The Efficacy and Safety of Clonidine Hydrochloride Topical Gel, vs Clonidine Hydrochloride Gel Comparator to Treat Painful Diabetic Neuropathy

Inclusion Criteria:

1. Subject is fluent in English and has provided written informed consent.

2. Subject is an outpatient ≥18 years of age at the time of the Screening Visit.

3. Subject has Type 1 or Type 2 diabetes mellitus with a hemoglobin A1C value < 10% andhas been stable on therapy (diet, oral anti-hyperglycemic, and/or insulin) for atleast six (6) months prior to the Screening Visit.

4. Subject is a male or non-pregnant, non-lactating female. Females must be practicing anacceptable method of birth control or be surgically sterile or postmenopausal (amenorrhea for ≥12 months). A negative pregnancy test at the Screening and Day 1visits is required for females of child-bearing potential. Double-barrier methods,hormonal contraceptives, and abstinence are acceptable birth control methods for thisstudy.

5. Subject has chronic pain attributable to a symmetrical stocking distributionneuropathy in the lower extremities for at least six (6) months. Pain should beclearly localized to the area of neuropathy (feet), and subjects should be able todistinguish the target pain from other painful areas and conditions.

6. Subject has an average pain score relevant to the target pain in the feet of ≥4 on an 11 point numerical pain rating scale over the previous 24 hours at the ScreeningVisit.

7. Subject meets a pre-specified, minimum numerical pain rating scale score followingcapsaicin skin challenge.

8. Subject must satisfactorily complete Accurate Pain Reporting and Minimizing PlaceboResponse Training.

9. Subject must have moderate to severe pain during the Screening Run-in Phase.

10. Subjects must be 75 to 110% compliant with application of study drug during theScreening Run-in Phase

11. Subject has been medically stable for at least 30 days prior to the Screening Visit,and in the opinion of the Investigator, is in otherwise good general health based onmedical history, physical examination, electrocardiogram, and laboratory evaluation.

Exclusion Criteria:

1. Subject has neuropathy secondary to non-diabetic causes in the opinion of theInvestigator (e.g., vasculitis, familial neuropathy, alcoholism, pernicious anemia,hepatitis, malignancy, chronic inflammatory demyelinating polyneuropathy [CIDP], humanimmunodeficiency virus [HIV], medication-induced neuropathy, vitamin B12 deficiency).

2. Subject has a significant neurological disorder or condition that might confoundassessment of painful diabetic neuropathy (e.g., stroke with distal neurologicaldeficit, mononeuritis multiplex, lumbar radiculopathy).

3. Subject has a confounding disorder as determined by the Algorithm for ExcludingDisorders that Masquerade as Painful Diabetic Neuropathy.

4. Subject has other sustained pain with intensity at or greater than the bilateralneuropathic pain in the feet.

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

6. Subject is hypotensive with a resting diastolic blood pressure <60 mm Hg or a systolicblood pressure <90 mm Hg at the Screening or Day 1 Visit.

7. The subject has recent history (within the past 3 months) or current symptoms oforthostatic hypotension.

8. Subject has a history of foot or toe amputation or an active foot or toe ulcer.

9. Subject has any significant or unstable medical or psychiatric condition that, in theopinion of the Investigator, would interfere with his/her ability to participate inthe study.

10. Subject has a history of substance abuse disorder as defined by the Diagnostic andStatistical Manual of Mental Disorders, 5th Edition, within the past year, has currentevidence of substance abuse disorder, is receiving medical treatment for drug abuse,or has a positive urine drug screen for a non-prescribed substance of abuse.

11. Subject is receiving or has received within 30 days prior to the Screening Visit anyprohibited medications or is anticipated to receive after the start of the trial anynew prescription medication for their painful diabetic neuropathy. Subjects may beenrolled if stable on therapy for painful diabetic neuropathy.

12. Subject has symptomatic or severe coronary insufficiency, clinically significantcardiac conduction disturbances, myocardial infarction (within last 12 months),moderate to severe cerebrovascular disease, or severe chronic obstructive pulmonarydisease (COPD).

13. Subject has estimated creatinine clearance less than 50 mL/min (Cockcroft Gault) atthe Screening Visit.

14. Subject has serum alanine transaminase (ALT) or aspartate transaminase (AST) >3.0times the upper limit of normal or total bilirubin concentrations >2.0 times the upperlimit of normal at the Screening Visit.

15. Subject has received an investigational drug within 30 days prior to the ScreeningVisit.

16. Subject has been treated previously with clonidine topical gel or participated in aclonidine topical gel clinical study, including Study CLO 290.

17. Subject is currently taking or has taken clonidine (any formulation) over the past 4weeks.

18. Subject has known hypersensitivity or intolerance to clonidine.

19. Subject is receiving or has received ≤7 days prior to the start of the Screening Phase "alternative medicine" products or treatments (e.g., acupuncture, naturopathy,homeopathy, etc.) for management of pain.

20. Subject has a history of malignancy within the past 5 years except for successfullytreated non-metastatic basal cell or squamous cell carcinomas of the skin and/orlocalized carcinoma in situ of the cervix.

21. Subject is planning to have surgery during the course of the study.

22. Subject has significant skin changes on physical examination associated with eitherpedal edema or venous stasis disease.

23. Subject has any dermatologic condition of the lower extremities that could affectstudy drug absorption

24. Subject has current symptoms of depression with a Beck Depression Inventory II (BDIII) score >19 at the Screening Visit.