Study to Compare Safety and Tolerability of AKST1210 Column at 2 Blood Flow Rates in Subjects With ESRD on Hemodialysis

An Open Label Phase 1 Study to Compare the Safety and Tolerability of the AKST1210 Column at Different Blood-Flow Rates in Patients With End-Stage Renal Disease (ESRD) Undergoing Hemodialysis (HD)

This study is to evaluate the safety and tolerability of the AKST1210 column at blood-flow rates greater than 250 mL/min in subjects with end-stage renal disease (ESRD) undergoing hemodialysis (HD). The study will assess the safety, tolerability, and impact on HD parameters when the AKST1210 column is used at a blood-flow of up to 450 mL/min.

This is an open-label study in approximately 12 to 15 subjects between 40 and 75 years of age with ESRD on HD. The objective of this study is to explore the safety and tolerability of the AKST1210 column at blood-flow rates greater than 250 mL/min in subjects with ESRD undergoing HD. The proposed study will assess the safety, tolerability, and impact on HD parameters when the AKST1210 column is used at a blood-flow rates of up to 450 mL/min. Each participant, per the protocol, will be sequentially treated to each column and blood-flow rate combination.

The incidence of IDH events will be one factor used to determine column size/blood-flow rate escalation/de-escalation as well as discontinuation from the study. The planned duration of subject participation is approximately 12 weeks.

Inclusion Criteria:

1. Males and females aged 40 - 75 years, inclusive.
2. End Stage Renal Disease (ESRD) requiring HD.
3. Dialysis vintage ≥ 24 months.
4. Absence of clinically-relevant residual renal function.
5. Regular Hemodialysis (HD) sessions done at blood-flow rates between 400 and 500 mL/min, and with inter-dialysis intervals of 48 hours or more.
6. Stable health status for at least 4 weeks prior to screening based on medical history, and findings from physical examination, laboratory tests, vital signs, and ECG, as assessed by the investigator.
7. Life expectancy > 6 months (as determined by the investigator).
8. Body mass index (BMI) between 18 and 37 kg/m2, inclusive, with a minimum body weight of 52 kg.
9. Must be on stable doses (> 4 weeks) of all treatments for concomitant diseases (e.g., diabetes, hypertension), but this does not apply to medications for conditions related to ESRD (e.g., medications for calcium and phosphate control, anemia).
10. Must be able to follow the study protocol and receive the treatment in the established timeframe.
11. Must provide a signed and dated informed consent form.

Exclusion Criteria:

1. Patients for whom adequate anticoagulation cannot be achieved, such as those with severe anemia, severe hemorrhagic diathesis, severe gastrointestinal ulcers, or who are receiving anticoagulant medications for any reason other than as required for HD. Use of antiplatelet drugs (e.g., aspirin or clopidogrel) is allowed.

2. Patients for whom extracorporeal circulation therapy is contraindicated, such as those with severe cardiac insufficiency, acute myocardial infarction, severe cardiac arrhythmia, acute seizure disorder, or severe uncontrolled hypertension.

3. Patients with Kt/V < 1.2 during recent 8-week period prior to run-in.

4. History of hypersensitivity to heparin, including heparin-induced thrombocytopenia.

5. History of hypersensitivity to the AKST1210 column or its components.

6. Patients who are not anticipated to be able to tolerate blood-flow rates of 450 mL/min during HD (e.g., new vascular access that cannot be used with 14G or 15G needles).

7. Patients who are at higher risk for intradialytic hypotension (IDH) including:

   1. Medical records indicating the occurrence IDH (SBP < 90 mmHg) in more than 30% of HD sessions during a recent 8-week period prior to run-in;
   2. Patients requiring or expected to require extensive fluid management as determined by the investigator;
   3. Presence of pre-dialysis hypotension, defined as SBP < 90 mmHg and/or diastolic blood pressure (DBP) < 50 mmHg, before any of the last 3 dialysis sessions prior to screening;
   4. Diagnosis of IDH in medical records;
   5. Diagnosis of autonomic dysfunction;
   6. Patients who frequently require a ultrafiltration rate (UFR) above 13 mL/kg/h.

8. Patients who are pregnant or breast-feeding or who are planning to become pregnant. Female subjects must not be pregnant or breastfeeding. Women of childbearing potential (WOCBP) must have a negative serum pregnancy test at screening and prior to start of treatment. WOCBP and men must agree to use highly-effective contraception (Clinical Trial Facilitation Group 2014) prior to study entry. A woman is considered of childbearing potential following menarche and until becoming postmenopausal (no menses for at least 2 years without an alternative cause). Should a woman become pregnant or suspect she is pregnant while she or her male partner is participating in the study, she should inform her treating physician immediately.

9. Clotting disorders.

10. Sickle cell anemia, hereditary spherocytosis, or autoimmune hemolysis.

11. Clinically significant abnormalities on screening ECG including QT interval corrected for heart rate (QTc) using Fridericia's correction formula [QTcF] of ≥ 500 ms in men and ≥ 520 ms in women.

12. Delirium (encephalopathy).

13. Out of range value for complete blood count (CBC), complete metabolic panel, or coagulation that the investigator deems clinically significant.

14. Thyroid stimulating hormone (TSH) below 0.2 or above 6.0 milli-International unit (mIU)/L, and/or clinically-relevant abnormalities in T3 or T4.

15. Hemoglobin level < 9.0 g/dL.

16. Alanine aminotransferase (ALT) and/or aspartate transaminase (AST) > 3 times upper limit of normal.

17. Uncontrolled type 2 diabetes.

18. Concurrent or have recent participation in another interventional clinical trial. Prior clinical trial subjects must have discontinued investigational agents/devices at least 30 days prior to planned first use of the AKST1210 column.

19. History of severe depression/suicidality requiring hospitalization in the last 6 months.

20. Significant drug or alcohol abuse within the past 12 months.

21. Patients planning to receive renal transplantation during the study.

22. Patients with any other condition and/or situation the investigator believes may interfere with the safety of the subject during study participation, study conduct, or interpretation of study data.