Efficacy and safety of a combined therapy in the symptomatic treatment of diabetic sensorimotor polyneuropathy - a prospective, randomized, controlled, parallel group, double-blind, double-dummy 3-arm trial (ARIEL)

Ki vehet részt

• Written informed consent signed by the participants prior to any performance of trial-related screening procedures
• Diagnosed mild to moderate symptomatic DSPN defined by abnormal or non-evocable sural nerve conduction velocity and/or abnormal or non-evocable sural nerve action potential AND DSPN symptoms (signified by NTSS-6 >6) AND neuropathic signs (signified by NDS of 3-8)
• HbA1c ≤9.5 % at screening or at a time point between screening and randomization
• Willingness to avoid lifestyle changes or changes of diet during the trial (including start of drugs supporting weight loss)
• Participants must have completed and documented their baseline symptom assessment over seven consecutive days and the NTSS-6 questionnaire on the final day of symptom assessment, using the provided ePRO link, in accordance with the protocol-defined schedule within the seven days prior to the randomization visit
• Ability to follow trial restrictions
• Ability to attend scheduled visits at the Investigator site for the duration of the trial
• Existence of a possibility to receive SMS
• Male or female participants ≥18 years old at the time of screening
• Diagnosed diabetes type 1 or 2 (per American Diabetes Association criteria (ADA Standards of Care in Diabetes 2025)), with diagnosis established at least 1 year prior to screening
• Stable diabetes medication use (or stable insulin dose for insulin-dependent participants) in the last 3 months prior to screening, which is unlikely to be changed during the trial period, as judged by the investigator. In case of therapy with SGLT-2 inhibitors, the start of treatment must additionally be at least 26 weeks prior to screening
• Stable diabetes metabolism, defined as no metabolic decompensation within the last 3 months (severe hypoglycaemia with unconsciousness, hyperosmolar hyperglycemic state, or ketoacidosis) prior to randomisation
• Persistent or recurrent neuropathic symptoms (e.g., numbness, tingling, burning or stabbing pain, hypersensitivity) that have occurred at least within 3 months prior to randomization. These symptoms and their duration can be reported by the participant to the Investigator during anamnesis

Ki nem vehet részt

• Female participants with child-bearing potential not using any of the following effective birth control methods at least 2 months prior to randomization: a) oral contraceptives with a stable regimen; b) depomedroxyprogesterone; c) a double barrier method (either combining physical barrier methods e.g. condoms and diaphragm, or combining a physical barrier with a chemical barrier method, e.g. diaphragm/ condoms with spermicides); d) intrauterine device
• Treatment with glucagon-like peptide-1 receptor agonists (GLP-RA) within the last 12 months prior to randomization
• Any pharmacological treatment of chronic pain within the last 2 months prior to randomization. Exception is monotherapy with gabapentin up to 3000 mg/day, pregabalin up to 450 mg/day, or duloxetine up to 60 mg/day, without dose change within 2 months before randomization. For analgesia, standard doses of salicylates, ibuprofen or phenylacetic acid derivatives are allowed over a period of maximal 7 consecutive days, as well as rescue medication with paracetamol up to 3 g/day. Stable acetylsalicylic acid therapy in low doses for blood thinning purposes is also allowed
• A major cardiovascular event, such as myocardial infarction or stroke, or an acute malignant disease in the 12 months prior to randomization
• Current treatment with antidepressants (except stable duloxetine or selective serotonin reuptake inhibitors)
• Maximum neuropathic pain level > 9 over the previous 4 weeks on a NRS as assessed at screening
• Treatment lasting 5 days or longer with concomitant medication containing ALA, BEN B-vitamins, evening primrose oil, deproteinized hemoderivates of calf blood, or other drugs or supplements with potential influence on trial endpoints (e.g. antioxidants) within the last 2 months prior to randomization
• Treatment with cutaneous electrical nerve stimulation, muscle stimulation, or 8 % capsaicin patch within the last 2 months prior to randomization
• Any contraindication to the use of the trial medication, including known allergy/hypersensitivity
• Uncontrolled hypertension (systolic blood pressure >160 mm Hg, or diastolic blood pressure >100 mm Hg), with or without anti-hypertensive medication
• Severe or unstable depression or severe or unstable other psychiatric diseases with potential influence on trial endpoints, as judged by the Investigator
• Any other existing medical conditions, likely to affect the trial measures, as judged by the Investigator
• Neuropathy of any cause other than diabetes (e.g. vitamin B12 deficiency-, chemotherapy-, toxin-, drug- or autoimmune-induced neuropathies, peripheral neuropathies induced by damages of the spinal cord), myopathy, or other neurological diseases that might interfere with trial endpoints
• Currently active or history of alcohol abuse (defined as a regular intake of more than 24 units of alcohol per week for men and 12 units of alcohol per week for women; one unit of alcohol equals approximately 250 mL of beer, 100 mL of wine or 35 mL of spirits)
• Current or history of regular use of recreational drugs (except history of occasional or experimental cannabis use in the past, with no evidence of dependence)
• History of a disease (including cardiovascular, pulmonary, gastrointestinal, hematologic, or endocrine disease, or malignancy) that could potentially cause neuropathic pain or symptoms
• Significant hepatic disease (AST or ALT ≥3 times of upper limit of normal)
• Significant renal disease (eGFR <30 ml/min/1.73m2)
• Magnesium deficiency at screening which cannot be compensated until randomization
• Participation in another interventional clinical trial within 2 months preceding randomization. Participation in registries is allowed
• Living in the same household with another participant of this trial
• Pregnant or nursing women at screening
• Severe chronic pain of origin other than DPN which might interfere with the trial endpoints, based on medical history or physical examination (e.g. fibromyalgia)
• Bilateral lower extremity amputations (above the ankle). Individuals with unilateral lower extremity amputation may be included, provided that the remaining limb allows for reliable assessment of neuropathy-related endpoints and safe participation in study procedures