2.9 IU/L | Standard Deviation 2.18 |
| Everolimus | Endocrine Laboratory Values LH and FSH in Male Participants | 14 years age-FSH | 4.6 IU/L | Standard Deviation 4.29 |
| Everolimus | Endocrine Laboratory Values LH and FSH in Male Participants | 15 years age-LH | 2.5 IU/L | Standard Deviation 1.07 |
| Everolimus | Endocrine Laboratory Values LH and FSH in Male Participants | 15 years age-FSH | 3.3 IU/L | Standard Deviation 0.61 |
| Everolimus | Endocrine Laboratory Values LH and FSH in Male Participants | 16 years age-LH | 3.5 IU/L | Standard Deviation 0.32 |
| Everolimus | Endocrine Laboratory Values LH and FSH in Male Participants | 16 years age-FSH | 6.0 IU/L | Standard Deviation 3.01 |
Primary
Endocrine Laboratory Values of Estrogen in Female Participants
Estrogen is a steroid hormone associated with the female reproductive organs and is responsible for developing female sexual characteristics.
Time frame: Annually, starting at 10-year age until 16-year age (in both studies CRAD001M2301 and CRAD001M2305)
Population: Female participants in the FAS with at least one available value of the outcome measure. In each row, the number of participants with an available value at the specified timepoint is reported.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Everolimus | Endocrine Laboratory Values of Estrogen in Female Participants | 10 years age | 139.8 ng/L | — |
| Everolimus | Endocrine Laboratory Values of Estrogen in Female Participants | 11 years age | 80.5 ng/L | Standard Deviation 119.22 |
| Everolimus | Endocrine Laboratory Values of Estrogen in Female Participants | 12 years age | 43.7 ng/L | Standard Deviation 41.26 |
| Everolimus | Endocrine Laboratory Values of Estrogen in Female Participants | 13 years age | 50.0 ng/L | Standard Deviation 7.07 |
| Everolimus | Endocrine Laboratory Values of Estrogen in Female Participants | 14 years age | 139.0 ng/L | Standard Deviation 141.42 |
| Everolimus | Endocrine Laboratory Values of Estrogen in Female Participants | 15 years age | 47.7 ng/L | Standard Deviation 48.89 |
| Everolimus | Endocrine Laboratory Values of Estrogen in Female Participants | 16 years age | 149.7 ng/L | Standard Deviation 128.21 |
Primary
Endocrine Laboratory Values of Testosterone in Male Participants
Testosterone is the primary male hormone responsible for regulating sex differentiation, producing male sex characteristics, spermatogenesis, and fertility.
Time frame: Annually, starting at 10-year age until 16-year age (in both studies CRAD001M2301 and CRAD001M2305)
Population: Male participants in the FAS with at least one available value of the outcome measure. In each row, the number of participants with an available value at the specified timepoint is reported.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Everolimus | Endocrine Laboratory Values of Testosterone in Male Participants | 10 years age | 0.7 nmol/L | Standard Deviation 1.17 |
| Everolimus | Endocrine Laboratory Values of Testosterone in Male Participants | 11 years age | 2.5 nmol/L | Standard Deviation 4.6 |
| Everolimus | Endocrine Laboratory Values of Testosterone in Male Participants | 12 years age | 3.8 nmol/L | Standard Deviation 4.29 |
| Everolimus | Endocrine Laboratory Values of Testosterone in Male Participants | 13 years age | 4.3 nmol/L | Standard Deviation 4.04 |
| Everolimus | Endocrine Laboratory Values of Testosterone in Male Participants | 14 years age | 7.2 nmol/L | Standard Deviation 4.34 |
| Everolimus | Endocrine Laboratory Values of Testosterone in Male Participants | 15 years age | 12.9 nmol/L | Standard Deviation 6.28 |
| Everolimus | Endocrine Laboratory Values of Testosterone in Male Participants | 16 years age | 15.5 nmol/L | Standard Deviation 3.93 |
Primary
Number of Participants Who Achieved Tanner Stage V at or Before Age 16 (Females) or 17 (Males)
Tanner Staging, also known as Sexual Maturity Rating (SMR), is an objective classification system that providers use to document and track the development and sequence of secondary sex characteristics of children during puberty. Tanner Stage included two components for boys (testis and pubic hair) and two components for girls (breast development and pubic hair). Tanner Stage V: Males and females: Terminal hair that extends beyond the inguinal crease onto the thigh. Female Breast Development Scale: Areolar mound recedes into single breast contour with areolar hyperpigmentation, papillae development, and nipple protrusion. Male External Genitalia Scale: \> 20 ml (or \> 4.5 cm long)
Time frame: Annually, up to 14 years from the first visit in parent study CRAD001M2301 (including up to 9 years of follow-up in study CRAD001M2305)
Population: The Full Analysis Set for sexual development (FAS Puberty) consisted of all participants enrolled in this study.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Everolimus | Number of Participants Who Achieved Tanner Stage V at or Before Age 16 (Females) or 17 (Males) | Female | 4 Participants |
| Everolimus | Number of Participants Who Achieved Tanner Stage V at or Before Age 16 (Females) or 17 (Males) | Male | 6 Participants |
Primary
Number of Participants With Notably Low and Notably High Height and Body Mass Index (BMI) Standard Deviation Score (SDS)
Height and body weight (with minimal clothing, without shoes) were measured annually. The height standard deviation score (SDS) and BMI SDS were calculated based on height/BMI data collected during the study and published reference height/BMI information (De Onis M, et al. Development of a WHO growth reference for school-aged children and adolescents. Bull World Health Organ. 2007 Sep;85(9):660-7). The number of participants with height and BMI SDS values lower than the 5th percentile (notably low) or higher than the 95th percentile (notably high) are reported. The baseline corresponds to the last available assessment on or before the start of everolimus in the parent study CRAD001M2301. The assessment is performed up to age of 12 years.
