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)

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Woerwag Pharma GmbH & Co. KG

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Nutritional and Metabolic Diseases [C18], Diseases [C] - Nervous System Diseases [C10]

Decision date (initial)

2026-02-18

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Funding sources

Wörwag Pharma GmbH & Co. KG

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Safety

To assess whether a 16-week combined treatment provides superior effects on symptoms of diabetic sensorimotor polyneuropathy, compared to both pooled and individual monotherapies, based on a structured analytic strategy.

Secondary objectives 7

1. To assess whether a combined treatment provides superior effects on symptoms of DSPN, after 4, 8 and 12 weeks of therapy, compared to both pooled and individual monotherapies, based on a structured analytic strategy
2. To assess whether a combined treatment over a 16-week treatment period provides superior effects on symptoms and neurological deficits of DSPN compared to both pooled and individual monotherapies
3. To assess whether a combined treatment provides superior effects on neurological deficits and on neurological function, compared to both pooled and individual monotherapies over a 16-week treatment period
4. To assess whether a combined treatment compared to both pooled and individual monotherapies provides superior effects on symptoms of DSPN over a 16-week treatment period
5. To assess whether a 16-week combined treatment provides superior effects on quality of life, compared to both pooled and individual monotherapies
6. To assess whether a combined treatment compared to both pooled and individual monotherapies provides superior effects on change in clinical status after 8 and 16 weeks of therapy and 2 weeks after the end of treatment
7. To assess the safety of a combined treatment compared to both pooled and individual monotherapies over a 16-week treatment period

Conditions and MedDRA coding

Diabetic sensorimotor polyneuropathy (DSPN)

Study design 4 periods

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 13

1. Written informed consent signed by the participants prior to any performance of trial-related screening procedures
2. Ability to follow trial restrictions
3. Ability to attend scheduled visits at the Investigator site for the duration of the trial.
4. Existence of a possibility to receive SMS
5. Male or female participants ≥18 years old at the time of screening
6. 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
7. 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
8. 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
9. 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
10. 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)
11. HbA1c ≤9.5 % at screening or at a time point between screening and randomization.
12. Willingness to avoid lifestyle changes or changes of diet during the trial (including start of drugs supporting weight loss)
13. 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

Exclusion criteria 24

1. 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
2. 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
3. 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).
4. 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
5. History of a disease (including cardiovascular, pulmonary, gastrointestinal, hematologic, or endocrine disease, or malignancy) that could potentially cause neuropathic pain or symptoms
6. Maximum neuropathic pain level > 9 over the previous 4 weeks on a NRS as assessed at screening
7. Magnesium deficiency at screening which cannot be compensated until randomization
8. 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
9. Treatment with cutaneous electrical nerve stimulation, muscle stimulation, or 8 % capsaicin patch within the last 2 months prior to randomization.
10. Treatment with glucagon-like peptide-1 receptor agonists (GLP-RA) within the last 12 months prior to randomization
11. 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
12. Any contraindication to the use of the trial medication, including known allergy/hypersensitivity
13. Significant hepatic disease (AST or ALT ≥3 times of upper limit of normal)
14. Significant renal disease (eGFR <30 ml/min/1.73m2)
15. Uncontrolled hypertension (systolic blood pressure >160 mm Hg, or diastolic blood pressure >100 mm Hg), with or without anti-hypertensive medication
16. A major cardiovascular event, such as myocardial infarction or stroke, or an acute malignant disease in the 12 months prior to randomization
17. Severe or unstable depression or severe or unstable other psychiatric diseases with potential influence on trial endpoints, as judged by the Investigator
18. Current treatment with antidepressants (except stable duloxetine or selective serotonin reuptake inhibitors)
19. Any other existing medical conditions, likely to affect the trial measures, as judged by the Investigator
20. 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)
21. 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)
22. Participation in another interventional clinical trial within 2 months preceding randomization. Participation in registries is allowed
23. Living in the same household with another participant of this trial
24. Pregnant or nursing women at screening

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Change from baseline measurement to day 112 in neuropathy symptom characteristics

Secondary endpoints 12

1. Change from baseline measurement to day 28, day 56, and day 84 in neuropathy symptom characteristics
2. Change from baseline measurement to day 112 in neuropathy symptoms and neurological deficits
3. Change in sural nerve conduction velocity and sural sensory nerve action potential amplitude from baseline measurement to day 112
4. Change in the Neuropathy Disability Score (NDS) from baseline measurement to day 56 and day 112
5. Change in the Neuropathy Total Symptom Score-6 from baseline measurement to day 27, 55, 83 and 111
6. Changes in maximum pain assessed by NRS (4 weeks) from baseline measurement to day 56 and day 112
7. Changes in Quality of Life from baseline measurement to day 112
8. Effects on Patient Global Impression of Change score on days 56, 112, and 126
9. Treatment emergent adverse events (TEAE)
10. Subjective tolerability by physician and participant, evaluated at day 112
11. Changes in vital signs (seated blood pressure and heart rate) from baseline measurement (day 0) to days 56 and 112
12. Changes in safety laboratory data (blood parameters) from screening to day 112

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Comparator 2

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Woerwag Pharma GmbH & Co. KG

Sponsor organisation

Woerwag Pharma GmbH & Co. KG

Address

Flugfeld-Allee 24, Flugfeld Flugfeld

City

Boeblingen

Postcode

71034

Country

Germany

Scientific contact point

Organisation

Woerwag Pharma GmbH & Co. KG

Contact name

Dr. Susann Hofmockel

Public contact point

Organisation

Woerwag Pharma GmbH & Co. KG

Contact name

ARIEL Trial

Third parties 5

Locations

1 EU/EEA country · 10 investigational sites

By country

Investigational sites

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 13 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

2 submissions — initial application plus substantial / non-substantial modifications