Anemia in Chronic Kidney Disease Patients Not on Dialysis
Conditions
Keywords
anemia, chronic kidney disease, kidney disease, renal failure
Brief summary
A phase 3, multicenter, randomized, double-blind, parallel group study. Anemic subjects with chronic kidney disease (CKD) and not on dialysis will be randomized 1:1 to 1 of 2 dosing strategies to evaluate the proportion of subjects receiving at least one red blood cell (RBC) transfusion. In the haemoglobin (Hb)-based titration group, darbepoetin alfa doses will be titrated to maintain Hb ≥ 10.0 grams/deciliter (g/dL). In the fixed dose group, subjects will receive a fixed dose of darbepoetin alfa. Treatment group, darbepoetin alfa doses, and protocol specified Hb concentrations will be blinded. Subjects will be followed for approximately 2 years from the date of randomization.
Detailed description
The study is a phase 3, multicenter, randomized, double-blind, parallel group study designed to describe the benefits and potential risks of a new treatment strategy using a fixed dose of darbepoetin alfa in subjects with CKD and not on dialysis. Anemic subjects without recent use of an erythropoiesis stimulating agent (ESA) will be randomly allocated 1:1 to treatment with a fixed dose of darbepoetin alfa or to treatment with darbepoetin alfa using a Hb-based titration strategy, which has been the conventional dosing strategy. In the Hb-based titration group, darbepoetin alfa doses will be titrated to maintain Hb ≥ 10.0 g/dL. This study aims to estimate the incidence of RBC transfusions (administered as deemed clinically necessary) in each group and the difference in incidence of RBC transfusions between the 2 groups. In addition, multiple aspects, such as cumulative darbepoetin alfa dose, total number of units of transfusions, Hb concentration, Hb-related parameters (eg, Hb variability, excursions, rate of change), and adverse (eg, cardiovascular) events, will also be considered in order to determine a preferred dosing regimen. Treatment group, darbepoetin alfa doses, and protocol specified Hb concentrations will be blinded to the investigator, subjects and study team. Subjects will be followed for approximately 2 years from the date of randomization.
Interventions
BIOLOGICALDarbepoetin alfa
Darbepoetin alfa was presented as single use prefilled syringes (PFS). Investigational product was administered SC Q4W for the duration of the treatment period.
OTHERPlacebo
Placebo was presented as single use PFS. Participants received a SC placebo injection in place of darbepoetin alfa therapy when the dose of study drug was withheld per the dosing algorithm for the duration of the treatment period.
Sponsors
Amgen
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: * Clinical history of advanced CKD not on dialysis with at least 1 historic estimated glomerular filtration rate (eGFR) \< 45.0 mL/mi)/1.73 m2 at least 12 weeks prior to screening * Not currently receiving dialysis with an eGFR \< 45.0 mL/min/1.73m2, per the central laboratory during screening * Chronic anemia due to renal failure * Two Hb concentrations \< 10.0 g/dL, at least 2 weeks apart during screening using the modified Hb point of care (POC) device * Iron replete, defined as a transferrin saturation (TSAT) ≥ 20% and a ferritin ≥ 100 ng/mL, per the central laboratory during screening * Vitamin B12 and folate replete, defined as a vitamin B12 level \> 180 pg/mL and a folate concentration \> 7 nmol/L, per the central laboratory during screening * Clinically stable in the opinion of the investigator * Subject has provided written informed consent Key
Exclusion criteria
* Systemic hematologic disease (eg, sickle cell anemia, myelodysplastic syndrome, hematologic malignancy) * Current or prior malignancy within 5 years of screening, with the exception of non-melanoma skin cancers and cervical intraepithelial neoplasia * Treatment for any malignancy (eg, radiation, chemotherapy, hormone therapy, or biologics) within 5 years of screening, with the exception of locally excised non-melanoma skin cancer or cervical intraepithelial neoplasia * Female subject not willing to use highly effective methods of birth control during treatment and for 4 weeks after the end of treatment * Subject is pregnant or breast feeding, or might become pregnant during the study or within 4 weeks after the end of treatment * Currently receiving intravenous (IV) antibiotics for treatment of an active infection * Known Human Immunodeficiency Virus (HIV) positive * Currently receiving systemic immunosuppressive therapy with the exception of prednis(ol)one ≤ 10 mg per day (or the steroid equivalent) * History of any organ transplant * Currently enrolled in another interventional study (eg, studies which require medical device use or drug therapy or with protocol required procedures), or less than 4 weeks since ending another interventional