Immunogenicity, Safety, and Efficacy of Zarzio®/Filgrastim HEXAL® in Patients With Severe Chronic Neutropenia

• ClinicalTrials.gov Identifier: NCT01859637
• Recruitment Status: Terminated
• First Posted: May 22, 2013
• Results First Posted: March 28, 2016
• Last Update Posted: March 28, 2016
• Sponsor: Sandoz
• Collaborator: Sandoz GmbH
• Information provided by (Responsible Party): Sandoz

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Severe Chronic Neutropenia	Biological: Filgrastim	Phase 4

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

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 6 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Twelve-month Study on the Immunogenicity, Safety, and Efficacy of Zarzio®/Filgrastim HEXAL® in Patients With Severe Chronic Neutropenia
• Study Start Date: July 2011
• Actual Primary Completion Date: March 2014
• Actual Study Completion Date: September 2015

Arms and Interventions

Arm	Intervention/treatment
Experimental: Zarzio®/Filgrastim HEXAL®; Zarzio®/Filgrastim HEXAL® was administered according to Summary of Product Characteristics (SmPC). It was provided as solution for injection in prefilled syringes with two strengths at 300 μg/0.5 ml (30 MU) and 480 μg/0.5 ml (48 MU).	Biological: Filgrastim; 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.; Other Names: Zarzio®/Filgrastim HEXAL®; EP2006; rhG-CSF

Outcome Measures

Primary Outcome Measures :

1. Incidence of Anti- Recombinant Human Granulocyte Colony Stimulating Factor (rhG-CSF) Antibodies [ Time Frame: 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 Outcome Measures :

1. Number of Participants With Adverse Events (AEs) [ Time Frame: 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
2. Change in Absolute Neutrophile Count (ANC) [ 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. ]

   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.

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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.

Contacts and Locations

Locations

Germany

Medizinischen Hochschule (MHH) Hannover

Hannover, Germany

Sweden

Karolinska Institut

Stockholm, Sweden

Sponsors and Collaborators

Sandoz

Sandoz GmbH

Investigators

• Study Director: Roumen Nakov, MD, PhD; Sandoz Biopharmaceutical, Hexal AG, Germany

More Information

Publications:

Dale DC, Cottle TE, Fier CJ, Bolyard AA, Bonilla MA, Boxer LA, Cham B, Freedman MH, Kannourakis G, Kinsey SE, Davis R, Scarlata D, Schwinzer B, Zeidler C, Welte K. Severe chronic neutropenia: treatment and follow-up of patients in the Severe Chronic Neutropenia International Registry. Am J Hematol. 2003 Feb;72(2):82-93. Review.

Palmblad J, Papadaki HA. Chronic idiopathic neutropenias and severe congenital neutropenia. Curr Opin Hematol. 2008 Jan;15(1):8-14. Review.

Zeidler C, Welte K. Hematopoietic growth factors for the treatment of inherited cytopenias. Semin Hematol. 2007 Jul;44(3):133-7. Review.

• Responsible Party: Sandoz
• ClinicalTrials.gov Identifier: NCT01859637
• Other Study ID Numbers: EP06-401
• First Posted: May 22, 2013
• Results First Posted: March 28, 2016
• Last Update Posted: March 28, 2016
• Last Verified: February 2016

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: Since there are only six patients enrolled, all the patient data is already provided in the registry.

Keywords provided by Sandoz:

Filgrastim, immunogenicity, severe chronic neutropenia

Additional relevant MeSH terms:

Neutropenia; Agranulocytosis; Leukopenia; Leukocyte Disorders; Hematologic Diseases; Lenograstim; Adjuvants, Immunologic; Immunologic Factors; Physiological Effects of Drugs