Time frame: Baseline, annually up to Year 10 of treatment since the start of everolimus in parent study CRAD001M2301 (including a median of 5 years of exposure to everolimus in study CRAD001M2305)
Population: The Full Analysis Set (FAS) consisted of all participants enrolled in this study.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Everolimus | Number of Participants With Notably Low and Notably High Height and Body Mass Index (BMI) Standard Deviation Score (SDS) | Height SDS-notably low-Baseline | 2 Participants |
| Everolimus | Number of Participants With Notably Low and Notably High Height and Body Mass Index (BMI) Standard Deviation Score (SDS) | Height SDS-notably low-Year 1 | 1 Participants |
| Everolimus | Number of Participants With Notably Low and Notably High Height and Body Mass Index (BMI) Standard Deviation Score (SDS) | Height SDS-notably low-Year 2 | 2 Participants |
| Everolimus | Number of Participants With Notably Low and Notably High Height and Body Mass Index (BMI) Standard Deviation Score (SDS) | Height SDS-notably low-Year 3 | 2 Participants |
| Everolimus | Number of Participants With Notably Low and Notably High Height and Body Mass Index (BMI) Standard Deviation Score (SDS) | Height SDS-notably low-Year 4 | 2 Participants |
| Everolimus | Number of Participants With Notably Low and Notably High Height and Body Mass Index (BMI) Standard Deviation Score (SDS) | Height SDS-notably low-Year 6 | 1 Participants |
| Everolimus | Number of Participants With Notably Low and Notably High Height and Body Mass Index (BMI) Standard Deviation Score (SDS) | Height SDS-notably low-Year 7 | 1 Participants |
| Everolimus | Number of Participants With Notably Low and Notably High Height and Body Mass Index (BMI) Standard Deviation Score (SDS) | Height SDS-notably low-Year 8 | 0 Participants |
| Everolimus | Number of Participants With Notably Low and Notably High Height and Body Mass Index (BMI) Standard Deviation Score (SDS) | Height SDS-notably low-Year 9 | 0 Participants |
| Everolimus | Number of Participants With Notably Low and Notably High Height and Body Mass Index (BMI) Standard Deviation Score (SDS) | Height SDS-notably low-Year 10 | 0 Participants |
| Everolimus | Number of Participants With Notably Low and Notably High Height and Body Mass Index (BMI) Standard Deviation Score (SDS) | Height SDS-notably high-Baseline | 1 Participants |
| Everolimus | Number of Participants With Notably Low and Notably High Height and Body Mass Index (BMI) Standard Deviation Score (SDS) | Height SDS-notably high-Year 1 | 0 Participants |
| Everolimus | Number of Participants With Notably Low and Notably High Height and Body Mass Index (BMI) Standard Deviation Score (SDS) | Height SDS-notably high-Year 2 | 0 Participants |
| Everolimus | Number of Participants With Notably Low and Notably High Height and Body Mass Index (BMI) Standard Deviation Score (SDS) | Height SDS-notably high-Year 3 | 0 Participants |
| Everolimus | Number of Participants With Notably Low and Notably High Height and Body Mass Index (BMI) Standard Deviation Score (SDS) | Height SDS-notably high-Year 4 | 1 Participants |
| Everolimus | Number of Participants With Notably Low and Notably High Height and Body Mass Index (BMI) Standard Deviation Score (SDS) | Height SDS-notably high-Year 5 | 0 Participants |
| Everolimus | Number of Participants With Notably Low and Notably High Height and Body Mass Index (BMI) Standard Deviation Score (SDS) | Height SDS-notably high-Year 6 | 1 Participants |
| Everolimus | Number of Participants With Notably Low and Notably High Height and Body Mass Index (BMI) Standard Deviation Score (SDS) | Height SDS-notably high-Year 7 | 1 Participants |
| Everolimus | Number of Participants With Notably Low and Notably High Height and Body Mass Index (BMI) Standard Deviation Score (SDS) | Height SDS-notably high-Year 8 | 1 Participants |
| Everolimus | Number of Participants With Notably Low and Notably High Height and Body Mass Index (BMI) Standard Deviation Score (SDS) | Height SDS-notably high-Year 9 | 0 Participants |
| Everolimus | Number of Participants With Notably Low and Notably High Height and Body Mass Index (BMI) Standard Deviation Score (SDS) | Height SDS-notably high-Year 10 | 0 Participants |
| Everolimus | Number of Participants With Notably Low and Notably High Height and Body Mass Index (BMI) Standard Deviation Score (SDS) | BMI SDS-notably low-Baseline | 0 Participants |
| Everolimus | Number of Participants With Notably Low and Notably High Height and Body Mass Index (BMI) Standard Deviation Score (SDS) | BMI SDS-notably low-Year 1 | 0 Participants |
| Everolimus | Number of Participants With Notably Low and Notably High Height and Body Mass Index (BMI) Standard Deviation Score (SDS) | BMI SDS-notably low-Year 2 | 1 Participants |
| Everolimus | Number of Participants With Notably Low and Notably High Height and Body Mass Index (BMI) Standard Deviation Score (SDS) | BMI SDS-notably low-Year 4 | 0 Participants |
| Everolimus | Number of Participants With Notably Low and Notably High Height and Body Mass Index (BMI) Standard Deviation Score (SDS) | BMI SDS-notably low-Year 5 | 1 Participants |
