Trial Outcomes & Findings for NAD Therapy for Improving Memory and Brain Blood Flow in Older Adults With Mild Cognitive Impairment (NCT NCT03482167)

NCT ID: NCT03482167

Last Updated: 2025-04-04

Results Overview

Primary outcome was a change from baseline in any domain of cognitive function. For all outcomes, a higher score indicates better cognitive function: 1. California Verbal Learning Test III (CVLT-III) Index Scores. Ability learn and recall a list of words over 5 trials and again after a 20 minute delay. Each Index Score has a mean of 100 and a standard deviation of 15 based on normative dataset (Range = 55 - 145). 2. Wechsler Memory Scale IV (WMS-IV) Raw Scores. * Logical Memory I \& II: Range = 0-50 * Logical Memory II Recognition: Range = 0-30 * Visual Reproduction I \& II: Range = 0-43 * Visual Reproduction II Recognition Score: Range = 0-7 3. NIH Toolbox Fluid Composite Score. Composite Score has a mean of 100 and a standard deviation of 15 based on normative dataset (Range = 55 - 145) - based on several tests of fluid and crystallized cognition (episodic memory, attention, working memory, processing speed, executive function and language abilities).

• Recruitment status: COMPLETED
• Study phase: PHASE1/PHASE2
• Target enrollment: 64 participants
• Primary outcome timeframe: baseline and 12 weeks
• Results posted on: 2025-04-04

Participant Flow

Participants were screened for inclusion in this study at the University of Delaware between March 20, 2019 - August 21, 2023.

A total of 64 participants were consented into this study. Of these, 13 participants were withdrawn prior to randomization. Reasons for withdrawal inlcluded not meeting eligibility criteria (N = 7), failure to comply with study requirements (N = 1), voluntarily withdrawal by the participant (N = 2), or if a participant was lost to followup (N = 2).

Participant milestones

Measure	Placebo Placebo Placebo: Placebo	Nicotinamide Riboside Niagen® (ChromaDex, Inc.) 500 mg, twice daily Niagen®: 250 mg capsules (4 capsules daily)
Allocated to Intervention STARTED	26	26
Allocated to Intervention COMPLETED	25	24
Allocated to Intervention NOT COMPLETED	1	2
Received Intervention STARTED	25	24
Received Intervention COMPLETED	20	22
Received Intervention NOT COMPLETED	5	2

Reasons for withdrawal

Measure	Placebo Placebo Placebo: Placebo	Nicotinamide Riboside Niagen® (ChromaDex, Inc.) 500 mg, twice daily Niagen®: 250 mg capsules (4 capsules daily)
Allocated to Intervention Physician Decision	1	2
Received Intervention Adverse Event	3	1
Received Intervention Physician Decision	1	1
Received Intervention Withdrawal by Subject	1	0

Baseline Characteristics

Screening for MCI status occurred in-person until March 2020 when the study was temporarily stopped due to the COVID-19 pandemic. Prior to the pandemic, we used the BVMT, in-person, in our screening pipeline for MCI status. After the pandemic, we began doing most of our screenings using online video conferencing. Because the BVMT cannot easily be administered online, we switched to using the WMS Logical Memory Test.

