A randomized, double-blind, placebo-controlled study to assess the effects of high concentration capsaicin patch (Qutenza) on neuropathic symptoms, nerve fibers, and microcirculation in painful diabetic peripheral neuropathy

Trial ID: 2025-523597-17-00
Protocol: Q-HEAL-001
Sponsor: Deutsche Diabetes Forschungsgesellschaft e.V.

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Diseases & Conditions

Diabetic neuropathy

Objectives

The primary objective is to evaluate the efficacy of repeated treatment with capsaicin 8% cutaneous patch compared to placebo on skin innervation in patients with painful diabetic peripheral neuropathy. This objective addresses the fundamental question of whether repeated capsaicin application can modulate cutaneous nerve fiber density, which is clinically relevant for understanding the mechanism of action in neuropathic pain management and potential disease-modifying effects.

The secondary objectives include:

• To evaluate the efficacy of repeated treatment with capsaicin 8% cutaneous patch compared to placebo on cutaneous nerve regeneration
• To evaluate the efficacy of capsaicin 8% cutaneous patch compared to placebo on neuropathic symptom intensity and sleep interference
• To evaluate the efficacy of capsaicin 8% cutaneous patch compared to placebo on microcirculation and tissue oxygenation
• To evaluate the efficacy of capsaicin 8% cutaneous patch compared to placebo on sensory nerve function
• To evaluate the efficacy of single treatment with capsaicin 8% cutaneous patch compared to placebo on skin innervation
• To evaluate the effect of capsaicin 8% cutaneous patch compared to placebo on the cutaneous neurovascular network
• To evaluate the proportion of participants receiving capsaicin 8% cutaneous patch achieving a meaningful intensity reduction in neuropathic symptoms compared to placebo
• To evaluate the safety and tolerability of capsaicin 8% cutaneous patch compared to placebo, as measured by treatment-emergent adverse events, adverse events leading to study discontinuation and serious adverse events throughout the study
• To evaluate the use of rescue medication for neuropathic pain and the time to first intake of rescue medication following treatment with capsaicin 8% cutaneous patch

Participants

The sponsor did not provide information regarding the total number of participants enrolled in this clinical trial. The study population consisted of adults aged **18 to 80 years** with **diabetes mellitus** lasting at least one year and **painful diabetic sensorimotor polyneuropathy** (DSPN) of at least six months duration. Both **male** and **female** participants were included. Eligible individuals presented with pain in the feet and/or ankle caused by painful DSPN, with an average or maximum pain score of at least 4 points on the Numeric Pain Rating Scale within seven days before screening. Participants were required to have **dysesthesia** or **paresthesia** in the lower extremity caused by DSPN lasting at least six months, along with evidence of neuropathic deficits, abnormal nerve conduction studies, abnormal quantitative sensory testing, or reduced **intraepidermal nerve fiber density**. The trial population was selected based on documented diabetes according to American Diabetes Association criteria, with **HbA1c** levels below 10% at screening. Participants maintained stable glucose-lowering and analgesic treatment regimens for at least four weeks prior to enrollment and were required to keep their current analgesic treatment unchanged throughout the study duration. Female participants of childbearing potential were required to use acceptable contraceptive measures and demonstrate negative pregnancy tests at screening.

Plans and Procedures

This is a randomized, double-blind, placebo-controlled clinical trial designed to evaluate the effects of high concentration capsaicin patch (Qutenza 179 mg cutaneous patch) on neuropathic symptoms, nerve fibers, and microcirculation in patients with painful diabetic peripheral neuropathy. The study is classified as a Phase IV clinical trial. The primary objective is to evaluate the efficacy of repeated treatment with capsaicin 8% cutaneous patch compared to placebo on skin innervation. The trial will assess changes in intraepidermal nerve fiber density (IENFD) as well as various neuropathic pain measures, sensory testing parameters, and microcirculation markers.

Participants will be adults aged 18 to 80 years with diabetes mellitus lasting at least one year and painful diabetic sensorimotor polyneuropathy lasting at least six months. Eligible participants must have pain in the feet and/or ankle with an average or maximum Numeric Pain Rating Scale (NPRS) score of at least 4 points, presence of dysesthesia or paresthesia in the lower extremity, and evidence of neuropathic deficits or abnormal nerve conduction studies or reduced intraepidermal nerve fiber density. HbA1c levels must be below 10% at screening. Participants must be willing to maintain their current analgesic treatment unchanged during the study and must have a stable regimen of glucose-lowering and analgesic treatment for at least four weeks prior to screening.

