Darbepoetin Alfa in Patients With Anemic Low or Intermediate-1 Risk Myelodysplastic Syndrome (MDS)

• Sponsor: Amgen (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01362140
• Collaborator: (none)
• Enrollment: 147
• Locations: 72
• Arms: 2
• Actual Duration (Months): 68.8
• Patients Per Site: 2
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

The primary objective was to assess the superiority of darbepoetin alfa versus placebo on the incidence of red blood cell transfusions during the 24-week double-blind treatment period in anemic patients with low or intermediate-1 risk MDS.

Condition or Disease	Intervention/Treatment	Phase
MDS	Drug: Darbepoetin alfa; Drug: Placebo	Phase 3

Detailed Description

This study consists of a 3-week screening period, a 24-week double-blind treatment period, and a 48-week active treatment period and the long-term follow-up period.

An end of treatment period (EOTP) visit occurs at week 25, or 3 weeks after last dose of investigational product (IP) for participants who withdraw from the study. After entering the active treatment period, an end of active treatment period (EOATP) visit occurs at week 72 / 73, or 3 weeks after the last dose of darbepoetin alfa.

Long-term follow-up (LTFU) will occur every 26 weeks (± 4 weeks) from the EOATP visit (or EOTP visit if the participant does not enter the active treatment period) and will continue for a minimum of 3 years from the first dose of IP. Follow-up may occur through clinic visit or telephone contacts. Information on the participant's survival and progression to AML status will be collected during LTFU.

Study Design

• Study Type: Interventional
• Actual Enrollment: 147 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Supportive Care
• Official Title: A Multicenter, Randomised, Double-blind, Placebo-controlled Study of Darbepoetin Alfa for the Treatment of Anaemic Subjects With Low or Intermediate-1 Risk Myelodysplastic Syndrome (MDS)
• Actual Study Start Date: Dec 21, 2011
• Actual Primary Completion Date: Feb 11, 2015
• Actual Study Completion Date: Sep 14, 2017

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Darbepoetin alfa Participants received darbepoetin alfa 500 µg every three weeks (Q3W) for 24 weeks in the double-blind treatment period, and continued to receive darbepoetin alfa 500 µg Q3W during the active treatment period for an additional 48 weeks.	Drug: Darbepoetin alfa; Administered by subcutaneous injection every 3 weeks; Other Names: Aranesp
Placebo Comparator: Placebo Participants received placebo subcutaneous injection every 3 weeks (Q3W) for 24 weeks during the double-blind treatment period. From week 25 participants received darbepoetin alfa 500 µg Q3W during the active treatment period for 48 weeks.	Drug: Placebo; Administered by subcutaneous injection every 3 weeks

Outcome Measures

Primary Outcome Measures

1. Percentage of Participants With at Least One Red Blood Cell (RBC) Transfusion During the Double-blind Treatment Period [Week 5 to Week 25]

Secondary Outcome Measures

1. Percentage of Participants Who Achieved an Erythroid Response Based on International Working Group (IWG) 2006 Criteria in the Double-blind Treatment Period [Up to 24 weeks]

   International Working Group 2006 erythroid response was defined as achieving an initial ≥ 1.5 g/dL increase in hemoglobin from baseline and sustaining an average rise of ≥ 1.5 g/dL in a rolling 56-consecutive day period in the absence of RBC transfusion. Participants with no hemoglobin collected to the minimum time required to observe an IWG erythroid response (Week 13) were considered non-responders.

2. Number of Participants With Adverse Events [From first dose of study drug until the end of the double-blind treatment period; 24 weeks.]

   The severity of each adverse event was graded using the the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 grading scale, where grade 1 = mild, grade 2 = moderate, grade 3 = severe, grade 4 = life-threatening and grade 5 = death. Prespecified adverse events of interest for darbepoetin alfa, based on clinical data in anemic patients with cancer, included the following categories: hypersensitivity, cardiac failure, hypertension, malignancies, embolic and thrombolic events, venous thromboembolic events (VTEs), central nervous system vascular disorders, and ischemic heart disease.

3. Number of Participants With Disease Progression to Acute Myeloid Leukemia (AML) [24 weeks]

   Transformation to AML was assessed according to WHO guidelines in the absence of IP and any haematopoietic growth factors (2 weeks off dosing). Bone marrow and/or cytogenetic report confirmation of AML was required (marrow or peripheral blast cells ≥ 20%, presence of pathognomic AML cytogenetic change, or evidence of marrow blast criteria for erythroleukemia). A pathology report confirming other leukemias such as chloroma (granulocytic sarcoma, myeloid sarcoma) or leukemia cutis also constituted transformation to AML.

