Intra-nasal Naloxone for Treatment of Impaired Awareness of Hypoglycemia

This is a single center, single-blinded randomized cross over design trial, that will compare
the impact of IN naloxone vs. IN saline during experimental hypoglycemia on day one on the
responses to experimental hypoglycemia on day two. 18 participants will be studied twice, 8
weeks apart. On each occasion participants will undergo a 2 hour hypoglycemic clamp (target
50 mg/dl) in the morning and in the afternoon on day one and then again on the morning of day
2. During the morning clamps, samples will be collected for later measurement of serum
epinephrine, glucagon and cortisol levels and participants will be asked to complete a
hypoglycemia symptom questionnaire. 3 intranasal doses (4 mg each) of naloxone hydrochloride
or IN saline will be administered to the subject on day 1. Plasma will be collected for
measurement of naloxone concentrations on day 1 primary outcome is the difference in peak
epinephrine secretion during the morning episodes of hypoglycemia on days one and two, thus
each participant will have two observations: one from their naloxone experiment and one from
their saline experiment.

Secondary endpoint will be naloxone pharmacokinetics including maximum concentration (Cmax),
time to maximum concentration (Tmax) and area under the curve (AUC)

Inclusion Criteria:

1. Subjects are capable of giving informed consent.

2. Female subjects must be post-menopausal for at least 1 year, or surgically incapable
of bearing children, or practicing at least one or more of the following methods of
contraception for three months prior to, and during the study: hormonal, intrauterine
device (IUD), or barrier method in combination with a spermicide.

3. Subject should be medication free, other than hormonal birth control, for 48 hours
before through 24 hours after study drug administration. If the need for medication is
identified during this time period, it will be discussed with and approved by the PI.

Exclusion Criteria:

1. Women who are pregnant.

2. Women who are breastfeeding.

3. Subject has a known hypersensitivity to naloxone.

4. Subject with hypertension

5. Subject has a significant history of cardiac, neurologic, psychiatric, oncologic,
endocrine, metabolic, renal or hepatic disease

6. Subject has taken or used any investigational drug or device in the 30 days prior to
screening.

7. Subject has taken either prescribed or over the counter medication for 48 hours prior
to study drug administration on either of the study days, other than hormonal birth
control.

8. History of narcotic or heroin abuse.