Pharmacokinetics, Pharmacodynamics and Safety of Basis in Acute Kidney Injury Study

Study Overview
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Brief Summary
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This study will determine the pharmacokinetics, pharmacodynamics and safety of escalating doses of Basis following twice daily oral administration in patients with acute kidney injury (AKI). Basis is a commercially available nutritional supplement consisting of nicotinamide riboside (NR) and pterostilbene that acts to increase sirtuin activity.

Detailed Description
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Acute kidney injury (AKI) is common, growing in incidence, and associated with significant morbidity and mortality. Sirtuins are anti-aging enzymes that play a diverse role in cellular energy metabolism and gene regulation. Mice deficient in SIRT1 are more susceptible to developing AKI and sirtuin activation is a potential treatment for AKI. This is a randomized, double-blind, placebo-controlled, stepwise study of escalating doses of Basis (NR/pterostilbene) in patients with AKI. The study will potentially comprise up to four Steps. The purpose of the stepwise approach is to identify the dose of Basis that achieves at least a 50% and up to 100% increase in white blood cell (WBC) content of nicotinamide adenine dinucleotide (NAD+) without side-effects. During each Step, Basis (5 patients) or placebo (1 patient) will be given twice a day for 2 days. Patients will have frequent blood sampling performed for a 24 hour period following dosing on Day 1 and then at 48 hr. The measurements in blood will include NR/pterostilbene blood concentrations and NAD+ and NAAD (nicotinic acid adenine dinucleotide) concentrations in WBCs.

Official Title
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Randomized, Double-blind, Placebo-controlled, Stepwise Study of the Pharmacokinetics, Pharmacodynamics & Safety of Escalating Doses of Basis (Nicotinamide Riboside and Pterostilbene) in Patients With Acute Kidney Injury (AKI)

Conditions
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Acute Kidney Injury

Intervention / Treatment
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* Dietary Supplement: Basis
* Dietary Supplement: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female hospitalized patients, age ≥ 18 years. Patients who have developed AKI (defined by an increase in serum creatinine by ≥0.3 mg/dL within 48 hours; or an increase in serum creatinine to ≥1.5 times baseline, which is known or presumed to have occurred within the prior seven days). Adequate hematological and liver function, as assessed by the following laboratory requirements: Hemoglobin ≥10.0 g/dL Absolute neutrophil count (ANC) ≥1,500/mm3 Platelet count 100,000/mm3 Total bilirubin ≤1.5 x upper limit of normal (ULN). ALT and AST ≤2.5 x ULN. Able to provide written informed consent in compliance with the Human Investigation Review Committee (IRB). Exclusion Criteria: Exposure to any investigational agent within 30 days prior to enrollment. Known allergy to any of the study drugs or their excipients. Currently pregnant (confirmed with a positive serum pregnancy test) or nursing. Unstable or clinically significant concurrent medical condition, psychiatric illness or social situation that would, in the opinion of the investigator, jeopardize the safety of a subject and/or their compliance with the protocol. Baseline CKD stage 4-5 (eGFR<30 mL/minute/1.73 m2 as determined using the Modification of Diet in Renal Disease (MDRD) equation; in cases where the MDRD equation may not be suitable, a 24 hour urine creatinine clearance test may be substituted), prior to current hospitalization Any malignancy with the exception of cervical carcinoma in situ,nonmelanoma skin cancer, or superficial bladder tumors that have been successfully and curatively treated with no evidence of recurrent or residual disease.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Randomized 5 subjects in active arm (Basis) : 1 subject in control (placebo)
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Basis<br>Nicotinamide riboside (NR) and pterostilbene oral capsules 250mg/50mg (Step 1) twice daily for 2 days. If the study progresses to Steps 2, 3, and 4, then 2x, 3x, and 4x the doses in Step 1 will be administered. | Dietary Supplement: Basis<br>* NR is a form of vitamin B3; Pterostilbene is a natural dietary compound and the primary antioxidant component of blueberries<br>* Other names: nicotinamide riboside (NR) and pterostilbene;|
| Placebo Comparator: Placebo<br>Capsules identical in appearance and number to the agent used in Steps 1-4. | Dietary Supplement: Placebo<br>* Placebo capsule(s)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum plasma concentration [Cmax] of NR | Maximum plasma concentration [Cmax] of NR after oral administration of Basis | 2 days | 
| Maximum plasma concentration [Cmax] of pterostilbene | Maximum plasma concentration [Cmax] of pterostilbene after oral administration of Basis | 2 days | 
| Area Under the Curve [AUC] of NR | Area Under the Curve [AUC] of NR after oral administration of Basis | 2 days | 
| Area Under the Curve [AUC] of pterostilbene | Area Under the Curve [AUC] of pterostilbene after oral administration of Basis | 2 days | 
| Incidence of Treatment-Emergent Adverse Events (Safety) | Subjects will be interviewed to determine onset of nausea, abdominal pain, vomiting, diarrhea, or rash. Adverse events will be characterized as probably related, probably not related, or unknown | 2 days | 
| Incidence of Treatment-Emergent Laboratory Abnormalities (Safety) | comprehensive metabolic panel (including liver function tests), complete blood count | 2 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| NAD+ levels | To determine the increase in NAD+ levels in white blood cells (WBCs) following twice daily Basis administration | 2 days | 
| Dose finding for 50% increase in NAD+ levels in WBCs | Dose of Basis that leads to 50% increase in NAD+ levels in WBC | 2 days | 
| Dose finding for 100% increase in NAD+ levels in WBCs | Dose of Basis that leads to 100% increase in NAD+ levels in WBC | 2 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Pharmacokinetics, Pharmacodynamics