Acute Kidney Injury, SARS-CoV-2 Infection
Conditions
Brief summary
An interventional clinical trial using oral nicotinamide riboside (NR) in hospitalized patients with COVID-19 infection and acute kidney injury to determine the effect of NR on whole blood nicotinamide adenine dinucleotide (NAD+) levels and to evaluate safety of the use of NR.
Detailed description
The study team chose a treatment protocol with NR as a treatment for patients who will be admitted with COVID-19 related illness and develop AKI after admission. Treatment duration will be for 10 days and the primary study endpoint will be the change in whole blood NAD+ from baseline to end of treatment in NR group vs placebo group. The study team will evaluate whole blood NAD+ levels as a marker of efficacy and biological effect of NR.
Interventions
DRUGPlacebo
Placebo capsule containing inert ingredient
DRUGNicotinamide riboside
250 mg Nicotinamide riboside capsules
Sponsors
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
The University of Texas Health Science Center at San Antonio
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Masking description
The study drug (NR or placebo) packaging and labeling will be designed to maintain the blinding of the investigator's team and the participants.
Intervention model description
Prospective, double-blind, placebo-controlled clinical interventional trial
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Provision of signed and dated informed consent form from a participant or legally authorized representative (LAR); 2. Male or female, \>18 years old; 3. Hospitalized participants with a laboratory diagnosis of COVID-19 infection 4. Evidence of persistent AKI as defined by the Kidney Disease: Improving Global Outcomes (KDIGO) guidelines (Table 3); 5. Willing to adhere to the study intervention regimen;
Exclusion criteria
1. Hypersensitivity to nicotinamide riboside (NR); 2. Pregnant or lactating women confirmed with positive laboratory pregnancy tests as per local requirements; 3. eGFR \<15 mL/min/1.73 m2 as per the Chronic Kidney Disease Epidemiology Collaboration equation at admission lab; 4. Maintenance renal replacement therapy or initiation of renal replacement therapy before randomization 5. Currently on NR or nicotinamide or vitamin B3 (niacin) supplementation (multivitamins are allowed); 6. Concomitant cirrhosis of liver or acute liver failure; 7. Any medical history or condition that might, in the opinion of the attending physician, put the participant at significant risk if he/she were to participate in the trial; 8. Individuals with kidney transplant; 9. Individuals with blood platelet count \<100,000/microL
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Whole Blood NAD+ Level | Baseline to 10 days | Measure of NAD+ level in whole blood from treatment beginning to end |
| Number of Participants With Adverse Events of Grade 3 or Higher | Baseline to 10 days | Safety of NR in hospitalized patients with COVID-19 and AKI (defined as adverse event of Grade 3 or higher). Not every grade 3 event was considered to be serious. |
| Occurrence of Thrombocytopenia | Baseline to 10 days | Number occurrences of thrombocytopenia defined as \>25% decline in blood platelet count from baseline. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Area Under the Curve (AUC) | Baseline to 10 days | To determine the effect of NR on changes in AUC serum creatinine from baseline during the 10-day intervention |
| Change in Proteinuria | 30 days to 90 days | Measurement of change in proteinuria at 30-90 days post randomization |
| Effect of NR on Major Adverse Kidney Events (MAKE) | 30 days to 90 days | Number of occurrences of MAKE defined as doubling of serum creatinine, the initiation of long-term dialysis, or death from any cause. |
| Change in Estimated Glomerular Filtration Rate (eGFR) | 30 days to 90 days | Measurement of change in eGFR at 30-90 days post randomization |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Placebo Group Placebo capsules will be administered 2 capsules twice daily for 10 days
Placebo: Placebo capsule containing inert ingredient | 13 |
| Nicotinamide Riboside Group Nicotinamide riboside 250mg capsules will be administered 2 capsules twice daily for 10 days
Nicotinamide riboside: 250 mg Nicotinamide riboside capsules | 15 |
| Total | 28 |
Baseline characteristics
| Characteristic | Placebo Group | Nicotinamide Riboside Group | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 1 Participants | 3 Participants | 4 Participants |
| Age, Categorical Between 18 and 65 years | 12 Participants | 12 Participants | 24 Participants |
| Age, Continuous | 52.31 Years STANDARD_DEVIATION 8.25 | 52.40 Years STANDARD_DEVIATION 15.99 | 52.36 Years STANDARD_DEVIATION 12.76 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 2 Participants | 5 Participants | 7 Participants |
| Race (NIH/OMB) White | 10 Participants | 8 Participants | 18 Participants |
| Region of Enrollment United States | 13 participants | 15 participants | 28 participants |
| Sex: Female, Male Female | 7 Participants | 2 Participants | 9 Participants |
| Sex: Female, Male Male | 6 Participants | 13 Participants | 19 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 6 / 13 | 11 / 15 |
| other Total, other adverse events | 6 / 13 | 10 / 15 |
| serious Total, serious adverse events | 7 / 13 | 12 / 15 |
Outcome results
Primary
Change in Whole Blood NAD+ Level
Measure of NAD+ level in whole blood from treatment beginning to end
Time frame: Baseline to 10 days
Population: Analysis set is a modified intention to treat with participants receiving at least 1 dose of study drug.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo Group | Change in Whole Blood NAD+ Level | -0.02 μg/mL | Standard Deviation 0.02 |
| Nicotinamide Riboside Group | Change in Whole Blood NAD+ Level | 0.06 μg/mL | Standard Deviation 0.07 |
Primary
Number of Participants With Adverse Events of Grade 3 or Higher
Safety of NR in hospitalized patients with COVID-19 and AKI (defined as adverse event of Grade 3 or higher). Not every grade 3 event was considered to be serious.