study(s) or receiving investigational agent(s) * Known neutralizing anti-erythropoietic protein antibodies * Known sensitivity to any of the products to be administered during dosing * Previously enrolled in this study * Not expected to be available for protocol required study visits or procedures 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 comply with all required study procedures * Occurrence of stroke or myocardial infarction (MI) within 24 weeks of screening * Receipt of RBC transfusion within 8 weeks of screening * Occurrence of seizure, clinically relevant active bleeding (eg, gastrointestinal \[GI\] bleed) or any hospitalization within 8 weeks of screening * Receipt of any IV iron therapy within 4 weeks of screening * Changes in oral iron therapy within 4 weeks of screening * Receipt of ESA therapy within 4 weeks of screening * Diagnosis or treatment of malignancy, with the exception of non-melanoma skin cancers and cervical intraepithelial neoplasia during screening * Receipt of ESA therapy, RBC transfusions, IV iron therapy during screening * Changes in oral iron therapy during screening * Occurrence of stroke, MI, seizure, clinically relevant active bleeding (eg, GI bleed), any hospitalization or outpatient surgery during screening * Uncontrolled hypertension during screening. Defined in this study, as a mean systolic blood pressure \> 140 mmHg at both screening visits, or a mean systolic blood pressure \>/= 160 mmHg at any screening visit, or a mean diastolic blood pressure \>/= 90 mmHg at any screening visit. * Expected or scheduled change in oral iron therapy or receipt of IV iron therapy within 4 weeks after randomization * Expected or scheduled receipt of a RBC transfusion within 8 weeks after randomization * Expected or scheduled organ transplant within 24 weeks after randomization * Expected or scheduled initiation of dialysis within 24 weeks after randomization
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants in Receipt of 1 or More RBC Transfusions | From randomization until the end of study, up to week 101. | The percentage of participants receiving at least 1 RBC transfusion during the evaluation period was recorded for each treatment group. The evaluation period began from the date of randomization, and participants were censored at the last dose of investigational product plus 3 months or end of study, whichever was earlier (on-treatment approach). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Mean Number of Units of RBC Transfused | From randomization until the end of study, up to week 101. | The total number of units of RBC transfused per participant during the evaluation period was recorded for each treatment group. The evaluation period began from the date of randomization, and participants were censored at the last dose of investigational product plus 3 months or end of study, whichever was earlier (on-treatment approach). The mean total number of RBC units transfused per participant is presented. |
| Time to First RBC Transfusion | From randomization until the end of study, up to week 101. | Time to first RBC transfusion during the evaluation period was recorded for each treatment group. The evaluation period began from the date of randomization, and participants were censored at the last dose of investigational product plus 3 months or end of study, whichever was earlier (on-treatment approach). The time to first RBC transfusion is presented using Kaplan-Meier (KM) estimates at 6, 12, 18, and 24 months. |
| Mean Achieved Hb Concentration While Receiving Investigational Product | From week 13 until the end of study, up to week 101. | Average achieved Hb concentration while receiving investigational product was recorded as mean Hb using the area under the curve (AUC) method for each treatment group. The AUC of Hb was calculated according to the trapezoidal method, standardized as daily AUC. Participants with available Hb values from study day 85 (week 13) to the last dose date were included in the calculation. |
| Geometric Mean Cumulative Dose of Darbepoetin Alfa Per 4 Weeks | From randomization until the end of study, up to week 101. | Cumulative doses of darbepoetin alfa adjusted for investigation product exposure time (e.g. mean cumulative darbepoetin alfa dose per 4 weeks) were calculated for each treatment group using the total cumulative dose during the study divided by total number of weeks dosed then multiplied by 4. The geometric mean cumulative dose is presented. |
Countries
Puerto Rico, United States
Participant flow
Recruitment details
Anemic participants with chronic kidney disease and not on dialysis (CKD-ND) were enrolled at 126 study centers in the United States, from 30 July 2012 to 19 October 2017. The on-study duration was approximately 2 years, comprising of a 2- to 4-week screening period, a 96-week treatment period and a 4-week follow up period.
