Post-Authorisation Safety Study of Paediatric Patients Initiating Selumetinib: A Multiple-Country Prospective Cohort Study.
试验速览
- 阶段
- 不适用
- 状态
- 进行中（未招募）
- 发起方
- AstraZeneca
- 入组人数
- 124
- 试验地点
- 47
- 主要终点
- LVEF reduction
研究概览
简要总结
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:
- 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.
详细描述
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
研究设计
- 研究类型
- Observational
- 观察模型
- Cohort
- 时间视角
- Prospective
入排标准
- 年龄范围
- 3 Years 至 17 Years（Child）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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
排除标准
- •Have received treatment with a mitogen-activated protein kinase inhibitor before the index date
- •Are participating in an interventional study at index date
研究组 & 干预措施
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
结局指标
主要结局
LVEF reduction
时间窗: 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
时间窗: 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
时间窗: at routine clinical care throughout the follow up, with frequency of 6 to 12 months, up to 6 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
时间窗: at routine clinical care throughout the follow up, with frequency of 6 to 12 months, up to 6 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
时间窗: 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
时间窗: at routine clinical care throughout the follow up, with frequency of 6 to 12 months
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)
次要结局
- baseline data - demographics(At baseline - most recent assessments made within 365 days before the index date)
- Baseline data - Clinical characteristics(At baseline - most recent assessments made within 365 days before the index date)