PASS of Paediatric Patients Initiating Selumetinib

• ClinicalTrials.gov Identifier: NCT05388370
• Recruitment Status: Recruiting
• First Posted: May 24, 2022
• Last Update Posted: November 27, 2023
• Sponsor: AstraZeneca
• Information provided by (Responsible Party): AstraZeneca

Tracking Information

• First Submitted Date: April 12, 2022
• First Posted Date: May 24, 2022
• Last Update Posted Date: November 27, 2023
• Actual Study Start Date: May 23, 2022
• Estimated Primary Completion Date: May 23, 2027 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: May 23, 2022)

• LVEF reduction [ Time Frame: at routine clinical care throughout the follow up, with frequency of 6 to 12 months ]
  LVEF reduction will be detected as present or absent and when present if symptomatic or asymptomatic. All cardiac tests conducted will be collected Measured on routine echocardiogram or a cardiac MRI (CT, angiography, etc.) and then collected into the study from the medical records.
• Occurrence of Physeal dysplasia after treatment start [ Time Frame: at routine clinical care throughout the follow up, with frequency of 6 to 12 months ]
  Physeal dysplasia will be detected as present or absent based on the physician reading of: MRI: Knee (preferred) or wrist X-ray: Knee (preferred) and/or wrist to assess growth plate Height and weight records
• Rise of serum creatine phosphokinase levels AND concurrent musculoskeletal symptoms [ Time Frame: at routine clinical care throughout the follow up, with frequency of 6 to 12 months, up to 5 years ]
  A clinically meaningful rise in serum creatine phosphokinase (eg, above the normal limit or increase by 1 or more CTCAE grade shift) combined with musculoskeletal symptoms will be detected as present or absent based on the physician's reading, as a marker of potential myopathy
• Rise in transaminase (ALT and AST) and concurrent rise in bilirubin [ Time Frame: at routine clinical care throughout the follow up, with frequency of 6 to 12 months, up to 5 years ]
  A clinically meaningful rise in the measured levels (eg, above the normal limit or increase by 1 or more CTCAE grade shift) will be detected as present or absent, and when present if symptomatic or asymptomatic, as a marker of potential hepatotoxicity
• Cumulative incidence of ocular toxicity [ Time Frame: at routine clinical care throughout the follow up, with frequency of 6 to 12 months ]
  An abnormal ocular examination will be detected as present or absent based on the physician's reading, as a marker of potential ocular toxicity
• Cumulative incidence of Abnormal pubertal development [ Time Frame: at routine clinical care throughout the follow up, with frequency of 6 to 12 months ]
  Tanner staging criteria (Stages I-V). Abnormal pubertal development will require interpretation by the Investigator with respect to Tanner Stage in the context of the patient's age; recorded as normal or abnormal (if abnormal, further specified as delayed puberty or precocious puberty)

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: May 23, 2022)

• baseline data - demographics [ Time Frame: At baseline - most recent assessments made within 365 days before the index date ]
  Demographics: Age
• baseline data - demographics [ Time Frame: At baseline - most recent assessments made within 365 days before the index date ]
  sex
• baseline data - demographics [ Time Frame: At baseline - most recent assessments made within 365 days before the index date ]
  height (cm)
• baseline data - demographics [ Time Frame: At baseline - most recent assessments made within 365 days before the index date ]
  weight (kg)
• baseline data - demographics [ Time Frame: At baseline - most recent assessments made within 365 days before the index date ]
  Tanner staging level
• baseline data - demographics [ Time Frame: At baseline - most recent assessments made within 365 days before the index date ]
  Ethnicity (where allowed by GDPR/privacy laws)
• Baseline data - Clinical characteristics [ Time Frame: At baseline - most recent assessments made within 365 days before the index date ]
  PN(s) (number, location, classification and morbidities)
• Baseline data - Clinical characteristics [ Time Frame: At baseline - most recent assessments made within 365 days before the index date ]
  prior medication and relevant procedures, concomitant medications
• Baseline data - Clinical characteristics [ Time Frame: At baseline - most recent assessments made within 365 days before the index date ]
  date of initial NF1 and PN diagnosis, NF1 origin (familial or spontaneous), and any genetic testing results

• Original Secondary Outcome Measures: Same as current

Current Other Pre-specified Outcome Measures (submitted: May 23, 2022)

• Other Variables and Covariates [ Time Frame: at baseline and throughout follow-up, up to 5 years ]
  Height (cm)
• Other Variables and Covariates [ Time Frame: at baseline and throughout follow-up, up to 5 years ]
  Weight (kg)
• Other Variables and Covariates [ Time Frame: at baseline and throughout follow-up, up to 5 years ]
  Body surface area
• Other Variables and Covariates [ Time Frame: at baseline and throughout follow-up, up to 5 years ]
  Tanner staging (level from I to V)
• Other Variables and Covariates [ Time Frame: at baseline and throughout follow-up, up to 5 years ]
  Concomitant medications, including any medications used to treat AEs
• Other Variables and Covariates [ Time Frame: at baseline and throughout follow-up, up to 5 years ]
  Comorbidities
• Other Variables and Covariates [ Time Frame: at baseline and throughout follow-up, up to 5 years ]
  NF1-related clinical manifestation and complications
• Other Variables and Covariates [ Time Frame: at baseline and throughout follow-up, up to 5 years ]
  PN-related variables (including for any clinically important target PNs)
• Other Variables and Covariates [ Time Frame: at baseline and throughout follow-up, up to 5 years ]
  PN-related symptoms/morbidities

