E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Anaemia associated with chronic kidney disease |
|
E.1.1.1 | Medical condition in easily understood language |
Anaemia associated with chronic kidney disease |
|
E.1.1.2 | Therapeutic area | Body processes [G] - Physiological processes [G07] |
MedDRA Classification |
E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To compare the efficacy of daprodustat to placebo on mean change in Hgb levels |
|
E.2.2 | Secondary objectives of the trial |
To compare the proportion of participants achieving increases in Hgb when treated with daprodustat versus placebo.
To compare daprodustat to placebo for health related quality-of-life
To compare daprodustat to placebo on additional Hgb endpoints
To compare daprodustat to placebo on the time to rescue
To compare daprodustat to placebo for improving symptoms of anemia of CKD
To compare daprodustat to placebo on the severity and change in symptoms
To compare daprodustat to placebo for improving health related quality-of-life
To compare daprodustat to placebo on improving work productivity and regular daily activity impairment
To compare daprodustat to placebo on improving health status
To compare daprodustat to placebo on BP |
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Age
1. ≥ 18 years of age at the time of signing the informed consent.
Type of Participant and Disease Characteristics
2. CKD: Have CKD, confirmed at screening: Kidney Disease Outcomes Quality
Initiative (KDOQI) CKD stages 3, 4, or 5 defined by Estimated glomerular
filtration rate (eGFR) using the CKD Epidemiology Collaboration (CKD-EPI formula [Levey, 2009].
3. Hgb: Stable HemoCue Hgb from 8.5 to 10.5 at screening visit (Week -4) and
from 8.5 to 10.0 g/dL at randomization (Day 1) (Section 9.1 of the study protocol).
4. IV Iron: Participants may receive up to one IV iron dose within the 8 weeks prior to screening and NO IV iron use between screening visit and randomization (Day 1).
5. Oral Iron: If needed, participant may be on stable maintenance oral iron supplementation. There should be <50% change in overall dose and n change in type of iron prescribed doses in the 4 weeks prior to Day 1 randomization visit.
Sex
6. Male and female participants are eligible. A female participant is eligible to
participate if she is not pregnant (see Section 12.4), not breastfeeding, and at leastone of the following conditions applies:
Not a woman of childbearing potential (WOCBP) as defined in Section
12.4 (Appendix 4) of the study protocol, or
A WOCBP who agrees to follow the contraceptive guidance in
Appendix 4 of the study protocol during the treatment period and for at least 4 weeks after the last dose of study treatment.
Informed Consent
7. Capable of giving signed informed consent as described in Section 12.2
Appendix 2 of the study protocol which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol. |
|
E.4 | Principal exclusion criteria |
CKD Related Criteria
1. Dialysis: On dialysis or clinical evidence of impending need to initiate dialysis
within 180 days after randomization (Day 1).
2. Kidney Transplant: Planned living-related or living-unrelated kidney transplant
within 28 weeks after randomization (Day 1).
Anemia-Related Criteria
3. Transferrin saturation (TSAT) <15% (Screening only)
4. Ferritin <50 ng/mL (Screening only)
5. rhEPO or rhEPO analogues: History of rhEPO or rhEPO analogue use within
the 8 weeks prior to screening and rhEPO use between screening and
randomization (Day 1).
6. Transfusion: History of transfusion within the 8 weeks prior to screening and
transfusion between screening and randomization (Day 1).
7. Aplasias: History of bone marrow aplasia or pure red cell aplasia (PRCA)
8. Other causes of anemia: Megaloblastic anemia(untreated pernicious anemia and folate deficiency), thalassemia major, sickle cell disease or myelodysplastic
syndrome
9. Gastrointestinal (GI) bleeding: Evidence of actively bleeding gastric, duodenal,
or esophageal ulcer disease OR clinically significant GI bleeding ≤ 8 weeks prior
to screening through to randomization (Day 1)
Concomitant medication and other study treatment-related criteria
10. Severe Allergic reaction: History of severe allergic or anaphylactic reactions or
hypersensitivity to excipients in the investigational product.
