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

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.

• Basis (Dietary supplement), also known as nicotinamide riboside (NR) and pterostilbene: NR is a form of vitamin B3; Pterostilbene is a natural dietary compound and the primary antioxidant component of blueberries
• Placebo (Dietary supplement): Placebo capsule(s)

Primary outcomes

• Maximum plasma concentration [Cmax] of NR [2 days]: Maximum plasma concentration \[Cmax\] of NR after oral administration of Basis
• Maximum plasma concentration [Cmax] of pterostilbene [2 days]: Maximum plasma concentration \[Cmax\] of pterostilbene after oral administration of Basis
• Area Under the Curve [AUC] of NR [2 days]: Area Under the Curve \[AUC\] of NR after oral administration of Basis
• Area Under the Curve [AUC] of pterostilbene [2 days]: Area Under the Curve \[AUC\] of pterostilbene after oral administration of Basis
• Incidence of Treatment-Emergent Adverse Events (Safety) [2 days]: 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
• Incidence of Treatment-Emergent Laboratory Abnormalities (Safety) [2 days]: comprehensive metabolic panel (including liver function tests), complete blood count

Secondary outcomes

• NAD+ levels [2 days]: To determine the increase in NAD+ levels in white blood cells (WBCs) following twice daily Basis administration
• Dose finding for 50% increase in NAD+ levels in WBCs [2 days]: Dose of Basis that leads to 50% increase in NAD+ levels in WBC
• Dose finding for 100% increase in NAD+ levels in WBCs [2 days]: Dose of Basis that leads to 100% increase in NAD+ levels in WBC

Sex: All, ages: 18 Years to any

Inclusion Criteria:

1. Male or female hospitalized patients, age ≥ 18 years.
2. 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).
3. Adequate hematological and liver function, as assessed by the following laboratory requirements:

   1. Hemoglobin ≥10.0 g/dL
   2. Absolute neutrophil count (ANC) ≥1,500/mm3
   3. Platelet count 100,000/mm3
   4. Total bilirubin ≤1.5 x upper limit of normal (ULN).
   5. ALT and AST ≤2.5 x ULN.
4. Able to provide written informed consent in compliance with the Human Investigation Review Committee (IRB).

Exclusion Criteria:

1. Exposure to any investigational agent within 30 days prior to enrollment.
2. Known allergy to any of the study drugs or their excipients.
3. Currently pregnant (confirmed with a positive serum pregnancy test) or nursing.
4. 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.
5. 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
6. 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.

• Results publication: Simic P, Vela Parada XF, Parikh SM, Dellinger R, Guarente LP, Rhee EP. Nicotinamide riboside with pterostilbene (NRPT) increases NAD+ in patients with acute kidney injury (AKI): a randomized, double-blind, placebo-controlled, stepwise safety study of escalating doses of NRPT in patients with AKI. BMC Nephrol. 2020 Aug 13;21(1):342. doi: 10.1186/s12882-020-02006-1. PMID 32791973

• Eugene Rhee, MD, Principal investigator, Massachusetts General Hospital