アデノシンデアミナーゼ重度複合免疫不全症（ADA-SCID）の患者をフォローアップするための Strimvelis 登録研究

ADA-SCID subjects treated with Strimvelis

Subjects with ADA-SCID who have received Strimvelis (previously GSK2696273) gene therapy, comprising patients treated prior to marketing authorisation (i.e. clinical studies and compassionate use programs) and those treated after marketing authorisation. In this study will be also included patients for whom the gene therapy medicinal product has been prepared starting from mobilized peripheral blood (mPB)-derived CD34+ cells, treated under hospital exemption (HE) frame, according to the Italian Decree of the Ministry of Health, January 16th 2015, "Provisions on advanced therapy drugs prepared on a non-repetitive basis".

遺伝的：Strimvelis

Strimvelis is a CD34+ cell enriched dispersion of human autologous bone marrow derived hematopoietic stem/progenitor cells transduced with a retroviral vector containing the human ADA gene. It will be administered as an intravenous infusion once only.

In this study will be also included patients for whom the gene therapy medicinal product has been prepared starting from mobilized peripheral blood (mPB)-derived CD34+ cells, treated under hospital exemption (HE) frame, according to the Italian Decree of the Ministry of Health, January 16th 2015, "Provisions on advanced therapy drugs prepared on a non-repetitive basis".

Number (%) of subjects with fertility and positive pregnancy outcomes

Fertility and pregnancy related outcomes will be listed and/or summarised as appropriate. Number (%) of subjects with fertility and pregnancy outcome will be reported. If the registry remains open after an individual patient has been followed for 15 years post treatment, fertility and pregnancy related events and outcomes will continue to be solicited or spontaneously reported, every 2 years until the registry closes.

The number (%) of subjects with an abnormal retroviral insertion site (RIS) analysis.

Data from RIS will be collected only if an HCP has performed these tests (e.g. following suspected malignancy or after a diagnosis of malignancy). The number (%) of subjects with an abnormal result will be summarized.

Frequency of adverse events of special interest

The following adverse events of interest will be evaluated:

• AEs and SAEs related to medical or surgical procedures associated with Strimvelis™ administration (e.g. central venous catheter, busulfan conditioning).
• Oncogenesis.
• Autoimmunity/autoinflammatory events.
• Unsuccessful response to gene therapy.
• Risks related to short shelf-life of product.
• Non-immunologic manifestations of ADA-SCID (e.g. hepatic steatosis, cognitive defects, behavioral abnormalities, hearing impairment).
• Risks related to residuals present in the drug product administered to the patient.
• Hypersensitivity to the product.
• Replication competent retrovirus.

The number (%) of patients experiencing AESIs in each of these categories along with the number of events will be summarized by System Organ Class (SOC) and Preferred Term (PT).

Frequency of reported AEs and SAEs/ADRs

The number (%) of patients experiencing AEs along with the number of events will be summarized by System Organ Class (SOC) and Preferred Term (PT).

• overall;
• by severity grade;
• AEs grade 3 or higher;
• AEs related to treatment;
• SAEs;
• SAEs grade 3 or higher;
• SAEs related to treatment;
• AEs leading to study discontinuation. These summaries will be repeated for the rate of events per person year.

Actual values of laboratory blood test results (i.e. biochemistry, haematology) at each annual visits.

The baseline evaluation for each parameter will be the final evaluation prior to treatment with Strimvelis™.

For each parameter, the actual value will be summarized at each annual visit using descriptive statistics.

Laboratory evaluations will be flagged against the normal range as low/normal/high. For each parameter, the number (%) of subjects with evaluations that were low/normal/high relative to the normal range will be summarized by annual visit. Out of range values will be assessed for their clinical significance. For each parameter, the number (%) of subjects with clinically significant evaluations will be summarized by annual visit and at any time post-treatment.

Overall Survival

Number and cause of deaths and time to onset of fatal events will be summarised. Starting time will be the date of therapy administration.

