A Phase 4 interventional study of Everolimus in Growth and Development, sponsored by Novartis Pharmaceuticals. Completed at 6 sites in 3 countries. Open to participants aged 0 Years to 17 Years. Per ClinicalTrials.gov, last updated 2024-08-09.
Sponsored by Novartis Pharmaceuticals · Phase 4, Interventional, and Other
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.
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.
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Exclusion Criteria:
All patients will have been previously treated with everolimus as part of CRAD001M2301. Continued treatment with everolimus is allowed but not required for participation in this study.
Drug: Everolimus
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.
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)
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)
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)
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)
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)
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)
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.
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)
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)
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Participants took part in 6 investigative sites in 3 countries.
| Milestone | Everolimus |
|---|---|
| Started | 15 |
| Safety analysis set | 14 |
| Completed | 13 |
| Not completed | 2 |
| Withdrew: Physician decision | 1 |
| Withdrew: Death | 1 |
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)
| Participants | Everolimus |
|---|---|
| Female | 4 |
| Male | 6 |
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.
| Participants | Everolimus |
|---|---|
| Height SDS-notably low-Baseline | 2 |
| Height SDS-notably low-Year 1 | 1 |
| Height SDS-notably low-Year 2 | 2 |
| Height SDS-notably low-Year 3 | 2 |
| Height SDS-notably low-Year 4 | 2 |
| Height SDS-notably low-Year 5 | 2 |
| Height SDS-notably low-Year 6 | 1 |
| Height SDS-notably low-Year 7 | 1 |
| Height SDS-notably low-Year 8 | 0 |
| Height SDS-notably low-Year 9 | 0 |
| Height SDS-notably low-Year 10 | 0 |
| Height SDS-notably high-Baseline | 1 |
| Height SDS-notably high-Year 1 | 0 |
| Height SDS-notably high-Year 2 | 0 |
| Height SDS-notably high-Year 3 | 0 |
| Height SDS-notably high-Year 4 | 1 |
| Height SDS-notably high-Year 5 | 0 |
| Height SDS-notably high-Year 6 | 1 |
| Height SDS-notably high-Year 7 | 1 |
| Height SDS-notably high-Year 8 | 1 |
| Height SDS-notably high-Year 9 | 0 |
| Height SDS-notably high-Year 10 | 0 |
| BMI SDS-notably low-Baseline | 0 |
| BMI SDS-notably low-Year 1 | 0 |
| BMI SDS-notably low-Year 2 | 1 |
| BMI SDS-notably low-Year 3 | 0 |
| BMI SDS-notably low-Year 4 | 0 |
| BMI SDS-notably low-Year 5 | 1 |
| BMI SDS-notably low-Year 6 | 2 |
| BMI SDS-notably low-Year 7 | 0 |
| BMI SDS-notably low-Year 8 | 1 |
| BMI SDS-notably low-Year 9 | 2 |
| BMI SDS-notably low-Year 10 | 1 |
| BMI SDS-notably high-Baseline | 4 |
| BMI SDS-notably high-Year 1 | 1 |
| BMI SDS-notably high-Year 2 | 1 |
| BMI SDS-notably high-Year 3 | 0 |
| BMI SDS-notably high-Year 4 | 1 |
| BMI SDS-notably high-Year 5 | 1 |
| BMI SDS-notably high-Year 6 | 1 |
| BMI SDS-notably high-Year 7 | 2 |
| BMI SDS-notably high-Year 8 | 2 |
| BMI SDS-notably high-Year 9 | 1 |
| BMI SDS-notably high-Year 10 | 1 |
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.
| IU/L | Everolimus |
|---|---|
| 10 years age-LH | 1.0 ± 1.47 |
| 10 years age-FSH | 1.5 ± 1.34 |
| 11 years age-LH | 1.0 ± 0.77 |
| 11 years age-FSH | 1.7 ± 1.11 |
| 12 years age-LH | 1.8 ± 1.22 |
| 12 years age-FSH | 2.1 ± 0.67 |
| 13 years age-LH | 2.4 ± 2.26 |
| 13 years age-FSH | 2.9 ± 1.81 |
| 14 years age-LH | 2.9 ± 2.18 |
| 14 years age-FSH | 4.6 ± 4.29 |
| 15 years age-LH | 2.5 ± 1.07 |
| 15 years age-FSH | 3.3 ± 0.61 |
| 16 years age-LH | 3.5 ± 0.32 |
| 16 years age-FSH | 6.0 ± 3.01 |
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.
