Co-primary (tested in parallel for non-inferiority):-To compare daprodustat to darbepoetin alfa for CV safety (non-inferiority)-To compare daprodustat to darbepoetin alfa for Hgb efficacy(non-inferiority)
ID
Source
Brief title
Condition
- Renal disorders (excl nephropathies)
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
- Time to first occurrence of adjudicated major adverse cardiovascular event
(MACE) [composite of all-cause mortality, non-fatal myocardial infarction (MI)
and non-fatal stroke]
- Mean change in Hgb between baseline and evaluation period (EP, mean over
Weeks 28 to 52)
Secondary outcome
Time to first occurrence of adjudicated
-MACE
-MACE or a thromboembolic event (vascular access thrombosis, deep vein
thrombosis or pulmonary embolism)
-MACE or a hospitalization for heart failure (HF)
Time to progression of CKD
Veiligheid:
-Incidence and severity of AEs and serious adverse events (SAEs) including AEs
of special interest
-Reasons for discontinuation of randomized treatment
-Absolute values and changes from baseline
Background summary
Daprodustat (GSK1278863) is a hypoxia-inducible factor prolyl hydroxylase
inhibitor (HIF-PHI) currently being investigated as a treatment for anemia
associated with CKD in both dialysis and ND subjects, with adequate safety and
efficacy having been demonstrated in clinical trials up to 24 weeks* duration.
Both pre-clinical and clinical data show that daprodustat stimulates
erythropoietin (EPO) production, resulting in increased erythropoiesis and
elevation in Hgb concentrations. These increases in Hgb are achieved with peak
plasma EPO exposures substantially lower than those observed with rhEPOs.
Based on its mechanism of action to stimulate erythropoiesis via inhibition of
HIF-prolyl hydroxylase enzymes, daprodustat is postulated to be associated with
fewer MACE (Major Adverse Cardiovascular Event) by raising Hgb without the
supraphysiologic EPO concentrations associated with rhEPO therapy, thereby
potentially avoiding blood pressure (BP) elevations and other adverse effects
of high EPO levels.
A Phase 2B clinical trial in ND subjects with anemia associated with CKD
demonstrated that daprodustat can correct and maintain Hgb up to 24 weeks, with
minimal effects on plasma EPO concentration. Daprodustat treatment for up to 24
weeks demonstrated an adverse event (AE) profile consistent with the patient
population.
This Phase 3 study will evaluate the safety and the efficacy of daprodustat
compared to darbepoetin alfa for the treatment of anemia associated with CKD in
ND subjects. Both co-primary endpoints must meet non-inferiority of daprodustat
to darbepoetin alfa for the study to be successful and for analyses to progress
to testing principal secondary endpoints. Data from this trial are intended to
support the use of daprodustat for the treatment of anemia associated with CKD
in patients not on dialysis.
Study objective
Co-primary (tested in parallel for non-inferiority):
-To compare daprodustat to darbepoetin alfa for CV safety (non-inferiority)
-To compare daprodustat to darbepoetin alfa for Hgb efficacy(non-inferiority)
Study design
This is a randomized, open-label (sponsor blind), active-controlled,
parallel-group, multi-center, event-driven study in ND subjects with anemia
associated with CKD.
This study will comprise four study periods: a 4-week screening period, a
4-week placebo run-in period, a treatment period, and a follow-up period. Prior
erythropoietin-stimulating agents (ESA1) therapy, if present, continues during
the screening and run-in periods.
The total duration of the study is dependent upon the accumulation of 945
adjudicated first MACE (i.e., it is event-driven) unless review of interim data
by the Independent Data Monitoring Committee (IDMC) recommends bringing the
study to an earlier close.
Subjects will be stratified by region, by whether they are currently using an
ESA, and by participation in the ambulatory blood pressure monitoring (ABPM)
sub-study.
Following stratification, subjects will be randomized 1:1 to receive oral
daprodustat or subcutaneous (SC) darbepoetin alfa.
