Please select the eligibility criteria that correspond to the clinical trial below.
Title: A 9-Month Open-Label Extension Study of the Long-Term Safety of DVS SR in Outpatients With Pain Associated With Diabetic Peripheral Neuropathy
Brief Summary: The purpose of the study is to learn if long-term treatment with DVS SR is safe for treating the pain and other symptoms associated with diabetic peripheral neuropathy.


Options:
A: Inclusion Criteria:

1. Signed Informed Consent. Patients must have willingness and complete competence to cooperate and language barriers must not preclude adequate understanding
2. Diabetes mellitus (Type I or II), as defined by the American Diabetes Association 1997, lasting \> 1 year
3. Males or females 18 to 64 years (older patients are excluded because of age-related changes in reflexes, quantitative sensory testing endpoints, and nerve conduction endpoints)
4. Patient must have a symmetric sensory-motor peripheral polyneuropathy attributable to diabetes mellitus following a thorough evaluation for other causes of neuropathy determined by performing complete medical and neurological examinations including physical and neurological history, history of medications, history of exposure to other toxins, and laboratory studies
5. Severity of diabetic polyneuropathy must be Stage 1 or 2a
6. Insulin regimen, weight, diet, and activity level must be relatively stable in the opinion of the investigator (for example, HbA1C must not vary by more than ± 2 Vol.% within 6 months preceding the study i.e. if the index measure = 10% the range would be 8-12%)
7. NIS\[LL\]+7 tests ≥ 97.5 percentiles (corresponding to 4.43 transformed score points)
8. NIS\[LL\] ≥ 2 points (NIS\[LL\] is based on questions 17-24, 28, 29, 34, 35, and 37 of the NIS)
9. One of the following:

   * an abnormality of nerve conduction attributes in two separate nerves, i.e. ≥99th percentile for DL or ≤1st percentile for NCV or amplitude or
   * an abnormality of HRDB, i.e. ≤ 1st percentile
10. TSS (feet) ≤5
11. Females must either be surgically sterilised (tubal ligation, bilateral oophorectomy, or hysterectomy) or at least 1 year postmenopausal or practicing an acceptable method of contraception, including oral contraceptives with a stable regimen for at least two months, depo-medroxyprogesterone, a barrier method alone (diaphragm, condoms, or contraceptive sponge with spermicidals), or an IUD that has been in place for at least two months

Exclusion Criteria:

1. Patients with proximal asymmetric neuropathy, cranial neuropathies, truncal radiculopathy, pan dysautonomia, diabetic plexopathies, or acute or active mononeuropathies (including cranial neuropathies, post-herpetic neuralgias, etc.), the presence of which might obscure accurate assessment of severity of the diabetic polyneuropathy under assessment, with the exception of carpal tunnel syndrome (CTS) or tardy ulnar neuropathy (TUN) or both
2. Neuropathy of any cause other than diabetes mellitus which might interfere with the assessment of the severity of dPNP Other neurologic diseases that may produce weakness, sensory loss, or autonomic symptoms or test abnormality which might interfere with the assessment of the severity of dPNP Myopathy of any cause which might interfere with the assessment of the severity of dPNP
3. Peripheral vascular disease severe enough to cause intermittent claudication or ischemic ulcers or limb ischemia
4. Patients with a history of ophthalmological findings suggesting a high risk for visual loss i.e., significant maculopathy or proliferative retinopathy
5. Psychiatric, psychological, or behavioural symptoms that would interfere with the patient's ability to participate in the trial
6. Patients with any active neoplastic disease except basal cell carcinoma
7. Patients with atrial fibrillation unless controlled and stabilised by medication (changed to this criterion by Amendment 1)
8. Patients with clinically significant cardiac, pulmonary, gastrointestinal, hematologic, or endocrine disease (other than diabetes) that may confound interpretation of the study results or prevent the patient from completing the study
9. Patients who have had organ transplants of any kind
10. Patients with significant hepatic or renal disease (ASAT or ALAT \>2 times normal, serum creatinine \>1.8 mg/dL (\>159 µmol/l) for males or \>1.6 mg/dL (\>141 µmol/l) for females)
11. Patients with a recent history (within last 12 months) of drug or alcohol abuse
12. Use of any investigational drug within the last 6 months
13. History of severe or anaphylactic reaction to multiple drugs, sulfur products, or biologic products (changed to this criterion by Amendment 1)
14. Ketoacidosis or hypoglycaemia within last 3 months resulting in hospital admission
15. Antioxidant therapy (vitamins E \> 400IU, C \> 200mg, and beta-Carotene \> 30mg) or pentoxyphylline within last 1 month before start of trial
16. Use of evening primrose oil or any other gamma-linolenic acid containing substance within the last 3 months
17. Use of thioctic acid \> 50mg/day within last 3 months
18. History of use of medications or vitamins known to cause peripheral neuropathy including but not limited to use of phenytoin or carbamazepine over 15 or more years, or use of pyridoxine \> 100mg/d within the past 12 months
19. Bilateral sural nerve biopsies
20. Existing foot ulcers
21. Pregnant or lactating females
22. Continued use of medications listed in protocol 6.3.3 (first paragraph)
23. Medication non-compliance (deviation of more than ±10% of dosages to be taken (1 tablet/day))
B: Inclusion Criteria:

