Nicotinamide Riboside for Diabetic Neuropathy

At the current time there is no effective disease modifying therapy for diabetic neuropathy
(DN). Previous failed trials of therapy have often targeted individuals with advanced, severe
neuropathy. There is a particularly strong incentive to treat neuropathy early in its course
while the severity is still mild and to target participants who have impaired glucose
tolerance (IGT) or who have well controlled type 2 diabetes mellitus (T2DM). The proposed
study design employs a quantifiable early measure of DN, intraepidermal nerve fiber density
(IENFD) of the thigh, allowing for accurate assessment of actual nerve fiber density over
time, while also incorporating measures of pain and quality of life. Preclinical data
supports the use of NR as a potential therapy for diabetic neuropathy. Phase I data indicates
safety in humans.

The most common form of diabetes mellitus, T2DM, is projected to affect an estimated 366
million people worldwide by 2030. The lifetime incidence of polyneuropathy is approximately
45% and neuropathy of any type approximately 59% of in patients with T2DM. Studies of nerve
conduction tests performed at the time of diabetes mellitus diagnosis demonstrate that
neuropathy is already present in patients when the neuropathy is still subclinical.
Furthermore, DN leads to severe morbidity, high mortality, major physical disability, poor
quality of life, and high cost with estimated total annual costs of $22 billion
(www.diabetes.org). Due to the complex structure and anatomy of the peripheral nervous
system, DN presents with a very broad spectrum of clinical symptoms and deficits, including
severe pain, sensory deficits, foot ulcers and amputations. Despite the high morbidity
associated with DN, most randomized clinical trials evaluating therapies for established DN
have been disappointing. To date there is no pathogenetic treatment for this condition.
Currently, tight glycemic control is the only convincing strategy to prevent or delay the
development of DN in patients with type 1 diabetes mellitus. There is less convincing
evidence that tight glycemic control improves neuropathy with T2DM.

DN is a diffuse, symmetrical injury to the entire peripheral nervous system. The smallest Aδ
thinly-myelinated fibers and the unmyelinated C-fibers are likely the earliest to undergo
damage in the natural history of DN. These fibers mediate pain, temperature discrimination,
touch perception and autonomic responses, and constitute over 80% of peripheral nerve fibers.
When determining the effect of a therapeutic intervention in DN it is important to utilize
outcome measures that best identify change in disease. Although both large and small fiber
neuropathy occur in T2DM, a small-fiber neuropathy is more common. Importantly, developing
appropriate endpoints has been a problem in DN because many of the endpoints have proved too
insensitive in clinical trials. For example, there is a need to establish content validity in
clinical scales. IENFD is a sensitive and reliable measure in determining change in early DN.
Furthermore, IENFD directly correlates with increasing DN severity, and is safe as easy to
perform and IENFD currently represents a gold standard in measuring change in small fiber
neuropathy. Thus, IENFD was selected as the most appropriate endpoint measure in this
clinical trial. The morphometric quantification of IENFD is easily measured from a skin
biopsy and this is used as part of routine clinical practice. The skin biopsy is a minimally
invasive procedure and less than 1% of participants have mild adverse events such as
bleeding, infection, or delayed healing. Inter-observer variability for the assessment of
IENFD demonstrates good agreement, especially with assessment at the thigh. Patient refusal
rate for this procedure is minimal (less than 1 %).

This is a phase II, single center, randomized, double-blind, placebo-controlled clinical
trial to evaluate the effect of NR compared to placebo on measures of small fiber neuropathy
in participants with IGT or T2DM and mild DN. Participants with be randomly assigned to
either NR 0.5 grams twice a day (total 1 gram/day) or matched placebo in a 1:1 ratio.
Participants in the active group will start with a 1 gram/day dose because of the very low
risk of adverse events with NR. The 1 gram/day dose will be taken continuously for 6 months.
In addition (if they have not already received this information) all participants will be
given general diabetic nutritional advice and general advice to exercise for approximately
150 minutes per week. This represents current standard of care information provided to all
patients with impaired glucose regulation and DN.

Primary efficacy measure: change in the thigh IENFD at 6 months compared to baseline.
Secondary efficacy measure: change in the distal leg IENFD at 6 months compared to baseline.

Inclusion Criteria:

1. Impaired glucose tolerance or controlled type 2 diabetes mellitus at the time of
screening or within three months of screening*.

2. The hemoglobin A1c may be normal, but should be less than 9%.

3. If diabetic participants are on medication, they should be stable on medication for at
least 3 months prior to entering the study. Addition or change in antidiabetic
medication (if on medication) after enrollment does not affect participation or group
assignment.

4. Impaired glucose regulation is the most likely cause of the neuropathy.

5. Mild diabetic polyneuropathy as defined by the Toronto Diabetic Neuropathy Expert
Group consensus criteria.

6. Age 30 (to exclude patients with type 1 diabetes) to 80 years inclusive.

7. Medically stable at the time of enrollment.

8. Willing to accept randomization assignment and compliance with the study procedures.

Exclusion Criteria:

1. Women of childbearing potential must be using an acceptable method of contraception to
prevent pregnancy when they are enrolled in the study.

2. Patient must agree to take an alternative medication to Warfarin or Factor X
inhibitors when undergoing a skin biopsy.

3. Neuropathy due to factors other than type 2 diabetes mellitus based on careful
clinical and laboratory evaluation by the study physicians.

4. Abnormal liver function tests, including alanine transaminase, aspartate transaminase,
alkaline phosphatase, and bilirubin.

5. Current severe medical conditions that are active on the day of screening.