Diabetic Sensorimotor Polyneuropathy MedDRA version: 9.1 Level: LLT Classification code 10012685 Term: Diabetic polyneuropathy
Conditions
Interventions
Product Name: Ranirestat
Product Code: AS3201-G000-291
Pharmaceutical Form: Tablet
INN or Proposed INN: Ranirestat
CAS Number: 147254-64
Sponsors
Eisai Limited
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. Male or female subjects aged between 18 and 75 years old at screening 2. Subjects with type 1 or type 2, insulin-dependent or non insulin-dependent diabetes mellitus, with a diagnosis at least 12 months prior to screening 3. Subjects whose glycemic control has been optimized and stable for at least 3 months prior to screening. Optimal glycemic control refers to the best possible diabetic control that an individual subject can attain with usual standards of care. Stable control refers to no dose changes to existing medications for glycemic control (other than insulin) and no medications being initiated for glycemic control in the 3 months prior to screening 4. Subjects with a history of distal symmetric polyneuropathy, secondary to diabetes, diagnosed in accordance with the American Academy of Neurology criteria: • Abnormal nerve conduction velocity of the sural nerve (= 1st percentile, corrected for age; table will provided by the Neurological Core Laboratory in the manual of electrophysiological testing procedures). If recordings are technically acceptable, absent sural nerve responses provide clear evidence of an “abnormal” response. • Abnormal peroneal motor nerve conduction velocity (= 1st percentile, corrected for age; table will provided by the Neurological Core Laboratory in manual of electrophysiological testing procedures). Peroneal responses must be present, with an evoked compound muscle action potential in the extensor digitorum brevis muscle =500 µV. Peroneal motor nerve conduction velocity must be greater than a value defined as 20% of the lower limit of normal (e.g. if the lower limit of normal is 40 m/sec, peroneal motor nerve conduction velocity must be = than 32 m/sec). Peroneal motor nerve conduction velocity will be recorded bilaterally on two separate occasions within 1-21 days of each other during the prerandomization period; both sets of recordings must fulfil the above criteria. • Decreased/absent ankle reflexes AND/OR decreased distal sensation in the lower limbs • Neuropathy Total Symptom Score-6 = 1 (at visit 1 and at visit 2) 5. Female subjects, who are of non-reproductive potential (=12 months post-menopausal or surgically sterile) or who are using adequate contraception which includes abstinence or double barrier methods (diaphragm and condom with spermicidal cream, intrauterine device and condom with spermicidal cream). Male subjects with partners of child-bearing potential must also use adequate contraception 6. Subjects must be able to read, understand, and provide written informed consent before enrolling in the study at screening Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age range F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range
Exclusion criteria
Exclusion criteria: 1. History of diabetic foot ulcers (Wagner grade =1) or lower extremity amputation 2. Diabetic amyotrophy or non-diabetic cause of lower limb neuropathy/neuropathic symptoms (e.g.sequelae of cerebrovascular disease, lumbar radiculopathy, entrapment neuropathy etc) 3. Subjects with a history of hypothyroidism or B12/folate deficiency or subjects with a low serum folate, vitamin B12 or elevated thyroid-stimulating hormone at screening, as defined by the central laboratory normal limits range 4. History or evidence of drug or alcohol abuse 5. History of known or suspected diagnosis of acquired immune deficiency syndrome, or who have tested seropositive for human immunodeficiency virus antibody or antigen previously 6. Significant cardiovascular disease such as: • Peripheral arterial occlusive disease (Fontaine Stage =IIa) • Clinically significant (in the opinion of the investigator) abnormal 12-lead electrocardiogram • New York Heart Association =class III heart failure 7. Significant hepatic disease, e.g. • Repeated alanine aminotransferase, aspartate transaminase, alkaline phosphatase > 2x the upper limit of normal at screening or total bilirubin >1.5x the upper limit of normal at screening • Positive result from hepatitis B or C screening tests or a history of a positive test at screening 8. History of hypoglycaemia resulting in loss of consciousness, diabetic ketoacidosis or hyperglycaemic hyperosmolar non-ketotic coma in the 3 months prior to screening 9. Morbid obesity (body mass index >40 kg/m2) at screening 10. Calculated creatinine clearance <50 mL/min at screening (see Appendix 2) 11. History of carcinoma within 5 years prior to screening, with the exception of basal cell carcinoma 12. Current major depressive disorder, bipolar disorder or a past history of suicide attempt or deliberate self-harm 13. Subjects who have received an investigational medicinal product within 3 months prior to the screening visit or subjects who have participated in a previous study with ranirestat 14. Clinically significant illness (e.g. unstable pulmonary, hematologic, renal, neurological or psychiatric disease etc) which, in the opinion of the investigator, would compromise a subject’s suitability to participate in the study for reasons of safety or would confound the efficacy assessments
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Secondary Objective: 1. To determine the effect of 40 mg and 80 mg ranirestat relative to placebo on signs and symptoms of diabetic sensorimotor polyneuropathy 2. To evaluate overall safety and tolerability of 40 mg and 80 mg ranirestat ; Main Objective: To determine the effect of 40 mg and 80 mg ranirestat on peroneal motor nerve conduction velocity relative to placebo in subjects with mild to moderate diabetic sensorimotor polyneuropathy ; Primary end point(s): Change from baseline in peroneal motor nerve conduction velocity relative to placebo at 24 months on the full analysis population. | — |
Countries
Belgium, Estonia, Hungary, United Kingdom
Outcome results
None listed