The HF-AF ENERGY Trial: Attenuate atrial fibrillation with nicotinamide riboside (niagen)

Zie protocol page 8 & 9.

Atrial fibrillation (AF) and heart failure (HF) are the two dominant
cardiovascular diseases of this century. Failure rates of AF therapy in HF
patients are high, particularly when AF becomes more persistent. Therefore, the
need for novel, less-invasive therapy is higher than ever. We recently observed
that AF causes a significant reduction in nicotinamide adenine dinucleotide
(NAD+) levels and consequently deteriorate the mitochondrial function due to
DNA damage-induced activation of the DNA repair protein ADP-ribose-polymerase 1
(PARP1) in atrial tissue of patients with AF. In line, we showed that
supplementation with NAD+ or nutraceutical treatment with nicotinamide
conserves the energy metabolisms and protects against electrophysiological
dysfunction and AF in experimental model systems for AF. Nicotinamide is the
building block of NAD+ and mainly present in the mitochondria. NAD+ plays a key
role in the energy metabolism in cells, especially cells which are metabolic
very active such as cardiomyocytes. Nicotinamide riboside (NR) is a registered
form of vitamin B3 and a potent inducer of NAD+ levels in humans without
causing serious side effects.

Experimental and human studies have shown that supplementation with NR raises
NAD+ levels, which protect against dilated cardiomyopathy, ischemic heart
disease and heart failure. Although experimental studies revealed important
evidence for nicotinamide to protect against heart diseases by conserving the
NAD+ levels, it is unknown whether nicotinamide riboside can restore NAD+
metabolism in ischemic and/or non-ischemic heart failure patients with AF and
subsequent prevent AF onset and progression. Therefore, the main objective of
the current proposal is to reveal the impact of nicotinamide riboside (Tru
Niagen® ChromaDex) on blood-based energy metabolites and proteostasis levels
(including NAD+/NADH) in ischemic and/or non-ischemic heart disease patients
with paroxysmal or persistent AF. Furthermore, it is examined whether niagen
reduces the AF burden (sum of the duration of all episodes divided by the
duration of observation periods). This is determined by utilizing rhythm
monitoring software of implantable cardiac devices (ICD) enabling monitoring
detection of the cardiac rhythm.

Positive outcomes of this first therapeutic study aimed at protection from
cardiomyocyte damage and subsequently reduction of AF burden in HF patients
will be a major breakthrough in the therapy of AF. In addition, it will
provide, for the first time, novel therapeutic options for AF in patients with
ischemic and/or non-ischemic heart disease.

Primary objective: Our primary objective is to investigate whether niagen
normalizes blood-based energy metabolites, mitochondrial levels and
proteostasis levels.

Secondary objective: To examine whether niagen reduces AF burden in patients
with ischemic and/or non-ischemic heart disease.

Patients that come to the outpatient clinic of Cardiology will be screened for
fitting the inclusion criteria. Patients will be informed about the HF-AF
ENERGY trial and asked for informed consent. Laboratory tests will be performed
for testing mitochondrial biomarkers, energy metabolite levels, and various
proteostasis markers in the blood. Echocardiography will be done for baseline
measurement, if patients did not have an echocardiography in the previous 3
months. Furthermore, clinical history of the patient, including start date/year
of AF, diagnosis date, symptoms, AF incidence and prior AF therapy/treatments
is evaluated. A start date of oral intake of the niagen supplement will be
chosen with the patient. The patient will receive the niagen capsules (enough
for 4 months). The patient starts with 500 mg (2 capsules) per day, move up to
1000 mg (4 capsules) per day, then take 1500 mg (6 capsules), and eventually
take 2000 mg (8 capsules) per day, with a duration of one week for each
incremental increase. After 4 weeks, patients have reached the maximum dose
(1000 mg, twice daily) and will continue on this dose until the end of the
study (Week 16). The study will stop 4 months after the start date. The
supplements (TRU NIAGEN® ChromaDex 250 mg) will be taken twice a day: for the
first week: 1 capsule in the morning, 1 capsule in the evening. Week 2: 2
capsules in the morning, and 2 capsules in the evening. Week 3: 3 capsules in
the morning, and 3 capsules in the evening. The patient have reached the final
dose in week 4: 4 capsules in the morning and 4 capsules in the evening. This
patient continue on this dose until the end of the study (Week 16). If, at any
step, a dose increase is not tolerated, the maximum previously-tolerated dose
will be continued through to week 16. Patients will be asked to fill in a diary
where they keep track of their supplement intake and potential side-effects.
After 4 months, patients are evaluated at our outpatient clinic of Cardiology,
which will be the endpoint. This evaluation will consist of history taking, as
well as blood sampling and echocardiographic examination. AF therapy, AF
symptoms, HF symptoms and possible side effects of niagen are evaluated. The
answers will be filled in on a questionnaire. Finally, the patient diary is
checked together with the patient for compound intake, plus the remaining pills
will be collected.

