Co-primary (tested in parallel for non-inferiority):- To compare daprodustat to rhEPO for CV safety (non-inferiority)- To compare daprodustat to rhEPO 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)
Average monthly IV iron dose (mg)/subject to Week 52
Safety:
-Incidence and severity of AEs and serious adverse events (SAEs) including AEs
of special interest
-Reasons for discontinuation of study treatment
-Absolute values and changes from baseline in laboratory parameters, BP and
heart rate (HR)
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 non-dialysis (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 rhEPO.
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 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 dialysis subjects with anemia associated with CKD
demonstrated that daprodustat can 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 in dialysis subjects with anemia associated with CKD will
evaluate the safety and efficacy of daprodustat compared to rhEPO, the current
standard of care, as co-primary endpoints, following switch from ESAs. Both
co-primary endpoints must meet non-inferiority of daprodustat to rhEPO 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 on
dialysis.
Study objective
Co-primary (tested in parallel for non-inferiority):
- To compare daprodustat to rhEPO for CV safety (non-inferiority)
- To compare daprodustat to rhEPO 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 dialysis subjects with
anemia associated with CKD who are currently treated with ESAs2.
- 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
ESA therapy continues during the screening and run-in periods.
- The treatment period consists of :
1. The stabilization period, defined as the period from Day 1 to Week 28 during
which randomized treatment will be dose titrated to achieve the appropriate Hgb
target
2. The maintenance period, defined as the period from the end of the
stabilization period (Week 28) to the end of treatment (variable per subject),
to assess long term safety and efficacy.
o The efficacy evaluation period (EP) is defined as the period from
Week 28 to Week 52 during which Hgb efficacy will primarily be assessed.
- 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 IDMC recommends bringing the study to an earlier close.
- All subjects will remain in the study (including subjects receiving kidney
transplant), regardless of whether they continue with randomized treatment
(unless consent for any further follow up is withdrawn), until the target
number of first adjudicated MACE has occurred. At that point, the sponsor will
notify investigators to have subjects come in for an End of Study visit within
a pre-defined time period.
- Subjects will be stratified by dialysis type [HD or PD], by region, and by
participation in the ABPM sub-study. Dialysis type and region are considered to
be stratification factors that are potentially prognostic of study endpoints
while participation in the ABPM sub-study is an administrative stratification
factor intended solely to ensure a similar number of sub-study subjects in each
of the two randomized groups
-Following stratification, subjects will be randomized 1:1 to receive oral
daprodustat or rhEPO (IV epoetin alfa for HD subjects and SC darbepoetin alfa
for PD subjects). A central randomization approach will be used to protect
against potential selection bias due to the open-label design. The sponsor is
blinded to treatment assignment in the main study and ABPM sub-study.
- Both treatment arms (daprodustat and rhEPO) 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 (Section 6.3.3). 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 (Section 6.12) 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
(Section 6.12).
Intervention
oral daprodustat
or rhEPO [intravenous (IV) epoetin alfa 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. ESAs: Use of any approved ESA for at least the 6 weeks prior to screening
and between screening and randomization.
3. Hgb concentration measured by HemoCue (range is specified in protocol)
4. Dialysis: On dialysis > 90 days prior to screening and continuing on the
same mode of dialysis from screening (Week -8) through to randomization (Day 1).
5. Frequency of Dialysis:
* - HD: *2 times/week
* - PD: * 5 times/week
* - Home HD: (*2times/week)
6. Compliance with placebo [randomization (Day 1) only]: *80% and * 120%
compliance with placebo during run-in period (NOTE: this is in addition to ESA
treatment).
7. 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) or randomization (Day 1),
unless otherwise specified.
CKD related criteria
1. Kidney transplant: Planned living-related or living-unrelated kidney
transplant within 52 weeks after study start (Day 1).
Anemia related criteria
2. Ferritin (screening only): *100 ng/mL (*100 ug/L).
3. Transferrin saturation (TSAT) (screening only): *20%. If TSAT is 18-20%,
then a retest using a new blood sample can be obtained within 7 days of the
final laboratory report; the final retest value must be >20% to confirm
eligibility.
4. Aplasias: History of bone marrow aplasia of pure red cell aplasia.
5. Other causes of anemia: Untreated pernicious anemia, thalassemia major,
sickle cell disease or myelodysplastic syndrome.
6. 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
7. MI or acute coronary syndrome: *4 weeks prior to screening through to
randomization (Day 1).
8. Stroke or transient ischemic attack: *4 weeks prior to screening through to
randomization (Day 1).
9. Heart failure (HF): Chronic Class IV HF, as defined by the New York Heart
Association (NYHA) functional classification system.
10. Current uncontrolled hypertension: Current uncontrolled hypertension as
determined by the investigator that would contraindicate the use of rhEPO.
11. 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
12. 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 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.
13. 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 14.
Severe allergic reactions: History of severe allergic or anaphylactic reactions
or hypersensitivity to excipients in the investigational product
(refer to daprodustat IB), or epoetin alfa or darbepoetin alfa (refer to
product labeling).
15. Drugs and supplements Use of strong inhibitors of CYP2C8 (e.g.,
gemfibrozil) or strong inducers of CYP2C8 (e.g., rifampin/rifampicin).
16. 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).
17. Prior treatment with daprodustat: Any prior treatment with daprodustat for
treatment duration of > 30 days.
General health-related criteria
18. Females ONLY: Subject is pregnant [as confirmed by a positive serum 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 of the protocol.
19. 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
rhEPO) 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 | EUCTR2016-000541-31-NL |
| ClinicalTrials.gov | NCT02879305 |
| CCMO | NL58801.056.16 |