| Everolimus | Number of Participants With Notably Low and Notably High Height and Body Mass Index (BMI) Standard Deviation Score (SDS) | BMI SDS-notably low-Year 6 | 2 Participants |
| Everolimus | Number of Participants With Notably Low and Notably High Height and Body Mass Index (BMI) Standard Deviation Score (SDS) | BMI SDS-notably low-Year 7 | 0 Participants |
| Everolimus | Number of Participants With Notably Low and Notably High Height and Body Mass Index (BMI) Standard Deviation Score (SDS) | BMI SDS-notably low-Year 8 | 1 Participants |
| Everolimus | Number of Participants With Notably Low and Notably High Height and Body Mass Index (BMI) Standard Deviation Score (SDS) | BMI SDS-notably low-Year 9 | 2 Participants |
| Everolimus | Number of Participants With Notably Low and Notably High Height and Body Mass Index (BMI) Standard Deviation Score (SDS) | BMI SDS-notably high-Baseline | 4 Participants |
| Everolimus | Number of Participants With Notably Low and Notably High Height and Body Mass Index (BMI) Standard Deviation Score (SDS) | BMI SDS-notably high-Year 3 | 0 Participants |
| Everolimus | Number of Participants With Notably Low and Notably High Height and Body Mass Index (BMI) Standard Deviation Score (SDS) | BMI SDS-notably high-Year 4 | 1 Participants |
| Everolimus | Number of Participants With Notably Low and Notably High Height and Body Mass Index (BMI) Standard Deviation Score (SDS) | Height SDS-notably low-Year 5 | 2 Participants |
| Everolimus | Number of Participants With Notably Low and Notably High Height and Body Mass Index (BMI) Standard Deviation Score (SDS) | BMI SDS-notably low-Year 3 | 0 Participants |
| Everolimus | Number of Participants With Notably Low and Notably High Height and Body Mass Index (BMI) Standard Deviation Score (SDS) | BMI SDS-notably low-Year 10 | 1 Participants |
| Everolimus | Number of Participants With Notably Low and Notably High Height and Body Mass Index (BMI) Standard Deviation Score (SDS) | BMI SDS-notably high-Year 1 | 1 Participants |
| Everolimus | Number of Participants With Notably Low and Notably High Height and Body Mass Index (BMI) Standard Deviation Score (SDS) | BMI SDS-notably high-Year 2 | 1 Participants |
| Everolimus | Number of Participants With Notably Low and Notably High Height and Body Mass Index (BMI) Standard Deviation Score (SDS) | BMI SDS-notably high-Year 5 | 1 Participants |
| Everolimus | Number of Participants With Notably Low and Notably High Height and Body Mass Index (BMI) Standard Deviation Score (SDS) | BMI SDS-notably high-Year 6 | 1 Participants |
| Everolimus | Number of Participants With Notably Low and Notably High Height and Body Mass Index (BMI) Standard Deviation Score (SDS) | BMI SDS-notably high-Year 7 | 2 Participants |
| Everolimus | Number of Participants With Notably Low and Notably High Height and Body Mass Index (BMI) Standard Deviation Score (SDS) | BMI SDS-notably high-Year 8 | 2 Participants |
| Everolimus | Number of Participants With Notably Low and Notably High Height and Body Mass Index (BMI) Standard Deviation Score (SDS) | BMI SDS-notably high-Year 9 | 1 Participants |
| Everolimus | Number of Participants With Notably Low and Notably High Height and Body Mass Index (BMI) Standard Deviation Score (SDS) | BMI SDS-notably high-Year 10 | 1 Participants |
Secondary
Number of Participants With Treatment Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs)
Number of participants with treatment emergent AEs (any AE regardless of seriousness), AEs led to study treatment discontinuation, SAEs and SAEs led to study treatment discontinuation.
Time frame: From enrollment in study CRAD001M2305 until end of study, up to approximately 9 years.
Population: The Safety Set included all pediatric patients enrolled who had at least one-post baseline safety assessment.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Everolimus | Number of Participants With Treatment Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) | At least one AE | 12 Participants |
| Everolimus | Number of Participants With Treatment Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) | At least one SAE | 6 Participants |
| Everolimus | Number of Participants With Treatment Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) | AE leading to discontinuation | 0 Participants |
| Everolimus | Number of Participants With Treatment Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) | SAE leading to discontinuation | 0 Participants |
Secondary
Participants Age at Menarche/Thelarche (Females) or Adrenarche (Males)
Menarche is defined as the first menstrual period in a female adolescent. Menarche typically occurs between the ages of 10 and 16, with the average age of onset being 12.4 years. Thelarche is the beginning of adult breast development, marks the onset of puberty in the majority of women and occurs at a mean age of 10 years. Adrenarche refers to the time during puberty when the adrenal glands increase their production and secretion of adrenal androgens. Potential delayed puberty in girls is defined as failure to attain Tanner Stage II (for both breast development and pubic hair) by age 13, or absence of menarche by age 15 or within 5 years of attainment of Tanner Stage II. Potential delayed puberty in boys is defined as failure to attain Tanner Stage II (for both testis and pubic hair) by age 14.
