Anemia, Neoplasms
Conditions
Keywords
Epoetin alfa (EPREX, ERYPO)
Brief summary
The purpose of the study is to evaluate the safety of epoetin alfa in patients with cancer who have chemotherapy-related anemia.
Detailed description
Epoetin alfa is an agent similar to a hormone produced in the kidney (ie, erythropoietin) that functions to increase the amount of red blood cells made in the bone marrow. This is a randomized (study drug assigned by chance), open-label (patients and their doctors will know the identity of study drug administered), safety study of 2 dosing regimens (doses and schedules) of epoetin alfa administered to patients with cancer who have chemotherapy-related anemia. Anemia is a lack of red blood cells that can result in symptoms of weakness, shortness of breath, fatigue, tiredness, and decreased activity. The primary outcome measure in the study is the number of patients in each treatment group with at least 1 clinically relevant and objectively confirmed (adjudicated) thrombovascular event (TVE) reviewed by an independent adjudication committee from Day 1 (baseline or the day of the first dose) through Week 16. An external review of relevant clinical data and medical imaging studies by an Adjudication Committee will be performed in a blinded fashion for confirmation of TVEs. The Adjudication Committee will confirm TVEs by reviewing all images (X-ray, Computed tomography \[CT\] scan, ultrasound, Magnetic Resonance Imaging \[MRI\] scan, etc) and other diagnostic procedures auch as coagulation tests or electrocardiograms in combination with a clinical patient profile as described for each specific type of TVE. Only TVEs that are determined by the Adjudication Committee to be clinically relevant and objectively confirmed will be counted in the analysis for the primary endpoint. Approximately 500 patients, who have cancer, are receiving chemotherapy, and are anemic, will take part in the study. Patients will participate in the study for up to 32 weeks (this includes a 2-week screening period to determine eligibility for the study, a 26-week treatment period, and a 4-week follow-up period to have end-of-study assessments \[tests\] performed). The length of participation in the study depends on the length of time the patient is receiving chemotherapy and epoetin alfa; patients in the study may receive up to a maximum of 26 weeks of treatment with epoetin alfa. Patients will be randomly assigned (assigned by chance like flipping a coin) to 1 of 2 treatment groups (Epoetin Alfa QW or Epoetin Alfa TIW). Patients assigned to the Epoetin Alfa QW Group will receive epoetin alfa at an initial dosage of 450 IU/kg once a week and patients assigned to Epoetin Alfa TIW Group will receive epoetin alfa 150 IU/kg 3 times a week by subcutaneous (underneath the skin) injection. Injections will be given preferably on Monday for patients in the Epoetin Alfa QW Group and on Mondays, Wednesdays, and Fridays for patients in the Epoetin Alfa TIW Group. During the study, patients will visit the study center weekly to have a blood sample collected to measure the amount of hemoglobin (red blood cells) in the blood. Depending on the hemoglobin level, the dose of epoetin alfa may be increased or decreased. Regardless of treatment group, if anemia does not improve in patients after 4 weeks of treatment, the dose of epoetin alfa will be increased to 300 IU/kg 3 times a week. If anemia does not improve after 4 weeks at the increased dose level of epoetin alfa (300 IU/kg 3 times a week), treatment with epoetin alfa will be stopped. In addition, during the study, patients may also receive treatment with iron supplements if the level of iron in the blood is low. During the study, safety will be monitored by evaluating adverse events and findings from clinical laboratory tests, 12-lead electrocardiograms (ECGs), blood pressure measurements, and physical examinations. Patients will receive epoetin alfa at an initial dose of 450 IU/kg once a week or 150 IU/kg 3 times a week by subcutaneous injection, preferably in the abdomen, for up to 4 weeks after the last dose of chemotherapy for a maximum of 26 weeks. Injections for Epoetin Alfa QW Group will be at the study center and for Epoetin TIW Group, the 1st weekly injection will be at the study center and the 2nd and 3rd weekly injections will be at the study center or at home by self-administration.
Interventions
DRUGEpoetin alfa 450 IU/kg once a week
450 IU/kg once a week by subcutaneous injection preferably in the abdomen for up to 4 weeks after the last dose of chemotherapy for a maximum of 26 weeks.
DRUGEpoetin alfa 150 IU/kg 3 times a week
150 IU/kg 3 times a week by subcutaneous injection preferably in the abdomen for up to 4 weeks after the last dose of chemotherapy for a maximum of 26 weeks.