* Diagnosis of Type 2 diabetes mellitus
* Coronary arteriogram showing one or more vessels amenable to revascularization (greater than or equal to 50% stenosis)
* Objective documentation of ischemia OR subjectively documented typical angina with greater than or equal to 70% stenosis in at least one artery
* Suitability for coronary revascularization by at least one of the available methods (does not require the ability to achieve complete revascularization)
* Ability to perform all tasks related to glycemic control and risk factor management

Exclusion Criteria:

* Definite need for invasive intervention as determined by the attending cardiologist
* Prior bypass surgery (CABG) or prior catheter-based intervention within the 12 months before study entry
* Planned intervention for disease in bypass graft(s) if the patient is randomly assigned to a strategy of initial revascularization
* Class III or IV CHF
* Creatinine greater than 2.0 mg/dL
* HbA1c greater than 13%
* Need for major vascular surgery concomitant with revascularization (e.g., carotid endarterectomy)
* Left main stenosis greater than or equal to 50%
* Non-cardiac illness expected to limit survival
* Hepatic disease (ALT greater than 2 times the ULN)
* Fasting triglycerides greater than 1000 mg/dL in the presence of moderate glycemic control (HbA1c less than 9.0%)
* Current alcohol abuse
* Chronic steroid use judged to interfere with the control of diabetes, exceeding 10 mg of Prednisone per day or the equivalent
* Pregnancy, known, suspected, or planned in 5 years after study entry
* Geographically inaccessible or unable to return for follow-up
* Enrolled in a competing randomized trial or clinical study
* Unable to understand or cooperate with protocol requirements

Patients with Type 2 diabetes mellitus and CAD documented by coronary arteriography will be eligible for the trial if revascularization is not required for prompt control of severe or unstable angina. Diabetic patients who are being treated with insulin or oral hypoglycemic drugs will be eligible as well as diabetic patients treated with diet and exercise alone provided that a diagnosis of diabetes can be confirmed by record review or that a fasting plasma glucose (FPG) greater than 125/mg/dL (7.0 mmol/L) can be obtained. The determination of suitability for BARI 2D will be made by a physician-investigator at each participating institution on clinical grounds at the time of coronary angiography.

Significant CAD will be defined as at least one stenosis greater than 50%. Angina and ischemia will be assessed by use of patient self-report, physician examination, and appropriate diagnostic measures including exercise myocardial perfusion imaging, exercise echocardiography, exercise electrocardiography, and IV dipyridamole or adenosine myocardial perfusion imaging or invasively by doppler or pressure wire. Objective documentation of myocardial ischemia includes any of the following:

1. Exercise or pharmacologically-induced:

   1. Greater than or equal to 1 mm of horizontal or downsloping ST depression or elevation for greater than or equal to 60-80 milliseconds after the end of the QRS complex
   2. Myocardial perfusion defect
   3. Myocardial wall motion abnormality
2. Stabilized, prior acute coronary syndrome with CK-MB or troponin elevation or with new, greater than or equal to 0.5 mm ST depression or elevation, or T wave inversion of greater than or equal to 3 mm in 2 contiguous ECG leads
3. Doppler or pressure wire showing coronary flow reserve (CFR) less than 2.0 or fractional flow reserve (FFR) less than 0.75

Among patients without documented ischemia, only patients with stenosis greater than or equal to 70% presenting with classic anginal symptoms will be eligible for randomization.
C: Inclusion Criteria:

* Diabetes type 1 or 2
* Painful symptoms of diabetic neuropathy in the lower extremities extremities for at least 6 months

Exclusion Criteria:

* Major Depression
* Uncontrolled diabetes
D: Inclusion Criteria:

* Outpatients who have completed double-blind treatment in study 322 (NCT01050218) for DPN. Subjects must have completed all scheduled evaluations, with no major protocol violations and no events that, in the opinion of the investigator, would preclude the subject's entry into the long-term open-label study.
* Women of childbearing potential must have a negative serum pregnancy test on day 91 of the short-term study. A woman of childbearing potential is one who is biologically capable of becoming pregnant. "Biologically capable" includes women who are using contraceptives or whose sexual partners are either sterile or using contraceptives. Sexually active women participating in the study who are biologically capable of becoming pregnant must use a medically acceptable form of contraception during the study and for at least 15 days after the last dose of test article. Medically acceptable forms of contraception include oral contraceptives, transdermal, injectable, or implantable methods, intrauterine devices, or properly used double-barrier contraception, eg, condom plus diaphragm.

Exclusion Criteria:

* Presence of any new and/or clinically important medical condition that might compromise subject safety (including, but not limited to, significant changes in glycemic control).
* Pregnancy, lactation, or plans to become pregnant during the study.
* Use of prohibited treatments.
* Meets any of the exclusion criteria listed for study 322 (NCT01050218).

Answer: D