Time frame: Up to approximately 14.4 years from the first dose of everolimus in parent study CRAD001M2301 (including up to 9 years of follow-up in study CRAD001M2305)
Population: The Safety Set included all pediatric patients enrolled who had at least one-post baseline safety assessment. At each row, only participants without menarche (females), thelarche (females) and adrenarche (males) prior to start of everolimus in the parent study CRAD001M2301 are included in the analysis.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Everolimus | Participants Age at Menarche/Thelarche (Females) or Adrenarche (Males) | Menarche | 12.5 years |
| Everolimus | Participants Age at Menarche/Thelarche (Females) or Adrenarche (Males) | Thelarche | 10.2 years |
| Everolimus | Participants Age at Menarche/Thelarche (Females) or Adrenarche (Males) | Adrenarche | 11.0 years |
Secondary
Participants Age at Tanner Stage II, III, IV, V
Tanner Staging, also known as Sexual Maturity Rating (SMR), is an objective classification system that providers use to document and track the development and sequence of secondary sex characteristics of children during puberty. Pubic Hair Scale Stages: II-Downy hair III-Scant terminal hair IV-Terminal hair that fills the entire triangle overlying the pubic region V-Terminal hair that extends beyond the inguinal crease onto the thigh Female Breast Development Scale Stages: II-Breast bud palpable under the areola (1st pubertal sign in females) III-Breast tissue palpable outside areola; no areolar development IV-Areola elevated above the contour of the breast, forming a double scoop appearance V-Areolar mound recedes into single breast contour with areolar hyperpigmentation, papillae development, and nipple protrusion Male External Genitalia Scale Stages: II- 2.5 to 3.3 cm long, 1st pubertal sign in males III- 3.4 to 4.0 cm long IV- 4.1 to 4.5 cm long V- or \> 4.5 cm long
Time frame: Up to approximately 14.4 years from the first dose of everolimus in parent study CRAD001M2301 (including up to 9 years of follow-up in study CRAD001M2305)
Population: The Full Analysis Set for sexual development (FAS Puberty) consisted of all participants enrolled in this study.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Everolimus | Participants Age at Tanner Stage II, III, IV, V | Tanner stage II-pubic hair-male | 11.8 years |
| Everolimus | Participants Age at Tanner Stage II, III, IV, V | Tanner stage II-genitalia | 11.9 years |
| Everolimus | Participants Age at Tanner Stage II, III, IV, V | Tanner stage III-pubic hair-male | 13.3 years |
| Everolimus | Participants Age at Tanner Stage II, III, IV, V | Tanner stage III-genitalia | 12.6 years |
| Everolimus | Participants Age at Tanner Stage II, III, IV, V | Tanner stage IV-pubic hair-male | 14.2 years |
| Everolimus | Participants Age at Tanner Stage II, III, IV, V | Tanner stage IV-genitalia | 14.2 years |
| Everolimus | Participants Age at Tanner Stage II, III, IV, V | Tanner stage V-pubic hair-male | 16.4 years |
| Everolimus | Participants Age at Tanner Stage II, III, IV, V | Tanner stage V-genitalia | 16.4 years |
| Everolimus | Participants Age at Tanner Stage II, III, IV, V | Tanner stage II-pubic hair-female | 10.4 years |
| Everolimus | Participants Age at Tanner Stage II, III, IV, V | Tanner stage II-Breast | 11.5 years |
| Everolimus | Participants Age at Tanner Stage II, III, IV, V | Tanner stage III-pubic hair-female | 12.2 years |
| Everolimus | Participants Age at Tanner Stage II, III, IV, V | Tanner stage III-Breast | 12.5 years |
| Everolimus | Participants Age at Tanner Stage II, III, IV, V | Tanner stage IV-pubic hair-female | 13.4 years |
| Everolimus | Participants Age at Tanner Stage II, III, IV, V | Tanner stage IV-Breast | 13.8 years |
| Everolimus | Participants Age at Tanner Stage II, III, IV, V | Tanner stage V-pubic hair-female | 16.0 years |
| Everolimus | Participants Age at Tanner Stage II, III, IV, V | Tanner stage V-Breast | NA years |
Secondary
TAND Checklist: Number of Participants Achieved Basic Developmental Milestones and the Age at Which Participants Achieved the Basic Developmental Milestones
Tuberous Sclerosis Complex (TSC) is associated with a range of neuropsychiatric disorders which refers to as TAND (TSC-Associated-Neuropsychiatric-Disorders). A specific TAND Checklist has been developed to assess Behavioral, Psychiatric, Intellectual, Academic, Neuropsychological and Psychosocial areas. This outcome measure assesses the TAND checklist part about basic development skills. Baseline is defined as the first available assessment on or after the enrollment date of the CRAD001M2305 study. Overall consists of all responses including baseline.
Time frame: From enrollment in study CRAD001M2305 until end of study, up to approximately 9 years.
Population: The Full Analysis Set (FAS) consisted of all participants enrolled in this study.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Everolimus | TAND Checklist: Number of Participants Achieved Basic Developmental Milestones and the Age at Which Participants Achieved the Basic Developmental Milestones | First smile-baseline | 2.9 age (months) | Standard Error 1.85 |
| Everolimus | TAND Checklist: Number of Participants Achieved Basic Developmental Milestones and the Age at Which Participants Achieved the Basic Developmental Milestones | First smile-overall | 2.9 age (months) | Standard Error 1.85 |
| Everolimus | TAND Checklist: Number of Participants Achieved Basic Developmental Milestones and the Age at Which Participants Achieved the Basic Developmental Milestones | Sat without support-baseline | 7.5 age (months) | Standard Error 3.68 |
| Everolimus | TAND Checklist: Number of Participants Achieved Basic Developmental Milestones and the Age at Which Participants Achieved the Basic Developmental Milestones | Sat without support-overall | 7.5 age (months) | Standard Error 3.68 |
| Everolimus | TAND Checklist: Number of Participants Achieved Basic Developmental Milestones and the Age at Which Participants Achieved the Basic Developmental Milestones | Walked without holding on-baseline | 16.5 age (months) | Standard Error 8.23 |
| Everolimus | TAND Checklist: Number of Participants Achieved Basic Developmental Milestones and the Age at Which Participants Achieved the Basic Developmental Milestones | Walked without holding on-overall | 16.5 age (months) | Standard Error 8.23 |
| Everolimus | TAND Checklist: Number of Participants Achieved Basic Developmental Milestones and the Age at Which Participants Achieved the Basic Developmental Milestones | First used single words other than mama or dada-baseline | 29.5 age (months) | Standard Error 24.81 |
| Everolimus | TAND Checklist: Number of Participants Achieved Basic Developmental Milestones and the Age at Which Participants Achieved the Basic Developmental Milestones | First used single words other than mama or dada-overall | 29.5 age (months) | Standard Error 24.81 |
| Everolimus | TAND Checklist: Number of Participants Achieved Basic Developmental Milestones and the Age at Which Participants Achieved the Basic Developmental Milestones | First used two words/short phrases-baseline | 33.2 age (months) | Standard Error 16.66 |
| Everolimus | TAND Checklist: Number of Participants Achieved Basic Developmental Milestones and the Age at Which Participants Achieved the Basic Developmental Milestones | First used two words/short phrases-overall | 34.3 age (months) | Standard Error 19.77 |
| Everolimus | TAND Checklist: Number of Participants Achieved Basic Developmental Milestones and the Age at Which Participants Achieved the Basic Developmental Milestones | Toilet trained during the day-baseline | 46.2 age (months) | Standard Error 31.22 |
| Everolimus | TAND Checklist: Number of Participants Achieved Basic Developmental Milestones and the Age at Which Participants Achieved the Basic Developmental Milestones | Toilet trained during the day-overall | 51.5 age (months) | Standard Error 35.89 |
| Everolimus | TAND Checklist: Number of Participants Achieved Basic Developmental Milestones and the Age at Which Participants Achieved the Basic Developmental Milestones | Toilet trained at night-baseline | 52.5 age (months) | Standard Error 35.6 |
| Everolimus | TAND Checklist: Number of Participants Achieved Basic Developmental Milestones and the Age at Which Participants Achieved the Basic Developmental Milestones | Toilet trained at night-overall | 60.1 age (months) | Standard Error 43.23 |
Secondary
TAND Checklist: Number of Participants With Behavioral Disorders
Tuberous Sclerosis Complex (TSC) is associated with a range of neuropsychiatric disorders which refers to as TAND (TSC-Associated-Neuropsychiatric-Disorders). A specific TAND Checklist has been developed to assess Behavioral, Psychiatric, Intellectual, Academic, Neuropsychological and Psychosocial areas. Behavioral level- This level refers to any observed behaviors that may cause concern to the individual. Behavioral presentations include anxiety, depressed mood, aggressive behaviors, temper tantrums, attention-related behaviors (such as difficulty concentrating, hyperactivity, impulsivity), social, and communication-related behaviors (such as speech and language delays, poor eye contact, difficulties in relationships with peers, repetitive behaviors), self-injurious behaviors, and eating or sleep difficulties. Baseline is defined as the first available assessment on or after the enrollment date of the CRAD001M2305 study. Overall consists of all responses including baseline.
