Acute Illness, Inflammation
Conditions
Keywords
Nicotinamide riboside, NAD+, Epigenetics, Aging, PARP
Brief summary
Patients will receive oral nicotinamide riboside or placebo and clinical and paraclinical outcome will be determined
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.
Interventions
DRUGNicotinamide riboside
Nicotinamide riboside in different doses
DRUGPlacebo
Placebo
Sponsors
ChromaDex, Inc.
Oslo University Hospital
Study design
Allocation
RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
SUPPORTIVE_CARE
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
The safety committee will have access to unblinded results during the study.
Intervention 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.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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. | Up to 90 days | Days |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Days on antibiotics from inclusion to end of trial | 90 days and 65 weeks | Days |
| Days from inclusion to first antibiotic free day | Up to 90 days | Days |
| Change in mitochondrial biogenesis - mitochondrial DNA quantification | Baseline to 90 days | Change from baseline in the amount of mitochondrial DNA at the start and end of the 90 days of NR treatment (mtDNA quantification) |
| Mitochondrial biogenesis - Respiratory Chain Enzyme Analysis | Baseline and 90 days | Change from baseline in mitochondrial function at the start and end of the 4 weeks of NR treatment (Respiratory chain enzyme analysis) |
| Number of newly diagnosed infections from inclusion to end of trial | 90 days and 65 weeks | Number |
| Change in NAD+ (nicotinamide adenosine dinucleotide) and related metabolite blood levels | Baseline, day 7 and day 90 | 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. |
| Number of readmissions to hospital | Up to 90 days | Number |
| Safety - change in blood analytes | Up to 90 days | 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 |
| Safety - adverse events | Up to 90 days | Adverse events classified according to CTCAE |
| Time to normalization of urine production | Up to 90 days | Measured in ml/hour |
| Mortality | At 90 days, 65 weeks and 10 years | Number of deaths |
| 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. | Up to 90 days | Days |
| Time to normalization of blood pressure | Up to 90 days | Hours/days |
| Change in blood pressure during the study period | Baseline and 90 days and 65 weeks | mmHg |
| Days on respiratory support | Up to 90 days | Days |
| Number of days with temperature above 38 at any point from inclusion to discharge. | Up to 90 days | Days |
| Number of days with temperature above 38 at any point from inclusion to discharge divided on number of days from inclusion to discharge | 90 days | Number of days |
| Duration of stay in ICU after randomization | Up to 90 days | Days |
| Number of newly diagnosed infections with identified agent from inclusion to end of trial | 90 days and 65 weeks | Number |
| Highest CRP from inclusion to end of trial | Up to 90 days | CRP value |
| Changes in DNA methylation clocks | At baseline, 90 days and 65 weeks. | 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. |
| Changes in DNA methylation measured by the Illumina DNA methylation BeadArray | At baseline, 90 days and 65 weeks. | 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. |
| Change in quality of life | 14 days prior to admission, baseline, 90 days and 65 weeks | EQ-5D-5L (Quality of life instrument developed by the EuroQol group). Scores ranging from 11111 (full health) to 33333/55555 (worst health). |
| Change in Katz activities of daily living | 14 days prior to admission, baseline, 90 days and 65 weeks | Measured at pre-baseline (-14 days), 90 days and 65 weeks. Score 0-6 describing increasing levels of independency. |
| Change in MoCA | Day 7, 90 and at 65 weeks | MoCA (Montreal Cognitive Assessment): Score 0-30. Score of 26 or over is considered normal. Lower scores indicates cognitive impairment. |
| Trail Making Test A | Day 7, 90 and at 65 weeks | Time in seconds |
| Trail Making Test B | Day 7, 90 and at 65 weeks | Time in seconds |
| Change in forward and backward recall | Day 7, 90 and at 65 weeks | Test result change over the study period |
| Change in NEWS score from -4 hours to 0 hours before first tablet to 1,3, 7 days after first capsule | 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 | NEWS (National Early Warning Score): Score 0-20. High scores indicate high degree of illness. |
| Change in ECOG status | 14 days prior to admission, baseline, day 7, day 90 and week 65 | Eastern Cooperative Oncology Group (0-5, higher is worse) |
| Change in GSC | Day 1, 3 and 7 | Glasgow Coma Scale |
| Change in 4 meter walking test | Baseline, day 7, day 90 and week 65 | Time in seconds |
| Change in clinical Frailty Score | Baseline, day 7, day 90 and week 65 | Time in seconds |
| Change in grip strength over three months | Baseline, day 7, day 90 and at 65 weeks | Kg measured with a handheld dynamometer |
| Change in CAM-ICU | Baseline and day 1,3,7, and every week of hospitalization in ICU | CAM-ICU (Confusion Assessment Method for the ICU): Algorithm of Yes/No questions. |
| Changes in hearing | At baseline, 7 and 90 days and 65 weeks | Audiogram |
| Change in left ventricular ejection fraction | Baseline, day 7 and at 90 days | Measured with echocardiography |
Other
| Measure | Time frame | Description |
|---|---|---|
| Subgroup analysis - age | Ut to 90 days | The correlation between age and the primary outcome will be measured. |
| Subgroup analysis - epigenetic age | Ut to 90 days | The correlation between biological age measured by the DNA methylation based method GrimAge (Steve Horvath, 2019 and the primary outcome will be measured. |
| Subgroup analysis - CRP | Ut to 90 days | The primary outcome will be analyzed stratified by the maximum measured value of C-reactive protein in plasma of the patient during the hospitalization. |
| Subgroup analysis - aminoglycosides | Ut to 90 days | Changes in hearing over the study period will be measured with an audiometer stratified analyses based on the administration of aminoglycosides will be conducted. |
| Subgroup analysis - NR doses | Ut to 90 days | The primary outcome will be analyzed stratified by NR dose given to participants. |
| Subgroup analysis - gender | Ut to 90 days | The primary outcome will be analyzed stratified by gender |
Countries
Norway
Outcome results
None listed