Both treatment arms (daprodustat and darbepoetin alfa) will follow a protocol-
specified randomized treatment dose adjustment algorithm to achieve and/or
maintain Hgb within the target range of 10-11 g/dL. Dose changes will be made
programmatically by the Interactive Response
Technology (IRT) system for both randomized treatment arms.
To ensure subjects remain iron replete and to minimize the potential for iron
overload during the study, the investigator will follow the iron management
criteria from randomization through the end of the study treatment period.
A rescue algorithm is provided to minimize subjects having an inadequate
response to the treatment for their anemia for an extended period of time and
to enable consistency in the application of rescue therapy across the study.
GSK will provide randomized treatment: daprodustat or darbepoetin alfa.
Intervention
oral daprodustat or subcutaneous (SC) darbepoetin alfa
Study burden and risks
The study drug, the reference drugs and the study procedures have certain risks
and may lead to discomforts.This protocol employs precautions to mitigate known
and potential risks to randomized subjects (please refer to appendix 4). These
include the close monitoring of the patient, close monitoring of Hgb, specific
guidance for dose adjustments and unblinded monitoring of safety data by an
IDMC.
In clinical trials of up to 24 weeks in duration, in subjects with anemia
associated with CKD, daprodustat has been shown to treat Hgb to target range.
Daprodustat may present several important advantages over rhEPO and other ESAs.
It is an oral medication and does not require cold-chain storage as does rhEPO,
thus increasing ease of use for patients and health care providers. After
administration of daprodustat, data suggest that the increases in Hgb are
achieved with EPO exposure lower than those observed with rhEPO. Treatment of
anemia of CKD with rhEPO is associated with increased CV risk which is
postulated to be related to the associated increases in EPO exposure with
rhEPO; therefore, daprodustat has the potential to raise Hgb without the same
CV risk associated with rhEPO. Other potential benefits include possibly
improving iron availability for erythropoiesis, the potential to successfully
treat rhEPO hyporesponders, and the potential to treat anemia without causing
rhEPO-induced hypertension.
Given these precautions, as well as the potential benefit that daprodustat
holds for the treatment of anemia associated with CKD compared to the current
standard, the overall benefit risk balance is considered to be positive.
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Listed location countries
Age
Inclusion criteria
A subject will be eligible for inclusion in this study only if all of the
following criteria apply at screening (Week -8) and randomization (Day 1),
unless otherwise specified. , 1.Age (confirm at screening only): 18 to 99
years of age (inclusive). , 2.CKD stage (confirm at screening only): Kidney
Disease Outcomes Quality Initiative (KDOQI) CKD stages 3, 4, or 5 defined by
eGFR using the CKD Epidemiology Collaboration (CKD-EPI) formula [Levey, 2009].,
3.ESAs: , *Group 1 (not using ESAs): No ESA use within the 6 weeks prior to
screening and no ESA use between screening and randomization (Day 1)., *Group 2
(ESA users): Use of any approved ESA (see footnote in protocol) for the 6 weeks
prior to screening and continuing between screening and randomization.,
4.HemoCue Hgb (range is specified in protocol): Hgb defined by ESA use,
5.Compliance with placebo [randomization (Day 1) only]: *80% and *120%
compliance with placebo during run-in period (NOTE: for ESA users, this is in
addition to ESA treatment)., 6.Informed consent (screening only): capable of
giving signed informed consent which includes compliance with the requirements
and restrictions listed in the consent form and in this protocol.