| Participants | Everolimus |
|---|---|
| At least one AE | 12 |
| At least one SAE | 6 |
| AE leading to discontinuation | 0 |
| SAE leading to discontinuation | 0 |
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.
| years | Everolimus |
|---|---|
| Menarche | 12.5 (11.0 to 13.6) |
| Thelarche | 10.2 (9.1 to NA) |
| Adrenarche | 11.0 (10.0 to 11.6) |
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
| years | Everolimus |
|---|---|
| Tanner stage II-pubic hair-male | 11.8 (10.2 to NA) |
| Tanner stage II-genitalia | 11.9 (10.4 to NA) |
| Tanner stage III-pubic hair-male | 13.3 (11.3 to NA) |
| Tanner stage III-genitalia | 12.6 (11.3 to 14.2) |
| Tanner stage IV-pubic hair-male | 14.2 (11.3 to NA) |
| Tanner stage IV-genitalia | 14.2 (11.3 to NA) |
| Tanner stage V-pubic hair-male | 16.4 (15.3 to NA) |
| Tanner stage V-genitalia | 16.4 (12.7 to NA) |
| Tanner stage II-pubic hair-female | 10.4 (7.3 to 11.8) |
| Tanner stage II-Breast | 11.5 (9.9 to 11.8) |
| Tanner stage III-pubic hair-female | 12.2 (10.4 to 12.8) |
| Tanner stage III-Breast | 12.5 (10.4 to 14.6) |
| Tanner stage IV-pubic hair-female | 13.4 (11.6 to 14.5) |
| Tanner stage IV-Breast | 13.8 (12.7 to 14.6) |
| Tanner stage V-pubic hair-female | 16.0 (13.8 to NA) |
| Tanner stage V-Breast | NA (13.8 to NA) |
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.
| age (months) | Everolimus |
|---|---|
| First smile-baseline | 2.9 ± 1.85 |
| First smile-overall | 2.9 ± 1.85 |
| Sat without support-baseline | 7.5 ± 3.68 |
| Sat without support-overall | 7.5 ± 3.68 |
| Walked without holding on-baseline | 16.5 ± 8.23 |
| Walked without holding on-overall | 16.5 ± 8.23 |
| First used single words other than "mama" or "dada"-baseline | 29.5 ± 24.81 |
| First used single words other than "mama" or "dada"-overall | 29.5 ± 24.81 |
| First used two words/short phrases-baseline | 33.2 ± 16.66 |
| First used two words/short phrases-overall | 34.3 ± 19.77 |
| Toilet trained during the day-baseline | 46.2 ± 31.22 |
| Toilet trained during the day-overall | 51.5 ± 35.89 |
| Toilet trained at night-baseline | 52.5 ± 35.60 |
| Toilet trained at night-overall | 60.1 ± 43.23 |
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.
| IU/L | Everolimus |
|---|---|
| 10 years age-LH | 5.1 ± 3.89 |
| 10 years age-FSH | 3.4 ± 2.68 |
| 11 years age-LH | 3.2 ± 2.47 |
| 11 years age-FSH | 3.5 ± 1.61 |
| 12 years age-LH | 7.8 ± 6.73 |
| 12 years age-FSH | 5.6 ± 2.43 |
| 13 years age-LH | 4.4 ± 3.08 |
| 13 years age-FSH | 5.0 ± 0.80 |
| 14 years age-LH | 5.3 ± 6.97 |
| 14 years age-FSH | 2.6 ± 2.05 |
| 15 years age-LH | 7.5 ± 10.96 |
| 15 years age-FSH | 2.5 ± 2.28 |
| 16 years age-LH | 3.7 ± 2.69 |
| 16 years age-FSH | 2.8 ± 2.05 |
Testosterone is the primary male hormone responsible for regulating sex differentiation, producing male sex characteristics, spermatogenesis, and fertility.
| nmol/L | Everolimus |
|---|---|
| 10 years age | 0.7 ± 1.17 |
| 11 years age | 2.5 ± 4.60 |
| 12 years age | 3.8 ± 4.29 |
| 13 years age | 4.3 ± 4.04 |
| 14 years age | 7.2 ± 4.34 |
| 15 years age | 12.9 ± 6.28 |
| 16 years age | 15.5 ± 3.93 |
Estrogen is a steroid hormone associated with the female reproductive organs and is responsible for developing female sexual characteristics.
