Clinical trial NCT03176628: Pharmacokinetics, Pharmacodynamics and Safety of Basis in Acute Kidney Injury Study
Official title: 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)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Acute Kidney Injury
Keywords: Pharmacokinetics
Pharmacodynamics
Lead sponsor: Massachusetts General Hospital
Sponsor class: OTHER
Collaborators: name: Elysium Health
First posted: 2017-06-05
Enrollment: 24
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Randomized 5 subjects in active arm (Basis) : 1 subject in control (placebo)
Primary purpose: OTHER

Brief summary: 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: 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.

Eligibility criteria: 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.

Primary outcomes:
measure: Maximum plasma concentration [Cmax] of NR
timeFrame: 2 days
measure: Maximum plasma concentration [Cmax] of pterostilbene
timeFrame: 2 days
measure: Area Under the Curve [AUC] of NR
timeFrame: 2 days
measure: Area Under the Curve [AUC] of pterostilbene
timeFrame: 2 days
measure: Incidence of Treatment-Emergent Adverse Events (Safety)
timeFrame: 2 days
measure: Incidence of Treatment-Emergent Laboratory Abnormalities (Safety)
timeFrame: 2 days
Secondary outcomes:
measure: NAD+ levels
timeFrame: 2 days
measure: Dose finding for 50% increase in NAD+ levels in WBCs
timeFrame: 2 days
measure: Dose finding for 100% increase in NAD+ levels in WBCs
timeFrame: 2 days
Other outcomes:
Locations:
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
Study officials:
affiliation: Massachusetts General Hospital
name: Eugene Rhee, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.