Trial Information

Darbepoetin-alpha and i.v. Iron Administration After Autologous Hematopoietic Stem Cell Transplantation : a Prospective Randomized Trial

1. Outline:

A 3-arm prospective randomized study of darbepoetin alpha administration after
autologous PBSC transplantation. Patients in the first arm will receive neither
darbepoetin alpha nor i.v. iron. Patients in the second arm will receive darbepoetin
alpha (Aranesp) alone starting on day 28 after the transplant. Patients in the third
arm will receive darbepoetin alpha (Aranesp) and i.v. iron saccharate (Venofer). The
plan is to include 25 patients in each arm.

In September 2006, all 75 planned patients have been included. Whereas preliminary
analysis shows that Aranesp therapy significantly improves Hb recovery after autologous
PBSC transplantation, the additional impact of Venofer therapy remains statistically
not significant. However, this is a very important point, because Venofer therapy could
potentially improve response and decrease the overall cost of treatment. Therefore, to
increase the statistical power of the study, 50 additional patients will be included.
Randomisation will now become limited to arms 2 (Aranesp) and 3 (Aranesp + Venofer).

2. Randomization:

Patients will be randomized 1:1:1 between the "Control", "Aranesp alone" and "Aranesp +
Venofer" arms. Randomization will be carried out following a computer-generated
randomization list blinded for personnel involved in clinical care of the patients.

Randomization will be carried out centrally in Liège by faxing the inclusion form at
the following number : 32-4-3668855. This should be done around day 21 post-transplant.

Starting in September 2006, patients will be randomized 1:1 between the "Aranesp alone"
and "Aranesp + Venofer" arms, using a computer-generated randomization list.

3. Study drug administration:

- Darbepoetin alpha administration : Darbepoetin alpha (Aranesp) will be
administered s.c. at the dose of 300 µg. The first dose will be given on day 28
and the following doses at 2-wk intervals around days 42, 56, 70, 84, 98, and 112
post-transplant. Once the target Hb (13 g/dL) has been attained, the dose of
Aranesp will be reduced by half to 150 µg. If the Hb increases to > 14 g/dL,
Aranesp will be withheld and resumed at the dose of 150 µg when the Hb decreases <
13 g/dL. If the Hb decreases to < 12 g/dL, the dose of Aranesp will be increased
to 300 µg again.

- Iron administration: Iron saccharate (Venofer) will be administered i.v. at the
dose of 200 mg (2 vials of Venofer) on days 28, 42, and 56 after the transplant.
Venofer will be diluted in 250 ml saline and infused over 60 minutes. Iron will be
omitted in patients with severe iron overload (serum ferritin > 2500 µg/L in the
absence of inflammation or liver necrosis) or elevated transferrin saturation (TS
> 60%) between days 21 and 56. No iron supplementation will be allowed in arm 1.
No iron supplementation will be allowed in arm 2 before day 70 after the
transplant. In arms 2 and 3, if patients have evidence of functional iron
deficiency (Transferrin saturation < 20%) on day 70 or later, they may receive 300
mg of Venofer over 90 min, for a minimum of 2 doses.

4. Transfusions:

One red blood cell (RBC) unit will be transfused if Hb value is between 7.0 and 7.9
g/dL. Two RBC units will be transfused if Hb value is below 7 g/dL. Platelets will be
transfused if needed, as per the institution's standards.

5. Follow-up:

- Clinical follow-up : Potential toxicities associated with Aranesp or Venofer will
be carefully monitored per the institution's standards. Blood pressure will be
recorded around days 28, 42, 56, 70, 84, 98, 112, and 126 after the transplant.
Serious adverse events (such as infections, bleeding, disease progression, any
hospitalization) will be recorded. In case of serious adverse event judged as
potentially related to Aranesp or Venofer, the principal investigator will be
immediately notified so as to jointly decide on possible discontinuation of either
drug.

Quality-of-life (QOL) evaluations will be carried out at baseline (day 28) as well as
on days 70 and 126 after the transplant, i.e. after 3 and 7 doses of Aranesp therapy.
This will be accomplished by providing the patient will the validated FACT-anemia
questionnaire. The questionnaire will be filled out by the patient and returned to the
principal investigator.

- Laboratory analyses: Complete blood counts will be determined in an automated cell
counter. Percentage and absolute reticulocyte count will be obtained locally by an
automated cytofluorometric method. Serum erythropoietin (Epo) levels will be
measured centrally in Liège on stored samples by a commercially available
radioimmunoassay (Incstar Corp., Stillwater, MN, USA). Based on regression
equations obtained in appropriate reference subjects between Hct on the one hand
and log (Epo) on the other, predicted log (Epo) values are derived for each Hct
and O/P ratios of observed/predicted Epo values will be calculated. Serum soluble
transferrin receptor (sTfR), a quantitative measure of total erythropoietic
activity, will be measured centrally in Liège on stored samples by a commercially
available ELISA (R&D, Minneapolis, MN, USA). Normal values range from 3,000 to
7,000 µg/L. Serum iron, transferrin saturation and ferritin, as well as standard
biochemical values, will be measured locally by standard methods.

On days 28 and 42, 5 ml of blood without anticoagulant will be collected and
centrifuged within 2 hours, serum will be separated and 2 ml of serum will be stored at
-28°C. Stored samples will be collected by the local investigator and finally stored in
Liège. Serum Epo and soluble TfR will be assayed later on all samples simultaneously.

6. Data collection and analysis:

Data will be collected at each center on protocol forms. The coordinating data manager from
Liège will verify the completeness and accuracy of data collected. The coordinating data
manager will be responsible for entering these data into the central database. All
statistical analyses will be performed centrally in Liège.