• Original Other Pre-specified Outcome Measures: Same as current

Descriptive Information

• Brief Title: PASS of Paediatric Patients Initiating Selumetinib
• Official Title: Post-Authorisation Safety Study of Paediatric Patients Initiating Selumetinib: A Multiple-Country Prospective Cohort Study

Brief Summary

Neurofibromatosis type 1 (NF1) is a rare, autosomal dominant genetic disorder that is caused by germline mutations in the NF1 tumour suppressor gene, which encodes the tumour suppressor protein neurofibromin 1. Plexiform neurofibromas (PN) are histologically benign nerve sheath tumours, which typically grow along large nerves and plexi.

On 5 March 2020, a centralised Marketing Authorisation Application was submitted to the European Medicines Agency (EMA), Marketing Authorisation in EU was granted on 17 Jun 2021.

As part of the approval process, a Risk Management Plan (RMP) was developed and submitted to the EMA to summarise the safety concerns emerging from the clinical development program. The RMP included additional pharmacovigilance plans for a noninterventional Post-authorisation Safety Study (PASS) to further characterise the safety of selumetinib in paediatric patients with NF1-related PN in routine clinical practice.

The planned non-interventional PASS will address gaps in knowledge identified by the RMP, including the important identified risk and some of the potential risks and missing information on long-term developmental toxicity in children, by characterising the safety profile associated with selumetinib use among paediatric patients (ages > 8 to < 18 years old) with a diagnosis of NF1 with symptomatic, inoperable PN.

This study is a specific obligation in the context of a conditional marketing authorisation for selumetinib (ie, Category 2 PASS). Study results will contribute to updating the safety profile of selumetinib in a relatively large population of patients with different personal characteristics across multiple health care systems and patterns of real-world clinical practice in the European Union (EU) and in the UK.

The study will enrol 2 cohorts:

1. The Base Cohort includes all enrolled patients aged 3 to < 18 years.
2. The Nested Prospective Cohort will include the subset of Base Cohort patients aged 8 to < 18 years who have not reached Tanner Stage V on the index date.

Detailed Description

Neurofibromatosis type 1 (NF1) is a rare, autosomal dominant genetic disorder that is caused by germline mutations in the NF1 tumour suppressor gene, which encodes the tumour suppressor protein neurofibromin 1. Plexiform neurofibromas (PN) are histologically benign nerve sheath tumours, which typically grow along large nerves and plexi.

On 5 March 2020, a centralized Marketing Authorisation Application was submitted to the European Medicines Agency (EMA), Marketing Authorization in EU was granted on 17 Jun 2021.

As part of the approval process, a Risk Management Plan (RMP) was developed and submitted to the EMA to summarise the safety concerns emerging from the clinical development program. The RMP included additional pharmacovigilance plans for a non-interventional Post-authorisation Safety Study (PASS) to further characterise the safety of selumetinib in paediatric patients with NF1-related PN in routine clinical practice.

The RMP version 1.0 (succession 4) approved by EMA on 22 April 2021 had 1 important identified risk with selumetinib treatment:

-LVEF reduction

The RMP also identified 5 important potential risks with selumetinib treatment:

• Physeal dysplasia
• Ocular toxicity
• Myopathy
• Hepatotoxicity
• Choking on the capsule Long-term exposure (including long-term safety data on developmental toxicity in children) was identified in the RMP as an area of missing information.

The planned non-interventional PASS will address gaps in knowledge identified by the RMP, including the important identified risk and some of the potential risks and missing information on long-term developmental toxicity in children, by characterising the safety profile associated with selumetinib use among paediatric patients (ages > 8 to < 18 years old) with a diagnosis of NF1 with symptomatic, inoperable PN.

This study is a specific obligation in the context of a conditional marketing authorisation for selumetinib (ie, Category 2 PASS). Study results will contribute to updating the safety profile of selumetinib in a relatively large population of patients with different personal characteristics across multiple health care systems and patterns of real-world clinical practice in the European Union (EU) and in the UK.

The primary objective of this study is:

- To characterise the safety of selumetinib, including up to 5 years of long-term safety, in paediatric patients with NF1-related symptomatic, inoperable PN, 8 to < 18 years old who have not reached Tanner Stage V at the start of selumetinib treatment (Nested Prospective Cohort).

The secondary objective of this study is:

- To describe the demographic and clinical profile of the paediatric population 3 to < 18 years old with NF1-related symptomatic inoperable PN who start selumetinib in routine clinical practice (Base Cohort).