4. Number of Participants With Malignancies Other Than AML, Basal Cell Carcinoma, or Squamous Cell Carcinoma of the Skin [Up to 24 weeks]

5. Number of Participants Who Developed Neutralizing Antibodies to Darbepoetin Alfa [Baseline and end of double-blind treatment period (24 weeks)]

   Two validated assays were used to detect the presence of anti-darbepoetin alfa antibodies. Samples were first tested in an immunoassay to detect antibodies capable of binding to darbepoetin alfa. Samples confirmed to be positive for binding antibodies were subsequently tested in a cell-based assay to determine neutralizing activity against darbepoetin alfa. If a sample was positive for binding antibodies and demonstrated neutralizing activity at the same time point, the sample was defined as positive for neutralizing antibodies. The number of participants who developed antibodies to darbepoetin alfa is defined as participants who were neutralizing antibody positive post-baseline with a negative or no result at baseline.

6. Change From Baseline in Functional Assessment of Chronic Illness Therapy - Fatigue (FACIT-F) [Baseline, and weeks 13 and 25]

   The FACIT-Fatigue scale was a 13-item self-administered questionnaire that assesses both the physical and functional consequences of fatigue. Each question is answered on a 5-point scale, where 0 means "not at all," and 4 means "very much." The FACIT-Fatigue scale score ranges from 0 to 52, with higher scores denoting lower levels of fatigue. A positive change from baseline score indicates an improvement. End of treatment period (EOTP) analysis includes last available values.

7. Change From Baseline in EuroQol-5D (EQ-5D) Visual Analog Scale (VAS) [Baseline, and weeks 13 and 25]

   The EQ-5D visual analog scale (VAS) is a global evaluation of overall health state with scores ranging from 0 (worse health state a participant can imagine) to 100 (best health state a participant can imagine). End of treatment period (EOTP) analysis includes last available values.

8. Percentage of Participants With a Clinically Meaningful Improvement in Fatigue [Baseline to week 24]

   The FACIT-Fatigue scale was a 13-item self-administered questionnaire that assesses both the physical and functional consequences of fatigue. Each question is answered on a 5-point scale, where 0 means "not at all," and 4 means "very much." The FACIT-Fatigue scale score ranges from 0 to 52, with higher scores denoting lower levels of fatigue. Clinically meaningful improvement in fatigue is defined as an increase of ≥ 3 points in the FACIT-Fatigue subscale score, from baseline to EOTP.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Low or intermediate-1 risk MDS patients per International Prognostic Scoring System (IPSS) at the time of randomisation, as determined by complete blood count (CBC) during screening and bone marrow examination and marrow cytogenetic analysis performed within 16 weeks prior to randomisation. Subject cannot have been rendered low or intermediate-1 risk by prior disease modifying therapy. Bone marrow slides must be available for centralized review at any time throughout the study

• World Health Organization (WHO) classification of refractory anemia (RA), refractory anemia with ring sideroblasts (RARS), refractory cytopenias with multilineage dysplasia (RCMD), MDS-unclassified (MDSU), MDS with isolated del(5q) (5q- syndrome) or refractory anaemia with excess blasts-1 (RAEB-1)

• Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1 assessed during screening

• Haemoglobin level ≤ 10.0 g/dL as assessed by the local laboratory; sample obtained within 7 days prior to randomisation (retest during screening is acceptable)

• Adequate transferrin saturation (Tsat) (≥ 15%) and serum ferritin (≥ 10 ng/mL) as assessed by the central laboratory during screening (supplementation and retest during screening is acceptable)

• Adequate serum folate (≥ 4.5 nmol/L [≥ 2.0 ng/mL]) or RBC folate (≥ 317 nmol/L [≥ 140 ng/mL]) as assessed by the local laboratory during screening (supplementation and retest during screening is acceptable)

• Adequate vitamin B12 (≥ 148 pmol/L [≥ 200 pg/mL]) as assessed by the local laboratory during screening (supplementation and retest during screening is acceptable)

• 18 years of age or older

• Subject or subject's legally acceptable representative has provided informed consent -

Exclusion Criteria:

• Previously diagnosed with intermediate-2 or high risk MDS per IPSS

• Therapy-related or secondary MDS

• History of acute leukemia

• Evidence of bone marrow collagen fibrosis

• Inherited anaemia (eg, haemoglobinopathy, thalassemia, red cell membrane defect, red cell enzyme deficiency), active hemorrhage, red cell aplasia, haemolytic anaemia

• History of malignancies other than curatively treated non-melanoma skin or in situ carcinoma

• History of thrombosis within 6 months prior to randomisation

• Previous bone marrow or stem cell transplantation

• Uncontrolled angina, uncontrolled heart failure, or uncontrolled cardiac arrhythmia as determined by the investigator at screening. Subjects with known myocardial infarction within 6 months prior to randomisation

