A Phase 2 Prospective, Randomized, Double-Arm, Deferred Treatment, Open Label, Repeat Dose, Safety and Efficacy Sudy of Autologous Neo-Kidney Augment™ (NKA) in Subjects With Type 2 Diabetes and Chronic Kidney Disease
Multi-center, prospective, open-label, randomized, double-arm, deferred treatment study whereby eligible subjects will be randomized 1:1 after kidney biopsy to receive up to 2 injections of NKA (made from expanded autologous selected renal cells) into the biopsied kidney beginning as soon as NKA can be prepared, or the same series of up to 2 injections given 6 months (+4 weeks) apart beginning 12 months after renal biopsy
Based on preclinical data, the dose of NKA will be 3 x 106 cells/g estimated kidney weight (gKWest). Since the concentration of SRC per mL of NKA is 100 x 106 cells/mL, the dosing volume will be 3.0 mL for each 100 g of kidney weight.
Subjects will be randomized (1:1) to the Active Treatment Group or the Deferred Treatment Group following renal biopsy. Subjects in the Active Treatment Group will receive their first NKA injection as soon as the NKA product is manufactured and shipped to the clinical site. After 6 months (+4 weeks), a second injection will be given, as appropriate. In contrast, subjects in the "Deferred Treatment Group" will undergo a period of observation after renal biopsy. During this time, they will receive contemporaneous, standard-of-care therapy for CKD while undergoing follow-up evaluations every 3 months similar to subjects in the Active Treatment Group. After 12 months , subjects from the Deferred Treatment Group will receive a series of up to two NKA injections given 6 months (+4 weeks) apart, as appropriate. Consequently, the study design includes a randomized control group receiving standard-of-care treatment for the first 12 months and a randomized, active treatment group receiving up to two NKA injections and follow-up evaluations during the same period of time. In addition, each subject's baseline rate of renal decline, based on adequate historical, clinical data obtained 18 months prior to NKA injection, will serve as a comparator for monitoring the rate of progression of renal insufficiency over time.
The rate of progression of renal insufficiency for the Active Treatment Group (assessed via serial measurements of eGFR pre-randomization through 24 months after the last NKA injection) will be compared against that of the Deferred Treatment Group (ie, contemporaneous control group). In addition, each subject's baseline rate of eGFR decline (derived from adequate historical, clinical data) will be compared against the individual subject's rate of eGFR decline through 24 months following the final NKA treatment. The rate of progression of renal insufficiency from subjects (if any) who received a single NKA injection may be compared against that from subjects who received two NKA injections.
Subjects will complete the KDQOL survey, which is a kidney-specific measure of health-related quality of life (ie, Kidney Disease and Quality of Life™ [KDQOL™-36] Version 1) and the EQ-5D-5L. Scores from the Active Treatment Group will be compared against scores from the Deferred Treatment Group. Subjects from the Deferred Treatment Group will comprise the contemporaneous control group for the analysis of KDQOL scores. In addition, each subject's baseline scores will be compared against the individual subject's KDQOL scores obtained through 24 months after the last NKA injection. Additionally, KDQOL scores from subjects who received a single NKA injection may be compared against scores from subjects who received two injections.
30 Years to 80 Years
Accepting Healthy Volunteers?
1. The subject is male or female, 30 to 80 years of age on the date of informed consent.
2. The subject has an established diagnosis of T2DM.
3. The subject has an established diagnosis of diabetic nephropathy as the underlying cause of renal disease.
4. The subject has an established diagnosis of CKD not requiring renal dialysis, defined as having an eGFR between 20 and 50 mL/min/1.73m2 inclusive at the Screening Visit and prior to NKA injection.
5. The subject has blood pressure less than 150/90 at the Screening Visit, prior to renal biopsy, and prior to NKA injection(s). At the time of the biopsy and injections, the subject's BP should notbe significantly below the previously recorded stable pressure.
6. The subject has stable blood pressure and is maintained on a stable anti-hypertensive medication regimen, if treatment for hypertension is necessary. If treatment includes an angiotensinconverting-enzyme inhibitor (ACEI) or an angiotensin receptor blocker (ARB), that treatment must have been initiated at least 8 weeks prior to renal biopsy. Treatment must be stable during the 6-week period immediately prior to NKA injection. Stable treatment is defined as dose adjustment to no less than one half of the current dosage or to no more than 2 times the current dosage. Dose interruptions up to 7 days due to medical necessity are allowed.
7. A minimum of 2 measurements of eGFR or sCr should be obtained at least 3 months apart prior to the Screening Visit or within the previous 18 months to define the rate of progression of CKD. The subject should have adequate, historical clinical data to provide a reasonable estimate of the rate of progression of CKD. The Medical Monitor may be consulted to ensure there is sufficient data.
