Chronic Renal Disease, Renal Anemia
Conditions
Keywords
Hypoxia inducible factor prolyl hydroxylase inhibitor., Erythropoietin stimulating agent, Chronic renal disease, renal anemia
Brief summary
DS-1093a is an inhibitor of hypoxia-inducible factor prolyl hydroxylases, and is expected to produce transient dose / exposure dependent increases in erythropoietin levels in subjects with chronic kidney disease (CKD). This study will be conducted in 2 parts. Part A will involve subjects with stage 3b or 4 CKD, and will be an open, non-controlled parallel group investigation of three single doses of DS-1093a (6 subjects/dose), in which allocation to dose will be randomised. On completion of this part of the study an optional fourth dose may be tested to gain a more complete understanding of the PK/PD behaviour of DS-1093a. Part B will be an open, non-controlled investigation of a single dose of DS-1093a in CKD subjects (n=6) receiving haemodialysis. The dose for Part B will be determined based on the data from Part A.
Interventions
DRUGDS-1093a
DS-1093a, single oral doses up to 50 mg
Sponsors
PRA Health Sciences
Daiichi Sankyo
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
BASIC_SCIENCE
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
* Male and female patients aged 18 - 70 years (inclusive). * Female patients must be of non-childbearing potential (post-menopause or surgical sterilization). In women younger than 60 years a follicle-stimulating hormone (FSH) test will be conducted to confirm post-menopausal status (i.e., FSH ≥ 30 mU/mL). * Part A: CKD stage 3b (eGFR: \< 45 to ≥ 30 mL/min) or stage 4 (eGFR: \< 30 to ≥ 15 mL/min). The CKD-EPI equation will be used for the eGFR estimation. * Part B: Patients on chronic haemodialysis for at least 6 months and stable Hb levels (i.e., +/- 1 g/dL) for the last 6 months. * Patient can be washed out from ESAs for at least 3 weeks (2 weeks prior to dosing and 1 week post-dose). * Baseline Hb level ≥10 g/dL. * Willingness to give written consent to participate after reading the ICF, and after having the opportunity to discuss the trial with the Investigator or his delegate. * Male patients must be willing to use a reliable method of contraception during the trial, and for 4 months afterwards
Exclusion criteria
* Use of ESAs within 2 weeks prior to dosing. * Uncontrolled hypertension despite optimal medical therapy, defined as \> 160/100 mmHg after 10 minutes of rest at screening, and \> 180/110 mmHg after 10 minutes of rest on Day -1 pre-dose. * Known haemoglobinopathy. * Acute renal failure (as judged by the Investigator). * History of kidney transplant regardless of functionality. * Start of any new medication or any changes to a current dosage within 7 days prior to study drug administration. * Chronic liver disease. * Positive hepatitis B surface antigen (HBsAg) or hepatitis C virus (HCV) antibody test. * Positive test for human immunodeficiency virus (HIV)-1 or HIV-2. * A history of gastrointestinal bleeding. * History of a thrombotic event (e.g., myocardial infarction, stroke or transient ischemic attack, peripheral embolism, venous thromboembolism, etc.) * Patients with poorly controlled diabetes despite optimal medical therapy. * A history of cancer, except basal cell skin cancer, squamous cell skin cancer, or cervical cancer (if judged by the Investigator to be in full remission). * Hypersensitivity to any components of the study drug. * Requirement for any concomitant medication that cannot be withheld on Day 1 until 4 hours post-dose (insulin is allowed to cover the breakfast, if necessary). * Clinically relevant abnormal medical history, physical findings, ECG, or laboratory values at the screening assessments that could interfere with the objectives of the trial or the safety of the patient. * Participation in another investigational drug trial within 30 days prior to dosing (or 5 times the half-life of the drug, whichever is longer) or exposure to more than three new investigational agents within 12 months prior to enrolment. * Abuse of drugs or alcohol during the 2 years before the first dose of trial medication. * Ingestion of alcohol within 72 hours prior to dosing and during confinement. Outside the in-house period, regular alcohol consumption must not exceed 16 units for males and 7 units for females per week (1 unit equals 340 mL of beer, 115 mL of wine or 43 mL of spirits). * Positive drug screen (if not due to concomitant medication) or alcohol breath test at screening and/or Day -1. * Patients who smoke more than 10 cigarettes per day (or equivalent), and who would not be able to abstain from smoking during the in-house period. * Concomitant use of medications known to affect the elimination of serum creatinine (e.g., trimethoprim or cimetidine) and competitors of renal tubular secretion (e.g., probenecid) within 30 days before dosing. * Use of a strong inducer or inhibitor of CYP enzymes, during the 30 days before dosing. * Use of any other prohibited medication. * Loss of more than 400 mL blood, or donation of blood, plasma, platelets, or any other blood components, during the 3 months before the trial, or unwilling to abstain from donating during the study and for 3 months after receipt of the final dose of trial medication. * Possibility that the patient will not cooperate with the requirements of the protocol
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in serum erythropoietin concentrations | 6 days | Change in serum erythropoietin concentrations compared to baseline, and derived EPO parameters, up to 6 days post-dose |
| Plasma concentrations of DS-1093a | 28 days | Plasma concentrations of DS-1093a and derived PK parameters up to 28 days post-dose. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change from baseline for composite haematology parameters | 28 days | Change from baseline for haematology parameters (reticulocyte count, haemoglobin concentration, haematocrit, red blood cell count) up to 28 days post-dose. |
| Change from baseline for composite iron metabolism parameters | 7 days | Change from baseline for iron metabolism parameters (serum concentrations of iron, transferrin, transferrin saturation, hepcidin-25) up to 7 days post-dose. |
| Change from baseline for serum concentrations of vascular endothelial growth factor | 7 days | Change from baseline for serum concentrations of vascular endothelial growth factor up to 7 days post-dose |
| Number and severity of adverse events | 28 days | Safety and tolerability up to 28 days post-dose |
Countries
Czechia, Hungary
Outcome results
None listed