Time frame: Baseline to 10 days
Population: Analysis set is a modified intention to treat with participants receiving at least 1 dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo Group | Number of Participants With Adverse Events of Grade 3 or Higher | 8 participants |
| Nicotinamide Riboside Group | Number of Participants With Adverse Events of Grade 3 or Higher | 12 participants |
Primary
Occurrence of Thrombocytopenia
Number occurrences of thrombocytopenia defined as \>25% decline in blood platelet count from baseline.
Time frame: Baseline to 10 days
Population: Analysis set is a modified intention to treat with participants receiving at least 1 dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo Group | Occurrence of Thrombocytopenia | 1 participants |
| Nicotinamide Riboside Group | Occurrence of Thrombocytopenia | 1 participants |
Secondary
Change in Area Under the Curve (AUC)
To determine the effect of NR on changes in AUC serum creatinine from baseline during the 10-day intervention
Time frame: Baseline to 10 days
Population: Analysis set is a modified intention to treat with participants receiving at least 1 dose of study drug.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo Group | Change in Area Under the Curve (AUC) | 17.1 mg/dL x day |
| Nicotinamide Riboside Group | Change in Area Under the Curve (AUC) | 17.9 mg/dL x day |
Secondary
Change in Estimated Glomerular Filtration Rate (eGFR)
Measurement of change in eGFR at 30-90 days post randomization
Time frame: 30 days to 90 days
Population: Analysis set is a modified intention to treat with participants receiving at least 1 dose of study drug. Limited number of participants (n \<5) for whom serum creatinine values (change in estimated Glomerular Filtration Rate or eGFR) were available at 30d and 90d.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo Group | Change in Estimated Glomerular Filtration Rate (eGFR) | 30-day | 86.38 mL/min/1.73m^2 | Standard Deviation 23.35 |
| Placebo Group | Change in Estimated Glomerular Filtration Rate (eGFR) | 90-day | 112.08 mL/min/1.73m^2 | — |
| Nicotinamide Riboside Group | Change in Estimated Glomerular Filtration Rate (eGFR) | 30-day | 79.02 mL/min/1.73m^2 | Standard Deviation 58.12 |
| Nicotinamide Riboside Group | Change in Estimated Glomerular Filtration Rate (eGFR) | 90-day | 129.91 mL/min/1.73m^2 | — |
Secondary
Change in Proteinuria
Measurement of change in proteinuria at 30-90 days post randomization
Time frame: 30 days to 90 days
Population: Analysis set is a modified intention to treat with participants receiving at least 1 dose of study drug. Proteinuria was not routinely assessed in a hospital setting for COVID patients and an additional measurement was not performed due to infectious concerns.
Secondary
Effect of NR on Major Adverse Kidney Events (MAKE)
Number of occurrences of MAKE defined as doubling of serum creatinine, the initiation of long-term dialysis, or death from any cause.
Time frame: 30 days to 90 days
Population: Analysis set is a modified intention to treat with participants receiving at least 1 dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo Group | Effect of NR on Major Adverse Kidney Events (MAKE) | 6 Number of MAKE events |
| Nicotinamide Riboside Group | Effect of NR on Major Adverse Kidney Events (MAKE) | 12 Number of MAKE events |