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Trial registered on ANZCTR


Registration number
ACTRN12618001830280p
Ethics application status
Not yet submitted
Date submitted
28/10/2018
Date registered
9/11/2018
Date last updated
9/11/2018
Date data sharing statement initially provided
9/11/2018
Type of registration
Prospectively registered

Titles & IDs
Public title
Trial of prophylactic GCSF (white cell growth factor) use to prevent low white cell counts in people re-exposed to clozapine
Scientific title
Prospective cohort study evaluating prophylactic GCSF to prevent recurrent clozapine-associated neutropenia on clozapine re-challenge
Secondary ID [1] 296448 0
None
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Neutropenia 310224 0
Schizophrenia 310225 0
Adverse drug reaction 310226 0
Condition category
Condition code
Blood 308957 308957 0 0
Other blood disorders
Mental Health 308958 308958 0 0
Schizophrenia

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
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
Intervention code [1] 312773 0
Prevention
Intervention code [2] 312774 0
Treatment: Drugs
Comparator / control treatment
No control group
Control group
Uncontrolled

Outcomes
Primary outcome [1] 307923 0
Rate of recurrent neutropenia (absolute neutrophil count <1.5) assessed using regular complete blood examination assay.
Monitoring of complete blood examinations will occur weekly for the first 18 weeks of treatment and monthly thereafter if a stable ANC is achieved. If participants return an ANC of 1.5-2.0 or ANC >30 full blood count frequency will be increased to twice weekly until a stable ANC and filgrastim dosing regimen is achieved.
Timepoint [1] 307923 0
Cumulative rates at 12 months post-treatment.
Primary outcome [2] 307924 0
Continued prescription of clozapine without haematological toxicity using data linkage to medical records and prescription records.
Timepoint [2] 307924 0
Cumulative rates at 12 months post-treatment.
Secondary outcome [1] 353356 0
Mean change in psychiatric symptom severity using positive, negative and total PANSS scores
Timepoint [1] 353356 0
18 weeks, 6 months, 12 months post-treatment.
Secondary outcome [2] 353357 0
Qualitative acceptability of filgrastim treatment using study specific questionnaire.
Timepoint [2] 353357 0
18 weeks, 6 months, 12 months post-treatment.
Secondary outcome [3] 353358 0
Side effect and safety profile using linkage to medical records, study specific questionnaire and symptom directed physical examination.
Common side effects of clozapine are weight gain, metabolic syndrome, diabetes, hypersalivation, nausea, severe constipation, tachycardia and nocturnal enuresis. Rare life-threatening adverse events include seizure, myocarditis, cardiomyopathy and venous or arterial thromboembolism.
Common side effects of filgrastim are bony pain and cytokine symptoms. Rare life-threatening adverse events include drug hypersensitivity reaction and splenic rupture.
Timepoint [3] 353358 0
Weekly for the first 18 weeks then at 6 months and 12 months post-treatment.

Eligibility
Key inclusion criteria
1. Schizophrenia confirmed by the Structured Clinical Interview for DSM-IV (SCID-5)
2. Treatment resistance defined as little or no symptomatic response to at least two antipsychotic trials of adequate duration (six weeks)
3. Previously diagnosis of clozapine-associated neutropenia defined as absolute neutrophil count of <1.5 whilst prescribed a therapeutic dose of clozapine (50-900mg daily in divided doses)
4. Considered by their treating psychiatrist as likely to benefit from clozapine re-challenge or previously documented symptom response to clozapine which has not been maintained on alternative antipsychotic drugs
5. Ability to understand study risks and benefits, and to provide informed consent
Minimum age
18 Years
Maximum age
65 Years
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Non-haematological contraindication to prescription of clozapine
2. Previous hypersensitivity reaction to filgrastim
3. Active haematological malignancy, active solid organ malignancy requiring cytotoxic therapy or cytotoxic exposure within one year of study screening
4. Existing or planned pregnancy or current breastfeeding
5. Absolute neutrophil count <2.0 at study entry

Study design
Purpose of the study
Prevention
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
None. Open label study.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
N/A
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Single group
Other design features
Phase
Phase 2
Type of endpoint(s)
Efficacy
Statistical methods / analysis
Proof of concept study to determine whether prophylactic use of filgrastim allows for successful clozapine re-challenge and prevention of recurrent neutropenia. The recruitment target is 20. Analysis of primary outcome will be descriptive and comparative to historical controls of clozapine re-challenge without growth factor support. Primary outcome will be reported as rates of recurrent neutropenia and rate of participants continuing clozapine at 12 months. Safety reporting will be descriptive. Repeated mean PANSS scores at follow-up will be compared using paired samples t-test.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
SA
Recruitment hospital [1] 12294 0
Lyell McEwin Hospital - Elizabeth Vale
Recruitment hospital [2] 12295 0
The Adelaide Clinic - Gilberton
Recruitment postcode(s) [1] 24486 0
5112 - Elizabeth Vale
Recruitment postcode(s) [2] 24487 0
5081 - Gilberton

Funding & Sponsors
Funding source category [1] 301044 0
Hospital
Name [1] 301044 0
Lyell McEwan Hospital
Address [1] 301044 0
Haydown Rd
Elizabeth Vale
South Australia
5112
Country [1] 301044 0
Australia
Primary sponsor type
University
Name
University of Queensland
Address
St Lucia
Queensland
4072
Country
Australia
Secondary sponsor category [1] 300642 0
University
Name [1] 300642 0
University of Adelaide
Address [1] 300642 0
Adelaide
South Australia
5000
Country [1] 300642 0
Australia

Ethics approval
Ethics application status
Not yet submitted
Ethics committee name [1] 301799 0
Central Adelaide Local Health Network Human Research Ethics Committee (EC00192)
Ethics committee address [1] 301799 0
1 Port Rd
Adelaide
South Australia
5000
Ethics committee country [1] 301799 0
Australia
Date submitted for ethics approval [1] 301799 0
09/11/2018
Approval date [1] 301799 0
Ethics approval number [1] 301799 0
Pending

Summary
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.
Trial website
None
Trial related presentations / publications
None
Public notes
None

Contacts
Principal investigator
Name 88146 0
Dr Nicholas Myles
Address 88146 0
SA Pathology
Frome Rd
Adelaide
South Australia
5000
Country 88146 0
Australia
Phone 88146 0
+61 406103437
Fax 88146 0
Email 88146 0
nicholas_myles@hotmail.com
Contact person for public queries
Name 88147 0
Dr Nicholas Myles
Address 88147 0
SA Pathology
Frome Rd
Adelaide
South Australia
5000
Country 88147 0
Australia
Phone 88147 0
+61 406103437
Fax 88147 0
Email 88147 0
nicholas_myles@hotmail.com
Contact person for scientific queries
Name 88148 0
Dr Nicholas Myles
Address 88148 0
SA Pathology
Frome Rd
Adelaide
South Australia
5000
Country 88148 0
Australia
Phone 88148 0
+61 406103437
Fax 88148 0
Email 88148 0
nicholas_myles@hotmail.com

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Undecided
No/undecided IPD sharing reason/comment
Awaiting approval from ethics application.
What supporting documents are/will be available?
No other documents available
Summary results
No Results