None listed
Conditions
Brief summary
Background: clozapine is the most effect antipsychotic drug for treatment-refractory schizophrenia. Approximately 3.8% of people prescribed clozapine develop neutropenia which necessitates discontinuation of drug. Cessation of clozapine often results in psychotic rebound symptoms and may deny highly disabled patients the only effective means of psychotic symptom control. Despite this clozapine rechallenge is rarely undertaken due to concerns about the morbidity of recurrent neutropenia and lack of evidence based rechallenge strategies. One option for clozapine rechallenge is the concomitant use of prophylactic granulocyte-colony stimulating factor (G-CSF) to prevent recurrent neutropenia. However, there is limited current literature reporting the safety and efficacy of such an approach. A recent review identified 23 cases of clozapine rechallenge using prophylactic G-CSF in people previously experiencing clozapine associated neutropenia. This review reported a success rate of 70% at follow-up of one year with a favourable safety profile. However, the protocol for rechallenge was not standardised across cases, analysis was retrospective in most cases and there was risk of reporting bias given most data were derived from case series or single case reports. Further prospective evaluation of prophylactic G-CSF use for clozapine rechallenge in people previously experiencing clozapine associated neutropenia would be beneficial to determine the safety and efficacy of such an approach. Principals and rationale of therapeutic strategy: G-CSF has an established evidence base for the prevention of chemotherapy induced neutropenia and is also effective at augmenting neutrophil counts in people with congenital neutropenic syndromes and immunologically mediated neutropenia. Furthermore, G-CSF is beneficial in reducing the duration of clozapine-associated neutropenia following drug cessation. In people previously experiencing clozapine-associated neutropenia who are re-exposed to clozapine, G-CSF could plausibly augment neutrophil counts to prevent recurrent neutropenia. Hypothesis: use of regular G-CSF can be used safely in people previously experiencing clozapine-associated neutropenia during re-initiation of clozapine to prevent recurrent neutropenia and facilitate ongoing use of clozapine.
Interventions
Filgrastim will be administered prophylactically from the day of clozapine re-initiation for a total duration of 12 months. The initial dosing will be three times a week. Dosage will be determined based on weight to approximate a total dose of 5mcg/kg. Participants will be educated to self-administer the subcutaneous doses or have administration performed at home by district nursing staff. The dosing regimen will be titrated based on trough absolute neutrophil counts (ANC) aiming to achieve an A
Filgrastim will be administered prophylactically from the day of clozapine re-initiation for a total duration of 12 months. The initial dosing will be three times a week. Dosage will be determined based on weight to approximate a total dose of 5mcg/kg. Participants will be educated to self-administer the subcutaneous doses or have administration performed at home by district nursing staff. The dosing regimen will be titrated based on trough absolute neutrophil counts (ANC) aiming to achieve an ANC in the normal range between 2.0 – 7.0x109/l. Dosing schedule will be titrated based on trough ANC as follows: - ANC 1.5-2.0: increase dosing frequency to daily - ANC 2.0-15.0: continue three times a week dosing - ANC >15 on two separate occasions: reduce to twice a week dosing - ANC >30: reduce to once a week dosing - ANC >30 on two separate occasions or ANC >40 on one occasion: hold filgrastim and reduce to once a week dosing once ANC is within 2.0-15
Sponsors
University of Queensland
Study design
Allocation
Non-randomised trial
Intervention model
Single group
Primary purpose
Prevention
Masking
Open (masking not used)
Eligibility
Sex/Gender
All
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
1. Aged 18-64 years 2. Clinical diagnosis of schizophrenia according to DSM-V criteria 3. Treatment resistance defined as little or no symptomatic response to at least two antipsychotic trials of adequate duration (six weeks) and a previous trial of clozapine 4. Previously diagnosis of clozapine-associated neutropenia defined as absolute neutrophil count of <1.5 whilst prescribed a therapeutic dose of clozapine (50-900mg daily) 5. Considered by their treating psychiatrist to be likely to benefit from clozapine re-challenge or previously documented symptom response to clozapine which has not been maintained on alternative antipsychotic drugs 6. Ability to understand study risks and benefits, and to provide informed consent
Exclusion criteria
1. Non-haematological contraindication to prescription of clozapine 2. Currently prescribed clozapine 3. Previous hypersensitivity reaction or allergy to G-CSF 4. Active haematological malignancy, active solid organ malignancy requiring cytotoxic or myelosuppressive therapy or cytotoxic exposure within one year of study screening 5. Existing or planned pregnancy or current breastfeeding 6. Absolute neutrophil count <2.0 at study entry 7. Homozygous sickle cell anaemia 8. Pre-existing moderate or severe thrombocytopenia (platelet count <100x109/L) 9. Pre-existing moderate or severe splenomegaly (craniocaudal diameter >150mm) 10. Active glomerulonephritis, aortitis and/or pulmonary haemorrhage
Outcome results
None listed