G63.2
Conditions
Interventions
Group 1: Milgamma mono 300 (API: Benfotiamine),
2x 300 mg daily for 12 months
Group 2: Placebo
Sponsors
WÖRWAG Pharma GmbH & Co. KG
Eligibility
Sex/Gender
All
Age
18 Years to No maximum
Inclusion criteria
Inclusion criteria: • Informed consent signed and dated • Diabetes mellitus type 2 according to the American Diabetes Association criteria (2017), lasting =1 year • Stable diabetes metabolism, defined as no metabolic decompensation within the last 3 months (severe hypoglycemia with unconsciousness, ketoacidosis) • According to the investigator’s opinion no further optimizing potential in diabetic control • Age: =18 years • Neuropathic symptoms =6 months • Presence of mild to moderate diabetic sensorimotor polyneuropathy (DSPN) with Neuropathy Disability Score (NDS) 3-8 points confirmed by at least one of the following: reduced sural sensory nerve conduction velocity (SNCV), sural sensory nerve action potential (SNAP), peroneal motor nerve conduction velocity (MNCV), tibial MNCV • Measurable sural SNCV, peroneal MNCV or tibial MNCV above detection limit • CNFL <1SD below the mean of control subjects • At least 1 palpable pulse of posterior tibial artery or dorsal artery on each side of the foot • Stable diabetes medication without optimizing potential • Stable insulin dose for insulin-dependent patients within the last 3 months • HbA 1c <9.5% • Acceptable contraceptive measures with female patients in childbearing potential Ability to meet the study center visits for the study duration
Exclusion criteria
Exclusion criteria: • Subjects with secondary forms of diabetes such as due to pancreatitis • Contraindications, known allergy, or hypersensitivity to benfotiamine or other ingredients of the study medication or local anesthetics • Neuropathy of any cause other than diabetes which might interfere with neurological assessment • Severe pain other than of neuropathic origin that might impair the assessment of neuropathic pain • Diseases with mixed pain components • Pain level >9 over 24 h on a numerical 11-Point rating scale • Proximal asymmetric neuropathy or neuropathic symptoms of the trunk or proximal lower limbs • Foot ulcer or infection • Currently active or history of alcohol abuse (defined as an intake of more than 24 units of alcohol per week; one unit of alcohol equals approximately 250 ml of beer, 100 ml of wine or 35 ml of spirits) or drug addiction (including soft drugs like cannabis products) • Peripheral arterial occlusive disease Fontaine stage II-IV • Neoplasms • Chronic kidney disease with severely decreased estimated glomerular filtration rate (eGFR) 95 mmHg and/or SBP >160 mmHg), unless clearly documented to be white-coat hypertension • Clinical or laboratory evidence of hepatic dysfunction or disease; laboratory evidence defined as any of the following parameters: alkaline phosphatase, ALT, AST or bilirubin >3x ULN, except for a mild rise in bilirubin considered to be due to Gilbert’s condition. • Generalized immune diseases (e.g. HIV-positive, autoimmune diseases, connective tissue diseases) • Endocrine diseases like hyper- or hypothyroidism • Treatment, lasting at least 5 days or longer, with alpha-lipoic acid, B-vitamins, evening primrose oil, or deproteinized hemoderivates of calf blood, containing low-molecular weight compounds of up to 5.000 Da or with other substances with interaction to the study product (e.g. 5-fluorouracil) or affecting study endpoints within the last 3 months before screening, except for daily intake of B-vitamins amounting to less than 1500 % of the recommended daily allowance (RDA) lasting until one month prior to screening. • Treatment with cutaneous electrical nerve stimulation, muscle stimulation or acupuncture within the last month • Treatment of neuropathic pain with antidepressants, anticonvulsants, sodium channel blockers, opioids, neuroleptics, and capsaicin 8% patch within the last 3 months prior to screening, except for a monotherapy with Gabapentin, Pregabalin or Duloxetin without relevant dose change within the last 2 months prior to screening and during the study • Mental, psychiatric or other conditions compromising data collection and understanding of written or oral instructions during the study • Present or previous chronic alcohol abuse and/or abuse of other drugs • Pregnant women or nursing mothers • Participation in another clinical trial study within the last 3 months • Ability and willingness to abstain from alcohol and from engaging in strenuous physical activity from
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Corneal confocal microscopy (CCM): corneal nerve fiber length (CNFL) (Baseline and after 6 and 12 months) | — |
Secondary
| Measure | Time frame |
|---|---|
| The following Parameter at baseline and after 6 and 12 months: Morphometric assessment • Corneal nerve fiber density (CNFD), corneal nerve branch density (CNBD) • Skin biopsy • Motor and sensory nerve conduction velocity • Vibration perception threshold (VPT) • Warm and cold thermal detection thresholds (TDT) at the thenar eminence and dorsum of the foot (TSA II) • Cardiovascular autonomic function tests • Spontaneous baroreflex sensitivity (BRS) (Finometer • Pupillography (AMTech): latency, reaction time, baseline diameter, amplitude, contraction time, dilatation time • Neuropad (quantitative and qualitative color change) (TrigoCare) • Sudoscan (Impeto Medical): Electrochemical skin conductance (ESC) of both hands and feet Skin function tests • Lightguide tissue spectrophotometry (O2C) • Skin autofluorescence (AGE Reader) Clinical examination and questionnaires • Neuropathy Disability Score (NDS) • Neuropathy Impairment Score – Lower Limbs (NIS-LL; subscore sensory function, reflexes) • Michigan Neuropathy Screening Instrument (MNSI, examination part) • Modified Toronto Clinical Neuropathy Score (mTCNS) • Neuropathy Symptom Score (NSS) • Total Symptom Score (TSS) • Neuropathic Pain Symptom Inventory (NPSI) • 11-Point numerical pain rating scale (day, night, 24 h) • Brief Pain Inventory (BPI) • Survey of Autonomic Symptoms (SAS) General health, safety, and economic evaluation • Patient Global Impression of Change (PGIC) • Physical functioning (BPI) • Quality of life (EQ-5D-5L) • Short Form 36 (SF-36) Health Survey • PHQ-9 depression questionnaire • MOS-12 Sleep Scale • Questionnaire on health-related resource use and expenditure • Cost-utility analysis (CUA) • Safety and tolerability Blood samples Safety analysis [Technical Laboratory, Thiamine analytics in whole blood [external certified laboratory] • Biomarkers of inflammation in serum/plasma [Research Group Inflammation, -- Pro- and anti-inflammatory cytokines, ch | — |
Countries
Germany
Contacts
Public ContactGidon Bönhof
Deutsches Diabetes Zentrum
Outcome results
None listed