Long-term Monitoring of Growth and Development of Pediatric Patients Previously Treated With Everolimus (EXIST-LT)

Long-term Follow-up Study to Monitor the Growth and Development of Pediatric Patients Previously Treated With Everolimus in Study CRAD001M2301 (EXIST-LT)

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.

Study Overview

• Status: Completed
• Conditions: Growth and Development
• Intervention / Treatment: Drug: Everolimus

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.

• Study Type: Interventional
• Enrollment (Actual): 15
• Phase: Phase 4

Contacts and Locations

Study Locations

• Belgium
  • Brussel, Belgium, 1090
    • Novartis Investigative Site
• Russian Federation
  • Moscow, Russian Federation, 127412
    • Novartis Investigative Site
• United States
  • California
    • Los Angeles, California, United States, 90095
      • University Of California LA SC
  • Minnesota
    • Saint Paul, Minnesota, United States, 55102
      • Minnesota Epilepsy Group
  • Ohio
    • Cincinnati, Ohio, United States, 45229-3039
      • Cinn Children Hosp Medical Center SC
  • Texas
    • Dallas, Texas, United States, 75219
      • Texas Scottish Rite Hos for Child SC

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 second to 17 years (Child)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Everolimus; 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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)	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.	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.	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.	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.	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.	Annually, starting at 10-year age until 16-year age (in both studies CRAD001M2301 and CRAD001M2305)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	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.	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	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.	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.	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.	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.	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.	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.	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.	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.	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.	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.	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.	From enrollment in study CRAD001M2305 until end of study, up to approximately 9 years.

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals
• Investigators: Study Director: Novartis Pharmaceuticals, Novartis Pharmaceuticals

Study record dates

Study Major Dates

• Study Start (Actual): December 17, 2014
• Primary Completion (Actual): December 18, 2023
• Study Completion (Actual): December 18, 2023

Study Registration Dates

• First Submitted: December 1, 2014
• First Submitted That Met QC Criteria: January 9, 2015
• First Posted (Estimated): January 14, 2015

Study Record Updates

• Last Update Posted (Actual): August 9, 2024
• Last Update Submitted That Met QC Criteria: August 6, 2024
• Last Verified: July 1, 2024

More Information

Terms related to this study

• Keywords: RAD001; TSC-associated SEGA,; height,; weight,; Tanner Stage,; growth development,; everolimus,
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Protein Kinase Inhibitors; MTOR Inhibitors; Everolimus
• Other Study ID Numbers: CRAD001M2305; 2013-003795-13 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD Plan Description

Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations.

This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No