| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| anemia associated with chronic kidney disease |
|
| E.1.1.1 | Medical condition in easily understood language |
| anemia associated with chronic kidney disease |
|
| E.1.1.2 | Therapeutic area | Body processes [G] - Physiological processes [G07] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10064848 |
| E.1.2 | Term | Chronic kidney disease |
| E.1.2 | System Organ Class | 10038359 - Renal and urinary disorders |
|
| 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 effect of daprodustat to darbepoetin alfa on endothelial function |
|
| E.2.2 | Secondary objectives of the trial |
-To further compare the effect of daprodustat to darbepoetin alfa on endothelial function
-To compare the effect of daprodustat to darbepoetin alfa on endothelium-independent vasodilation
-To compare the effect of daprodustat to darbepoetin alfa on basal endothelial NO synthesis
-To compare the effect of daprodustat on the FBF response to acetylcholine, sodium nitroprusside and L-NMMA between Day 42 and Day 1
-To compare the effect of darbepoetin alfa on the FBF response to acetylcholine, sodium nitroprusside and L-NMMA between Day 42 and Day 1
-To compare the effect of daprodustat to darbepoetin alfa on vascular compliance
-Assess safety and tolerability |
|
| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Non-Contact, Optical Forearm Plethysmography (NC-OFP) Sub-Study
To compare FBF measurements between noncontact plethysmography and strain-guage plethysmography
Please see Appendix 8 of the study protocol |
|
| E.3 | Principal inclusion criteria |
Age
1. Participant must be at least 18 years of age inclusive, at the time of signing the
informed consent.
Type of Participant and Disease Characteristics
2. Participants who are Stage 3, 4 or 5 CKD defined by eGFR using the CKD Epidemiology Collaboration (CKD-EPI) formula (Levey, 2009).
3. Hgb as measured by HemoCue at screening visit and Day 1 is ≤ 11.0 g/dL (≤ 110 g/L).
4. Palpable brachial artery as assessed at screening.
5. Participants,if necessary, may be on stable maintenance oral iron supplementation supplementation(<50% change in overall dose and compliance of 80% of prescribed doses in the 4 weeks prior to and including the screening period). If participants have been on intravenous (IV) iron, then participants will not have received IV iron for 4 weeks prior to the Day 1 visit.
Sex
6. Male or female
a. Female participants:
A female participant is eligible to participate if she is not pregnant (see Appendix 5 of the study protocol), not breastfeeding, and at least one of the following conditions applies:
(i) Not a woman of childbearing potential (WOCBP) as defined in Appendix 5 of the study protocol
OR
(ii) A WOCBP who has been on an approved form of contraceptive as defined in
Appendix 5 of the study protocol for the 4 weeks prior to Day 1 and agrees to follow the contraceptive guidance in Appendix 5 until the follow-up visit.
Informed Consent
7. Capable of giving signed informed consent as described in Appendix 3 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 |
Medical Conditions
1. On dialysis or clinical evidence of impending need to initiate dialysis within 12
weeks of Day 1.
2. Planned kidney transplant within 12 weeks of Day 1.
3. Presence of an arteriovenous (AV) fistula.
Prior/Concomitant Therapy
4. rhEPO use within the 12 weeks prior to the screening visit and through Day 1.
5. History of severe allergic or anaphylactic reactions or hypersensitivity to the study treatment or challenge agents, or excipients in the study treatments or challenge agents (see daprodustat IB for list of excipients, and the Study Reference Manual (SRM) for product sheets for darbepoetin alfa and the challenge agents).
6. Planned use of any prescription or non-prescription drugs or dietary supplements that are prohibited from screening until all assessments on Day 42 have been successfully completed (see Section 7.7.2 of the study protocol).
Prior/Concurrent Clinical Study Experience
7. The participant has participated in a clinical trial and has received an experimental investigational product within the prior 30 days or within 5 half lives of the investigational product (whichever is longer) prior to screening and through Day 1.
Diagnostic assessments
8. At or below the lower limit of the reference range at screening for Vitamin B12 (may rescreen in a minimum of 8 weeks).
9. Ferritin ≤ 50 ng/mL (≤ 50 μg/L) at screening.
10. Transferrin saturation (TSAT) ≤ 15% (0.15) at screening.
11. Folate < 2.0 ng/mL (4.5 nmol/L; may rescreen in a minimum of 8 weeks) at
screening.