Baseline characteristics by cohort

Measure	Placebo n=25 Participants Placebo Placebo: Placebo	Nicotinamide Riboside n=24 Participants Niagen® (ChromaDex, Inc.) 500 mg, twice daily Niagen®: 250 mg capsules (4 capsules daily)	Total n=49 Participants Total of all reporting groups
Age, Continuous	71 years STANDARD_DEVIATION 7 • n=25 Participants	72 years STANDARD_DEVIATION 8 • n=24 Participants	72 years STANDARD_DEVIATION 8 • n=49 Participants
Sex: Female, Male Female	18 Participants n=25 Participants	13 Participants n=24 Participants	31 Participants n=49 Participants
Sex: Female, Male Male	7 Participants n=25 Participants	11 Participants n=24 Participants	18 Participants n=49 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	1 Participants n=25 Participants	1 Participants n=24 Participants	2 Participants n=49 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	24 Participants n=25 Participants	23 Participants n=24 Participants	47 Participants n=49 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=25 Participants	0 Participants n=24 Participants	0 Participants n=49 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=25 Participants	0 Participants n=24 Participants	0 Participants n=49 Participants
Race (NIH/OMB) Asian	2 Participants n=25 Participants	0 Participants n=24 Participants	2 Participants n=49 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=25 Participants	0 Participants n=24 Participants	0 Participants n=49 Participants
Race (NIH/OMB) Black or African American	7 Participants n=25 Participants	1 Participants n=24 Participants	8 Participants n=49 Participants
Race (NIH/OMB) White	16 Participants n=25 Participants	22 Participants n=24 Participants	38 Participants n=49 Participants
Race (NIH/OMB) More than one race	0 Participants n=25 Participants	1 Participants n=24 Participants	1 Participants n=49 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=25 Participants	0 Participants n=24 Participants	0 Participants n=49 Participants
APOE ε4 Carrier	10 Participants n=25 Participants	10 Participants n=24 Participants	20 Participants n=49 Participants
APOE Genotype ε2/ε2	0 Participants n=25 Participants	0 Participants n=24 Participants	0 Participants n=49 Participants
APOE Genotype ε2/ε3	6 Participants n=25 Participants	4 Participants n=24 Participants	10 Participants n=49 Participants
APOE Genotype ε2/ε4	2 Participants n=25 Participants	0 Participants n=24 Participants	2 Participants n=49 Participants
APOE Genotype ε3/ε3	9 Participants n=25 Participants	10 Participants n=24 Participants	19 Participants n=49 Participants
APOE Genotype ε3/ε4	8 Participants n=25 Participants	9 Participants n=24 Participants	17 Participants n=49 Participants
APOE Genotype ε4/ε4	0 Participants n=25 Participants	1 Participants n=24 Participants	1 Participants n=49 Participants
Mini Mental State Exam (MMSE)	27 Units on a scale STANDARD_DEVIATION 2 • n=25 Participants	26 Units on a scale STANDARD_DEVIATION 2 • n=24 Participants	27 Units on a scale STANDARD_DEVIATION 2 • n=49 Participants
Clinical Dementia Rating - Global Score	0.4 units on a scale STANDARD_DEVIATION 0.2 • n=25 Participants	0.4 units on a scale STANDARD_DEVIATION 0.2 • n=24 Participants	0.4 units on a scale STANDARD_DEVIATION 0.2 • n=49 Participants
Revised Hopkins Verbal Learning Test (HVLT-R) Total Recall Memory	39 T-Score STANDARD_DEVIATION 8 • n=25 Participants	38 T-Score STANDARD_DEVIATION 8 • n=24 Participants	39 T-Score STANDARD_DEVIATION 8 • n=49 Participants
Revised Brief Visuospatial Memory Test (BVMT-R) Total Recall Score	35 T-Score STANDARD_DEVIATION 13 • n=4 Participants • Screening for MCI status occurred in-person until March 2020 when the study was temporarily stopped due to the COVID-19 pandemic. Prior to the pandemic, we used the BVMT, in-person, in our screening pipeline for MCI status. After the pandemic, we began doing most of our screenings using online video conferencing. Because the BVMT cannot easily be administered online, we switched to using the WMS Logical Memory Test.	33 T-Score STANDARD_DEVIATION 8 • n=8 Participants • Screening for MCI status occurred in-person until March 2020 when the study was temporarily stopped due to the COVID-19 pandemic. Prior to the pandemic, we used the BVMT, in-person, in our screening pipeline for MCI status. After the pandemic, we began doing most of our screenings using online video conferencing. Because the BVMT cannot easily be administered online, we switched to using the WMS Logical Memory Test.	35 T-Score STANDARD_DEVIATION 8 • n=12 Participants • Screening for MCI status occurred in-person until March 2020 when the study was temporarily stopped due to the COVID-19 pandemic. Prior to the pandemic, we used the BVMT, in-person, in our screening pipeline for MCI status. After the pandemic, we began doing most of our screenings using online video conferencing. Because the BVMT cannot easily be administered online, we switched to using the WMS Logical Memory Test.
Revised Wechsler Memory Scale (WMS-R) - Logical Memory I	8 units on a scale STANDARD_DEVIATION 3 • n=21 Participants • Screening for MCI status occurred in-person until March 2020 when the study was temporarily stopped due to the COVID-19 pandemic. Prior to the pandemic, we used the BVMT, in-person, in our screening pipeline for MCI status. After the pandemic, we began doing most of our screenings using online video conferencing. Because the BVMT cannot easily be administered online, we switched to using the WMS Logical Memory Test.	8 units on a scale STANDARD_DEVIATION 3 • n=16 Participants • Screening for MCI status occurred in-person until March 2020 when the study was temporarily stopped due to the COVID-19 pandemic. Prior to the pandemic, we used the BVMT, in-person, in our screening pipeline for MCI status. After the pandemic, we began doing most of our screenings using online video conferencing. Because the BVMT cannot easily be administered online, we switched to using the WMS Logical Memory Test.	8 units on a scale STANDARD_DEVIATION 3 • n=37 Participants • Screening for MCI status occurred in-person until March 2020 when the study was temporarily stopped due to the COVID-19 pandemic. Prior to the pandemic, we used the BVMT, in-person, in our screening pipeline for MCI status. After the pandemic, we began doing most of our screenings using online video conferencing. Because the BVMT cannot easily be administered online, we switched to using the WMS Logical Memory Test.