• Uncontrolled hypertension defined as systolic blood pressure ≥ 160 mmHg and/or diastolic blood pressure ≥ 100 mmHg at screening

• Clinically significant systemic infection or uncontrolled chronic inflammatory disease (ie, rheumatoid arthritis, inflammatory bowel disease) as determined by the investigator at screening

• History of seizure disorder (subject with previous history of seizure disorder will be eligible for the study if he/she had no evidence of seizure activity within 5 years of randomisation and is currently free of antiseizure medication)

• Previous or ongoing use of erythropoiesis-stimulating agent (ESA) therapy, eg, recombinant human erythropoietin (rHuEpo), darbepoetin alfa

• High transfusion demand: receiving a total of ≥ 4 units of RBC transfusion during either of 2 consecutive 8-week periods (ie, days -113 to -57 or days -56 to 0) prior to randomisation

• Received any RBC transfusion within 14 days prior to randomisation

• Received cytotoxic chemotherapy for any oncologic indication or planning to receive cytotoxic chemotherapy during the double-blind treatment period of the study

• Received biologic response modifiers (eg, thalidomide, lenalidomide, arsenic trioxide, azacitidine, decitabine) to treat MDS or planning to receive biologic response modifiers during the double-blind treatment period of the study

• Received myeloablative or craniospinal radiation or planning to receive myeloablative or craniospinal radiation during the double-blind treatment period of the study

• Received granulocyte colony stimulating factor (G-CSF) therapy within 30 days prior to randomization or planning to receive G-CSF therapy during the double-blind treatment period of the study (temporary use of G-CSF for neutropenia with fever and/or infection is acceptable)

• Abnormal renal function (serum creatinine level > 2 times the upper limit of the respective normal range [ULN]) as assessed by the central laboratory at screening

• Abnormal liver function (total bilirubin > 2 times, alanine aminotransferase [ALT] or aspartate aminotransferase [AST] > 3 times ULN) as assessed by the central laboratory at screening. (Subjects with abnormal bilirubin at screening due to documented Gilbert's Disease are eligible if all other criteria are met.)

• Serum endogenous erythropoetin (EPO) level > 500 mU/mL as assessed by the central laboratory at screening

• Known seropositivity for human immunodeficiency virus (HIV) or diagnosis of acquired Immunodeficiency syndrome (AIDS), positive for hepatitis B surface antigen, or seropositive for hepatitis C virus

• Subjects with active ethanol abuse, as judged by the investigator

• Currently enrolled in another investigational device or drug study, or less than 30 days since ending another investigational device or drug study(s), or receiving other investigational agent(s)

• Female subject is not willing to use highly effective contraception during treatment and for at least 1 month after the end of treatment

• Female subject is pregnant or planning to become pregnant within 1 month after the end of treatment

• Subject has known sensitivity to any of the products to be administered during dosing

• Subject has previously been randomised into this study

• Subject will not be available for protocol-required study visits, to the best of the subject and investigator's knowledge

• Subject has any kind of disorder that, in the opinion of the investigator, may compromise the ability of the subject to give written informed consent and/or to comply with all required study procedures

• Confirmed history of neutralising antibody activity to rHuEpo or darbepoetin alfa

