Nicotinamide Riboside in Hospitalized Patients

Study Overview
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Brief Summary
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Patients will receive oral nicotinamide riboside or placebo and clinical and paraclinical outcome will be determined

Detailed Description
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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.

Official Title
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Shorter Recovery Time After Critical Illness

Conditions
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Inflammation, Acute Illness

Intervention / Treatment
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* Drug: Nicotinamide riboside
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: 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). Preferably: Previously included in the Janus Cohort or any other cohort or study with stored biological samples. Exclusion Criteria: Allergy to NR or ingredients in capsules or placebo. Patients expected to pass away within 90 days. Patients unable to give their consent 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. Pregnancy or breastfeeding * Any cancer not in full remission for >10 years Use of St John's Wort based supplements during the past 30 days Patient has undergone solid organ transplantation Participation in any clinical trial with unknown medications Major gastrointestinal or other internal bleeding past week Logistical challenges after discharge. Patient must be able to attend follow up. The treating physician considers the patient unfit or unable to participate. *All fertile women must have a human chorionic gonadotropin test.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Supportive Care
Allocation: Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: Participants will be randomized to placebo or nicotinamide riboside (NR) in increasing doses. The safety of each dose will be evaluated before commencing the next phase. In each phase nicotinamide or placebo will be administered. The patients will use NR for 90 days. When all patients have completed their NR treatment the study will be unblinded and the follow-up visits at one year later and further on will be unblinded.
Masking: Quadruple


Arms and Interventions

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

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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NAD+, Nicotinamide riboside, Epigenetics, Aging, PARP