Pre-assignment details
Participants were randomized in a 1:1 ratio to 1 of 2 darbepoetin alfa dosing strategies (hemoglobin \[Hb\]-based titration group or fixed dose group). Randomization was stratified by red blood cell (RBC) transfusion received within 12 months prior to randomization (yes/no) and site practice setting (nephrology/non-nephrology).
Participants by arm
| Arm | Count |
|---|---|
| Hb-Based Titration Group Participants received darbepoetin alfa as a SC injection, Q4W for up to 96 weeks. The dose of darbepoetin alfa was titrated based on the Hb concentration on the date of the visit, the corresponding Hb ROR, and the previously assigned dose. Doses were reduced if Hb exceeded 10.5 g/dL or Hb ROR exceeded 1.0 g/dL/4W. When darbepoetin alfa therapy was withheld per the dosing algorithm, placebo was administered. The starting dose of darbepoetin alfa was 0.45 mcg/kg and the protocol specified doses ranged from 10 to 300 mcg. | 377 |
| Fixed Dose Group Participants received darbepoetin alfa as a SC injection Q4W at the same dose as assigned at the time of randomization for the duration of the 96-week treatment period. There was 1 exception to the fixed dose strategy: if the Hb was \> 12.0 g/dL, darbepoetin alfa therapy was withheld and placebo administered. Once the Hb fell to \< 10.0 g/dL, darbepoetin alfa therapy resumed at the same dose. The starting dose of darbepoetin alfa was 0.45 mcg/kg and the protocol specified doses ranged from 10 to 300 mcg. | 379 |
| Total | 756 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 36 | 39 |
| Overall Study | Decision by sponsor | 5 | 7 |
| Overall Study | Lost to Follow-up | 28 | 23 |
| Overall Study | Withdrawal by Subject | 76 | 84 |
Baseline characteristics
| Characteristic | Hb-Based Titration Group | Fixed Dose Group | Total |
|---|---|---|---|
| Age, Continuous | 69.2 years STANDARD_DEVIATION 13.5 | 69.5 years STANDARD_DEVIATION 13.1 | 69.4 years STANDARD_DEVIATION 13.3 |
| Age, Customized 18 - 64 years | 129 Participants | 134 Participants | 263 Participants |
| Age, Customized 65 - 74 years | 97 Participants | 96 Participants | 193 Participants |
| Age, Customized 75 - 84 years | 105 Participants | 97 Participants | 202 Participants |
| Age, Customized >=85 years | 46 Participants | 52 Participants | 98 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 92 Participants | 95 Participants | 187 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 285 Participants | 284 Participants | 569 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Previous RBC transfusions No | 232 Participants | 239 Participants | 471 Participants |
| Previous RBC transfusions Yes | 145 Participants | 140 Participants | 285 Participants |
| Race/Ethnicity, Customized American Indian or Alaska Native | 1 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Asian | 25 Participants | 21 Participants | 46 Participants |
| Race/Ethnicity, Customized Black or African American | 125 Participants | 134 Participants | 259 Participants |
| Race/Ethnicity, Customized Mixed race/Other | 1 Participants | 5 Participants | 6 Participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander | 5 Participants | 4 Participants | 9 Participants |
| Race/Ethnicity, Customized White | 220 Participants | 215 Participants | 435 Participants |
| Sex: Female, Male Female | 223 Participants | 218 Participants | 441 Participants |
| Sex: Female, Male Male | 154 Participants | 161 Participants | 315 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 38 / 377 | 38 / 377 |
| other Total, other adverse events | 292 / 377 | 300 / 377 |
| serious Total, serious adverse events | 190 / 377 | 175 / 377 |
Outcome results
Primary
Percentage of Participants in Receipt of 1 or More RBC Transfusions
The percentage of participants receiving at least 1 RBC transfusion during the evaluation period was recorded for each treatment group. The evaluation period began from the date of randomization, and participants were censored at the last dose of investigational product plus 3 months or end of study, whichever was earlier (on-treatment approach).
Time frame: From randomization until the end of study, up to week 101.