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Research Site	Innsbruck		Austria	6020
2	Research Site	Linz		Austria	4020
3	Research Site	Salzburg		Austria	5020
4	Research Site	Wien		Austria	1140
5	Research Site	Brugge		Belgium	8000
6	Research Site	Bruxelles		Belgium	1200
7	Research Site	Charleroi		Belgium	6000
8	Research Site	Gent		Belgium	9000
9	Research Site	Haine Saint Paul - La Louviere		Belgium	7100
10	Research Site	Hasselt		Belgium	3500
11	Research Site	Leuven		Belgium	3000
12	Research Site	Liege		Belgium	4000
13	Research Site	Ottignies		Belgium	1340
14	Research Site	Roeselare		Belgium	8800
15	Research Site	Sint-Niklaas		Belgium	9100
16	Research Site	Brno		Czechia	625 00
17	Research Site	Hradec Kralove		Czechia	500 05
18	Research Site	Olomouc		Czechia	775 20
19	Research Site	Ostrava-Poruba		Czechia	708 52
20	Research Site	Praha 10		Czechia	100 34
21	Research Site	Praha 2		Czechia	128 08
22	Research Site	Praha 2		Czechia	128 20
23	Research Site	Praha 5		Czechia	150 06
24	Research Site	Zlin		Czechia	760 01
25	Research Site	Avignon Cedex 9		France	84902
26	Research Site	Bobigny cedex		France	93009
27	Research Site	Caen		France	14033
28	Research Site	Lyon Cédex 3		France	69437
29	Research Site	Lyon		France	69009
30	Research Site	Nantes Cedex 1		France	44035
31	Research Site	Nice Cedex 3		France	06202
32	Research Site	Paris Cedex 10		France	75475
33	Research Site	Paris		France	75015
34	Research Site	Pontoise Cedex		France	95301
35	Research Site	Toulouse Cedex 9		France	31059
36	Research Site	Vandoeuvre les Nancy		France	54511
37	Research Site	Dresden		Germany	01307
38	Research Site	Göttingen		Germany	37075
39	Research Site	Hannover		Germany	30625
40	Research Site	Köln		Germany	50677
41	Research Site	Leipzig		Germany	04103
42	Research Site	Mannheim		Germany	68167
43	Research Site	Regensburg		Germany	93053
44	Research Site	Rotenburg (Wümme)		Germany	27356
45	Research Site	Ulm		Germany	89081
46	Research Site	Athens		Greece	11527
47	Research Site	Athens		Greece	12462
48	Research Site	Ioannina		Greece	45110
49	Research Site	Patra		Greece	26500
50	Research Site	Thessaloniki		Greece	57010
51	Research Site	Alessandria		Italy	15100
52	Research Site	Bologna		Italy	40138
53	Research Site	Genova		Italy	16132
54	Research Site	Milano		Italy	20122
55	Research Site	Palermo		Italy	90146
56	Research Site	Pavia		Italy	27100
57	Research Site	Pesaro		Italy	61100
58	Research Site	Pisa		Italy	56127
59	Research Site	Reggio Calabria		Italy	89124
60	Research Site	Rionero In Vulture PZ		Italy	85028
61	Research Site	Roma		Italy	00161
62	Research Site	San Giovanni Rotondo FG		Italy	71013
63	Research Site	Udine		Italy	33100
64	Research Site	Zaragoza	Aragón	Spain	50009
65	Research Site	Salamanca	Castilla León	Spain	37007
66	Research Site	Barcelona	Cataluña	Spain	08003
67	Research Site	Valencia	Comunidad Valenciana	Spain	46010
68	Research Site	Valencia	Comunidad Valenciana	Spain	46026
69	Research Site	Basel		Switzerland	4031
70	Research Site	Luzern		Switzerland	6000
71	Research Site	Muensterlingen		Switzerland	8596
72	Research Site	Zurich		Switzerland	8091

Sponsors and Collaborators

• Amgen

Investigators

• Study Director: MD, Amgen

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• AmgenTrials clinical trials website

Publications

• Platzbecker U, Symeonidis A, Oliva EN, Goede JS, Delforge M, Mayer J, Slama B, Badre S, Gasal E, Mehta B, Franklin J. A phase 3 randomized placebo-controlled trial of darbepoetin alfa in patients with anemia and lower-risk myelodysplastic syndromes. Leukemia. 2017 Sep;31(9):1944-1950. doi: 10.1038/leu.2017.192. Epub 2017 Jun 19.

• Responsible Party: Amgen
• ClinicalTrials.gov Identifier: NCT01362140
• Other Study ID Numbers: 20090160; 2009-016522-14
• First Posted: May 30, 2011
• Last Update Posted: Dec 19, 2017
• Last Verified: Nov 1, 2017

• Keywords provided by Amgen: Randomized; Darbepoetin alfa; Myelodysplastic Syndromes; Placebo-controlled; low risk MDS; intermediate-1 risk MDS; International Prognostic Scoring System
• Additional relevant MeSH terms: Preleukemia; Myelodysplastic Syndromes; Darbepoetin alfa

Study Results

Participant Flow

Recruitment Details	This study was conducted at 49 centers in 9 countries. Participants were enrolled from 21 December 2011 to 06 January 2014. Results are reported for the double-blind treatment period of the study, with a 07 October 2015 data cut-off; the study is ongoing.
Pre-assignment Detail	Eligible participants were randomized in a 2:1 ratio to receive darbepoetin alfa or placebo. Randomization was stratified by International Prognostic Scoring System (IPSS) category (low vs intermediate-1 risk) established at screening.