Study design
The HF-AF ENERGY trial is an intervention study with a planned duration of 36
months to test whether niagen has a positive effect on AF burden, metabolite,
proteostasis and energy levels. For the study we want to include 20 patients.
This is based on a calculation that niagen increases NAD+ levels by 35%.

Research Product: nicotinamide riboside (Tru Niagen® ChromaDex®)
- Dosage: 2 x 1000 mg per day. The initial dose will be 1 capsule twice daily,
followed by weekly up-titration by 1 capsule/dose to a final dose of 4 capsules
(1000mg) twice daily at the end of Week 4. Participants will be continued on
the final dose up to the final follow up visit (week 16).
- Total duration study: 36 months **Allow us to include patients at different
time points**
- Observation period: 4 months (determine AF burden and baseline metabolite,
proteostasis and energy levels)
- Supplementation period: 4 months
- End point: after 4 months niagen treatment (determine effect of niagen on AF
burden, metabolite, proteostasis and energy levels)

Part 1 (0-36 months):
1. Inclusion 20 patients
2. Determination baseline blood sample values
3. Determination AF burden
4. Niagen supplementation (4 months)

Visit 1 - start of the observation period
- Discuss AF- and clinical history with the patient (previous therapy,
incidence AF, symptoms)
- Blood samples (venipuncture) max. 4 tubes of blood (4x7ml) (tests
proteostasis, mitochondrial biomarkers and energy markers, including NAD+/NADH)
- Determine the starting date of niagen intake
- Informing about a supplement diary for niagen intake, AF episodes, AF
symptoms, side effects
- Echocardiographic examination (evaluation of Left Ventricle function and
atrial size)

Visit 2 - 4 months after taking niagen supplement = endpoint
- Clinical evaluation
- Blood samples (venipuncture) max. 4 tubes of blood (4x7ml) (tests
proteostasis biomarkers and energy markers, including NAD+/NADH) (difference
pre- and post-supplementation)
- Echocardiographic examination
- Calculate AF burden (difference pre- and post-supplementation)
- Review patient food diary, check niagen intake
- Collecting the remaining niagen supplements

Patients will be taking the commercially available dietary supplement
nicotinamide riboside (Tru Niagen® ChromaDex®), a form of vitamin B3. In
earlier studies, this compound was shown to enhance NAD+ levels, a coenzyme
which is present in reduced levels in patients with AF. The initial dose will
be 1 capsule twice daily, followed by weekly up-titration by 1 capsule/dose to
a final dose of 4 capsules (1000mg) twice daily at the end of Week 4.
Participants will be continued on the final dose up to the final follow up
visit (week 16). If, at any step, a dose increase is not tolerated, the maximum
previously-tolerated dose will be continued through to week 16.

Neither the patient, nor the investigators are in any way compensated for their
participation with regards to this study. For participants of this study
Participants may experience less AF which will be associated with less
complications and symptoms. Niagen did not cause any serious side-effects in
clinical studies. In addition, this study may provide more insight into the
mechanism of AF by investigating the presence and extent of metabolic and
electrical changes. Knowledge is important as it may benefit future preventive
or curative AF therapies.

The risk of niagen supplementation is considered to be very low, since studies
have shown no serious adverse effects for using niagen. To date, studies have
reported minimal side effects from clinical studies with niagen. The minimal
observed side effects are: changes in glucose and insulin sensitivity but these
values are within the normal range, mild nausea, mild sleeping problems, mild
headache symptoms. However, niagen has not been extensively studies in heart
failure patients. Therefore, we will closely monitor all subjects for adverse
events during the study period. The extra tests for this study (blood draw,
echocardiography) also have minimal risks. Therefore, the risks associated with
participation in the HF-AF ENERGY trial study are low. The burden associated
with participation in this study is estimated to be minimal. The intake of
supplements takes a maximum of 5 minutes per day.