Event (Intervention) free survival

Event (Intervention) free survival will be evaluated using the time in years from treatment with Strimvelis to either the first intervention (Hematopoietic Stem Cell Transplant or >3 months of Enzyme Replacement Therapy). Summary statistics, proportions and rates will be provided.

Growth

Growth (i.e. height and weight) percentiles will be calculated and compared to World Health Organisation (WHO) standard growth charts.

Number and proportion of patients with severe infections, and associated length of stay

Severe infections, defined as infections requiring hospitalization or prolonging hospitalization, will be identified from the adverse event data. The rate of infection will be calculated as number of severe infections divided by the person-years of observation after treatment with Strimvelis™.

The cumulative number (%) of patients with severe infections and the cumulative rate of severe infections will be presented at each year post treatment along their 95% CI.

The number (%) of subjects falling into each category for pediatric development and quality of life assessments

Pediatric development assessments will include:

• whether the child is attending a school appropriate for age
• whether the child is in an age-appropriate grade/class at school
• whether the child requires special educational support (e.g. dedicated tutor)
• participation in sports as desired by child
• requirement for hearing aid(s)
• impact of the child's health on the guardian's employment. For each of these assessments, the number (%) of subjects falling into each category for these assessments will be summarized over time. For Karnofsky and Lansky scores, the actual value and change from baseline will be summarized at each annual visit using descriptive statistics.

Patient (or proxy) reported Peds-QL

Data from patient (or proxy) reported outcome measures and development questionnaires [e.g. Peds-QL] where they are used routinely as part of a physician's standard of care or where permitted by local authorities as non-interventional assessments, will also be summarised. Absolute scores will be calculated.

The number (%) of subjects requiring use of treatments of interest

The medications/treatments of interest in this study are ERT, HSCT, Immunoglobulins, radiotherapy and cytotoxic agents. Categorical responses for whether subjects have received these treatments are captured per annual visit. The number (%) of subjects requiring each of these treatments and any of these treatments will be summarized at each annual visit throughout the follow-up period and overall. For ERT, the duration of treatment and number of patients requiring more than three months of continuous treatment will be summarized.

Immune reconstitution

Peripheral lymphocytes and T cell function from response to mitogens will be evaluated. Actual counts and the change from baseline will be summarized at each annual visit using summary statistics (n, mean, 95% CI, SD, geometric mean, (gCV), minimum, median, maximum).

Systemic metabolite detoxification

Systemic metabolite detoxification will be assessed using dAXP levels in RBCs and ADA activity in plasma, RBCs and lymphocytes. Actual values and the change from baseline will be summarized at each annual visit using summary statistics (n, mean, 95% CI, SD, geometric mean, gCV, minimum, median, maximum). The geometric mean and 95% CI will be plotted over time. In addition, individual plots over time will be produced.

Adequate ADA activity is defined as a level of >= 210 nmol/h/mg, adequate dAXP in RBC is defined as < 100 nmol/mL. The number (%) of patients with adequate levels of ADA activity and dAXP will be summarized.

Vector copy number, measured in PBMCs (peripheral blood mononuclear cells) and subpopulations.

Vector copy number (VCN) will be measured in PBMCs and and subpopulations CD3+, CD4+, CD8+, CD19+, CD15+ and CD56+ cells and summarized. VCN will be summarized by visit using summary statistics (n, mean, 95% CI, SD, geometric mean, gCV, minimum, median, maximum).

Response to childhood vaccinations

Response to vaccinations against tetanus toxoid, diphtheria, pertussis, hepatitis B, hemophilius influenzae B (HIB), pneumococcus and measles, mumps and rubella (MMR) will be assessed.

The number of subjects receiving each vaccination and any vaccination will be summarized along with the number (%) of those subjects with a positive response. The exact binomial 95% confidence interval will be provided for each response category of each vaccination type.