Time frame: From enrollment in study CRAD001M2305 until end of study, up to approximately 9 years.
Population: The Full Analysis Set (FAS) consisted of all participants enrolled in this study.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Everolimus | TAND Checklist: Number of Participants With Behavioral Disorders | Anxiety-overall | 13 Participants |
| Everolimus | TAND Checklist: Number of Participants With Behavioral Disorders | Depressed mood-baseline | 6 Participants |
| Everolimus | TAND Checklist: Number of Participants With Behavioral Disorders | Depressed mood-overall | 8 Participants |
| Everolimus | TAND Checklist: Number of Participants With Behavioral Disorders | Extreme shyness-baseline | 5 Participants |
| Everolimus | TAND Checklist: Number of Participants With Behavioral Disorders | Extreme shyness-overall | 7 Participants |
| Everolimus | TAND Checklist: Number of Participants With Behavioral Disorders | Temper Tantrums-baseline | 9 Participants |
| Everolimus | TAND Checklist: Number of Participants With Behavioral Disorders | Mood swings-baseline | 10 Participants |
| Everolimus | TAND Checklist: Number of Participants With Behavioral Disorders | Mood swings-overall | 12 Participants |
| Everolimus | TAND Checklist: Number of Participants With Behavioral Disorders | Aggressive outbursts-baseline | 7 Participants |
| Everolimus | TAND Checklist: Number of Participants With Behavioral Disorders | Aggressive outbursts-overall | 11 Participants |
| Everolimus | TAND Checklist: Number of Participants With Behavioral Disorders | Temper Tantrums-overall | 12 Participants |
| Everolimus | TAND Checklist: Number of Participants With Behavioral Disorders | Self-injury, such as hitting self, biting self, scratching self-baseline | 3 Participants |
| Everolimus | TAND Checklist: Number of Participants With Behavioral Disorders | Self-injury, such as hitting self, biting self, scratching self-overall | 5 Participants |
| Everolimus | TAND Checklist: Number of Participants With Behavioral Disorders | Absent or delayed onset of language to communicate-baseline | 11 Participants |
| Everolimus | TAND Checklist: Number of Participants With Behavioral Disorders | Absent or delayed onset of language to communicate-overall | 12 Participants |
| Everolimus | TAND Checklist: Number of Participants With Behavioral Disorders | Repeating words or phrases over and over again-baseline | 9 Participants |
| Everolimus | TAND Checklist: Number of Participants With Behavioral Disorders | Repeating words or phrases over and over again-overall | 12 Participants |
| Everolimus | TAND Checklist: Number of Participants With Behavioral Disorders | Poor eye contact-baseline | 6 Participants |
| Everolimus | TAND Checklist: Number of Participants With Behavioral Disorders | Poor eye contact-overall | 8 Participants |
| Everolimus | TAND Checklist: Number of Participants With Behavioral Disorders | Repetitive behaviours, such as doing the same thing over and over again-baseline | 9 Participants |
| Everolimus | TAND Checklist: Number of Participants With Behavioral Disorders | Repetitive behaviours, such as doing the same thing over and over again-overall | 11 Participants |
| Everolimus | TAND Checklist: Number of Participants With Behavioral Disorders | Very rigid or inflexible about how to do things or not liking change in routines-baseline | 8 Participants |
| Everolimus | TAND Checklist: Number of Participants With Behavioral Disorders | Very rigid or inflexible about how to do things or not liking change in routines-overall | 11 Participants |
| Everolimus | TAND Checklist: Number of Participants With Behavioral Disorders | Overactivity/hyperactivity, such as being constantly on the go-baseline | 8 Participants |
| Everolimus | TAND Checklist: Number of Participants With Behavioral Disorders | Overactivity/hyperactivity, such as being constantly on the go-overall | 9 Participants |
| Everolimus | TAND Checklist: Number of Participants With Behavioral Disorders | Difficulty paying attention or concentrating-baseline | 13 Participants |
| Everolimus | TAND Checklist: Number of Participants With Behavioral Disorders | Restlessness or fidgetiness, such as wriggling or squirming-baseline | 13 Participants |
| Everolimus | TAND Checklist: Number of Participants With Behavioral Disorders | Restlessness or fidgetiness, such as wriggling or squirming-overall | 14 Participants |
| Everolimus | TAND Checklist: Number of Participants With Behavioral Disorders | Impulsivity, such as butting in, not waiting turn-baseline | 10 Participants |
| Everolimus | TAND Checklist: Number of Participants With Behavioral Disorders | Sleep difficulties, such as with falling asleep or waking-baseline | 6 Participants |
| Everolimus | TAND Checklist: Number of Participants With Behavioral Disorders | Sleep difficulties, such as with falling asleep or waking-overall | 8 Participants |
| Everolimus | TAND Checklist: Number of Participants With Behavioral Disorders | Anxiety-baseline | 12 Participants |
| Everolimus | TAND Checklist: Number of Participants With Behavioral Disorders | Difficulties getting on with other people of similar age-baseline | 9 Participants |
| Everolimus | TAND Checklist: Number of Participants With Behavioral Disorders | Difficulties getting on with other people of similar age-overall | 10 Participants |