Arm/Group Title	Placebo	Darbepoetin Alfa
Arm/Group Description	Participants received placebo subcutaneous injection every 3 weeks (Q3W) for 24 weeks.	Participants received darbepoetin alfa 500 µg Q3W for 24 weeks.
Period Title: Overall Study
STARTED	49	98
Received Treatment	49	97
COMPLETED	39	87
NOT COMPLETED	10	11

Baseline Characteristics

Arm/Group Title	Placebo	Darbepoetin Alfa	Total
Arm/Group Description	Participants received placebo subcutaneous injection every 3 weeks (Q3W) for 24 weeks.	Participants received darbepoetin alfa 500 µg Q3W for 24 weeks.	Total of all reporting groups
Overall Participants	49	97	146
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	72.4 (9.3)	72.4 (9.4)	72.4 (9.4)
Sex: Female, Male (Count of Participants)
Female	20 40.8%	46 47.4%	66 45.2%
Male	29 59.2%	51 52.6%	80 54.8%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	1 2%	2 2.1%	3 2.1%
Not Hispanic or Latino	45 91.8%	90 92.8%	135 92.5%
Unknown or Not Reported	3 6.1%	5 5.2%	8 5.5%
Race/Ethnicity, Customized (participants) [Number]
White	49 100%	97 100%	146 100%
IPSS Risk Category (participants) [Number]
Low	25 51%	49 50.5%	74 50.7%
Intermediate-1	24 49%	48 49.5%	72 49.3%
World Health Organization (WHO) Classification of MDS (participants) [Number]
Refractory anemia (RA)	13 26.5%	9 9.3%	22 15.1%
RA with ringed sideroblasts (RARS)	4 8.2%	17 17.5%	21 14.4%
Refractory cytopenia multilineage dysplasia (RCMD)	19 38.8%	45 46.4%	64 43.8%
MDS, unclassified (MDS-U)	1 2%	1 1%	2 1.4%
MDS associated with isolated del(5q)	2 4.1%	11 11.3%	13 8.9%
Refractory anemia with excess blasts-1 (RAEB-1)	10 20.4%	13 13.4%	23 15.8%
Refractory anemia with excess blasts-2 (RAEB-2)	0 0%	0 0%	0 0%
Unknown	0 0%	1 1%	1 0.7%
Time since MDS Diagnosis (months) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [months]	11.7 (17.6)	12.4 (16.7)	12.2 (16.9)
Hemoglobin (g/dL) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [g/dL]	9.10 (0.87)	9.23 (0.70)	9.19 (0.76)

Outcome Measures

1. Primary Outcome

Title	Percentage of Participants With at Least One Red Blood Cell (RBC) Transfusion During the Double-blind Treatment Period
Time Frame	Week 5 to Week 25

Outcome Measure Data

Analysis Population Description

Transfusion Primary Analysis Set which includes all randomized and consented participants who received at least 1 dose of study drug and who had an end of treatment period (EOTP) visit ≥ day 29 (ie, start of week 5).

Arm/Group Title	Placebo	Darbepoetin Alfa
Arm/Group Description	Participants received placebo subcutaneous injection every 3 weeks (Q3W) for 24 weeks.	Participants received darbepoetin alfa 500 µg Q3W for 24 weeks.
Measure Participants	49	97
Number [percentage of participants]	59.2 120.8%	36.1 37.2%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Darbepoetin Alfa
	Comments	The primary hypothesis to be tested was that the percentage of participants with at least 1 RBC transfusion from week 5 to the EOTP was lower in the darbepoetin alfa group than in the placebo group. This hypothesis was confirmed if the incidence of RBC transfusion in the darbepoetin alfa group was lower and had a p-value < 0.05 from a 2-sided Chi-square test.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.008
	Comments
	Method	Chi-squared
	Comments

2. Secondary Outcome

Title	Percentage of Participants Who Achieved an Erythroid Response Based on International Working Group (IWG) 2006 Criteria in the Double-blind Treatment Period
Description	International Working Group 2006 erythroid response was defined as achieving an initial ≥ 1.5 g/dL increase in hemoglobin from baseline and sustaining an average rise of ≥ 1.5 g/dL in a rolling 56-consecutive day period in the absence of RBC transfusion. Participants with no hemoglobin collected to the minimum time required to observe an IWG erythroid response (Week 13) were considered non-responders.
Time Frame	Up to 24 weeks

Outcome Measure Data

Analysis Population Description

Primary analysis set participants with a central laboratory baseline hemoglobin value

Arm/Group Title	Placebo	Darbepoetin Alfa
Arm/Group Description	Participants received placebo subcutaneous injection every 3 weeks (Q3W) for 24 weeks.	Participants received darbepoetin alfa 500 µg Q3W for 24 weeks.
Measure Participants	35	75
Number (95% Confidence Interval) [percentage of participants]	0.0 0%	14.7 15.2%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Darbepoetin Alfa
	Comments	If the primary hypothesis was confirmed, the secondary hypothesis to be tested was that the percentage of participants achieving an IWG erythroid response during the 24-week double-blind treatment period was greater in the darbepoetin alfa group than in the placebo group. This hypothesis was confirmed if erythroid response was higher in the darbepoetin alfa group and the p-value was < 0.05 from a 2-sided Cochran-Mantel-Haenszel test using the IPSS as a stratification factor.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.017
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments	The overall 2-sided CMH test with IPSS score as stratification factor.