11. Drugs and supplements: Use of strong inhibitor of CYP2C8 (e.g.,gemfibrozil)
or strong inducers of CYP2C8 (e.g., rifampin/rifampicin).
12. Ferric Citrate: Ferric citrate use within 4 weeks prior to randomization (Day 1)
Prior Clinical Study Experience
13. Other interventional study participation: Use of another investigational agent or screening to randomization (day 1). a Note: at screening this exclusion applies to use of the investigational agent within 30 days or within five half lives (whichever is longer).
14. Prior treatment with daprodustat: Any prior treatment with daprodustat for a
treatment duration of >30 days.
Cardiovascular Disease-Related Criteria
15. MI or acute coronary syndrome: within the 8 weeks prior to screening through to randomization. (Day 1)
16. Stroke or transient ischemic attack: within the 8 weeks prior to screening
through to randomization. (Day 1)
17. Heart failure: Chronic Class IV heart failure, as defined by the New York Heart
Association (NYHA) functional classification system
18. QTcB (Day 1): QTcB >500 msec or QTcB >530 msec in participants with bundle
branch block. There is no QTc exclusion for participants with a predominantly
paced rhythm.
Other Disease Related Criteria
19. Liver Disease-Related Criteria:
Alanine transaminase (ALT) >2x upper limit of normal (ULN) at screening(Week -4).
Bilirubin >1.5xULN at screening (Week -4). 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) is acceptable if participant otherwise meets entry criteria.
20. 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 ≥8 weeks prior to screening.
Other Exclusion
21. Other Conditions: Any other condition, clinical or laboratory abnormality, or
examination finding that the investigator considers would put the participant at
unacceptable risk, which may affect study compliance or prevent understanding of the aims or investigational procedures or possible consequences of the study.
22. Current uncontrolled hypertension: current uncontrolled hypertension as determined by the investigator. |
|
E.5 End points |
E.5.1 | Primary end point(s) |
Mean change in Hgb between baseline and the Evaluation Period(EP, mean over
week 24 to week 28 inclusive) |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
Evaluation period is mean over week 24 to week 28 inclusive |
|
E.5.2 | Secondary end point(s) |
% of participants having a Hgb increase of ≥1.0 g/dL from baseline to EP.
Mean Change in SF-36 Vitality domain between baseline and Week 28
N (%) responders, defined as mean Hgb within range.
% time Hgb in range Mean change in Hgb from baseline.
Time to stopping study treatment due to meeting rescue criteria
Mean change from baseline by domain and overall symptom score on the Chronic Kidney Disease - Anemia
Questionnaire (CKD-AQ) symptom questionnaire
Change from baseline in PGI-S
Mean Change in individual items of the SF-36 Vitality Domain from baseline.
Mean Change in SF-36 Physical Function domain from baseline.
N (%) of patients currently employed on the WPAI-ANS-CPV
Change from baseline in percent and mean hours work time missed on the WPAI-ANS-CPV
Change from baseline in percent impaired (equivalent) on the WPAI-ANS-CPV
Change from baseline in overall percent work impairment (equivalent) on the WPAI-ANS-CPV
Change from baseline in percent activity impairment on the WPAI-ANS-CPV
Change in EQ-5D-5L utility score from baseline.
Change in EQ-VAS score from baseline.
Change from baseline in SBP, DBP, and MAP at week 28
N (%) with at least one BP exacerbation event during the study |
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. from baseline at any post-baseline visit.
2. between baseline and Week 28
|
|
E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | Yes |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 5 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 58 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Argentina |
Australia |
Brazil |
Canada |
France |
Italy |
Korea, Republic of |
Mexico |
Poland |
Romania |
United Kingdom |
United States |
|
E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 2 |
E.8.9.1 | In the Member State concerned months | 9 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 9 |
E.8.9.2 | In all countries concerned by the trial days | 0 |