Severe Chronic Neutropenia
Conditions
Keywords
Filgrastim, immunogenicity, severe chronic neutropenia
Brief summary
Purpose of the study is to investigate the safety, immunogenicity and the efficacy of Zarzio®/Filgrastim HEXAL® under chronic administration for 12 months in patients diagnosed with severe chronic neutropenia.
Detailed description
This was a prospective, open-label, non-comparative study. Eligible patients with Severe Chronic Neutropenia received Zarzio® for 12 months. Study visits were scheduled for screening, start of treatment with Zarzio®/Filgrastim HEXAL®, 6 weeks after start of treatment and at months 3, 6, 9 and 12. Immunogenicity assessment: Patients were screened for anti-recombinant human granulocyte colony stimulating factor (rhG-CSF) antibodies at screening (Visit 01) and at every study visit with the exception of Visit 02 (start of treatment). The evaluation of the immune response to rhG-CSF administration was made by a three-step procedure comprising a validated binding antibody screening and confirmatory radioimmunoprecipitation assay (RIP). Samples positive for binding antibodies in the confirmatory RIP assay were evaluated for neutralizing antibodies using a validated cell-based neutralization antibody assay (NAB). Efficacy: Complete blood counts with differential white blood cell counts were performed and absolute neutrophil count (ANC) were calculated at every study visit. For each time point the neutrophil counts are summarized by the SAF set using descriptive statistics for the ANC as well as for the changes from baseline. Safety: Adverse events are listed for the safety population set (SAF) (term, date of AE onset, date of AE resolved, AE duration, severity grade, relationship to study drug, action taken, SAE). Additionally, the following variables were also listed: Serum human chorionic gonadotropin (hCG) pregnancy test, Physical examination, vital signs (pulse, blood pressure), weight (kg), height (cm), Laboratory (hematology, clinical chemistry, urinalysis) values
Interventions
BIOLOGICALFilgrastim
Zarzio®/Filgrastim HEXAL® solution for injection was provided in prefilled syringes with two strengths at 300 μg/0.5 ml (30 MU) and 480 μg/0.5 ml (48 MU). Dosage and duration for each patient is as per the recommendations in the SmPC.
Sponsors
Sandoz GmbH
Sandoz
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Patients with established congenital, cyclic or idiopathic severe chronic neutropenia having an indication for treatment with Sandoz' filgrastim according to the SmPC of the product 2. Patients ≥ 18 years of age at the day of inclusion 3. Written informed consent of patient
Exclusion criteria
. 1. Chemotherapy-induced neutropenia 2. Neutropenia in combination with confirmed diagnosis of autoimmune disease, e.g. rheumatoid arthritis, Felty's syndrome, or systemic lupus erythematosus 3. Myelodysplastic syndrome or leukemia 4. Thrombocytopenia (platelets \< 50.000/mm3) or anemia (hemoglobin \< 8 g/dl) with the exception of patients with Shwachman-Diamond syndrome, glycogen storage disease 1b, or Barth's syndrome 5. Sickle cell disease 6. History of malignancy of any organ system, treated or untreated, with the exception of localized basal cell carcinoma of the skin 7. For patients with congenital severe chronic neutropenia only: Any cytogenetic aberrations in bone marrow aspirates with results not older than six months suspicious for malignant transformation. 8. Known or suspected hypersensitivity to rhG-CSF products 9. Known or suspected hypersensitivity to any of the excipients of Sandoz' filgrastim product 10. Positive result of anti-rhG-CSF antibody assessment at screening 11. Absolute and relative contraindications as specified in the SmPC of Sandoz' filgrastim 12. Drug abuse, substance abuse, or alcohol abuse 13. Use of any other investigational drug at the time of enrollment, or within 30 days or 5 half-lives prior to enrollment, whichever is longer 14. Patients unwilling and/or who are not capable of ensuring compliance with the provisions of the study protocol 15. Pregnant or breastfeeding women where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive serum hCG laboratory test 16. Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, UNLESS they are using a highly effective method of birth control (i.e. one that results in a less than 1% per year failure rate when used consistently and correctly, such as implants, injectables, combined oral contraceptives and intrauterine devices (IUDs)). Periodic abstinence (e.g. calendar, ovulation, symptothermal, post-ovulation methods) is not acceptable.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of Anti- Recombinant Human Granulocyte Colony Stimulating Factor (rhG-CSF) Antibodies | screening, 3, 6, 9 and 12 months | Incidence of anti-rhG-CSF antibodies was monitored. Patients were screened for anti-rhG-CSF antibodies at screening and at each study except visit 02 (start of treatment = baseline). Evaluation of immune response to rhG-CSF administration was made by a three-step procedure comprising a validated binding antibody screening and confirmatory radioimmunoprecipitation assay (RIP) and a validated cell-based neutralization antibody assay (NAB). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Adverse Events (AEs) | 12 months | Patients experiencing AEs by system organ class and preferred term (PT) and number of events. Patients with more than one AE coded to the same PT were counted once per PT |