The test product is Qutenza 179 mg cutaneous patch containing capsaicin for cutaneous use, with a maximum daily dose of 716 mg and a maximum treatment period of one day per application. The placebo is a capsaicin 0.04% cutaneous patch. The estimated recruitment start date is February 2026, with an estimated study completion date of March 2028.

The primary endpoint is the change from baseline in IENFD (PGP9.5) at the site with repeated treatment at Week 35 compared to placebo. Secondary endpoints include changes in IENFD with different markers (GAP-43), intraepidermal nerve fiber length (IENFL), and dermal nerve fiber length (DNFL) at Week 35, changes in pain and neuropathy symptom scores (NPRS, PDQ7, NPSI, TSS, NSS) and quality of life measures (MOS-12) at Weeks 11, 25, and 35, changes in laser Doppler flowmetry (LDF) and tissue oxygenation, changes in quantitative sensory testing (QST) and monofilament testing, changes in skin biopsy vascular markers, and the proportion of participants with symptom improvement. Safety endpoints include the number and severity of treatment-emergent adverse events (AEs), serious adverse events (SAEs), and the use of rescue medication.

The study involves multiple visits throughout the trial duration. The screening visit includes assessment of eligibility criteria, medical history, physical examination, nerve conduction studies or quantitative sensory testing, skin biopsies for baseline nerve fiber density assessment, and pregnancy testing for women of childbearing potential. Follow-up visits occur at Week 11, Week 25, and Week 35, during which repeated assessments of pain scores, neuropathy symptoms, sensory function, microcirculation parameters, and skin biopsies are performed. The treatment phase involves application of the capsaicin patch or placebo at baseline and repeated treatment at specified intervals. The end-of-study visit occurs at Week 35 and includes final assessments of all efficacy and safety parameters, including skin biopsies for nerve fiber density and vascular marker analysis.

The expected duration of participant involvement is approximately 35 weeks from randomization to the final study visit. Participants may be withdrawn from the study early if they experience unacceptable adverse events, require prohibited concomitant medications, fail to comply with study procedures, withdraw consent, become pregnant during the study, or if the investigator determines that continuation is not in the participant's best interest. Early termination may also occur if there are significant changes in the participant's analgesic regimen that cannot be maintained stable throughout the study period.

Treatment

The experimental treatment consists of Qutenza, a high-concentration capsaicin 8% cutaneous patch containing 179 mg of the active substance. Capsaicin is a chemical substance administered via cutaneous use. The maximum daily dose is 716 mg, with a maximum total dose of 716 mg per treatment application. The maximum treatment period is 1 day per application cycle. The study involves repeated treatment applications with the capsaicin patch. Qutenza is manufactured by Grünenthal GmbH and holds marketing authorization under the centralized procedure with the authorization number EU/1/09/524/002.

The placebo treatment consists of a capsaicin 0.04% cutaneous patch, which serves as the control comparator in this randomized, double-blind, placebo-controlled study. This low-concentration formulation is designed to maintain blinding while providing minimal active treatment effect compared to the experimental high-concentration capsaicin patch. The placebo patch is administered via the same cutaneous route as the active treatment to ensure methodological consistency and participant blinding throughout the trial.

Efficacy

Efficacy will be assessed through multiple parameters evaluating nerve fiber changes, neuropathic symptoms, and microcirculation in painful diabetic peripheral neuropathy. The primary endpoint is the change from baseline in intraepidermal nerve fiber density (IENFD) measured by PGP9.5 immunostaining at the site with repeated treatment at Week 35 compared to placebo. Secondary endpoints include changes from baseline in IENFD measured by GAP-43, intraepidermal nerve fiber length (IENFL), and dermal nerve fiber length (DNFL) using both PGP9.5 and GAP-43 markers at the site with repeated treatment at Week 35 compared to placebo. Additional assessments of nerve fiber parameters will be conducted at Week 11 and Week 35 at the site with single treatment only. Skin biopsy analysis will measure CD31 area and CD31-PGP9.5 co-localization at sites with single and repeated treatment, evaluating changes from baseline and from Week 10 at Week 35 compared to placebo.