12. High sensitivity C-reactive protein (hs-CRP) ≥ 50 μg/(≥ 50 mg/L) at screening.
Other Exclusions
13. Myocardial infarction or acute coronary syndrome ≤ 12 weeks prior to screening and through Day 1.
14. Hospitalization for greater than 24 hours ≤ 12 weeks prior to screening and through Day 1.
15. Stroke or transient ischemic attack ≤ 12 weeks prior to screening and through Day 1.
16. Class IV heart failure, as defined by the New York Heart Association (NYHA)
functional classification system.
17. Resting systolic blood pressure > 170 mmHg or diastolic blood pressure > 100 mmHg at screening visit or current uncontrolled hypertension as determined by the investigator.
18. QT interval corrected for heart rate using Bazett’s formula (QTcB): QTcB >500 msec, or QTcB >530 msec in participants with bundle branch block. There is
no QTc exclusion for participants with a predominantly ventricular paced rhythm.
19. Active chronic inflammatory disease that could impact erythropoiesis. A partial list can be found in the Study Reference Manual (SRM).
20. History of bone marrow aplasia or pure red cell aplasia.
21. Conditions, other than anemia of CKD, which can affect erythropoiesis. A partial list can be found in the SRM.
22. Evidence of actively bleeding gastric, duodenal, or esophageal ulcer disease OR
clinically significant GI bleeding from ≤ 8 weeks prior to screening and through Day 1.
23. Liver disease (any of the following):
-Alanine transaminase (ALT) > 2x upper limit of normal (ULN; screening only)
-Bilirubin > 1.5x ULN (screening only)
NOTE: Isolated bilirubin > 1.5 x ULN is acceptable if bilirubin is fractionated
and direct bilirubin < 35%
-Current or chronic history of liver disease, or known hepatic or biliary
abnormalities (with the exception of Gilbert's syndrome or asymptomatic
gallstones).
24. Major surgery within the 12 weeks prior to screening and through Day 1, or planned during the study.
25. Anticipated or planned vascular access surgery (i.e., AV fistula) within the 12 weeks prior to screening and through the Day 42 assessments.
26. Received a tissue heart valve replacement or repair within the 6 months prior to screening or has received a mechanical heart valve replacement.
27. Blood transfusion within 6 weeks prior to screening and through Day 1, or an
anticipated need for blood transfusion during the study.
28. Clinical evidence of an acute infection, or history of infection requiring IV antibiotic therapy from 8 weeks prior to screening and through Day 1.
NOTE: Prophylactic oral antibiotics are allowed.
29. History of malignancy within the two years prior to screening and through Day 1 or currently receiving treatment for cancer, with the exception of localized squamous cell or basal cell carcinoma of the skin definitively treated 12 weeks prior to Day 1.
30. Platelet count < 50,000/μL.(<50 GI/L)
31. History of a bleeding disorder (e.g., hemophilia).
32. 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. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Change in FBF ratio from Day 1 to Day 42 in response to acetylcholine |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Day 1 and Day 42 of treatment period |
|
| E.5.2 | Secondary end point(s) |
-Change in the absolute FBF from Day 1 to Day 42 in response to
acetylcholine
-Change in FBF ratio from Day 1 to 42 in response to sodium
nitroprusside
-Change in the absolute FBF from Day 1 to Day 42 in response to sodium nitroprusside
-Change in FBF ratio from Day 1 to Day 42 in response to L-NMMA
-Change in the absolute FBF from Day 1 to Day 42 in response to LNMMA
-Change in FBF ratio in response to each individual challenge agent at Day 42 vs Day 1 in participants treated with daprodustat
-Change in the absolute FBF in response to each individual challenge agent at Day 42 vs Day 1 in participants treated with daprodustat
-Change in FBF ratio in response to each individual challenge agent at
Day 42 vs Day 1 in participants treated with darbepoetin alfa
-Change in the absolute FBF in response to each individual challenge agent at Day 42 vs Day 1 in participants treated with darbepoetin alfa
-Change in Augmentation Index (an indicator of arterial stiffness) as estimated by radial arterial pulse contours from Day 1 to 42
-Change in pulse wave velocity (PWV) from Day 1 to Day 42 (AEs) and serious adverse events (SAEs) including AEs of special interest
-Reasons for discontinuation of randomized study treatment
-Absolute values and changes from baseline in clinical laboratory
parameters, ECG parameters, blood pressure (BP) and heart rate (HR) |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Day 1 and Day 42 of treatment period |
|
| 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 | No |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | Yes |
| 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 | No |
| 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) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| 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 | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| 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) | Yes |
| E.8.2.2 | Placebo | No |
| 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 | 4 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | No |
| 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 | 0 |
| 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 | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
Print