| Everolimus | TAND Checklist: Number of Participants With Behavioral Disorders | Difficulty paying attention or concentrating-overall | 15 Participants |
| Everolimus | TAND Checklist: Number of Participants With Behavioral Disorders | Impulsivity, such as butting in, not waiting turn-overall | 12 Participants |
| Everolimus | TAND Checklist: Number of Participants With Behavioral Disorders | Difficulties with eating, such as eating too much, too little, unusual things-baseline | 5 Participants |
| Everolimus | TAND Checklist: Number of Participants With Behavioral Disorders | Difficulties with eating, such as eating too much, too little, unusual things-overall | 8 Participants |
Secondary
TAND Checklist: Number of Participants With Different Levels of Intellectual Ability
Tuberous Sclerosis Complex (TSC) is associated with a range of neuropsychiatric disorders which refers to as TAND (TSC-Associated-Neuropsychiatric-Disorders). A specific TAND Checklist has been developed to assess Behavioral, Psychiatric, Intellectual, Academic, Neuropsychological and Psychosocial areas. At intellectual level, it is described the intellectual developmental abilities of an individual to identify their overall functional and adaptive behaviors in comparison with others of the same chronological age. This level is the combination of formal measures of intellectual ability (such as IQ-type tests) and evaluation of adaptive behaviors (such as self-care, daily living skills, communication, and social abilities in daily life). All the responses are categorical in nature from the TAND Checklist. The frequency of (baseline and) worst-post baseline is summarized.
Time frame: From enrollment in study CRAD001M2305 until end of study, up to approximately 9 years.
Population: The Full Analysis Set (FAS) consisted of all participants enrolled in this study.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Everolimus | TAND Checklist: Number of Participants With Different Levels of Intellectual Ability | Normal Intellectual Ability | 1 Participants |
| Everolimus | TAND Checklist: Number of Participants With Different Levels of Intellectual Ability | Mild-Moderate Intellectual Disability | 8 Participants |
| Everolimus | TAND Checklist: Number of Participants With Different Levels of Intellectual Ability | Severe - Profound Intellectual Disability | 3 Participants |
| Everolimus | TAND Checklist: Number of Participants With Different Levels of Intellectual Ability | Missing | 3 Participants |
Secondary
TAND Checklist: Number of Participants With Different Levels of Intelligence Quotient
Tuberous Sclerosis Complex (TSC) is associated with a range of neuropsychiatric disorders which refers to as TAND (TSC-Associated-Neuropsychiatric-Disorders). A specific TAND Checklist has been developed to assess Behavioral, Psychiatric, Intellectual, Academic, Neuropsychological and Psychosocial areas. At intellectual level, it is described the intellectual developmental abilities of an individual in comparison with others of the same chronological age. All the responses are categorical in nature from the TAND Checklist. The frequency of (baseline and) worst-post baseline is summarized.
Time frame: From enrollment in study CRAD001M2305 until end of study, up to approximately 9 years.
Population: The Full Analysis Set (FAS) consisted of all participants enrolled in this study.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Everolimus | TAND Checklist: Number of Participants With Different Levels of Intelligence Quotient | Profound Intellectual Disability (IQ <20) | 1 Participants |
| Everolimus | TAND Checklist: Number of Participants With Different Levels of Intelligence Quotient | Normal Intellectual Ability (IQ > 80) | 2 Participants |
| Everolimus | TAND Checklist: Number of Participants With Different Levels of Intelligence Quotient | Borderline Intellectual Ability (IQ 70-80) | 2 Participants |
| Everolimus | TAND Checklist: Number of Participants With Different Levels of Intelligence Quotient | Mild Intellectual Disability (IQ 50-69) | 1 Participants |
| Everolimus | TAND Checklist: Number of Participants With Different Levels of Intelligence Quotient | Moderate Intellectual Disability (IQ 35-49) | 5 Participants |
| Everolimus | TAND Checklist: Number of Participants With Different Levels of Intelligence Quotient | Severe Intellectual Disability (IQ 21-34) | 0 Participants |
| Everolimus | TAND Checklist: Number of Participants With Different Levels of Intelligence Quotient | Missing | 4 Participants |
Secondary
TAND Checklist: Number of Participants With Different Levels of Mobility
Tuberous Sclerosis Complex (TSC) is associated with a range of neuropsychiatric disorders which refers to as TAND (TSC-Associated-Neuropsychiatric-Disorders). A specific TAND Checklist has been developed to assess Behavioral, Psychiatric, Intellectual, Academic, Neuropsychological and Psychosocial areas. This outcome measure assesses the TAND checklist part about mobility. All the responses are categorical in nature from the TAND Checklist. The frequency of (baseline and) worst-post baseline is summarized.
Time frame: From enrollment in study CRAD001M2305 until end of study, up to approximately 9 years.