PRIMARY outcome

Timeframe: baseline and 12 weeks

Population: Number of cases analyzed for select cognitive tests differs from overall number analyzed due to missing data.

Primary outcome was a change from baseline in any domain of cognitive function. For all outcomes, a higher score indicates better cognitive function:

1. California Verbal Learning Test III (CVLT-III) Index Scores. Ability learn and recall a list of words over 5 trials and again after a 20 minute delay. Each Index Score has a mean of 100 and a standard deviation of 15 based on normative dataset (Range = 55 - 145).

2. Wechsler Memory Scale IV (WMS-IV) Raw Scores.

• Logical Memory I & II: Range = 0-50
• Logical Memory II Recognition: Range = 0-30
• Visual Reproduction I & II: Range = 0-43
• Visual Reproduction II Recognition Score: Range = 0-7

3. NIH Toolbox Fluid Composite Score. Composite Score has a mean of 100 and a standard deviation of 15 based on normative dataset (Range = 55 - 145) - based on several tests of fluid and crystallized cognition (episodic memory, attention, working memory, processing speed, executive function and language abilities).

Outcome measures

Measure	Placebo n=20 Participants Placebo Placebo: Placebo	Nicotinamide Riboside n=22 Participants Niagen® (ChromaDex, Inc.) 500 mg, twice daily Niagen®: 250 mg capsules (4 capsules daily)
Cognitive Scores at Baseline and Week 12 CVLT3 Trial 1-5 Index Score (Baseline)	96 score on a scale Standard Error 4	99 score on a scale Standard Error 4
Cognitive Scores at Baseline and Week 12 CVLT3 Trial 1-5 Index Score (Week 12)	101 score on a scale Standard Error 3	103 score on a scale Standard Error 4
Cognitive Scores at Baseline and Week 12 CVLT3 Delayed Recall Index Score (Baseline)	93 score on a scale Standard Error 3	93 score on a scale Standard Error 4
Cognitive Scores at Baseline and Week 12 CVLT3 Delayed Recall Index Score (Week 12)	97 score on a scale Standard Error 4	100 score on a scale Standard Error 4
Cognitive Scores at Baseline and Week 12 CVLT3 Total Recall Index Score (Week 12)	99 score on a scale Standard Error 3	101 score on a scale Standard Error 4
Cognitive Scores at Baseline and Week 12 WMS-IV Logical Memory I Total Raw Score (Baseline)	18 score on a scale Standard Error 1	20 score on a scale Standard Error 2
Cognitive Scores at Baseline and Week 12 WMS-IV Logical Memory II Total Raw Score (Baseline)	15 score on a scale Standard Error 1	15 score on a scale Standard Error 2
Cognitive Scores at Baseline and Week 12 WMS-IV Logical Memory II Total Raw Score (Week 12)	16 score on a scale Standard Error 2	19 score on a scale Standard Error 2
Cognitive Scores at Baseline and Week 12 WMS-IV Logical Memory II Recognition Total Raw Score (Week 12)	23 score on a scale Standard Error 1	24 score on a scale Standard Error 1
Cognitive Scores at Baseline and Week 12 CVLT3 Total Recall Index Score (Baseline)	95 score on a scale Standard Error 4	96 score on a scale Standard Error 4
Cognitive Scores at Baseline and Week 12 WMS-IV Logical Memory I Total Raw Score (Week 12)	21 score on a scale Standard Error 1	25 score on a scale Standard Error 2
Cognitive Scores at Baseline and Week 12 WMS-IV Logical Memory II Recognition Total Raw Score (Baseline)	23 score on a scale Standard Error 1	22 score on a scale Standard Error 1
Cognitive Scores at Baseline and Week 12 WMS-IV Visual Reproduction I Total Raw Score (Baseline)	29 score on a scale Standard Error 1	29 score on a scale Standard Error 2
Cognitive Scores at Baseline and Week 12 WMS-IV Visual Reproduction I Total Raw Score (Week 12)	30 score on a scale Standard Error 2	30 score on a scale Standard Error 2
Cognitive Scores at Baseline and Week 12 WMS-IV Visual Reproduction II Total Raw Score (Baseline)	17 score on a scale Standard Error 2	17 score on a scale Standard Error 2
Cognitive Scores at Baseline and Week 12 WMS-IV Visual Reproduction II Total Raw Score (Week 12)	19 score on a scale Standard Error 2	18 score on a scale Standard Error 2
Cognitive Scores at Baseline and Week 12 WMS-IV Visual Reproduction II Recognition Total Raw Score (Baseline)	5 score on a scale Standard Error 0.001	5 score on a scale Standard Error 0.001
Cognitive Scores at Baseline and Week 12 WMS-IV Visual Reproduction II Recognition Total Raw Score (Week 12)	6 score on a scale Standard Error 0.001	5 score on a scale Standard Error 0.001
Cognitive Scores at Baseline and Week 12 NIH Toolbox Fluid Cognition Score (Baseline)	87 score on a scale Standard Error 2	84 score on a scale Standard Error 3
Cognitive Scores at Baseline and Week 12 NIH Toolbox Fluid Cognition Score (Week 12)	89 score on a scale Standard Error 3	84 score on a scale Standard Error 3

