Trial Information

Subcutaneous (SC) vs. Intravenous (IV) Granulocyte Colony Stimulating Factors (G-CSF) for the Treatment of Neutropenia in Hospitalized Haemato-oncological Patients: Randomized Controlled Trial

Granulocyte colony stimulating factors (G-CSFs) stimulate the proliferation and
differentiation of myeloid progenitor cells, improve cell survival and affect some end-cell
functions, through binding to G-CSF receptors present on all cells of the neutrophilic
granulocyte lineage. Filgrastim (recombinant G-CSF) is frequently used among patients with
cancer including those with haematological malignancies. In-vivo studies and studies in
healthy people show that SC administration of CSF results in lower peak but more prolonged
and stable levels of G-CSF as compared with Intravenous (IV) administration, with similar or
higher neutrophil counts. It is safe to assume that IV administration of G-CSFs would be
more comfortable to patients when hospitalized, especially during or after chemotherapy when
most patients have a central catheter and are thrombocytopenic. However, it is necessary
to ensure that the same effects are obtained with both methods of administration.

Objectives: To compare the time to neutropenia resolution with Intravenous (IV) versus
Subcutaneous (SC) filgrastim administration among patients with acute leukemia, lymphoma or
multiple myeloma in hospital. Secondarily, the investigators aim to assess comparative rates
of infection, adverse effects and patients' satisfaction.

Methods: The investigators plan a randomized controlled trial comparing the effects of IV
versus SC filgrastim (Neupogen®) given as per clinical indication on neutrophil counts in
hospitalized patients. The investigators will include patients hospitalized in
haemato-oncology ward starting filgrastim for the treatment of chemotherapy-induced
neutropenia. The investigators will compare SC vs. IV filgrastim, both given as a single
daily dose of 5 mcg/kg (rounded to 300 mcg or 480 mcg). No blinding will be used. Patients
will be approached to obtain informed consent and randomized to the mode of filgrastim
administration after the decision to administer the drug has been made. Patients will be
crossed over to the alternative study arm on the subsequent chemotherapy course, if
filgrastim is clinically indicated.

Outcomes:

Primary efficacy: Time to stable neutrophil recovery, defined as the number of days from
start of filgrastim (day 1) until the neutrophil count has reached >500/mcL for 3
consecutive days.

Primary safety: 30-day mortality or documented infection (CDI, MDI, bacteremia or probable/
proven IFI, see definitions below) within the chemotherapy course (before or after
neutrophil recovery).

Secondary outcomes will include rates of infection, fever days, hospital stay, patient's
satisfaction, other clinical endpoints and adverse events.

The investigators will assess the distribution pattern of the time to neutrophil recovery
and compare groups using Student's t-test or the Mann-Whitney U test, as appropriate. The
investigators will construct Kaplan-Meier curves for time to neutrophil recovery and compare
treatment arms using a two-tailed log rank test. Dichotomous outcomes will be compared using
a chi-square test. A sample of 96 patients with AML (48 in each group) was calculated to
demonstrate equivalence allowing a 2-day difference between treatment arms (power of 90%,
alpha 0.05).

Interim analysis and stopping rules: We will conduct interim analyses for safety assessment
after every 50 patients recruited. Stopping rules will be based on the primary safety
outcome (p<0.1 for stopping) and deaths alone (p<0.2 for stopping).