Population: The Full Analysis Set (FAS) consisted of all participants enrolled in this study.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Everolimus | TAND Checklist: Number of Participants With Different Levels of Mobility | Wheelchair | 1 Participants |
| Everolimus | TAND Checklist: Number of Participants With Different Levels of Mobility | Needs significant support | 1 Participants |
| Everolimus | TAND Checklist: Number of Participants With Different Levels of Mobility | Some difficulty | 0 Participants |
| Everolimus | TAND Checklist: Number of Participants With Different Levels of Mobility | Completely mobile | 10 Participants |
| Everolimus | TAND Checklist: Number of Participants With Different Levels of Mobility | Missing | 3 Participants |
Secondary
TAND Checklist - Number of Participants With Different Levels of Physical Dependency
Tuberous Sclerosis Complex (TSC) is associated with a range of neuropsychiatric disorders which refers to as TAND (TSC-Associated-Neuropsychiatric-Disorders). A specific TAND Checklist has been developed to assess Behavioral, Psychiatric, Intellectual, Academic, Neuropsychological and Psychosocial areas. This outcome measure assesses the TAND checklist part about physical dependency. All the responses are categorical in nature from the TAND Checklist. The frequency of (baseline and) worst-post baseline is summarized.
Time frame: From enrollment in study CRAD001M2305 until end of study, up to approximately 9 years.
Population: The Full Analysis Set (FAS) consisted of all participants enrolled in this study.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Everolimus | TAND Checklist - Number of Participants With Different Levels of Physical Dependency | Dependent on others | 4 Participants |
| Everolimus | TAND Checklist - Number of Participants With Different Levels of Physical Dependency | Some self-care skills | 7 Participants |
| Everolimus | TAND Checklist - Number of Participants With Different Levels of Physical Dependency | Independent | 1 Participants |
| Everolimus | TAND Checklist - Number of Participants With Different Levels of Physical Dependency | Missing | 3 Participants |
Secondary
TAND Checklist: Number of Participants With Difficulty in Specific Brain Skills
Tuberous Sclerosis Complex (TSC) is associated with a range of neuropsychiatric disorders which refers to as TAND (TSC-Associated-Neuropsychiatric-Disorders). A specific TAND Checklist has been developed to assess Behavioral, Psychiatric, Intellectual, Academic, Neuropsychological and Psychosocial areas. Neuropsychological evaluations are used to describe the strengths and weaknesses of brain referenced systems used for learning, thinking, and behavior regulation. Baseline is defined as the first available assessment on or after the enrollment date of the CRAD001M2305 study. Overall consists of all responses including baseline.
Time frame: From enrollment in study CRAD001M2305 until end of study, up to approximately 9 years.
Population: The Full Analysis Set (FAS) consisted of all participants enrolled in this study.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Everolimus | TAND Checklist: Number of Participants With Difficulty in Specific Brain Skills | Visuo-spatial tasks-overall | 13 Participants |
| Everolimus | TAND Checklist: Number of Participants With Difficulty in Specific Brain Skills | Getting disoriented-baseline | 7 Participants |
| Everolimus | TAND Checklist: Number of Participants With Difficulty in Specific Brain Skills | Memory-baseline | 7 Participants |
| Everolimus | TAND Checklist: Number of Participants With Difficulty in Specific Brain Skills | Memory-overall | 12 Participants |
| Everolimus | TAND Checklist: Number of Participants With Difficulty in Specific Brain Skills | Attention-baseline | 12 Participants |
| Everolimus | TAND Checklist: Number of Participants With Difficulty in Specific Brain Skills | Attention-overall | 14 Participants |
| Everolimus | TAND Checklist: Number of Participants With Difficulty in Specific Brain Skills | Dual-tasking/ Multi-tasking-baseline | 12 Participants |
| Everolimus | TAND Checklist: Number of Participants With Difficulty in Specific Brain Skills | Dual-tasking/ Multi-tasking-overall | 14 Participants |
| Everolimus | TAND Checklist: Number of Participants With Difficulty in Specific Brain Skills | Visuo-spatial tasks-baseline | 8 Participants |
| Everolimus | TAND Checklist: Number of Participants With Difficulty in Specific Brain Skills | Executive skills-baseline | 10 Participants |
| Everolimus | TAND Checklist: Number of Participants With Difficulty in Specific Brain Skills | Executive skills-overall | 15 Participants |
| Everolimus | TAND Checklist: Number of Participants With Difficulty in Specific Brain Skills | Getting disoriented-overall | 12 Participants |
Secondary
TAND Checklist - Number of Participants With Psychiatric Disorders
Tuberous Sclerosis Complex (TSC) is associated with a range of neuropsychiatric disorders which refers to as TAND (TSC-Associated-Neuropsychiatric-Disorders). A specific TAND Checklist has been developed to assess Behavioral, Psychiatric, Intellectual, Academic, Neuropsychological and Psychosocial areas. For psychiatric disorders some behaviors of concern are examined and evaluated in the context of the individual's overall developmental level and in terms of their biological, psychological, and social profile. Baseline is defined as the first available assessment on or after the enrollment date of the CRAD001M2305 study. Overall consists of all responses including baseline.
Time frame: From enrollment in study CRAD001M2305 until end of study, up to approximately 9 years.