SECONDARY outcome

Timeframe: baseline and 12 weeks

Relative (percent) change in blood velocity of the middle cerebral artery (MCA) per mmHg change in end-tidal carbon dioxide (ETCO2) during a brief period of hypercapnia.

Hypercapnia was induced by prospective end-tidal targeting (RespirAct, Thornhill Medical) in which a target change in end-tidal CO2 of +9mmHg was set. Data were only analyzed if ETCO2 changed by at least 6mmHg. All data were then normalized to the absolute change in ETCO2.

Outcome measures

Measure	Placebo n=2 Participants Placebo Placebo: Placebo	Nicotinamide Riboside n=5 Participants Niagen® (ChromaDex, Inc.) 500 mg, twice daily Niagen®: 250 mg capsules (4 capsules daily)
Cerebrovascular Reactivity at Baseline and 12 Weeks Percent change in MCA velocity per mmHg change in ETCO2 - Baseline	3.2 % change in MCAv (m/sec) per mmHg ETCO2 Standard Error 1.9	1.1 % change in MCAv (m/sec) per mmHg ETCO2 Standard Error 1.0
Cerebrovascular Reactivity at Baseline and 12 Weeks Percent change in MCA velocity per mmHg change in ETCO2 - Week 12	4.2 % change in MCAv (m/sec) per mmHg ETCO2 Standard Error 0.8	2.8 % change in MCAv (m/sec) per mmHg ETCO2 Standard Error 0.7

SECONDARY outcome

Timeframe: baseline and 12 weeks

Population: Number of cases analyzed for select cognitive tests differs from overall number analyzed due to missing data.

Total brain blood flow assessed by pseudo-continuous arterial spin labeling (pcASL). Total brain blood flow is measured in milliliters of blood per minute per 100 grams of brain tissue.

Outcome measures

Measure	Placebo n=20 Participants Placebo Placebo: Placebo	Nicotinamide Riboside n=22 Participants Niagen® (ChromaDex, Inc.) 500 mg, twice daily Niagen®: 250 mg capsules (4 capsules daily)
Total Brain Blood Flow at Baseline and 12 Weeks Baseline	47.1 ml/min/100g Standard Error 2.9	48.6 ml/min/100g Standard Error 4.3
Total Brain Blood Flow at Baseline and 12 Weeks Week 12	47.4 ml/min/100g Standard Error 2.7	55.5 ml/min/100g Standard Error 4.0

SECONDARY outcome

Timeframe: baseline and 12 weeks

Population: Number of cases analyzed for select cognitive tests differs from overall number analyzed due to missing data.

Carotid-femoral pulse wave velocity (CFPWV)

Outcome measures

Measure	Placebo n=20 Participants Placebo Placebo: Placebo	Nicotinamide Riboside n=22 Participants Niagen® (ChromaDex, Inc.) 500 mg, twice daily Niagen®: 250 mg capsules (4 capsules daily)
Aortic Stiffness at Baseline and 12 Weeks Baseline	8.9 m/sec Standard Error 0.4	9.8 m/sec Standard Error 0.4
Aortic Stiffness at Baseline and 12 Weeks Week 12	8.5 m/sec Standard Error 0.5	9.1 m/sec Standard Error 0.5

SECONDARY outcome

Timeframe: baseline and 12 weeks

Seated systolic and diastolic blood pressure assessed using automated oscillometric sphygmomanometer.

