Long-term Monitoring of Growth and Development of Pediatric Patients Previously Treated With Everolimus

NCT02338609 | Completed Phase 4 Results FDA Drug

• 2 other identifiers: CRAD001M23052013-003795-13
• Study Type: interventional
• Target: 15
• Locations: 3 countries
• Sites: 6

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.

Conditions

Growth and Development

Keywords

TSC-associated SEGA,; height,; weight,; Tanner Stage,; growth development,; everolimus,; RAD001

Outcome Measures

Primary Outcomes (6)

• 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 Outcomes (14)

• 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.

• 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)

• 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)

• 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.

• TAND Checklist: Number of Participants With Behavioral Disorders

  From enrollment in study CRAD001M2305 until end of study, up to approximately 9 years.

Study Arms (1)

Everolimus

EXPERIMENTAL

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

Interventions

Everolimus DRUG

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.

Everolimus

Eligibility Criteria

• Age: 0 Years - 17 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Novartis Pharmaceuticals: lead

Study Sites (6)

University Of California LA SC

Los Angeles, California, 90095, United States

Location

Minnesota Epilepsy Group

Saint Paul, Minnesota, 55102, United States

Location

Cinn Children Hosp Medical Center SC

Cincinnati, Ohio, 45229-3039, United States

Location

Texas Scottish Rite Hos for Child SC

Dallas, Texas, 75219, United States

Location

Novartis Investigative Site

Brussels, 1090, Belgium

Location

Novartis Investigative Site

Moscow, 127412, Russia

Location

MeSH Terms

Conditions

Body Weight

Interventions

Everolimus

Condition Hierarchy (Ancestors)

Signs and Symptoms; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Sirolimus; Macrolides; Lactones; Organic Chemicals

Limitations and Caveats

It was anticipated that maximum of 50 patients who have participated in Study M2301 would be eligible to enter Study M2305 if they consent to participate. However, only 15 patients were enrolled into this study, due to delays in study start-up at country level.

Results Point of Contact

• Title: Study Director
• Organization: Novartis Pharmaceuticals

novartis.email@novartis.com

+1 862-778-8300

Study Officials

• Novartis Pharmaceuticals

  Novartis Pharmaceuticals

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: NA
• Masking: NONE
• Purpose: OTHER
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 1, 2014
• First Posted: January 14, 2015
• Study Start: December 17, 2014
• Primary Completion: December 18, 2023
• Study Completion: December 18, 2023
• Last Updated: August 9, 2024
• Results First Posted: August 9, 2024

Record last verified: 2024-07

Data Sharing

• IPD Sharing: Will share

Locations

RU (1); US (4); BE (1)