Trial Information

A Randomised Controlled Trial of Prolonged Treatment With Darbepoetin Alpha With or Without Recombinant Human Granulocyte Colony Stimulating Factor (G-CSF) Versus Best Supportive Care in Patients With Low-Risk Myelodysplastic Syndromes

STUDY OBJECTIVES:

Primary objectives:

- To compare the Quality of Life of Low-risk MDS patients randomised to receive prolonged
treatment with EPO alone, EPO with G-CSF or best supportive care alone.

Secondary objectives:

- To compare the haemoglobin response and transfusion requirements of patients in each of
these arms.

- To compare the economics costs of treating patients in each arm, in order to derive a
cost:benefit analysis.

- To assess the utility of prognostic factor and predictive factor assessment, in
particular against the predictive model proposed by Hellstrom-Lindberg.

STUDY DESIGN:

This trial is a multi-centre, randomised, triple arm, open-label trial of EPO alone (with
best supportive care), EPO plus G-CSF (with best supportive care) and best supportive care
only in patients with low-risk myelodysplastic syndrome with symptomatic anaemia and/or red
cell transfusion dependence. Screening procedures will take place within 42 days of
randomisation.

Patients will be randomised in a 1:1:1 ratio to EPO and best supportive care, EPO with G-CSF
and best supportive care, or best supportive care only. Patients randomised to drug therapy
arms will receive EPO subcutaneously every fortnight ± G-CSF at least weekly, together with
red cell transfusions and other supportive care if required. Patients randomised to "best
supportive care" only will receive red cell transfusions and supportive care as required.
Study visits and selected study investigations will occur every 4 weeks for the first 24
weeks, then at 36 and 52 weeks.

Quality of life (FACT-An and EQ-5D) measures will be used for all arms of the study.

Analysis & Reporting:

Data will be analysed and reported for all endpoints after the final patient has completed
the 52 week follow-up.

Data Monitoring Committee:

An independent Data Monitoring Committee (DMC) will ensure the safety of patients enrolled
in the trial. This group will be the MRC Leukaemia LDMEC (Chair: Prof. Gordon Murray). The
DMC will meet at the commencement of recruitment and will formulate its guidelines for
safety and efficacy monitoring. The DMC will provide a report of their meetings to the TSC.
The DMC will meet at least annually and more frequently if needed.

Central Morphology Review:

Bone marrow biopsies/aspirates for all patients will be sent for central morphology review
to determine eligibility for the study. All screening aspirates and biopsies will be
reviewed centrally to confirm the diagnosis of MDS and the categorisation of the WHO/FAB
subtype. On-study and end of study bone marrows will also be reviewed. In addition,
centralised testing of specialist investigations will be performed.

STUDY ENDPOINTS:

Primary end point:

- Quality of life at 24 weeks (FACT-An & EQ-5D - the latter for use in health economic
analyses)

Secondary end points:

- Quality of life at 12, 36 and 52 weeks (FACT-An & EQ-5D)

- Overall erythroid response (major and minor) at 24 weeks (main analysis point) and also
at 12 and 52 weeks, as defined by the International Working Group (IWG) criteria

- Incidence of disease progression (i.e. to RAEB or AML)

- Overall survival

- Economic costs of managing anaemia in each arm of the study.

STUDY DURATION:

Patients will be monitored for all study endpoints up to 52 weeks. Patients responding to
EPO ± G-CSF will remain on therapy for 52 weeks. Beyond 52 weeks, patients will be followed
up indefinitely in order to assess duration of response, incidence of disease progression
and overall survival (through the Office of National Statistics).

TOTAL SAMPLE SIZE:

Three hundred & sixty(360) patients, one hundred & twenty (120) in each arm.

DOSING REGIMEN:

The treatment schedule uses the concept of 'frontloading' to give patients the highest doses
of EPO at the start of therapy in order to induce a response as quickly as possible. The
long-acting nature of darbepoetin alpha avoids excessive frequency of injections, but allows
delivery of high doses of EPO. At week 24, if no response is achieved, the study treatment
is deemed to have failed and is stopped and patients will receive 'best supportive care'
only.

Darbepoetin (120 patients):

- EPO (Aranesp®) 500 mcg s.c. once every 2 weeks.

1. If a rapid response is obtained (Hb increase > or = 2 g/dl in any 4 week period),
titrate down the dose frequency of EPO.

2. If major response, titrate EPO to lowest dose frequency that maintains the
response.

- At 24 weeks :

1. If no response, stop EPO and give supportive therapy only.

2. If minor response, continue EPO 500 mcg once every 2 weeks s.c.

3. If major response, titrate EPO to lowest dose frequency that maintains the
response.

Darbepoetine with Filgrastim (120 patients):

- G-CSF (Neupogen®) 300 mcg s.c. twice a week, 3-4 days apart.

- EPO (Aranesp®) 500 mcg s.c. once every 2 weeks.

1. If a rapid response is obtained (Hb increase > or = 2 g/dl in any 4 week period),
titrate down the dose frequency of EPO.

2. If major response, titrate EPO and G-CSF to lowest dose frequency that maintains
the response.

- At 24 weeks :

1. If no response, stop EPO and G-CSF and give supportive therapy only.

2. If minor response, continue EPO 500 mcg every 2 weeks s.c. and G-CSF 300 mcg s.c.
twice a week, 3-4 days apart.

3. If major response, titrate EPO and G-CSF to lowest dose frequency that maintains
the response.

Best Supportive Care (120 patients):

Patients randomised to no growth factor treatment will receive best supportive care, defined
as:

- Red cell transfusion support to achieve a predicted post-transfusion haemoglobin of
11.0 to 12.0 g/dl at a quantity & frequency such that the trough haemoglobin is never <
8.0 g/dl OR

- such that the patient is never excessively symptomatic, according to local
transfusion guidelines/policy.

STUDY DRUG SUPPLIES:

Darbepoetin (Aranesp®) pre-filled syringes 500 mcg and filgrastim (Neupogen®) pre-filled
syringes 300 mcg will be supplied by Amgen (UK)and provided free of charge.

SAFETY ASSESSMENTS:

- Vital signs

- Physical examination

- Clinical laboratory assessments

- Concomitant medications

- Adverse events

EFFICACY ASSESSMENTS:

- Quality of life assessments

- Number and frequency of red cell transfusions

- Clinical laboratory assessments

- Bone marrow aspirate assessments