Clinical trial NCT05388370: PASS of Paediatric Patients Initiating Selumetinib
Official title: Post-Authorisation Safety Study of Paediatric Patients Initiating Selumetinib: A Multiple-Country Prospective Cohort Study.
Study type: OBSERVATIONAL
Overall status: RECRUITING
Conditions: Neurofibromatosis Type 1
Lead sponsor: AstraZeneca
Sponsor class: INDUSTRY
First posted: 2022-05-24
Enrollment: 125
Sex: ALL
Minimum age (years): 3
Maximum age (years): 17
Standard ages: CHILD
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
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.

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 (age d 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 European countries and Israel.

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 (aged d 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 up to 52 specialist clinics for the treatment of pediatric patients with NF1 across up to 12 European countries and in Israel.

The primary objective of this study is:

- To characterise the safety of selumetinib, including up to 6 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).

The study observation period was anticipated to begin in Q2 of 2022, with some variation by country (actual start date was 23 May 2022). Patients will be enrolled after selumetinib access is commercially available and patients are able to receive the medicine as part of local 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 standard of care visits with the treating clinician (expected to occur every 6 to 12 months) for up to 6 years.

Eligibility criteria: Inclusion Criteria:

* Have been diagnosed with NF1 with symptomatic, inoperable PN
* Have initial treatment with selumetinib up to 6 months (i.e.182 days)prior to enrolment into the study (i.e. signature of the ICF)
* 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 an interventional study at index date

Primary outcomes:
measure: LVEF reduction
timeFrame: at routine clinical care throughout the follow up, with frequency of 6 to 12 months
measure: Occurrence of Physeal dysplasia after treatment start
timeFrame: at routine clinical care throughout the follow up, with frequency of 6 to 12 months
measure: Rise of serum creatine phosphokinase levels AND concurrent musculoskeletal symptoms
timeFrame: at routine clinical care throughout the follow up, with frequency of 6 to 12 months, up to 6 years
measure: Rise in transaminase (ALT and AST) and concurrent rise in bilirubin
timeFrame: at routine clinical care throughout the follow up, with frequency of 6 to 12 months, up to 6 years
measure: Cumulative incidence of ocular toxicity
timeFrame: at routine clinical care throughout the follow up, with frequency of 6 to 12 months
measure: Cumulative incidence of Abnormal pubertal development
timeFrame: at routine clinical care throughout the follow up, with frequency of 6 to 12 months
Secondary outcomes:
measure: baseline data - demographics
timeFrame: At baseline - most recent assessments made within 365 days before the index date
measure: baseline data - demographics
timeFrame: At baseline - most recent assessments made within 365 days before the index date
measure: baseline data - demographics
timeFrame: At baseline - most recent assessments made within 365 days before the index date
measure: baseline data - demographics
timeFrame: At baseline - most recent assessments made within 365 days before the index date
measure: baseline data - demographics
timeFrame: At baseline - most recent assessments made within 365 days before the index date
measure: baseline data - demographics
timeFrame: At baseline - most recent assessments made within 365 days before the index date
measure: Baseline data - Clinical characteristics
timeFrame: At baseline - most recent assessments made within 365 days before the index date
measure: Baseline data - Clinical characteristics
timeFrame: At baseline - most recent assessments made within 365 days before the index date
measure: Baseline data - Clinical characteristics
timeFrame: At baseline - most recent assessments made within 365 days before the index date
Other outcomes:
measure: Other Variables and Covariates
timeFrame: at baseline and throughout follow-up, up to 6 years
measure: Other Variables and Covariates
timeFrame: at baseline and throughout follow-up, up to 6 years
measure: Other Variables and Covariates
timeFrame: at baseline and throughout follow-up, up to 6 years
measure: Other Variables and Covariates
timeFrame: at baseline and throughout follow-up, up to 6 years
measure: Other Variables and Covariates
timeFrame: at baseline and throughout follow-up, up to 6 years
measure: Other Variables and Covariates
timeFrame: at baseline and throughout follow-up, up to 6 years
measure: Other Variables and Covariates
timeFrame: at baseline and throughout follow-up, up to 6 years
measure: Other Variables and Covariates
timeFrame: at baseline and throughout follow-up, up to 6 years
measure: Other Variables and Covariates
timeFrame: at baseline and throughout follow-up, up to 6 years
Locations:
city: Wien
country: Austria
facility: Research Site
city: Amiens
country: France
facility: Research Site
city: Angers
country: France
facility: Research Site
city: Bordeaux
country: France
facility: Research Site
city: Lille
country: France
facility: Research Site
city: Lyon
country: France
facility: Research Site
city: Marseille
country: France
facility: Research Site
city: Paris
country: France
facility: Research Site
city: Rennes
country: France
facility: Research Site
city: Strasbourg
country: France
facility: Research Site
city: Toulouse
country: France
facility: Research Site
city: Tours
country: France
facility: Research Site
city: Villejuif Cedex
country: France
facility: Research Site
city: Dresden
country: Germany
facility: Research Site
city: Duisburg
country: Germany
facility: Research Site
city: Hamburg
country: Germany
facility: Research Site
city: München
country: Germany
facility: Research Site
city: Tubingen
country: Germany
facility: Research Site
city: Petach Tikva
country: Israel
facility: Research Site
city: Ramat Gan
country: Israel
facility: Research Site
city: Tel Aviv-Yafo
country: Israel
facility: Research Site
city: Firenze
country: Italy
facility: Research Site
city: Genova
country: Italy
facility: Research Site
city: Milano
country: Italy
facility: Research Site
city: Padova
country: Italy
facility: Research Site
city: Pavia
country: Italy
facility: Research Site
city: Roma
country: Italy
facility: Research Site
city: Torino
country: Italy
facility: Research Site
city: Trieste
country: Italy
facility: Research Site
city: Rotterdam
country: Netherlands
facility: Research Site
city: Lisboa
country: Portugal
facility: Research Site
city: Porto
country: Portugal
facility: Research Site
city: Barcelona
country: Spain
facility: Research Site
city: Esplugues de Llobregat
country: Spain
facility: Research Site
city: Madrid
country: Spain
facility: Research Site
city: Malaga
country: Spain
facility: Research Site
city: Santiago de Compostela
country: Spain
facility: Research Site
city: Sevilla
country: Spain
facility: Research Site
city: Basel
country: Switzerland
facility: Research Site
city: Bern
country: Switzerland
facility: Research Site
city: Lausanne
country: Switzerland
facility: Research Site
city: St. Gallen
country: Switzerland
facility: Research Site
city: London
country: United Kingdom
facility: Research Site
city: Manchester
country: United Kingdom
facility: Research Site
city: Newcastle
country: United Kingdom
facility: Research Site
Study officials:
References:
citation: 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-
citation: 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.
citation: ISPE. Guidelines for good pharmacoepidemiology practices (GPP). Pharmacoepidemiol Drug Saf. 2008 Feb;17(2):200-8. doi: 10.1002/pds.1471. No abstract available.
citation: 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.
citation: 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.