DRUGEpoetin alfa 450 IU/kg once a week (QW)
450 IU/kg once a week (QW) by subcutaneous injection preferably in the abdomen for up to 4 weeks after the last dose of chemotherapy for a maximum of 26 weeks
DRUGEpoetin alfa 150 IU/kg 3 times a week (TIW)
150 IU/kg 3 times a week (TIW) by subcutaneous injection preferably in the abdomen for up to 4 weeks after the last dose of chemotherapy for a maximum of 26 weeks.
Sponsors
Johnson & Johnson Pharmaceutical Research & Development, L.L.C.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Any nonmyeloid tumor confirmed by cytology and/or histology * Day 1 baseline hemoglobin (Hb) level \<=11 g/dL * Expected to receive at least 12 weeks of chemotherapy after enrollment into the study * Eastern Cooperative Oncology Group (ECOG) performance status \<= 2
Exclusion criteria
* History of active second cancer except for adequately treated skin cancer and in situ (pre-invasive) cervical cancer * History of deep venous thrombosis (DVT) (blood clots in the veins of the thighs or legs) or pulmonary embolism (PE) (blood clot in the lungs) within 12 months before study entry or at any time if the event is related to the current cancer, which is defined as diagnosis of the cancer within 3 months of a DVT/PE episode or a DVT/PE following the cancer diagnosis/treatment * History of cardiovascular accident (CVA), transient ischemic attack (TIA) (stroke), acute coronary syndrome (ACS) (a condition indicating damage to the heart), or other arterial thrombosis (blood clots) within 6 months before study entry * Onset of seizures within 3 months before randomization or poorly controlled seizures * Brain tumor or brain metastasis from another malignancy or cardiac disease that is markedly or completely limiting, uncontrolled hypertension (high blood pressure), or anemia (a lack of red blood cells in the blood) for reasons other than cancer or chemotherapy * Specifically excluded concomitant medications or therapies including prophylactic anticoagulation therapy for recurrence of prior thrombovascular event (TVE) (warfarin, unfractionated heparin, low molecular weight heparin \[LMWH\], except for prevention of central venous catheter thrombosis at doses specified in the protocol, direct thrombin inhibitors, or anti-platelet drugs \[e.g., clopidogrel or ticlopidine\]), except for prophylaxis in patients with known cardiovascular disease
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With at Least 1 Clinically Relevant and Objectively Confirmed Thrombovascular Event From Randomization Through Week 16 | from randomization through Week 16 | Clinically relevant and objectively confirmed thrombovascular event (TVE) was determined by the Adjudication Committee from randomization through Week 16. Clinically relevant TVEs were defined as deep vein thrombosis (DVT) of the limbs; thromboses of other major veins; pulmonary embolism (PE);acute coronary syndrome (ACS);ischemic stroke of arterial or cardiac origin; cerebral venous thrombosis; and arterial thrombosis. Objectively confirmed was defined as the confirmation of the clinical diagnosis of a TVE by appropriate medical imaging studies and laboratory tests. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to First Positively Adjudicated Thrombovascular Event | during the study (randomization through week 26) | Analysis of time to first positively adjudicated thrombovascular event (TVE) measured from the date of randomization to the date of the first clinically relevant and objectively confirmed TVE as determined by the Adjudication Committee. Median time is non-estimable because of too few events, incidence was reported instead. |
| Number of Suspected Thrombovascular Events | during the study (randomization through week 26) | Number of participants who have at least 1 suspected thrombovascular events (TVEs) during the entire study. Suspected TVEs were defined as suspected TVEs during the entire study, whether clinically relevant and objectively confirmed by the Adjudication Committee or not, whether confirmed by the investigator or not. |
| Time to First Suspected Thrombovascular Event | during the study (randomization through week 26) | Analysis of time to first suspected thrombovascular event (TVE) measured from the date of randomization to the date of the first suspected TVE during the study. Median time is non-estimable because of too few events, incidence was reported instead. |
| Number of Positively Adjudicated Thrombovascular Events | during the study (randomization through week 26) | The number of participants who have at least 1 clinically relevant and objectively confirmed (adjudicated) thrombovascular event (TVE) during the study. |
| Number of Hemoglobin Responders | during the study (randomization through week 26) | Hemoglobin response was defined as a hemoglobin increase of ≥2 g/dL from baseline or reaching a hemoglobin concentration of 12 g/dL, regardless of dose adjustment. |
| Red Blood Cell Transfusions | during the study (randomization through week 26) | The number of participants who received at least 1 red blood cell (RBC) transfusion (packed RBC or whole blood) during the study. |
| Mortality | during the study (randomization through week 26) | Number of participants who died during the study. |
Participant flow
Recruitment details
This is a randomized, open-label, multicenter study evaluating thrombovascular events in participants with cancer receiving chemotherapy and administered Epoetin Alfa once weekly (QW) or three times a week (TIW) for the treatment of anemia.
