Registrační studie Strimvelis pro sledování pacientů se závažným kombinovaným imunodeficitem adenosindeaminázy (ADA-SCID)

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".

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).

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.

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.

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.

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.

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.

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.