Global Patient Registry to Monitor Long-term Safety and Effectiveness of Increlex® in Children and Adolescents With Severe Primary Insulin-like Growth Factor-1 Deficiency (SPIGFD).

Study Overview
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Brief Summary
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The Increlex® Global Registry is a descriptive, multicenter, observational, prospective, open-ended, non interventional, post-authorisation surveillance registry. The main purpose of this global registry is to collect, analyse and report safety data during and up to at least 5 years after the end of treatment in children and adolescents receiving Increlex® therapy for SPIGFD according to the locally approved product information.

Detailed Description
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This registry is a Post-Authorisation Safety Study called the Increlex® Global Registry which is intended primarily to monitor the safety of Increlex® therapy in children and adolescents with Severe Primary IGF-1 Deficiency and secondly to follow the effectiveness of this treatment. Patients who have already started Increlex® therapy before entering this registry may be included and data will be collected retrospectively. The countries participating in this registry are Austria, France, Germany, Italy, Poland, Spain, Sweden, United Kingdom and the USA

Official Title
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Global Patient Registry to Monitor Long-term Safety and Effectiveness of Increlex® in Children and Adolescents With Severe Primary Insulin-like Growth Factor-1 Deficiency (SPIGFD).

Conditions
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IGF1 Deficiency

Intervention / Treatment
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* Drug: Increlex®


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: For US : patients starting or planning to start or currently receiving treatment with Increlex® therapy for severe primary IGF-1 deficiency as defined by the US Increlex® prescribing information or for growth hormone (GH) gene deletion who have developed neutralizing antibodies to GH.For EU : patients starting or planning to start or currently receiving treatment with Increlex® therapy according to the locally approved product information. Parents or legally authorized representatives if applicable must give signed informed consent before any registry-related activities are conducted. Assent from the subject should also be obtained as appropriate Exclusion Criteria: Subject currently participating in an Increlex® clinical trial Subject currently participating in any clinical trial for growth retardation Patient with any contraindication to Increlex® or any condition subject to special warning as per the locally approved label For US patients, these include patients with hypersensitivity to the active substance or any of the excipients, patients with active or suspected neoplasia and patients with closed epiphyses. For EU patients: these include patients with hypersensitivity to the active substance or any of the excipients, patients with active or suspected neoplasia or any condition or medical history which increases the risk of benign or malignant neoplasia and patients with closed epiphyses

Ages Eligible for Study
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Minimum Age: 2 Years
Maximum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Intervention/Treatment |
| --- |
|Drug: Increlex®|Increlex® (mecasermin [rDNA origin] injection), 10 mg/ml solution for injection, 40-120mcg/kg BID or 0,04 to 0,12 mg/kg BID, as prescribed by physician|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of SAEs (including AESI of neoplasia) and all AEs, targeted AEs, deaths and withdrawals due to AEs. | Targeted AE includes hypersensitivity; scoliosis; immunogenicity (presence of antibodies if available); slipped capital femoral epiphysis, headache, otitis media, papilloedema, hypoglycaemia (suspected or documented - documented means blood level glucose < 50 mg/dL or 2.78 mmol/L), acromegalic facial changes, gynaecomastia, hearing loss, intracranial hypertension, lipohypertrophy at injection sites, sleep apnoea, tonsillar hypertrophy, cardiomegaly, oedema and myalgia. | During the treatment period up to 30 days after the last dose. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of SAEs (including AESI of neoplasia), targeted AEs, all AEs, deaths, withdrawals due to AEs, special situations and concomitant medications | In the overall population, and in the subset of children and adolescents exposed to Increlex® for at least 3 cumulative years excluding interruptions. | Within 5 years post-treatment | 
| Incidence of special situations and concomitant medications |  | During the treatment period an average of 5 years and within 5 years post-treatment | 
| Changes in height Standard Deviation Score (SDS) |  | From baseline at least up to 5 years or until the final adult height is achieved. | 
| Height velocity |  | From baseline at least up to 5 years or until the final adult height is achieved. | 
| Bone age development |  | From baseline at least up to 5 years or until the final adult height is achieved | 
| Body mass index (BMI) |  | From baseline at least up to 5 years or until the final adult height is achieved. | 
| Pubertal stage |  | From baseline at least up to 5 years or until the final adult height is achieved. | 
| Estimation of differences between predicted adult height (PAH) and final adult height (FAH) |  | From baseline at least up to 5 years or until the final adult height is achieved. | 
| Modelisation to identify predictive factors of height SDS change |  | From baseline at least up to 5 years or until the final adult height is achieved. | 
| Modelisation to identify predictive factors of Height velocity |  | From baseline at least up to 5 years or until the final adult height is achieved | 
| Modelisation to identify predictive factors of FAH |  | From baseline at least up to 5 years or until the final adult height is achieved | 
| Modelisation to identify predictive factors of pubertal (Tanner) stage |  | From baseline at least up to 5 years or until the final adult height is achieved | 
| Modelisation to identify predictive factors of bone age development |  | From baseline at least up to 5 years or until the final adult height is achieved | 
| Dose of Increlex® administrated |  | Periodically assessed during the study until treatment stop at least up to 5 years. | 
| Duration of Increlex exposure |  | Periodically assessed during the study until treatment stop at least up to 5 years. | 
| Description of effectiveness parameters height SDS according to average dose received and according to dose ranges (e.g. 4 dose ranges (≤50, ]50-80], ]80-110], > 110 μg/kg BID)). | This analysis will support the description of the lowest effective dose | Periodically assessed during the study until treatment stop at least up to 5 years. | 
| Description of effectiveness parameters height velocity according to average dose received and according to dose ranges (e.g. 4 dose ranges (≤50, ]50-80], ]80-110], > 110 μg/kg BID)). | This analysis will support the description of the lowest effective dose | Periodically assessed during the study until treatment stop at least up to 5 years. | 
| Biological assessment : baseline GH concentrations, IGF-1 levels, IGFBP-3 levels and binding proteins. |  | Throughout study at least up to 5 years. | 
| Presence or absence of gene deletion/mutation | including: GH gene, IGF-1 gene, FGF, PTPN11, GHR, D3-GHR, STAT5b, ALS, SHOX, PAPPA2 and any other genetic tests performed. | Throughout study at least up to 5 years. | 
| Changes in QoL assessment using EQ-5D in participant aged 4 and over. | The QoL will be assessed using the EQ-5D-Y paediatric questionnaire. The 5 domains and VAS will be described at each timepoint as well as the evolution from baseline. | At baseline, at year one, at least up to 5 years, at Final Adult Height. | 
| Description of neoplasia (benign and malignant) and hypoglycaemia |  | Within the first 3 years after treatment start, between 3 and 5 years and over 5 years. |