Population: The full analysis set included all randomized participants who received at least 1 dose of investigational product.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Hb-Based Titration Group | Percentage of Participants in Receipt of 1 or More RBC Transfusions | 24.40 Percentage of Participants |
| Fixed Dose Group | Percentage of Participants in Receipt of 1 or More RBC Transfusions | 24.14 Percentage of Participants |
95% CI: [-6.39, 5.85]
95% CI: [0.776, 1.285]Cochran-Mantel-Haenszel
Secondary
Geometric Mean Cumulative Dose of Darbepoetin Alfa Per 4 Weeks
Cumulative doses of darbepoetin alfa adjusted for investigation product exposure time (e.g. mean cumulative darbepoetin alfa dose per 4 weeks) were calculated for each treatment group using the total cumulative dose during the study divided by total number of weeks dosed then multiplied by 4. The geometric mean cumulative dose is presented.
Time frame: From randomization until the end of study, up to week 101.
Population: The full analysis set included all randomized participants who received at least 1 dose of investigational product.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Hb-Based Titration Group | Geometric Mean Cumulative Dose of Darbepoetin Alfa Per 4 Weeks | 50.7 mcg | Standard Error 2.7 |
| Fixed Dose Group | Geometric Mean Cumulative Dose of Darbepoetin Alfa Per 4 Weeks | 30.8 mcg | Standard Error 1.2 |
95% CI: [-26.1, -18.1]Hodges-Lehmann estimate
Secondary
Mean Achieved Hb Concentration While Receiving Investigational Product
Average achieved Hb concentration while receiving investigational product was recorded as mean Hb using the area under the curve (AUC) method for each treatment group. The AUC of Hb was calculated according to the trapezoidal method, standardized as daily AUC. Participants with available Hb values from study day 85 (week 13) to the last dose date were included in the calculation.
Time frame: From week 13 until the end of study, up to week 101.
Population: The full analysis set included all randomized participants who received at least 1 dose of investigational product.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Hb-Based Titration Group | Mean Achieved Hb Concentration While Receiving Investigational Product | 9.71 g/dL | Standard Error 0.04 |
| Fixed Dose Group | Mean Achieved Hb Concentration While Receiving Investigational Product | 9.41 g/dL | Standard Error 0.05 |
95% CI: [-0.46, -0.22]Hodges-Lehmann estimate
Secondary
Mean Number of Units of RBC Transfused
The total number of units of RBC transfused per participant during the evaluation period was recorded for each treatment group. The evaluation period began from the date of randomization, and participants were censored at the last dose of investigational product plus 3 months or end of study, whichever was earlier (on-treatment approach). The mean total number of RBC units transfused per participant is presented.
Time frame: From randomization until the end of study, up to week 101.
Population: The full analysis set included all randomized participants who received at least 1 dose of investigational product.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Hb-Based Titration Group | Mean Number of Units of RBC Transfused | 0.71 Units of transfused RBC |
| Fixed Dose Group | Mean Number of Units of RBC Transfused | 0.87 Units of transfused RBC |
95% CI: [0.81, 2.05]Negative binomial regression model
Secondary
Time to First RBC Transfusion
Time to first RBC transfusion during the evaluation period was recorded for each treatment group. The evaluation period began from the date of randomization, and participants were censored at the last dose of investigational product plus 3 months or end of study, whichever was earlier (on-treatment approach). The time to first RBC transfusion is presented using Kaplan-Meier (KM) estimates at 6, 12, 18, and 24 months.
Time frame: From randomization until the end of study, up to week 101.
Population: The full analysis set included all randomized participants who received at least 1 dose of investigational product.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Hb-Based Titration Group | Time to First RBC Transfusion | KM estimates at month 6 | 0.115 Months |
| Hb-Based Titration Group | Time to First RBC Transfusion | KM estimates at month 12 | 0.192 Months |
| Hb-Based Titration Group | Time to First RBC Transfusion | KM estimates at month 18 | 0.261 Months |
| Hb-Based Titration Group | Time to First RBC Transfusion | KM estimates at month 24 | 0.297 Months |
| Fixed Dose Group | Time to First RBC Transfusion | KM estimates at month 24 | 0.289 Months |
| Fixed Dose Group | Time to First RBC Transfusion | KM estimates at month 6 | 0.136 Months |
| Fixed Dose Group | Time to First RBC Transfusion | KM estimates at month 18 | 0.246 Months |
| Fixed Dose Group | Time to First RBC Transfusion | KM estimates at month 12 | 0.204 Months |
95% CI: [0.76, 1.35]Cox Proportional Hazard Model