3. Secondary Outcome

Title	Number of Participants With Adverse Events
Description	The severity of each adverse event was graded using the the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 grading scale, where grade 1 = mild, grade 2 = moderate, grade 3 = severe, grade 4 = life-threatening and grade 5 = death. Prespecified adverse events of interest for darbepoetin alfa, based on clinical data in anemic patients with cancer, included the following categories: hypersensitivity, cardiac failure, hypertension, malignancies, embolic and thrombolic events, venous thromboembolic events (VTEs), central nervous system vascular disorders, and ischemic heart disease.
Time Frame	From first dose of study drug until the end of the double-blind treatment period; 24 weeks.

Outcome Measure Data

Analysis Population Description

Safety Analysis Set, including all participants who received at least 1 dose of study drug. One participant in the placebo arm inadvertently received a dose of darbepoetin alfa and is counted in the darbepoetin alfa group for safety analyses.

Arm/Group Title	Placebo	Darbepoetin Alfa
Arm/Group Description	Participants received placebo subcutaneous injection every 3 weeks (Q3W) for 24 weeks.	Participants received darbepoetin alfa 500 µg Q3W for 24 weeks.
Measure Participants	48	98
Any adverse event (AE)	37 75.5%	80 82.5%
AE Grade ≥ 2	23 46.9%	42 43.3%
AE Grade ≥ 3	13 26.5%	15 15.5%
AE Grade ≥ 4	6 12.2%	5 5.2%
Serious adverse events (SAE)	8 16.3%	11 11.3%
AE leading to discontinuation of study drug	2 4.1%	3 3.1%
Fatal adverse events	2 4.1%	1 1%
Adverse events of special interest	13 26.5%	16 16.5%
Treatment-related adverse events (TRAE)	4 8.2%	5 5.2%
Treatment-related serious adverse events	0 0%	1 1%
TRAE leading to discontinuation of study drug	0 0%	1 1%
Treatment-related fatal adverse events	0 0%	0 0%

4. Secondary Outcome

Title	Number of Participants With Disease Progression to Acute Myeloid Leukemia (AML)
Description	Transformation to AML was assessed according to WHO guidelines in the absence of IP and any haematopoietic growth factors (2 weeks off dosing). Bone marrow and/or cytogenetic report confirmation of AML was required (marrow or peripheral blast cells ≥ 20%, presence of pathognomic AML cytogenetic change, or evidence of marrow blast criteria for erythroleukemia). A pathology report confirming other leukemias such as chloroma (granulocytic sarcoma, myeloid sarcoma) or leukemia cutis also constituted transformation to AML.
Time Frame	24 weeks

Outcome Measure Data

Analysis Population Description

Safety analysis set with available data

Arm/Group Title	Placebo	Darbepoetin Alfa
Arm/Group Description	Participants received placebo subcutaneous injection every 3 weeks (Q3W) for 24 weeks.	Participants received darbepoetin alfa 500 µg Q3W for 24 weeks.
Measure Participants	46	95
Number [participants]	1 2%	2 2.1%

5. Secondary Outcome

Title	Number of Participants With Malignancies Other Than AML, Basal Cell Carcinoma, or Squamous Cell Carcinoma of the Skin
Time Frame	Up to 24 weeks

Outcome Measure Data

Analysis Population Description

Safety analysis set

Arm/Group Title	Placebo	Darbepoetin Alfa
Arm/Group Description	Participants received placebo subcutaneous injection every 3 weeks (Q3W) for 24 weeks.	Participants received darbepoetin alfa 500 µg Q3W for 24 weeks.
Measure Participants	48	98
Number [participants]	0 0%	1 1%

6. Secondary Outcome

Title	Number of Participants Who Developed Neutralizing Antibodies to Darbepoetin Alfa
Description	Two validated assays were used to detect the presence of anti-darbepoetin alfa antibodies. Samples were first tested in an immunoassay to detect antibodies capable of binding to darbepoetin alfa. Samples confirmed to be positive for binding antibodies were subsequently tested in a cell-based assay to determine neutralizing activity against darbepoetin alfa. If a sample was positive for binding antibodies and demonstrated neutralizing activity at the same time point, the sample was defined as positive for neutralizing antibodies. The number of participants who developed antibodies to darbepoetin alfa is defined as participants who were neutralizing antibody positive post-baseline with a negative or no result at baseline.
Time Frame	Baseline and end of double-blind treatment period (24 weeks)

