Nicotinamide Riboside in Hospitalized Patients

Shorter Recovery Time After Critical Illness

Patients will receive oral nicotinamide riboside or placebo and clinical and paraclinical outcome will be determined

Study Overview

• Status: Completed
• Conditions: Inflammation; Acute Illness
• Intervention / Treatment: Drug: Placebo; Drug: Nicotinamide riboside

Detailed Description

Patients experiencing acute illness will often have a prolonged recovery time. The cause of this is unknown, but certain factors, like age, duration, and graveness of the illness, is associated with prolonged recovery. In this study, we will investigate whether nicotinamide riboside can shorten the recovery phase and improve outcome after acute illness.

• Study Type: Interventional
• Enrollment (Actual): 57
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Norway
  • Oslo, Norway, 0450
    • Oslo University Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion criteria:

1. Adults > 18 years old, admitted to hospital with tissue damage, can be included when they are considered medically stable though still expected to remain hospitalized for at least 7 more days (from inclusion).
2. Preferably: Previously included in the Janus Cohort or any other cohort or study with stored biological samples.

Exclusion Criteria:

1. Allergy to NR or ingredients in capsules or placebo.
2. Patients expected to pass away within 90 days.
3. Patients unable to give their consent

4. Unstable patients:

   i. Uncontrolled infection (clinical septicaemia, inadequate response to treatment, inadequate control of source of infection or at treating physician's discretion).

   ii. Mean arterial pressure <70 mm Hg and symptoms of hypotension. iii. Patients requiring dialysis at the time of inclusion or glomerular filtration rate <40 iv. Liver failure with Child-Pugh class B or C or any class associated with hepatic encephalopathy (any grade), alanin aminotransferase or aspartate aminotransferase >3 times upper limit v. Moderate to severe peripheral oedema and/or pulmonary oedema, any unstable cardiac rhythm, myocardial infarction with peak TNT >300 past week. Signs of elevated intracranial pressure (headache, vomiting and depressed global consciousness in conjunction with focal neurological signs, papilledema, spontaneous periorbital bruising and a triad of bradycardia, respiratory depression and hypertension).

   vi. Arterial pH <7.30 or >7.50 vii. Serum potassium under 3,2 or over 5 mmol/L.

5. Pregnancy or breastfeeding *
6. Any cancer not in full remission for >10 years
7. Use of St John's Wort based supplements during the past 30 days
8. Patient has undergone solid organ transplantation
9. Participation in any clinical trial with unknown medications
10. Major gastrointestinal or other internal bleeding past week
11. Logistical challenges after discharge. Patient must be able to attend follow up.
12. The treating physician considers the patient unfit or unable to participate. *All fertile women must have a human chorionic gonadotropin test.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Supportive Care
• Allocation: Randomized
• Interventional Model: Sequential Assignment
• Masking: Quadruple

Number of Arms

8

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Nicotinamide riboside 250 mg; One capsule of 250 mg each morning for three months	Drug: Nicotinamide riboside; Nicotinamide riboside in different doses
Experimental: Nicotinamide riboside 500 mg; One capsule of 250 mg each morning and afternoon for three months	Drug: Nicotinamide riboside; Nicotinamide riboside in different doses
Experimental: Nicotinamide riboside 1000 mg; Two capsules of 250 mg each morning and afternoon for three months	Drug: Nicotinamide riboside; Nicotinamide riboside in different doses
Experimental: Nicotinamide riboside 2000 mg; Four capsules of 250 mg each morning and afternoon for three months	Drug: Nicotinamide riboside; Nicotinamide riboside in different doses
Placebo Comparator: Placebo for 250 mg nicotinamide riboside; One capsule each morning for three months	Drug: Placebo; Placebo
Placebo Comparator: Placebo for 500 mg nicotinamide riboside; One capsule each morning and afternoon for three months	Drug: Placebo; Placebo
Placebo Comparator: Placebo for 1000 mg nicotinamide riboside; Two capsules each morning and afternoon for three months	Drug: Placebo; Placebo
Placebo Comparator: Placebo for 2000 mg nicotinamide riboside; Four capsules each morning and afternoon for three months	Drug: Placebo; Placebo