Outcome measures

Measure	Placebo n=20 Participants Placebo Placebo: Placebo	Nicotinamide Riboside n=22 Participants Niagen® (ChromaDex, Inc.) 500 mg, twice daily Niagen®: 250 mg capsules (4 capsules daily)
Blood Pressure at Baseline and 12 Weeks Systolic (Baseline)	124 mmHg Standard Error 3	132 mmHg Standard Error 3
Blood Pressure at Baseline and 12 Weeks Systolic (Week 12)	123 mmHg Standard Error 3	127 mmHg Standard Error 3
Blood Pressure at Baseline and 12 Weeks Diastolic (Baseline)	70 mmHg Standard Error 2	74 mmHg Standard Error 2
Blood Pressure at Baseline and 12 Weeks Diastolic (Week 12)	72 mmHg Standard Error 2	73 mmHg Standard Error 2

OTHER_PRE_SPECIFIED outcome

Timeframe: baseline and 12 weeks

Cerebrovascular reactivity to cognitive tasks

Outcome measures

Outcome data not reported

OTHER_PRE_SPECIFIED outcome

Timeframe: baseline and 12 weeks

functional brain connectivity assessed by MRI

Outcome measures

Outcome data not reported

OTHER_PRE_SPECIFIED outcome

Timeframe: baseline and 12 weeks

Functional MRI (fMRI) to cognitive task

Outcome measures

Outcome data not reported

OTHER_PRE_SPECIFIED outcome

Timeframe: baseline and 12 weeks

White and grey matter volume assessed by structural MRI

Outcome measures

Outcome data not reported

Adverse Events

Placebo

Serious events: 0 serious events

Other events: 12 other events

Deaths: 0 deaths

Nicotinamide Riboside

Serious events: 0 serious events

Other events: 8 other events

Deaths: 0 deaths

Serious adverse events

Adverse event data not reported

Other adverse events

Measure	Placebo n=25 participants at risk Placebo Placebo: Placebo	Nicotinamide Riboside n=24 participants at risk Niagen® (ChromaDex, Inc.) 500 mg, twice daily Niagen®: 250 mg capsules (4 capsules daily)
Skin and subcutaneous tissue disorders Pruritus	0.00% 0/25 • 12 weeks	4.2% 1/24 • Number of events 1 • 12 weeks
Nervous system disorders Headache	8.0% 2/25 • Number of events 2 • 12 weeks	0.00% 0/24 • 12 weeks
Gastrointestinal disorders Abdominal Pain	0.00% 0/25 • 12 weeks	8.3% 2/24 • Number of events 2 • 12 weeks
Infections and infestations COVID-19	0.00% 0/25 • 12 weeks	4.2% 1/24 • Number of events 1 • 12 weeks
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Breast Cancer	0.00% 0/25 • 12 weeks	4.2% 1/24 • Number of events 1 • 12 weeks
Infections and infestations Urinary Tract Infection	4.0% 1/25 • Number of events 2 • 12 weeks	0.00% 0/24 • 12 weeks
Gastrointestinal disorders Vomiting	4.0% 1/25 • Number of events 1 • 12 weeks	0.00% 0/24 • 12 weeks
Gastrointestinal disorders Diarrhea	4.0% 1/25 • Number of events 1 • 12 weeks	0.00% 0/24 • 12 weeks
Gastrointestinal disorders Flatulence	4.0% 1/25 • Number of events 1 • 12 weeks	0.00% 0/24 • 12 weeks
Nervous system disorders Insomnia	4.0% 1/25 • Number of events 1 • 12 weeks	0.00% 0/24 • 12 weeks
Musculoskeletal and connective tissue disorders Chest wall pain	8.0% 2/25 • Number of events 2 • 12 weeks	0.00% 0/24 • 12 weeks
Cardiac disorders Heart palpitations	4.0% 1/25 • Number of events 1 • 12 weeks	0.00% 0/24 • 12 weeks
Investigations Creatinine increased	0.00% 0/25 • 12 weeks	4.2% 1/24 • Number of events 1 • 12 weeks
Nervous system disorders Paresthesia	4.0% 1/25 • Number of events 1 • 12 weeks	0.00% 0/24 • 12 weeks
Psychiatric disorders Anxiety	0.00% 0/25 • 12 weeks	4.2% 1/24 • Number of events 1 • 12 weeks
Investigations Triglycerides increased	4.0% 1/25 • Number of events 1 • 12 weeks	4.2% 1/24 • Number of events 1 • 12 weeks

Additional Information

Christopher R. Martens, Ph.D.

University of Delaware

Phone: 302-831-7270

Email: cmartens@udel.edu

Results disclosure agreements

• Principal investigator is a sponsor employee
• Publication restrictions are in place