| Methods |
Phase II, double‐blind, multicenter, 2 x 2 factorial study. The 2 study factors were dose of darbepoetin alfa (500 lg Q3W versus 300 lg Q3W) and IV iron usage (IV iron versus no IV iron). The study was blinded to the dose of darbepoetin alfa administered and open label for IV iron administration. Eligible patients were randomized in a 1:1:1:1 ratio to 1 of 4 treatment arms: darbepoetin alfa 300 µg Q3W, darbepoetin alfa 500 µg Q3W, darbepoetin alfa 300 µg Q3W plus IV iron, and darbepoetin alfa 500 µg Q3W plus IV iron. Randomization was stratified by planned chemotherapy (platinum versus non‐platinum) and geographic region (North America versus Europe). Study length: 15 weeks Study conducted during: 18 December 2006 and 12 December 2007 Mean baseline serum ferritin range (291 to 332.3 ng/ml); mean baseline TSAT range (25.1% to 27.4%) |
| Participants |
Eligibility: ≥ 18 years old and had non‐myeloid cancer, CIA (Hb ≤ 10 g/dL), and no iron deficiency; patients were excluded if they had absolute iron deficiency (TSAT < 15% and serum ferritin < 10 ng/mL) Experimental arm: ESAs + IV iron: enrolled 122, analyzed 122 Control arm: ESAs only: enrolled 116, analyzed 116 Of the 238 participants dosed, 79% were white, 66% were female, and mean age was about 62 years. The most common tumor types were gastrointestinal, breast, and lung. |
| Interventions |
Experimental arm: darbepoetin alfa + oral iron dextran 400 mg Q3W (darbepoetin alfa was withheld at Hb > 13 g/dL) Control arm: ESAs only: darbepoetin alfa 500 mcg Q3W SC Darbepoetin alfa (Aranesp, Amgen, Thousand Oaks, CA) was supplied in 1 mL single‐dose vials as a clear, colorless, sterile protein solution. In the US, IV iron (provided as INFeD, Watson Pharma, Morristown, NJ) was supplied by a central pharmacy, CoramRx (Malvern, PA). In Europe, IV iron (provided as CosmoFer, Pharmacosmos, Denmark) was supplied via a central interactive voice response system. |
| Outcomes |
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| Notes |
Hematopoietic response defined as either a 2 g/dL increase from baseline in hemoglobin or a hemoglobin correction to ≥ 12 g/dL in the absence of any RBC transfusions in the preceding 28 days. Number of participants receiving RBC transfusions is reported. Participants who had received ≥ 1 RBC transfusions from week 1 to the end of study (Kaplan‐Meier estimates) are used for meta‐analysis. QOL was measured using FACT‐F; QOL parameters from baseline to end of treatment were reported Dose reductions for participants receiving darbepoetin alfa were allowed as follows: the dose was reduced to 200 µg Q3W or 300 µg Q3W, respectively, if a participant had a Hb level 12 g/dL with no other previous dose reductions or if a participant had a rapid rise in hemoglobin (defined as a > 1.5g/dL increase in hemoglobin within 21 days). After a second rapid rise in hemoglobin, the darbepoetin alfa dose was reduced to 150 µg Q3W or 250 µg Q3W, respectively, and further reduced to 100 µg Q3W or 200 µg Q3W, respectively, after a third rapid rise in hemoglobin. Thereafter, darbepoetin alfa dose was withheld when a subsequent rapid rise in hemoglobin occurred. Darbepoetin alfa dose was also withheld if a hemoglobin threshold (defined as Hb >13 g/dL) was reached, and was reinitiated when Hb fell to < 12 g/dL. Dose reduction and dose withholding rules did not apply if the participant had a RBC transfusion within 21 days prior to the next dosing visit. Authors state in the methods section that "patients could receive oral iron if they were not randomized to IV iron treatment." However, authors do not report the number of participants in the "ESAs only arm" who (may have) received oral iron supplementation. This was an industry‐funded trial. COI statement included: Drs. Auerbach, Webb, and Averyanova do not have conflicts to disclose. Dr. Ciuleanu is a member of the Amgen advisory board; Drs. Ciuleanu and Silberstein have received honoraria from Amgen. Mr. Shao was an employee of Amgen with ownership of Amgen stock at the time the study was conducted. Dr. Bridges is an employee of Amgen and owns Amgen stock. |
| Risk of bias |
| Bias |
Authors' judgement |
Support for judgement |
| Random sequence generation (selection bias) |
Low risk |
A randomization list was created and maintained by an independent randomization group at the study sponsor using permuted blocks. The randomization list was transmitted to an IVRS vendor for execution.
Enrollment and randomization were done by telephone and confirmed by facsimile |
| Allocation concealment (selection bias) |
Low risk |
A randomization list was created and maintained by an independent randomization group at the study sponsor using permuted blocks. The randomization list was transmitted to an IVRS vendor for execution.
Enrollment and randomization were done by telephone and confirmed by facsimile |
| Blinding (performance bias and detection bias)
All outcomes |
Unclear risk |
Participants were assigned blinded boxes of study medication using box numbers, which were recorded and reconciled. The study was blinded while ongoing and unblinded after all participants had completed the study. However, it is not clear whether or not the investigators were blinded |
| Incomplete outcome data (attrition bias)
All outcomes |
Low risk |
Efficay data were analyzed according to the ITT principle. Withdrawals and dropouts were described adequately |
| Selective reporting (reporting bias) |
Low risk |
Benefits and harms were reported as indicated in a prespecified method |
| Other bias |
High risk |
Data on alpha, beta errors, sample size calculation and delta were not reported; authors state in the methods section that "patients could receive oral iron if they were not randomized to IV iron supplementation." However, authors do not report the number of participants in the "ESAs only arm" who (may have) received oral iron supplementation |
