PASS of Paediatric Patients Initiating Selumetinib
Study Details
Study Description
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:
-
The Base Cohort includes all enrolled patients aged 3 to < 18 years.
-
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.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
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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:
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Physeal dysplasia
-
Ocular toxicity
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Myopathy
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Hepatotoxicity
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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:
-
The Base Cohort includes all enrolled patients aged 3 to < 18 years.
-
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 Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| 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 |
Outcome Measures
Primary Outcome Measures
- LVEF reduction [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 [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 [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 [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 [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 [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)
Secondary Outcome Measures
- baseline data - demographics [At baseline - most recent assessments made within 365 days before the index date]
Demographics: Age
- baseline data - demographics [At baseline - most recent assessments made within 365 days before the index date]
sex
- baseline data - demographics [At baseline - most recent assessments made within 365 days before the index date]
height (cm)
- baseline data - demographics [At baseline - most recent assessments made within 365 days before the index date]
weight (kg)
- baseline data - demographics [At baseline - most recent assessments made within 365 days before the index date]
Tanner staging level
- baseline data - demographics [At baseline - most recent assessments made within 365 days before the index date]
Ethnicity (where allowed by GDPR/privacy laws)
- Baseline data - Clinical characteristics [At baseline - most recent assessments made within 365 days before the index date]
PN(s) (number, location, classification and morbidities)
- Baseline data - Clinical characteristics [At baseline - most recent assessments made within 365 days before the index date]
prior medication and relevant procedures, concomitant medications
- Baseline data - Clinical characteristics [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
Other Outcome Measures
- Other Variables and Covariates [at baseline and throughout follow-up, up to 5 years]
Height (cm)
- Other Variables and Covariates [at baseline and throughout follow-up, up to 5 years]
Weight (kg)
- Other Variables and Covariates [at baseline and throughout follow-up, up to 5 years]
Body surface area
- Other Variables and Covariates [at baseline and throughout follow-up, up to 5 years]
Tanner staging (level from I to V)
- Other Variables and Covariates [at baseline and throughout follow-up, up to 5 years]
Concomitant medications, including any medications used to treat AEs
- Other Variables and Covariates [at baseline and throughout follow-up, up to 5 years]
Comorbidities
- Other Variables and Covariates [at baseline and throughout follow-up, up to 5 years]
NF1-related clinical manifestation and complications
- Other Variables and Covariates [at baseline and throughout follow-up, up to 5 years]
PN-related variables (including for any clinically important target PNs)
- Other Variables and Covariates [at baseline and throughout follow-up, up to 5 years]
PN-related symptoms/morbidities
Eligibility Criteria
Criteria
Inclusion Criteria:
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Have been diagnosed with NF1 with symptomatic, inoperable PN
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Have been newly prescribed at least one dose of selumetinib
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Are aged 3 years and above, and are < 18 years of age on the index date
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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
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Are at least 8 years old and
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Are prior to attainment of Tanner Stage V on the index date
Exclusion Criteria:
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Have received treatment with a mitogen-activated protein kinase inhibitor before the index date
-
Are participating in a randomised controlled trial
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Research Site | Duisburg | Germany |
Sponsors and Collaborators
- AstraZeneca
Investigators
None specified.Study Documents (Full-Text)
None provided.More Information
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-
- ICMJE 2014 International Committee of Medical Journal Editors (ICMJE). Recommendations for the conduct, reporting, editing, and publication of scholarly work in medical journals. 2014. Available at: http://www.icmje.org/icmje-recommendations.pdf
- ISPE. Guidelines for good pharmacoepidemiology practices (GPP). Pharmacoepidemiol Drug Saf. 2008 Feb;17(2):200-8.
- 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, Gøtzsche 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.
- D1346R00004