This study will be conducted in up to 36 specialist clinics for the treatment of paediatric patients with NF1 across 12 European countries. The study observation period is anticipated to begin in Q1 of 2022, with some variation by country. Patients will be enrolled after commercial launch of selumetinib in each participating country, when patients/physicians have access to medicine as part of standard clinical practice.

The target population for this study are patients with NF1 in the EU with symptomatic, inoperable PN who have been prescribed at least 1 dose of selumetinib and who are aged 3 to < 18 years at the start of selumetinib treatment, except for those patients receiving treatment with a mitogen-activated protein kinase inhibitor before the index date.

The study will enrol 2 cohorts:

1. The Base Cohort includes all enrolled patients aged 3 to < 18 years.
2. The Nested Prospective Cohort will include the subset of Base Cohort patients aged 8 to < 18 years who have not reached Tanner Stage V on the index date.

Patient screening will be conducted throughout the enrolment period and baseline data for all patients will be abstracted from medical records. Those meeting the criteria for enrolment in the Nested Prospective Cohort will be followed up during their routine encounters with the treating clinician (expected to occur every 6 to 12 months) for up to 5 years.

• Study Type: Observational
• Study Design: Observational Model: Cohort; Time Perspective: Prospective
• Target Follow-Up Duration: Not Provided
• Biospecimen: Not Provided
• Sampling Method: Non-Probability Sample
• Study Population: The target population for this study are patients with NF1 with symptomatic, inoperable PN who have been prescribed at least 1 dose of selumetinib and who are aged 3 to < 18 years at the start of selumetinib treatment, except for those patients receiving treatment with a mitogen-activated protein kinase inhibitor before the index date.
• Condition: Neurofibromatosis Type 1
• Intervention: Not Provided

Study Groups/Cohorts

• Base Cohort
  The Base Cohort includes all enrolled patients aged 3 to < 18 years.
• Nested Prospective Cohort
  The Nested Prospective Cohort will include the subset of Base Cohort patients aged 8 to < 18 years who have not reached Tanner Stage V on the index date

Publications *

• EMA2017b EMA. Guideline on good pharmacovigilance practices (GVP). Module VIII - Post-authorisation safety studies (EMA/813938/2011 Rev 3). European Medicines Agency; 09 October 2017b. Available at: https://www.ema.europa.eu/documents/scientificguideline/ guideline-good-pharmacovigilance-practices-gvp-
• Zhou Q. [Recommendations for the conduct, reporting, editing and publication of scholarly work in medical journals]. Zhonghua Gan Zang Bing Za Zhi. 2014 Oct;22(10):781-91. No abstract available. Chinese.
• ISPE. Guidelines for good pharmacoepidemiology practices (GPP). Pharmacoepidemiol Drug Saf. 2008 Feb;17(2):200-8. doi: 10.1002/pds.1471. No abstract available.
• KOSELUGO (selumetinib) KOSELUGO (selumetinib) capsules, for oral use, initial US Approval: 2020. Distributed by: AstraZeneca Pharmaceuticals LP, Wilmington, DE 19850. USPI revised April 2020, Reference ID 4590044.
• von Elm E, Altman DG, Egger M, Pocock SJ, Gotzsche PC, Vandenbroucke JP; STROBE Initiative. The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: guidelines for reporting observational studies. Lancet. 2007 Oct 20;370(9596):1453-7. doi: 10.1016/S0140-6736(07)61602-X.

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: May 23, 2022): 125
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: May 23, 2027
• Estimated Primary Completion Date: May 23, 2027 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Have been diagnosed with NF1 with symptomatic, inoperable PN
• Have been newly prescribed at least one dose of selumetinib
• Are aged 3 years and above, and are < 18 years of age on the index date
• Parent or legal guardian, as required by country-specific regulation, have provided informed consent (unless a country-specific waiver is obtained) Additional Criteria for Nested Prospective Cohort
• Are at least 8 years old and
• Are prior to attainment of Tanner Stage V on the index date

Exclusion Criteria:

• Have received treatment with a mitogen-activated protein kinase inhibitor before the index date
• Are participating in a randomised controlled trial

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 3 Years to 17 Years (Child)
• Accepts Healthy Volunteers: No

Contacts

Contact: AstraZeneca Clinical Study Information Center; 1-877-240-9479; information.center@astrazeneca.com

• Listed Location Countries: Austria, France, Germany, Portugal, Spain, Switzerland, United Kingdom

Administrative Information

• NCT Number: NCT05388370
• Other Study ID Numbers: D1346R00004
• Has Data Monitoring Committee: Not Provided

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: Yes
• Plan Description: The study protocol, study progress reports, and final study report will be included in regulatory communications in line with the RMP, PSUR, and other regulatory reporting requirements. Study reports will be prepared using a template following the GVP Module VIII Section B.6.3.
• Supporting Materials: Study Protocol
• Supporting Materials: Clinical Study Report (CSR)

• Current Responsible Party: AstraZeneca
• Original Responsible Party: Same as current
• Current Study Sponsor: AstraZeneca
• Original Study Sponsor: Same as current
• Collaborators: Not Provided
• Investigators: Not Provided
• PRS Account: AstraZeneca
• Verification Date: November 2023