Participants by arm
| Arm | Count |
|---|---|
| Epoetin Alfa QW epoetin alfa at an initial dosage of 450 IU/kg once a week (QW) | 242 |
| Epoetin Alfa TIW epoetin alfa at an initial dosage of 150 IU/kg 3 times a week (TIW) | 262 |
| Total | 504 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 0 | 4 |
| Overall Study | Chemotherapy Termination | 10 | 15 |
| Overall Study | Disease Progression | 7 | 7 |
| Overall Study | Lack of Efficacy | 5 | 7 |
| Overall Study | Lost to Follow-up | 6 | 8 |
| Overall Study | Physician Decision | 1 | 3 |
| Overall Study | Prematurely Termination of Trial | 9 | 10 |
| Overall Study | Protocol Violation | 1 | 1 |
| Overall Study | Withdrawal by Subject | 20 | 17 |
Baseline characteristics
| Characteristic | Epoetin Alfa QW | Total | Epoetin Alfa TIW |
|---|---|---|---|
| Age, Categorical <=18 years | 1 Participants | 2 Participants | 1 Participants |
| Age, Categorical >=65 years | 81 Participants | 169 Participants | 88 Participants |
| Age, Categorical Between 18 and 65 years | 160 Participants | 333 Participants | 173 Participants |
| Age Continuous | 58.8 years STANDARD_DEVIATION 13.35 | 58.1 years STANDARD_DEVIATION 13.44 | 57.5 years STANDARD_DEVIATION 13.53 |
| Region of Enrollment Bulgaria | 6 participants | 13 participants | 7 participants |
| Region of Enrollment France | 7 participants | 13 participants | 6 participants |
| Region of Enrollment Germany | 51 participants | 106 participants | 55 participants |
| Region of Enrollment Great Britain | 1 participants | 5 participants | 4 participants |
| Region of Enrollment Greece | 8 participants | 20 participants | 12 participants |
| Region of Enrollment Italy | 13 participants | 26 participants | 13 participants |
| Region of Enrollment Poland | 7 participants | 13 participants | 6 participants |
| Region of Enrollment Romania | 21 participants | 41 participants | 20 participants |
| Region of Enrollment Russia | 88 participants | 181 participants | 93 participants |
| Region of Enrollment Slovakia | 9 participants | 20 participants | 11 participants |
| Region of Enrollment Ukraine | 31 participants | 66 participants | 35 participants |
| Sex: Female, Male Female | 156 Participants | 337 Participants | 181 Participants |
| Sex: Female, Male Male | 86 Participants | 167 Participants | 81 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 157 / 242 | 151 / 262 |
| serious Total, serious adverse events | 53 / 242 | 64 / 262 |
Outcome results
Primary
Number of Participants With at Least 1 Clinically Relevant and Objectively Confirmed Thrombovascular Event From Randomization Through Week 16
Clinically relevant and objectively confirmed thrombovascular event (TVE) was determined by the Adjudication Committee from randomization through Week 16. Clinically relevant TVEs were defined as deep vein thrombosis (DVT) of the limbs; thromboses of other major veins; pulmonary embolism (PE);acute coronary syndrome (ACS);ischemic stroke of arterial or cardiac origin; cerebral venous thrombosis; and arterial thrombosis. Objectively confirmed was defined as the confirmation of the clinical diagnosis of a TVE by appropriate medical imaging studies and laboratory tests.
Time frame: from randomization through Week 16
Population: The modified intent-to-treat (mITT) population was defined to include all randomized participants who received at least 1 dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Epoetin Alfa QW | Number of Participants With at Least 1 Clinically Relevant and Objectively Confirmed Thrombovascular Event From Randomization Through Week 16 | 5 particpants |
| Epoetin Alfa TIW | Number of Participants With at Least 1 Clinically Relevant and Objectively Confirmed Thrombovascular Event From Randomization Through Week 16 | 10 particpants |
Comparison: The primary hypothesis was that the group of participants receiving epoetin alfa QW and the group of participants receiving epoetin alfa TIW would have similar incidence rate of participants with at least 1 clinically relevant and objectively confirmed TVE from randomization through Week 16.p-value: 0.24895% CI: [-0.051, 0.016]Chi-squared
p-value: 0.25495% CI: [0.18, 1.58]Regression, Logistic
Secondary
Mortality
Number of participants who died during the study.
