PASS of Paediatric Patients Initiating Selumetinib

NCT05388370 | Active Not Recruiting

• 1 other identifier: D1346R00004
• Study Type: observational
• Target: 124
• Locations: 10 countries
• Sites: 46

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. 1.The Base Cohort includes all enrolled patients aged 3 to \< 18 years.
2. 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.

Conditions

Neurofibromatosis Type 1

Outcome Measures

Primary Outcomes (6)

• LVEF reduction

  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.

  at routine clinical care throughout the follow up, with frequency of 6 to 12 months

• Occurrence of Physeal dysplasia after treatment start

  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

  at routine clinical care throughout the follow up, with frequency of 6 to 12 months

• Rise of serum creatine phosphokinase levels AND concurrent musculoskeletal symptoms

  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

  at routine clinical care throughout the follow up, with frequency of 6 to 12 months, up to 6 years

• Rise in transaminase (ALT and AST) and concurrent rise in bilirubin

  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

  at routine clinical care throughout the follow up, with frequency of 6 to 12 months, up to 6 years

• Cumulative incidence of ocular toxicity

  An abnormal ocular examination will be detected as present or absent based on the physician's reading, as a marker of potential ocular toxicity

  at routine clinical care throughout the follow up, with frequency of 6 to 12 months

• Cumulative incidence of Abnormal pubertal development

  Tanner stage 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)

  at routine clinical care throughout the follow up, with frequency of 6 to 12 months

Secondary Outcomes (9)

• baseline data - demographics

  At baseline - most recent assessments made within 365 days before the index date

• baseline data - demographics

  At baseline - most recent assessments made within 365 days before the index date

• baseline data - demographics

  At baseline - most recent assessments made within 365 days before the index date

• baseline data - demographics

  At baseline - most recent assessments made within 365 days before the index date

• baseline data - demographics

  At baseline - most recent assessments made within 365 days before the index date

Other Outcomes (9)

• Other Variables and Covariates

  at baseline and throughout follow-up, up to 6 years

• Other Variables and Covariates

  at baseline and throughout follow-up, up to 6 years

• Other Variables and Covariates

  at baseline and throughout follow-up, up to 6 years

Study Arms (2)

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

Eligibility Criteria

• Age: 3 Years - 17 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)
• 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.

You may qualify if:

• 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

You may not qualify if:

• Have received treatment with a mitogen-activated protein kinase inhibitor before the index date
• Are participating in an interventional study at index date

Sponsors & Collaborators

• AstraZeneca: lead

Study Sites (46)

Research Site

Vienna, Austria

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Amiens, France

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Angers, France

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Bordeaux, France

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Lille, France

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Lyon, France

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Marseille, France

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Paris, France

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Rennes, France

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Strasbourg, France

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Toulouse, France

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Tours, France

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Vandœuvre-lès-Nancy, France

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Villejuif, France

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Dresden, Germany

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Duisburg, Germany

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Hamburg, Germany

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Hanover, Germany

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München, Germany

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Tübingen, Germany

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Petah Tikva, Israel

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Ramat Gan, Israel

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Tel Aviv, Israel

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Florence, Italy

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Genova, Italy

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Milan, Italy

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Padua, Italy

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Pavia, Italy

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Roma, Italy

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Torino, Italy

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Trieste, Italy

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Rotterdam, Netherlands

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Lisbon, Portugal

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Porto, Portugal

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Barcelona, Spain

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Madrid, Spain

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Málaga, Spain

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Santiago de Compostela, Spain

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Seville, Spain

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Basel, Switzerland

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Bern, Switzerland

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Lausanne, Switzerland

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Sankt Gallen, Switzerland

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London, United Kingdom

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Manchester, United Kingdom

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Newcastle upon Tyne, United Kingdom

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Related Publications (5)

• 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-

  BACKGROUND

• International Committee Of Medical Journal Editors. [Recommendations for the conduct, reporting, editing and publication of scholarly work in medical journals (revised in January 2024): a Korean translation]. Ewha Med J. 2024 Oct;47(4):e48. doi: 10.12771/emj.2024.e48. Epub 2024 Oct 31. No abstract available. Korean.

  PMID: 40704003 BACKGROUND

• ISPE. Guidelines for good pharmacoepidemiology practices (GPP). Pharmacoepidemiol Drug Saf. 2008 Feb;17(2):200-8. doi: 10.1002/pds.1471. No abstract available.

  PMID: 17868186 BACKGROUND

• 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.

  BACKGROUND

• 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.

  PMID: 18064739 BACKGROUND

MeSH Terms

Conditions

Neurofibromatosis 1

Condition Hierarchy (Ancestors)

Neurofibromatoses; Neurofibroma; Nerve Sheath Neoplasms; Neoplasms, Nerve Tissue; Neoplasms by Histologic Type; Neoplasms; Neoplastic Syndromes, Hereditary; Neurocutaneous Syndromes; Nervous System Diseases; Heredodegenerative Disorders, Nervous System; Neurodegenerative Diseases; Peripheral Nervous System Diseases; Neuromuscular Diseases; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities

Study Design

• Study Type: observational
• Observational Model: COHORT
• Time Perspective: PROSPECTIVE
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 12, 2022
• First Posted: May 24, 2022
• Study Start: May 23, 2022
• Primary Completion (Estimated): May 23, 2028
• Study Completion (Estimated): May 23, 2028
• Last Updated: March 12, 2026

Record last verified: 2026-02

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, CSR

Locations

AU (1); IL (3); FR (13); IT (8); DE (6); CH (4); PT (2); ES (5); GB (3); NL (1)