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Length of stay from randomization to discharge from hospital to home or to an institution with a lower care level than a hospital for instance a long term care facility.	Days	Up to 90 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time to normalization of urine production	Measured in ml/hour	Up to 90 days
Mortality	Number of deaths	At 90 days, 65 weeks and 10 years
Length of stay from randomization to medically fit for discharge from hospital to home or to an institution with a lower care level than a hospital for instance a long term care facility.	Days	Up to 90 days
Time to normalization of blood pressure	Hours/days	Up to 90 days
Change in blood pressure during the study period	mmHg	Baseline and 90 days and 65 weeks
Days on respiratory support	Days	Up to 90 days
Number of days with temperature above 38 at any point from inclusion to discharge.	Days	Up to 90 days
Number of days with temperature above 38 at any point from inclusion to discharge divided on number of days from inclusion to discharge	Number of days	90 days
Duration of stay in ICU after randomization	Days	Up to 90 days
Number of newly diagnosed infections with identified agent from inclusion to end of trial	Number	90 days and 65 weeks
Number of newly diagnosed infections from inclusion to end of trial	Number	90 days and 65 weeks
Days on antibiotics from inclusion to end of trial	Days	90 days and 65 weeks
Days from inclusion to first antibiotic free day	Days	Up to 90 days
Highest CRP from inclusion to end of trial	CRP value	Up to 90 days
Changes in DNA methylation clocks	Changes in the published DNA methylation clocks by Steve Horvath (Multi tissue, 2013, Skin and Blood, 2018, PhenoAge 2017, GrimAge 2018, telomere length 2019) and Hannum (Hannum clock 2013), Yan Zhang (continous Zhang score, 2017), AgeLab01 (Poster, Gordon Conference, Biology of Aging, July, 2019). All clocks are algorithms based on the Illumina "EPIC" DNA methylation BeadArray.	At baseline, 90 days and 65 weeks.
Changes in DNA methylation measured by the Illumina DNA methylation BeadArray	Methylation sites (CpG sites) that are differentially changed in the intervention groups compared to the placebo group(s) over the studied time period. Correction for multiple testing will be done.	At baseline, 90 days and 65 weeks.
Change in quality of life	EQ-5D-5L (Quality of life instrument developed by the EuroQol group). Scores ranging from 11111 (full health) to 33333/55555 (worst health).	14 days prior to admission, baseline, 90 days and 65 weeks
Change in Katz activities of daily living	Measured at pre-baseline (-14 days), 90 days and 65 weeks. Score 0-6 describing increasing levels of independency.	14 days prior to admission, baseline, 90 days and 65 weeks
Change in MoCA	MoCA (Montreal Cognitive Assessment): Score 0-30. Score of 26 or over is considered normal. Lower scores indicates cognitive impairment.	Day 7, 90 and at 65 weeks
Trail Making Test A	Time in seconds	Day 7, 90 and at 65 weeks
Trail Making Test B	Time in seconds	Day 7, 90 and at 65 weeks
Change in forward and backward recall	Test result change over the study period	Day 7, 90 and at 65 weeks
Change in NEWS score from -4 hours to 0 hours before first tablet to 1,3, 7 days after first capsule	NEWS (National Early Warning Score): Score 0-20. High scores indicate high degree of illness.	Four hours before the first administration of NR, at administration of the first capsule and 1, 3 an 7 days after administration of first capsule
Change in ECOG status	Eastern Cooperative Oncology Group (0-5, higher is worse)	14 days prior to admission, baseline, day 7, day 90 and week 65
Change in GSC	Glasgow Coma Scale	Day 1, 3 and 7
Change in 4 meter walking test	Time in seconds	Baseline, day 7, day 90 and week 65
Change in clinical Frailty Score	Time in seconds	Baseline, day 7, day 90 and week 65
Change in grip strength over three months	Kg measured with a handheld dynamometer	Baseline, day 7, day 90 and at 65 weeks
Change in CAM-ICU	CAM-ICU (Confusion Assessment Method for the ICU): Algorithm of Yes/No questions.	Baseline and day 1,3,7, and every week of hospitalization in ICU
Changes in hearing	Audiogram	At baseline, 7 and 90 days and 65 weeks
Change in left ventricular ejection fraction	Measured with echocardiography	Baseline, day 7 and at 90 days
Mitochondrial biogenesis - Respiratory Chain Enzyme Analysis	Change from baseline in mitochondrial function at the start and end of the 4 weeks of NR treatment (Respiratory chain enzyme analysis)	Baseline and 90 days
Change in mitochondrial biogenesis - mitochondrial DNA quantification	Change from baseline in the amount of mitochondrial DNA at the start and end of the 90 days of NR treatment (mtDNA quantification)	Baseline to 90 days
Change in NAD+ (nicotinamide adenosine dinucleotide) and related metabolite blood levels	Blood samples will be analysed using high performance liquid chromatography-mass spectroscopy and kit-based analysis for levels of NAD+ and related metabolites including: nicotinamide-adenine dinucleotide phosphate, nicotinic acid adenine dinucleotide, nicotinamide, and nicotinamide mononucleotide.	Baseline, day 7 and day 90
Number of readmissions to hospital	Number	Up to 90 days
Safety - change in blood analytes	Change from baseline in safety blood analyte levels - Sodium potassium phosphate urea creatinine albumin bilirubin carbamide CRP ALP AST ALT LT GT amylase Mg ferritin hemoglobin leucocytes with subgroups thrombocytes Ca INR PH(venous) HCO3(venous) ProBNP HbA1c TSH fT4 folate homocysteine cholesterol LDL HDL CKMB TNT	Up to 90 days
Safety - adverse events	Adverse events classified according to CTCAE	Up to 90 days