Outcome Measure Data

Analysis Population Description

Safety analysis set participants with post-baseline antibody results

Arm/Group Title	Placebo	Darbepoetin Alfa
Arm/Group Description	Participants received placebo subcutaneous injection every 3 weeks (Q3W) for 24 weeks.	Participants received darbepoetin alfa 500 µg Q3W for 24 weeks.
Measure Participants	43	91
Number [participants]	0 0%	0 0%

7. Secondary Outcome

Title	Change From Baseline in Functional Assessment of Chronic Illness Therapy - Fatigue (FACIT-F)
Description	The FACIT-Fatigue scale was a 13-item self-administered questionnaire that assesses both the physical and functional consequences of fatigue. Each question is answered on a 5-point scale, where 0 means "not at all," and 4 means "very much." The FACIT-Fatigue scale score ranges from 0 to 52, with higher scores denoting lower levels of fatigue. A positive change from baseline score indicates an improvement. End of treatment period (EOTP) analysis includes last available values.
Time Frame	Baseline, and weeks 13 and 25

Outcome Measure Data

Analysis Population Description

FACIT-Fatigue Analysis Set, includes all participants in the primary analysis set who completed or partially completed both the baseline and at least 1 subsequent FACIT-F questionnaire.

Arm/Group Title	Placebo	Darbepoetin Alfa
Arm/Group Description	Participants received placebo subcutaneous injection every 3 weeks (Q3W) for 24 weeks.	Participants received darbepoetin alfa 500 µg Q3W for 24 weeks.
Measure Participants	42	90
Baseline (N = 42, 90)	32.9 (11.4)	33.1 (11.4)
Change from Baseline to Week 13 (n = 41, 85)	-0.9 (9.0)	2.7 (7.2)
Change from Baseline to Week 25 (n = 39, 85)	0.6 (5.5)	1.2 (8.9)
Change from Baseline to EOTP (n = 42, 90)	-0.5 (7.1)	1.1 (8.8)

8. Secondary Outcome

Title	Change From Baseline in EuroQol-5D (EQ-5D) Visual Analog Scale (VAS)
Description	The EQ-5D visual analog scale (VAS) is a global evaluation of overall health state with scores ranging from 0 (worse health state a participant can imagine) to 100 (best health state a participant can imagine). End of treatment period (EOTP) analysis includes last available values.
Time Frame	Baseline, and weeks 13 and 25

Outcome Measure Data

Analysis Population Description

The EQ-5D visual analog analysis set includes all participants in the primary analysis set who completed both the baseline and at least 1 subsequent visual analog scale.

Arm/Group Title	Placebo	Darbepoetin Alfa
Arm/Group Description	Participants received placebo subcutaneous injection every 3 weeks (Q3W) for 24 weeks.	Participants received darbepoetin alfa 500 µg Q3W for 24 weeks.
Measure Participants	42	90
Baseline (N = 42, 90)	64.4 (17.9)	64.8 (17.2)
Change from Baseline to Week 13 (n = 41, 83)	-1.9 (15.5)	2.9 (13.0)
Change from Baseline to Week 25 (n = 39, 81)	2.1 (15.3)	2.4 (13.5)
Change from Baseline to EOTP (n = 42, 89)	0.8 (15.7)	2.1 (13.1)

9. Secondary Outcome

Title	Percentage of Participants With a Clinically Meaningful Improvement in Fatigue
Description	The FACIT-Fatigue scale was a 13-item self-administered questionnaire that assesses both the physical and functional consequences of fatigue. Each question is answered on a 5-point scale, where 0 means "not at all," and 4 means "very much." The FACIT-Fatigue scale score ranges from 0 to 52, with higher scores denoting lower levels of fatigue. Clinically meaningful improvement in fatigue is defined as an increase of ≥ 3 points in the FACIT-Fatigue subscale score, from baseline to EOTP.
Time Frame	Baseline to week 24

Outcome Measure Data

Analysis Population Description

FACIT-fatigue analysis set

Arm/Group Title	Placebo	Darbepoetin Alfa
Arm/Group Description	Participants received placebo subcutaneous injection every 3 weeks (Q3W) for 24 weeks.	Participants received darbepoetin alfa 500 µg Q3W for 24 weeks.
Measure Participants	42	90
Number (95% Confidence Interval) [percentage of participants]	31.0 63.3%	35.6 36.7%