| ng/L | Everolimus |
|---|---|
| 10 years age | 139.8 |
| 11 years age | 80.5 ± 119.22 |
| 12 years age | 43.7 ± 41.26 |
| 13 years age | 50.0 ± 7.07 |
| 14 years age | 139.0 ± 141.42 |
| 15 years age | 47.7 ± 48.89 |
| 16 years age | 149.7 ± 128.21 |
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.
| Participants | Everolimus |
|---|---|
| Anxiety-baseline | 12 |
| Anxiety-overall | 13 |
| Depressed mood-baseline | 6 |
| Depressed mood-overall | 8 |
| Extreme shyness-baseline | 5 |
| Extreme shyness-overall | 7 |
| Mood swings-baseline | 10 |
| Mood swings-overall | 12 |
| Aggressive outbursts-baseline | 7 |
| Aggressive outbursts-overall | 11 |
| Temper Tantrums-baseline | 9 |
| Temper Tantrums-overall | 12 |
| Self-injury, such as hitting self, biting self, scratching self-baseline | 3 |
| Self-injury, such as hitting self, biting self, scratching self-overall | 5 |
| Absent or delayed onset of language to communicate-baseline | 11 |
| Absent or delayed onset of language to communicate-overall | 12 |
| Repeating words or phrases over and over again-baseline | 9 |
| Repeating words or phrases over and over again-overall | 12 |
| Poor eye contact-baseline | 6 |
| Poor eye contact-overall | 8 |
| Difficulties getting on with other people of similar age-baseline | 9 |
| Difficulties getting on with other people of similar age-overall | 10 |
| Repetitive behaviours, such as doing the same thing over and over again-baseline | 9 |
| Repetitive behaviours, such as doing the same thing over and over again-overall | 11 |
| Very rigid or inflexible about how to do things or not liking change in routines-baseline | 8 |
| Very rigid or inflexible about how to do things or not liking change in routines-overall | 11 |
| Overactivity/hyperactivity, such as being constantly on the go-baseline | 8 |
| Overactivity/hyperactivity, such as being constantly on the go-overall | 9 |
| Difficulty paying attention or concentrating-baseline | 13 |
| Difficulty paying attention or concentrating-overall | 15 |
| Restlessness or fidgetiness, such as wriggling or squirming-baseline | 13 |
| Restlessness or fidgetiness, such as wriggling or squirming-overall | 14 |
| Impulsivity, such as butting in, not waiting turn-baseline | 10 |
| Impulsivity, such as butting in, not waiting turn-overall | 12 |
| Difficulties with eating, such as eating too much, too little, unusual things-baseline | 5 |
| Difficulties with eating, such as eating too much, too little, unusual things-overall | 8 |
| Sleep difficulties, such as with falling asleep or waking-baseline | 6 |
| Sleep difficulties, such as with falling asleep or waking-overall | 8 |
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.
| Participants | Everolimus |
|---|---|
| Autism Spectrum Disorder (ASD), including autism, Asperger's-baseline | 4 |
| Autism Spectrum Disorder (ASD), including autism, Asperger's-overall | 7 |
| Attention Deficit Hyperactivity Disorder (ADHD)-baseline | 5 |
| Attention Deficit Hyperactivity Disorder (ADHD)-overall | 9 |
| Anxiety Disorder, including as panic, phobia, separation anxiety disorder-baseline | 4 |
| Anxiety Disorder, including as panic, phobia, separation anxiety disorder-overall | 7 |
| Depressive Disorder-baseline | 0 |
| Depressive Disorder-overall | 0 |
| Obsessive Compulsive Disorder-baseline | 2 |
| Obsessive Compulsive Disorder-overall | 2 |
| Psychotic Disorder, including schizophrenia-baseline | 0 |
| Psychotic Disorder, including schizophrenia-overall | 0 |
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.
| Participants | Everolimus |
|---|---|
| Reading-baseline | 12 |
| Reading-overall | 14 |
| Writing-baseline | 12 |
| Writing-overall | 14 |
| Spelling-baseline | 12 |
| Spelling-overall | 14 |
| Mathematics-baseline | 12 |
| Mathematics-overall | 14 |
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.