8. The subject is willing and able to refrain from NSAID consumption (including aspirin) as well as clopidogrel, prasugrel, or other platelet inhibitors during the period beginning 7 days before through 7 days after both the renal biopsy and NKA injection(s).
9. The subject is willing and able to refrain from consumption of fish oil and platelet aggregation inhibitors, such as dipryridamole (ie, Persantine®), during the period beginning 7 days before through 7 days after both the renal biopsy and NKA injection(s).
10. The subject is willing and able to cooperate with all aspects of the protocol.
11. The subject is willing and able to provide signed informed consent.
1. The subject has a history of type 1 diabetes mellitus.
2. The subject has a history of renal transplantation.
3. The subject has a serum HbA1c level greater than 10% at the Screening Visit.
4. The subject has uncontrolled diabetes (defined as metabolically unstable by the Investigator).
5. The subject has hemoglobin levels less than 9 g/dL prior to each NKA injection.
6. The subject has abnormal coagulation status as measured by activated partial thromboplastin time (APTT), prothrombin time-international normalized ratio (PT-INR), and/or platelet count at the Screening Visit.
7. The subject has a bleeding disorder(s) or is taking anticoagulants, such as Coumadin® (warfarin) or direct thrombin inhibitors that, in the judgment of the Investigator, would interfere with the performance of study procedures.
8. The subject has small kidneys (average size less than 9 cm) or has only one kidney, as assessed by ultrasound and/or MRI prior to renal biopsy, unless earlier radiology reports (generated within 1 year of the Screening Visit) are made available to confirm kidney size and number.
9. The subject has a known allergy or contraindication(s), or has experienced severe systemicreaction(s) to kanamycin or structurally similar aminoglycoside antibiotic(s)
10. The subject has a history of anaphylactic or severe systemic reaction(s) or contraindication(s) to human blood products or materials of animal origin (eg, bovine, porcine).
11. The subject is not a good candidate to undergo percutaneous NKA injection, in the judgment of the surgeon or physician who will perform the procedure. This includes individuals who are morbidly obese (defined as BMI greater than 45 kg/m2), have excessive fat surrounding the kidney, or who are otherwise at excessive risk for serious complications.
12. The subject has a history of severe systemic reaction(s) or any contraindication to local anesthetics or sedatives.
13. The subject has a clinically significant infection requiring parenteral antibiotics within 6 weeks of NKA injection.
14. The subject has acute kidney injury or has experienced a rapid decline in renal function during the last 3 months prior to NKA injection.
15. The subject has any of the following conditions prior to NKA injection: renal tumors, polycystic kidney disease, anatomic abnormalities that would interfere with the NKA injection procedure or evidence of a urinary tract infection.
16. The subject has incapacitating cardiac and/or pulmonary disorders.
17. The subject has a history of cancer within the past 3 years (excluding non-melanoma skin cancer and carcinoma in situ of the cervix).
18. The subject has clinically significant hepatic disease (ALT or AST greater than 3-times the upper limit of normal) as assessed at the Screening Visit.
19. The subject is positive for active infection with Hepatitis B Virus (HBV), or Hepatitis C Virus (HCV), and/or Human Immunodeficiency Virus (HIV) as assessed at the Screening Visit.
20. The subject has a history of active tuberculosis (TB) requiring treatment within the past 3 years.
21. The subject is immunocompromised or is receiving immunosuppressive agents, including individuals treated for chronic glomerulonephritis within 3 months of NKA injection. Note: inhaled corticosteroids and chronic low-dose corticosteroids (less than or equal to 7.5 mg per day) are permitted as are brief pulsed corticosteroids for intermittent symptoms (eg, asthma).
22. The subject has a life expectancy less than 2 years.
23. The female subject is pregnant, lactating (breast feeding), or planning a pregnancy during the course of the study. Or, the female subject is of child-bearing potential and is not using a highly effective method(s) of birth control, including sexual abstinence. Or, the female subject is unwilling to continue using a highly-effective method of birth control throughout the duration of the study. Note: A highly effective method of birth control is defined as one that results in a low failure rate (ie, less than one percent per year) when used consistently and correctly, such as implants, injectables, combined oral contraceptives, some intrauterine devices IUDs, sexual abstinence, or a vasectomized partner.
24. The subject has a history of active alcohol and/or drug abuse that, in the judgment of the Investigator, would impair the subject's ability to comply with the protocol.
25. The subject's health status would, in the judgment of the Investigator, be jeopardized by participating in the study.
26. The subject has used an investigational product within 3 months prior to NKA injection without receiving written consent from the Medical Monitor.