Time frame: during the study (randomization through week 26)
Population: All randomized participants who received at least 1 dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Epoetin Alfa QW | Mortality | 25 participants |
| Epoetin Alfa TIW | Mortality | 26 participants |
p-value: 0.8895% CI: [-0.0526, 0.0608]Chi-squared
Secondary
Number of Hemoglobin Responders
Hemoglobin response was defined as a hemoglobin increase of ≥2 g/dL from baseline or reaching a hemoglobin concentration of 12 g/dL, regardless of dose adjustment.
Time frame: during the study (randomization through week 26)
Population: All participants who were randomized, regardless of whether or not they received study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Epoetin Alfa QW | Number of Hemoglobin Responders | 179 participants |
| Epoetin Alfa TIW | Number of Hemoglobin Responders | 187 participants |
p-value: 0.51495% CI: [-0.056, 0.108]Chi-squared
Secondary
Number of Positively Adjudicated Thrombovascular Events
The number of participants who have at least 1 clinically relevant and objectively confirmed (adjudicated) thrombovascular event (TVE) during the study.
Time frame: during the study (randomization through week 26)
Population: The modified intent-to-treat (mITT) population used for safety analysis population included all randomized participants who received at least 1 dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Epoetin Alfa QW | Number of Positively Adjudicated Thrombovascular Events | 5 participants |
| Epoetin Alfa TIW | Number of Positively Adjudicated Thrombovascular Events | 13 participants |
p-value: 0.0895% CI: [-0.065, 0.007]Chi-squared
Secondary
Number of Suspected Thrombovascular Events
Number of participants who have at least 1 suspected thrombovascular events (TVEs) during the entire study. Suspected TVEs were defined as suspected TVEs during the entire study, whether clinically relevant and objectively confirmed by the Adjudication Committee or not, whether confirmed by the investigator or not.
Time frame: during the study (randomization through week 26)
Population: All randomized participants who received at least 1 dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Epoetin Alfa QW | Number of Suspected Thrombovascular Events | 9 participants |
| Epoetin Alfa TIW | Number of Suspected Thrombovascular Events | 20 participants |
p-value: 0.05995% CI: [-0.083, 0.005]Chi-squared
Secondary
Red Blood Cell Transfusions
The number of participants who received at least 1 red blood cell (RBC) transfusion (packed RBC or whole blood) during the study.
Time frame: during the study (randomization through week 26)
Population: All participants who were randomized, regardless of whether or not they received study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Epoetin Alfa QW | Red Blood Cell Transfusions | 38 participants |
| Epoetin Alfa TIW | Red Blood Cell Transfusions | 42 participants |
p-value: 0.9295% CI: [-0.071, 0.065]Chi-squared
Secondary
Time to First Positively Adjudicated Thrombovascular Event
Analysis of time to first positively adjudicated thrombovascular event (TVE) measured from the date of randomization to the date of the first clinically relevant and objectively confirmed TVE as determined by the Adjudication Committee. Median time is non-estimable because of too few events, incidence was reported instead.
Time frame: during the study (randomization through week 26)
Population: All randomized participants who received at least 1 dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Epoetin Alfa QW | Time to First Positively Adjudicated Thrombovascular Event | 5 participants |
| Epoetin Alfa TIW | Time to First Positively Adjudicated Thrombovascular Event | 13 participants |
p-value: 0.07395% CI: [0.14, 1.13]Log Rank
Secondary
Time to First Suspected Thrombovascular Event
Analysis of time to first suspected thrombovascular event (TVE) measured from the date of randomization to the date of the first suspected TVE during the study. Median time is non-estimable because of too few events, incidence was reported instead.
Time frame: during the study (randomization through week 26)
Population: All randomized participants who received at least 1 dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Epoetin Alfa QW | Time to First Suspected Thrombovascular Event | 9 participants |
| Epoetin Alfa TIW | Time to First Suspected Thrombovascular Event | 20 participants |
p-value: 0.05495% CI: [0.21, 1.03]Log Rank