Clinical symptom assessments will be performed using validated instruments at multiple timepoints. Changes from baseline in the Numeric Pain Rating Scale (NPRS), Pain Detect Questionnaire (PDQ7), Neuropathic Pain Symptom Inventory (NPSI), Total Symptom Score (TSS), Neuropathy Symptom Score (NSS), and Medical Outcomes Study 12-Item Short Form (MOS-12) will be evaluated at Week 11, Week 25, and Week 35 compared to placebo. The proportion of participants achieving improvement in NPRS, PDQ7, NPSI, TSS, and NSS items reflecting the intensity of general pain, burning pain, pressing pain, paroxysmal pain, evoked pain, dysesthesia, and paresthesia, if present at baseline, will be determined at the end of the study compared to placebo.

Microcirculation and sensory function will be assessed through laser Doppler flowmetry (LDF), tissue oxygenation measurements, quantitative sensory testing (QST), and monofilament testing at both standard and treated sites. Changes from baseline in these parameters will be evaluated at Week 11 and Week 35 compared to placebo. Additional efficacy-related outcomes include the proportion of participants requiring rescue medication, the frequency and amount of rescue medication used, and the time to first intake of rescue medication since randomization compared to placebo.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Written informed consent signed and dated
Diabetes mellitus according to the American Diabetes Association criteria (2017), lasting ≥1 year
Age: 18-80 years
Presence of painful diabetic sensorimotor polyneuropathy (DSPN) as judged by the investigator lasting ≥6 months
Presence of pain in the feet and/or ankle caused by painful DSPN as diagnosed by the investigator with an average or maximum NPRS of ≥4 points within 7 days before screening
Presence of dysesthesia or paresthesia in the lower extremity caused by DSPN as diagnosed by the investigator lasting ≥6 months
Presence of either i) neuropathic deficits in the lower extremity (reduced or absent achilles tendon reflexes, vibration sensation, temperature detection, pain perception, pressure sensation), ii) ≥1 abnormal nerve conduction study parameter in lower extremity peripheral nerves (reduced or not evoked peroneal or tibial motor nerve conduction velocity or sural sensory nerve conduction velocity or amplitude), iii) ≥1 abnormal quantitative sensory test at the lower extremity (temperature detection threshold, vibration perception threshold), or iv) reduced intraepidermal nerve fiber density at screening
HbA1c <10% at screening
If applicable, stable regimen of glucose-lowering and analgesic treatment for DSPN within 4 weeks prior to screening as judged by the investigator
Willingness to maintain current analgesic treatment unchanged during the course of the study
Ability and willingness to meet the study center visits and to undergo study procedures during the whole study duration
If applicable, willingness to take acceptable contraceptive measures by female participants in childbearing potential during the treatment phase
If applicable, negative urine pregnancy test by female participants in childbearing potential at screening

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Exclusion Criteria

Presence of pain caused by other conditions not clearly differentiated from pDPN as judged by the investigator
Conditions that might interfere with the assessment of pDPN as judged by the investigator
History of foot ulcers within the last 6 months prior to screening
History of amputations at the lower extremity excluding minor amputations due to traumatic events not related to diabetic foot syndrome
Treatment with Capsaicin 179 mg/8% patch within the last 6 months prior to screening or with any other topical analgesic pain treatment on the areas affected by neuropathic pain due to painful DSPN within the last 3 months prior to screening.
Concomitant analgesic treatment for painful DSPN with more than two substances, with medium or high potency opioids, or with electrical stimulation within the last 3 months prior to screening.
Substantial change in analgesic treatment regimen during the study as judged by the investigator
Contraindications, known allergy, or hypersensitivity to capsaicin or other ingredients of the study medication or local anesthetics
Average daily pain level ≥9 points NPRS within 7 days before screening
Intraepidermal nerve fiber density at screening <1 fiber/mm
Treatment with coumarins or heparin in a therapeutic dose or other contraindications against obtaining skin biopsies at the distal calf
Pregnant women or nursing mothers
Participation in another clinical trial study within the last 3 months prior to screening
Neoplasms, except for basal cell carcinoma (basalioma) or low-grade prostate cancer within 12 months prior to screening
Currently active or history of alcohol use disorder (>24 units of alcohol per week) or other substance-use disorders as judged by the investigator within the last 5 years
Uncontrolled high blood pressure (DBP >95 mmHg and/or SBP >160 mmHg), unless clearly documented to be white-coat hypertension, at screening
Severe resting tachycardia (HR >110 bpm) at screening
Mental, psychiatric or other conditions compromising data collection or understanding of written or oral instructions during the study