Adverse Events

Time Frame	From first dose of study drug to 24 weeks for participants who continued into the active treatment period or until 30 days after last dose (maximum of 28 weeks) for participants who did not continue.
Adverse Event Reporting Description	One participant randomized to the Placebo arm inadvertently received one 200 µg dose of darbepoetin alfa and is reported in the Darbepoetin alfa group for adverse events. Other Adverse Events summarizes the non-serious occurrences of adverse events that exceed the indicated frequency threshold.
Arm/Group Title	Placebo		Darbepoetin Alfa
Arm/Group Description	Participants received placebo subcutaneous injection every 3 weeks (Q3W) for 24 weeks.		Participants received darbepoetin alfa 500 µg Q3W for 24 weeks.
All Cause Mortality
	Placebo		Darbepoetin Alfa
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Placebo		Darbepoetin Alfa
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	8/48 (16.7%)		11/98 (11.2%)
Blood and lymphatic system disorders
Anaemia	0/48 (0%)		3/98 (3.1%)
Haemorrhagic anaemia	1/48 (2.1%)		0/98 (0%)
Leukocytosis	1/48 (2.1%)		0/98 (0%)
Thrombocytopenia	0/48 (0%)		1/98 (1%)
Cardiac disorders
Cardiac failure	1/48 (2.1%)		0/98 (0%)
Ear and labyrinth disorders
Vertigo positional	0/48 (0%)		1/98 (1%)
Gastrointestinal disorders
Proctitis haemorrhagic	0/48 (0%)		1/98 (1%)
General disorders
Asthenia	1/48 (2.1%)		0/98 (0%)
Non-cardiac chest pain	0/48 (0%)		1/98 (1%)
Infections and infestations
Abscess	0/48 (0%)		1/98 (1%)
Abscess of salivary gland	0/48 (0%)		1/98 (1%)
Gastrointestinal infection	1/48 (2.1%)		0/98 (0%)
Pneumonia	2/48 (4.2%)		2/98 (2%)
Staphylococcal sepsis	0/48 (0%)		1/98 (1%)
Urinary tract infection	0/48 (0%)		1/98 (1%)
Urosepsis	1/48 (2.1%)		0/98 (0%)
Investigations
Weight decreased	1/48 (2.1%)		0/98 (0%)
Musculoskeletal and connective tissue disorders
Osteoarthritis	0/48 (0%)		1/98 (1%)
Nervous system disorders
Cerebral haemorrhage	1/48 (2.1%)		0/98 (0%)
Renal and urinary disorders
Acute kidney injury	0/48 (0%)		1/98 (1%)
Renal failure	2/48 (4.2%)		0/98 (0%)
Reproductive system and breast disorders
Menorrhagia	0/48 (0%)		1/98 (1%)
Respiratory, thoracic and mediastinal disorders
Pneumonitis	0/48 (0%)		1/98 (1%)
Pulmonary arterial hypertension	1/48 (2.1%)		0/98 (0%)
Pulmonary embolism	0/48 (0%)		1/98 (1%)
Surgical and medical procedures
Cholecystectomy	0/48 (0%)		1/98 (1%)
Vascular disorders
Extremity necrosis	0/48 (0%)		1/98 (1%)
Hypertension	1/48 (2.1%)		0/98 (0%)
Other (Not Including Serious) Adverse Events
	Placebo		Darbepoetin Alfa
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	25/48 (52.1%)		56/98 (57.1%)
General disorders
Asthenia	5/48 (10.4%)		12/98 (12.2%)
Fatigue	4/48 (8.3%)		17/98 (17.3%)
Oedema peripheral	4/48 (8.3%)		3/98 (3.1%)
Pyrexia	1/48 (2.1%)		9/98 (9.2%)
Infections and infestations
Nasopharyngitis	3/48 (6.3%)		8/98 (8.2%)
Musculoskeletal and connective tissue disorders
Arthralgia	3/48 (6.3%)		6/98 (6.1%)
Back pain	2/48 (4.2%)		8/98 (8.2%)
Musculoskeletal pain	3/48 (6.3%)		0/98 (0%)
Myalgia	0/48 (0%)		5/98 (5.1%)
Nervous system disorders
Dizziness	3/48 (6.3%)		5/98 (5.1%)
Headache	1/48 (2.1%)		7/98 (7.1%)
Psychiatric disorders
Insomnia	3/48 (6.3%)		0/98 (0%)
Respiratory, thoracic and mediastinal disorders
Dyspnoea	2/48 (4.2%)		5/98 (5.1%)
Dyspnoea exertional	5/48 (10.4%)		6/98 (6.1%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The Clinical Trial Agreement generally does not restrict an investigator's discussion of trial results after completion. The Agreement permits Amgen a limited period of time to review material discussing trial results (typically up to 45 days and possible extension). Amgen may remove confidential information, but authors have final control and approval of publication content. For multicenter studies, the investigator agrees not to publish any results before the first multi-center publication.