| Change in Absolute Neutrophile Count (ANC) | Participants were followed for a duration of 12 months and ANC was assessed at baseline, week 6, Month 3, Month 6, Month 9 and Month 12. | To evaluate the efficacy of Zarzio®/Filgrastim HEXAL® in patients with SCN in terms of changes in absolute neutrophile count (ANC). Change from each visit to baseline in ANC for all patients is calculated. |
Countries
Germany, Sweden
Participant flow
Recruitment details
First patient in: 05-Jul-2011, last patient in: 12-Feb-2013. 2 sites (medical school and university hospital)
Participants by arm
| Arm | Count |
|---|---|
| Zarzio®/Filgrastim HEXAL® Open label single arm. All patients received Zarzio®/Filgrastim HEXAL® subcutaneously dosed as per recommendations in SmPC. | 6 |
| Total | 6 |
Baseline characteristics
| Characteristic | Zarzio®/Filgrastim HEXAL® |
|---|---|
| Age, Continuous | 45.0 years |
| Granulocyte Colony Stimulating Factor (G-CSF) pretreatment No | 0 participants |
| Granulocyte Colony Stimulating Factor (G-CSF) pretreatment Yes | 6 participants |
| Height | 165.0 cm |
| Race/Ethnicity, Customized Caucasian | 5 participants |
| Race/Ethnicity, Customized Latin American | 1 participants |
| Region of Enrollment Germany | 2 participants |
| Region of Enrollment Sweden | 4 participants |
| Severe Chronic Neutropenia (SCN) diagnosis Congenital neutropenia | 1 participants |
| Severe Chronic Neutropenia (SCN) diagnosis Cyclic neutropenia | 1 participants |
| Severe Chronic Neutropenia (SCN) diagnosis Idiopathic neutropenia | 4 participants |
| Sex: Female, Male Female | 5 Participants |
| Sex: Female, Male Male | 1 Participants |
| Weight | 67.0 kg |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 6 / 6 |
| serious Total, serious adverse events | 1 / 6 |
Outcome results
Primary
Incidence of Anti- Recombinant Human Granulocyte Colony Stimulating Factor (rhG-CSF) Antibodies
Incidence of anti-rhG-CSF antibodies was monitored. Patients were screened for anti-rhG-CSF antibodies at screening and at each study except visit 02 (start of treatment = baseline). Evaluation of immune response to rhG-CSF administration was made by a three-step procedure comprising a validated binding antibody screening and confirmatory radioimmunoprecipitation assay (RIP) and a validated cell-based neutralization antibody assay (NAB).
Time frame: screening, 3, 6, 9 and 12 months
Population: Safety population (SAF): All patients with at least one dose Zarzio®/Filgrastim HEXAL® and at least one post-baseline safety assessment. All six patients were screened for anti-rhG-CSF antibodies at all six study visits, except for one missing assessment (no sample was taken for patient 0204 at Visit 03, which was an optional visit).
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Zarzio®/Filgrastim HEXAL® | Incidence of Anti- Recombinant Human Granulocyte Colony Stimulating Factor (rhG-CSF) Antibodies | Visit 1 - negative | 6 participants |
| Zarzio®/Filgrastim HEXAL® | Incidence of Anti- Recombinant Human Granulocyte Colony Stimulating Factor (rhG-CSF) Antibodies | Visit 3 - negative | 5 participants |
| Zarzio®/Filgrastim HEXAL® | Incidence of Anti- Recombinant Human Granulocyte Colony Stimulating Factor (rhG-CSF) Antibodies | Visit 4 - negative | 6 participants |
| Zarzio®/Filgrastim HEXAL® | Incidence of Anti- Recombinant Human Granulocyte Colony Stimulating Factor (rhG-CSF) Antibodies | Visit 5 - negative | 6 participants |
| Zarzio®/Filgrastim HEXAL® | Incidence of Anti- Recombinant Human Granulocyte Colony Stimulating Factor (rhG-CSF) Antibodies | Visit 6 - negative | 6 participants |
| Zarzio®/Filgrastim HEXAL® | Incidence of Anti- Recombinant Human Granulocyte Colony Stimulating Factor (rhG-CSF) Antibodies | Visit 7 - negative | 6 participants |
Secondary
Change in Absolute Neutrophile Count (ANC)
To evaluate the efficacy of Zarzio®/Filgrastim HEXAL® in patients with SCN in terms of changes in absolute neutrophile count (ANC). Change from each visit to baseline in ANC for all patients is calculated.
Time frame: Participants were followed for a duration of 12 months and ANC was assessed at baseline, week 6, Month 3, Month 6, Month 9 and Month 12.
Population: Safety population (SAF): all patients with at least one dose Zarzio®/Filgrastim HEXAL® and at least one post-baseline safety assessment
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Zarzio®/Filgrastim HEXAL® | Change in Absolute Neutrophile Count (ANC) | ANC Visit 1 Screening to Baseline (Visit 2) | -1.252 10^9 cells/L |
| Zarzio®/Filgrastim HEXAL® | Change in Absolute Neutrophile Count (ANC) | ANC Visit 3 Week 6 to Baseline (Visit 2) | 6.873 10^9 cells/L |
| Zarzio®/Filgrastim HEXAL® | Change in Absolute Neutrophile Count (ANC) | ANC Visit 4 Month 3 to Baseline (Visit 2) | -0.198 10^9 cells/L |
| Zarzio®/Filgrastim HEXAL® | Change in Absolute Neutrophile Count (ANC) | ANC Visit 5 Month 6 to Baseline (Visit 2) | -0.711 10^9 cells/L |
| Zarzio®/Filgrastim HEXAL® | Change in Absolute Neutrophile Count (ANC) | ANC Visit 6 Month 9 to Baseline (Visit 2) | 1.506 10^9 cells/L |
| Zarzio®/Filgrastim HEXAL® | Change in Absolute Neutrophile Count (ANC) | ANC Visit 7 Month 12 to Baseline (Visit 2) | 1.579 10^9 cells/L |
Secondary
Number of Participants With Adverse Events (AEs)
Patients experiencing AEs by system organ class and preferred term (PT) and number of events. Patients with more than one AE coded to the same PT were counted once per PT
Time frame: 12 months
Population: Safety population (SAF): all patients with at least one dose Zarzio®/Filgrastim HEXAL® and at least one post-baseline safety assessment
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Zarzio®/Filgrastim HEXAL® | Number of Participants With Adverse Events (AEs) | 6 participants |