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Subgroup analysis - gender	The primary outcome will be analyzed stratified by gender	Ut to 90 days
Subgroup analysis - age	The correlation between age and the primary outcome will be measured.	Ut to 90 days
Subgroup analysis - epigenetic age	The correlation between biological age measured by the DNA methylation based method "GrimAge" (Steve Horvath, 2019 and the primary outcome will be measured.	Ut to 90 days
Subgroup analysis - CRP	The primary outcome will be analyzed stratified by the maximum measured value of C-reactive protein in plasma of the patient during the hospitalization.	Ut to 90 days
Subgroup analysis - aminoglycosides	Changes in hearing over the study period will be measured with an audiometer stratified analyses based on the administration of aminoglycosides will be conducted.	Ut to 90 days
Subgroup analysis - NR doses	The primary outcome will be analyzed stratified by NR dose given to participants.	Ut to 90 days
Subgroup analysis - NR doses	Grip strength measured in kg with a handheld dynamometer	Baseline, day 7, day 90 and at 65 weeks
Subgroup analysis - NR doses	MoCA will be analyzed stratified by NR dose: MoCA (Montreal Cognitive Assessment): Score 0-30. Score of 26 or over is considered normal. Lower scores indicates cognitive impairment.	Day 7, 90 and at 65 weeks

Collaborators and Investigators

• Sponsor: Oslo University Hospital
• Collaborators: ChromaDex, Inc.
• Investigators: Principal Investigator: Arne Søraas, PhD, Oslo University Hospital

Study record dates

Study Major Dates

• Study Start (Actual): October 1, 2019
• Primary Completion (Actual): December 1, 2022
• Study Completion (Actual): December 1, 2023

Study Registration Dates

• First Submitted: September 20, 2019
• First Submitted That Met QC Criteria: September 27, 2019
• First Posted (Actual): October 1, 2019

Study Record Updates

• Last Update Posted (Actual): May 20, 2024
• Last Update Submitted That Met QC Criteria: May 16, 2024
• Last Verified: May 1, 2024

More Information

Terms related to this study

• Keywords: Aging; NAD+; Epigenetics; PARP; Nicotinamide riboside
• Additional Relevant MeSH Terms: Pathologic Processes; Inflammation; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Vasodilator Agents; Antimetabolites; Micronutrients; Hypolipidemic Agents; Lipid Regulating Agents; Vitamins; Vitamin B Complex; Nicotinic Acids; Niacinamide; Niacin
• Other Study ID Numbers: 2017/1334C

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: Sharing of data will be restricted due to European General Data Protection Regulations (GDPR), but the study team will collaborate on analyzing data within these regulations.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No