Exclusion criteria
A subject will not be eligible for inclusion in this study if any of the
following criteria apply at screening (Week -8) and randomization (Day 1),
unless otherwise specified. , CKD related criteria, 1.Dialysis: On dialysis
or clinical evidence of impending need to initiate dialysis within 90 days
after study start (Day 1)., 2.Kidney transplant: Planned living-related or
living-unrelated kidney transplant within 52 weeks after study start (Day 1).,
Anemia-related criteria, 3.Ferritin (screening only): *100 ng/mL (*100 ug/L).,
4.Transferrin saturation (TSAT) (screening only): *20%. If the laboratory
report indicates TSAT is 18-20%, then up to two retests can be obtained using a
new blood sample. These retests may occur during screening and run-in up to two
weeks prior to anticipated randomization (Day 1); the final retest value must
be >20% to confirm eligibility., 5.Aplasias: History of bone marrow aplasia or
pure red cell aplasia., 6.Other causes of anemia: Untreated pernicious anemia,
thalassemia major, sickle cell disease or myelodysplastic syndrome.,
7.Gastrointestinal (GI) bleeding: Evidence of actively bleeding gastric,
duodenal, or esophageal ulcer disease OR clinically significant GI bleeding *4
weeks prior to screening through to randomization (Day 1)., CV disease-related
criteria, 8.MI or acute coronary syndrome: *4 weeks prior to screening through
to randomization (Day 1)., 9.Stroke or transient ischemic attack: *4 weeks
prior to screening through to randomization (Day 1)., 10.Heart failure (HF):
Chronic Class IV HF, as defined by the New York Heart Association (NYHA)
functional classification system., 11.Current uncontrolled hypertension:
Current uncontrolled hypertension as determined by the investigator., 12.QTcB
(Day 1): QTcB >500 msec, or QTcB >530 msec in subjects with bundle branch
block. There is no QTc exclusion for subjects with a predominantly ventricular
paced rhythm., Other disease-related criteria, 13.Liver disease: (any one of
the following): , *Alanine transaminase (ALT) >2x upper limit of normal
(ULN) (screening only)., *Bilirubin >1.5xULN (screening only)., NOTE:
Isolated bilirubin >1.5xULN is acceptable if bilirubin is fractionated and
direct bilirubin <35%., *Current unstable liver or biliary disease per
investigator assessment, generally defined by the presence of ascites,
encephalopathy, coagulopathy, hypoalbuminaemia, esophageal or gastric varices,
persistent jaundice, or cirrhosis., NOTE: Stable chronic liver disease
(including asymptomatic gallstones, chronic hepatitis B or C, or Gilbert*s
syndrome) are acceptable if subject otherwise meets entry criteria.,
14.Malignancy: History of malignancy within the 2 years prior to screening
through to randomization (Day 1) or currently receiving treatment for cancer,
or complex kidney cyst (e.g. Bosniak Category II F, III or IV) > 3cm. Note:
The only exception is localized squamous cell or basal cell carcinoma of the
skin that has been definitively treated 4 weeks prior to screening.,
Concomitant medication and other randomized treatment-related criteria,
15.Severe allergic reactions: History of severe allergic or anaphylactic
reactions or hypersensitivity to excipients in the investigational product
(refer to daprodustat IB) or darbepoetin alfa (refer to product labeling). ,
16.Drugs and supplements: Use of strong inhibitors of CYP2C8 (e.g.,
gemfibrozil) or strong inducers of CYP2C8 (e.g., rifampin/rifampicin).,
17.Other study participation: Use of other investigational agent or device
prior to screening through to randomization (Day 1).
*Note: at screening, this exclusion applies to use of the investigational agent
within 30 days or within five half lives (whichever is longer)., 18.Prior
treatment with daprodustat: Any prior treatment with daprodustat for a
treatment duration of >30 days., General health-related criteria, 19.Females
ONLY: Subject is pregnant [as confirmed by a positive urine human chorionic
gonadotrophin (hCG) test for females of reproductive potential (FRP) only],
subject is breastfeeding, or subject is of reproductive potential and does not
agree to follow one of the contraceptive options listed in the List of Highly
Effective Methods for Avoiding Pregnancy in Appendix 5. , 20.Other
Conditions: Any other condition, clinical or laboratory abnormality, or
examination finding that the investigator considers would put the subject at
unacceptable risk, which may affect study compliance (e.g., intolerance to
darbepoetin alfa) or prevent understanding of the aims or investigational
procedures or possible consequences of the study.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2016-000542-65-NL |
| ClinicalTrials.gov | NCT02876835 |
| CCMO | NL58802.056.16 |