| Participants | Everolimus |
|---|---|
| Memory-baseline | 7 |
| Memory-overall | 12 |
| Attention-baseline | 12 |
| Attention-overall | 14 |
| Dual-tasking/ Multi-tasking-baseline | 12 |
| Dual-tasking/ Multi-tasking-overall | 14 |
| Visuo-spatial tasks-baseline | 8 |
| Visuo-spatial tasks-overall | 13 |
| Executive skills-baseline | 10 |
| Executive skills-overall | 15 |
| Getting disoriented-baseline | 7 |
| Getting disoriented-overall | 12 |
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.
| Participants | Everolimus |
|---|---|
| Low self-esteem-baseline | 2 |
| Low self-esteem-overall | 6 |
| Very high levels of stress in families, for instance between siblings-baseline | 6 |
| Very high levels of stress in families, for instance between siblings-overall | 8 |
| Very high levels of stress between parents leading to significant relationship difficulties-baseline | 5 |
| Very high levels of stress between parents leading to significant relationship difficulties-overall | 7 |
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.
| Participants | Everolimus |
|---|---|
| Non-verbal | 2 |
| Simple language | 6 |
| Fluent | 4 |
| Missing | 3 |
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 | Everolimus |
|---|---|
| Dependent on others | 4 |
| Some self-care skills | 7 |
| Independent | 1 |
| Missing | 3 |
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.
| Participants | Everolimus |
|---|---|
| Wheelchair | 1 |
| Needs significant support | 1 |
| Some difficulty | 0 |
| Completely mobile | 10 |
| Missing | 3 |
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.
| Participants | Everolimus |
|---|---|
| Normal Intellectual Ability (IQ > 80) | 2 |
| Borderline Intellectual Ability (IQ 70-80) | 2 |
| Mild Intellectual Disability (IQ 50-69) | 1 |
| Moderate Intellectual Disability (IQ 35-49) | 5 |
| Severe Intellectual Disability (IQ 21-34) | 0 |
| Profound Intellectual Disability (IQ <20) | 1 |
| Missing | 4 |
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.
| Participants | Everolimus |
|---|---|
| Normal Intellectual Ability | 1 |
| Mild-Moderate Intellectual Disability | 8 |
| Severe - Profound Intellectual Disability | 3 |
| Missing | 3 |
Collected over From enrollment in study CRAD001M2305 until end of study, up to approximately 9 years.. Non-serious events are listed at a 1% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Everolimus | 1/14 (7.1%) | 6/14 (42.9%) | 12/14 (85.7%) |
| Event | Everolimus |
|---|---|
| PyrexiaGeneral disorders | 2/14 |
| PneumoniaInfections and infestations | 2/14 |
| SeizureNervous system disorders | 2/14 |
| DrowningGeneral disorders | 1/14 |
| Arthritis infectiveInfections and infestations | 1/14 |
| InfluenzaInfections and infestations | 1/14 |
| Staphylococcal infectionInfections and infestations | 1/14 |
| Near drowningInjury, poisoning and procedural complications | 1/14 |
| Post procedural complicationInjury, poisoning and procedural complications | 1/14 |
| Astrocytoma, low gradeNeoplasms benign, malignant and unspecified (incl cysts and polyps) | 1/14 |
| Event | Everolimus |
|---|---|
| PyrexiaGeneral disorders | 6/14 |
| Ear infectionInfections and infestations | 4/14 |
| NasopharyngitisInfections and infestations | 4/14 |
| SeizureNervous system disorders | 4/14 |
| AnaemiaBlood and lymphatic system disorders | 3/14 |
| DiarrhoeaGastrointestinal disorders | 3/14 |
| StomatitisGastrointestinal disorders | 3/14 |
| Seasonal allergyImmune system disorders | 3/14 |
| PneumoniaInfections and infestations | 3/14 |
| SinusitisInfections and infestations | 3/14 |
| Age, Continuous(years) | Everolimus |
|---|---|
| Mean | 6.390 ± 3.5647 |
| Sex: Female, Male(Participants) | Everolimus |
|---|---|
| Female | 8 |
| Male | 7 |
| Race/Ethnicity, Customized(Participants) | Everolimus |
|---|---|
| Black | 1 |
| Caucasian | 14 |
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