A Safety Study of Clonidine Hydrochloride Topical Gel, 0.1% in the Treatment of Painful Diabetic Neuropathy

Study CLO-311 is a multicenter, open-label, single-arm study to assess the long-term use of
Clonidine Gel in the treatment of pain associated with PDN. Subjects who have completed
their 12-week participation in Study CLO-290 or Study CLO-310 are eligible to rollover into
this study and receive active study drug in an open-label manner. All eligible subjects will
receive Clonidine Gel regardless of the blinded treatment they have received in the previous
double-blind study (Clonidine Gel or Placebo Gel). Study drug will be applied topically TID
to both feet for 12 months during an Open-Label Treatment Phase. Approximately 400 adult
subjects with PDN are estimated to enroll in this study.

Inclusion Criteria:

- The subject has provided written informed consent.

- The subject has Type 1 or Type 2 diabetes mellitus with glycemic control that has
been optimized on diet therapy, oral anti-hyperglycemic agents and/or insulin.

- The subject must be a male or non-pregnant, non-lactating female. Females must be
practicing an acceptable method of birth control, or be surgically sterile or
postmenopausal (amenorrhea for ≥12 months). Non-pregnancy will be confirmed (as
applicable) by a pregnancy test conducted at the Entry Visit. Double-barrier methods,
hormonal contraceptives, and abstinence are acceptable birth control methods for this
study.

- The subject has completed their 12-week participation according to the protocol in
the previously conducted double-blind study, CLO-290.

- The subject is medically stable at the end-of-study visit (Day 85) of Study CLO-290,
and in the opinion of the Investigator, is in otherwise good general health based on
physical examination, ECG, and laboratory evaluation.

- Subject has the capabilities of applying topical gel to both feet TID. A caregiver,
trained by the study staff to apply study medication, would be a suitable alternative
to self-application of the treatment.

Exclusion Criteria:

- The subject is using an implanted medical device (e.g., spinal cord stimulator,
intrathecal pump, or peripheral nerve stimulator) for the treatment of pain.

- The subject is clinically hypotensive with a resting diastolic blood pressure <60
mmHg or a systolic blood pressure <90 mmHg.

- The subject has recent history (within the past 3 months) or current symptoms of
orthostatic hypotension with a sudden fall in blood pressure on standing accompanied
by dizziness and lightheadedness.

- The subject has any significant or unstable medical or psychiatric condition that, in
the opinion of the Investigator, would interfere with his/her ability to participate
in the study.

- The subject has a history of substance abuse disorder as defined by DSM-IV-TR within
the past 6 months, has current evidence for substance abuse disorder, or is receiving
medicinal treatment for drug abuse.

- The subject has symptomatic or severe coronary insufficiency, clinically significant
cardiac conduction disturbances, myocardial infarction (within last 6 months),
cerebrovascular disease, or chronic obstructive pulmonary disease (COPD) requiring
oxygen therapy.

- The subject is likely to be noncompliant or unreliable in providing ratings as judged
by the Investigator.

- The subject has evidence of clinically significant peripheral vascular disease as
evidenced by a history of intermittent claudication or evidence of vascular ulcers,
including venous stasis ulcers.

- The subject is currently taking or has taken clonidine in any form other than
Clonidine Gel study drug (i.e., oral, transdermal patch) over the past 4 months.

- The subject has developed hypersensitivity or intolerance to clonidine.

- The subject is currently receiving any non-oral treatment that could affect
neuropathic pain.

- Subject has a history of malignancy within the past 5 years with the exception of
successfully treated non-metastatic basal cell or squamous cell carcinomas of the
skin and/or localized carcinoma in situ of the cervix.

- The subject has clinical evidence of pedal edema or venous stasis disease associated
with significant skin changes on physical examination.