pilot pk/pd study of ds-1093a in patients with chronic kidney disease

Conditions: Chronic Renal Disease; Renal Anemia

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.


Eligibility criteria:
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

Keywords: hypoxia inducible factor prolyl hydroxylase inhibitor. erythropoietin stimulating agent chronic renal disease renal anemia