Population: The Full Analysis Set (FAS) consisted of all participants enrolled in this study.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Everolimus | TAND Checklist - Number of Participants With Psychiatric Disorders | Autism Spectrum Disorder (ASD), including autism, Asperger's-baseline | 4 Participants |
| Everolimus | TAND Checklist - Number of Participants With Psychiatric Disorders | Attention Deficit Hyperactivity Disorder (ADHD)-baseline | 5 Participants |
| Everolimus | TAND Checklist - Number of Participants With Psychiatric Disorders | Attention Deficit Hyperactivity Disorder (ADHD)-overall | 9 Participants |
| Everolimus | TAND Checklist - Number of Participants With Psychiatric Disorders | Anxiety Disorder, including as panic, phobia, separation anxiety disorder-baseline | 4 Participants |
| Everolimus | TAND Checklist - Number of Participants With Psychiatric Disorders | Anxiety Disorder, including as panic, phobia, separation anxiety disorder-overall | 7 Participants |
| Everolimus | TAND Checklist - Number of Participants With Psychiatric Disorders | Depressive Disorder-baseline | 0 Participants |
| Everolimus | TAND Checklist - Number of Participants With Psychiatric Disorders | Depressive Disorder-overall | 0 Participants |
| Everolimus | TAND Checklist - Number of Participants With Psychiatric Disorders | Obsessive Compulsive Disorder-baseline | 2 Participants |
| Everolimus | TAND Checklist - Number of Participants With Psychiatric Disorders | Obsessive Compulsive Disorder-overall | 2 Participants |
| Everolimus | TAND Checklist - Number of Participants With Psychiatric Disorders | Psychotic Disorder, including schizophrenia-baseline | 0 Participants |
| Everolimus | TAND Checklist - Number of Participants With Psychiatric Disorders | Psychotic Disorder, including schizophrenia-overall | 0 Participants |
| Everolimus | TAND Checklist - Number of Participants With Psychiatric Disorders | Autism Spectrum Disorder (ASD), including autism, Asperger's-overall | 7 Participants |
Secondary
TAND Checklist - Number of Participants With Psychological Issues
Tuberous Sclerosis Complex (TSC) is associated with a range of neuropsychiatric disorders which refers to as TAND (TSC-Associated-Neuropsychiatric-Disorders). A specific TAND Checklist has been developed to assess Behavioral, Psychiatric, Intellectual, Academic, Neuropsychological and Psychosocial areas. At psychosocial level it is considered important determinants of quality of life, such as self-esteem, family functioning, parental stress, and relationship difficulties. All these are markers of resilience and burden of care, and all the psychosocial factors may be amenable to intervention and support. Baseline is defined as the first available assessment on or after the enrollment date of the CRAD001M2305 study. Overall consists of all responses including baseline.
Time frame: From enrollment in study CRAD001M2305 until end of study, up to approximately 9 years.
Population: The Full Analysis Set (FAS) consisted of all participants enrolled in this study.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Everolimus | TAND Checklist - Number of Participants With Psychological Issues | Low self-esteem-baseline | 2 Participants |
| Everolimus | TAND Checklist - Number of Participants With Psychological Issues | Low self-esteem-overall | 6 Participants |
| Everolimus | TAND Checklist - Number of Participants With Psychological Issues | Very high levels of stress in families, for instance between siblings-baseline | 6 Participants |
| Everolimus | TAND Checklist - Number of Participants With Psychological Issues | Very high levels of stress in families, for instance between siblings-overall | 8 Participants |
| Everolimus | TAND Checklist - Number of Participants With Psychological Issues | Very high levels of stress between parents leading to significant relationship difficulties-baseline | 5 Participants |
| Everolimus | TAND Checklist - Number of Participants With Psychological Issues | Very high levels of stress between parents leading to significant relationship difficulties-overall | 7 Participants |
Secondary
TAND Checklist - Number of Participants With Scholastic Issues
Tuberous Sclerosis Complex (TSC) is associated with a range of neuropsychiatric disorders which refers to as TAND (TSC-Associated-Neuropsychiatric-Disorders). A specific TAND Checklist has been developed to assess Behavioral, Psychiatric, Intellectual, Academic, Neuropsychological and Psychosocial areas. At academic level, it is described the specific learning disorders associated with school performance, such as reading, writing, mathematics, and spelling. Baseline is defined as the first available assessment on or after the enrollment date of the CRAD001M2305 study. Overall consists of all responses including baseline.
Time frame: From enrollment in study CRAD001M2305 until end of study, up to approximately 9 years.
Population: The Full Analysis Set (FAS) consisted of all participants enrolled in this study.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Everolimus | TAND Checklist - Number of Participants With Scholastic Issues | Reading-baseline | 12 Participants |
| Everolimus | TAND Checklist - Number of Participants With Scholastic Issues | Reading-overall | 14 Participants |
| Everolimus | TAND Checklist - Number of Participants With Scholastic Issues | Writing-baseline | 12 Participants |
| Everolimus | TAND Checklist - Number of Participants With Scholastic Issues | Spelling-overall | 14 Participants |
| Everolimus | TAND Checklist - Number of Participants With Scholastic Issues | Mathematics-baseline | 12 Participants |
| Everolimus | TAND Checklist - Number of Participants With Scholastic Issues | Writing-overall | 14 Participants |
| Everolimus | TAND Checklist - Number of Participants With Scholastic Issues | Spelling-baseline | 12 Participants |
| Everolimus | TAND Checklist - Number of Participants With Scholastic Issues | Mathematics-overall | 14 Participants |
Secondary
TAND Checklist - Number of Participants With Varied Levels of Language Skills
Tuberous Sclerosis Complex (TSC) is associated with a range of neuropsychiatric disorders which refers to as TAND (TSC-Associated-Neuropsychiatric-Disorders). A specific TAND Checklist has been developed to assess Behavioral, Psychiatric, Intellectual, Academic, Neuropsychological and Psychosocial areas. Neuropsychological evaluations are used to describe the strengths and weaknesses of brain referenced systems used for learning, thinking, and behavior regulation. These include language skills (including non-verbal, simple language, fluence of language). All the responses are categorical in nature from the TAND Checklist. The frequency of (baseline and) worst-post baseline is summarized.
Time frame: From enrollment in study CRAD001M2305 until end of study, up to approximately 9 years.
Population: The Full Analysis Set (FAS) consisted of all participants enrolled in this study.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Everolimus | TAND Checklist - Number of Participants With Varied Levels of Language Skills | Non-verbal | 2 Participants |
| Everolimus | TAND Checklist - Number of Participants With Varied Levels of Language Skills | Simple language | 6 Participants |
| Everolimus | TAND Checklist - Number of Participants With Varied Levels of Language Skills | Fluent | 4 Participants |
| Everolimus | TAND Checklist - Number of Participants With Varied Levels of Language Skills | Missing | 3 Participants |