Efficacy of A Non-Invasive Botulinum Toxin Microneedle Pad for the Treatment of Secondary Raynaud's Phenomenon

Phase 3Not Yet RecruitingNCT07759557

Khon Kaen University72 enrolled

Overview

Raynaud's Phenomenon (RP), a vasospastic disorder causing digital ischemia and potential tissue necrosis, is effectively treated with Botulinum Toxin Type A (BTX-A) in refractory cases. However, standard administration requires painful, invasive injections that risk infection and localized muscle weakness. To address these limitations, this randomized, placebo-controlled, parallel-group study evaluates a microneedle delivery system designed to reach the dermis while avoiding systemic circulation. By penetrating 70-80% of their height, these microneedles aim to improve hand function and symptom scores for adult systemic sclerosis patients through a more comfortable, portable, and less invasive method that increases delivery surface area while minimizing pain.

Background Botulinum toxin-A (BTX-A) has demonstrated effectiveness in treating Raynaud's phenomenon in systemic sclerosis (RP-SSc) by improving hand function and condition scores. The current standard of care requires BTX-A to be administered via multiple, painful invasive injections, which carry recognized risks including local infection at injection sites and transient localized intrinsic hand muscle weakness due to toxin diffusion. Microneedles are developed to reduce injection pain and provide a less invasive method than conventional injections. This study evaluates the efficacy and adverse reactions of a BTX-A microneedle pad compared with 2% topical isosorbide dinitrate (ISDN) cream for the treatment of RP-SSc. The microneedles are specifically designed to penetrate the epidermis and reach the dermis layer. This design facilitates localized drug delivery while ensuring the needle tips do not reach blood vessels, preventing the drug from entering systemic circulation. The microneedle array is engineered with an evaluated penetration depth of around 70-80% of its height. The targeted insertion sites for the microneedles are located on the lateral and slightly dorsal aspects of the proximal finger base. Study Design and Treatment Arms The trial is a randomized, placebo-controlled, parallel-group study. Group A (Botox) receives a one-time BTX-A microneedle pad (10 units per pad) applied once on the affected hand plus topical placebo cream applied three times daily. Group B (Nitrate) receives a placebo microneedle pad (normal saline) applied once plus 2% topical ISDN cream applied three times daily. Drug Preparation and Administration The investigational BTX-A product is supplied as a sterile, vacuum-dried powder in a single-use vial containing 100 Units, which is reconstituted with 0.9% sterile, preservative-free sodium chloride to achieve a concentration of 10 units/mL. The medication is divided and administered to both lateral sides of the digits, with 5 units (0.5 mL) administered per side. The 2% ISDN topical emulsion is compounded by mixing the crushed equivalent of 400 sublingual tablets (5 mg per tablet) with 85 g of a semisolid hydrophilic base. The ISDN preparation is divided into 10 g units and assigned a 6-month expiration date when stored at temperatures between 2 and 8°C. Study Procedures and Follow-up Schedule Baseline evaluations include medical history, serological tests, demographic data, vital signs, physical examinations, clinical characteristics of SSc, concomitant medications, and comorbidities. Routine laboratory assessments include complete blood count, erythrocyte sedimentation rate, c-reactive protein, renal function, liver function, urinalysis, creatine kinase, thyroid function test, chest radiography, pulmonary function test, and echocardiography. Follow-up evaluations occur at Week 1, Week 4, and Week 12 post-treatment to monitor vital signs, physical examinations, clinical characteristics of SSc, routine laboratory assessments, concomitant medications, drug compliance, and complications such as intrinsic hand muscle weakness. Withdrawal, Rescue Therapy, and Termination CriteriaParticipants will be withdrawn from the study if they develop active systemic infection, localized infection at microneedle pad sites, serious adverse events relating to BTX-A (such as weakened hand grip or paresthesia), severe local allergic reactions, intolerable pain from microneedle application, inability to tolerate wearing the patch until full absorption, worsening Raynaud's phenomenon, new digital ulcers, gangrene, severe headache, need for hospitalization, undergo hand surgery during the study, or self-withdraw. Participants withdrawn due to severe Raynaud's phenomenon or increased digital ulcer size will receive rescue therapy with a systemic vasodilator. Participants requiring rescue medication will continue to be followed for the full 12-week study period, and their data will be included in the Intention-to-Treat (ITT) analysis in compliance with ICH-GCP E6 (R3). The study will be terminated if the prevalence of serious adverse events (weakened hand grip, paresthesia) in the BTX-A microneedle pad group exceeds 20% (7 cases), or if 15% of enrolled participants (6 cases) experience intolerable pain from the pad, bleeding, or local infection.

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

Inclusion Criteria: 1. SSc patients aged between 18 and 70 years 2. Diagnosed according to ACR/EULAR 2013 classification criteria20 3. Having RP with/without DU on fingers or toes 4. Understand and able to read and write Thai language 5. Stable steroid, immunosuppressant, and vasodilator including CCB, PDE5i for at least 4 weeks before enrollment Exclusion Criteria: 1. History of allergy or hypersensitivity to Botulinum toxin or ISDN 2. Overlap with other connective tissue diseases 3. Documented having peripheral arterial disease or vasculitis that affected vascular supply of fingers or toes 4. Current use of 2% ISDN cream for treatment of RP 5. Current use vasoconstrictor or medication that has vasoconstrictor effect such as ergotamine sulfate, beta-blocker 6. Pregnancy and lactating patients 7. Bedridden and confined to no self-care 8. Evidence of active malignant disease 9. Active infection or sepsis 10. Localized infection of hand 11. Impaired of intrinsic muscle hand function 12. Active smoker 13. Prior upper extremity vascular surgery, including surgical sympathectomy within 1 month before enrollment

Outcomes

Primary Outcomes

Change from baseline in distal digit temperature at 4 Weeks

The change in distal digit temperature is evaluated using an infrared thermometer from baseline to 4 weeks after treatment.

Time frame: Baseline and 4 weeks after treatment

Secondary Outcomes

Change from baseline in Raynaud's Phenomenon pain severity score on the Visual Analogue Scale (VAS)

The change in pain severity related to Raynaud's phenomenon is assessed using the Visual Analogue Scale (VAS). The VAS ranges from a minimum value of 0 to a maximum value of 100, where 0 represents no pain and 100 represents the worst imaginable pain. Higher scores indicate a worse outcome (greater pain intensity).

Time frame: Baseline to 1 week, baseline to 4 weeks, and baseline to 12 weeks after treatment

Number of participants experiencing local adverse events at the application site

The safety and tolerability of the intervention are evaluated by recording the number of participants who develop localized adverse events (including erythema, bleeding, dermatitis, local infection, or intolerable pain) at the microneedle pad application site.

Time frame: 1 week, 4 weeks, and 12 weeks after treatment

Change from baseline in Raynaud's Condition Score (RCS)

The daily clinical severity and frequency of Raynaud's phenomenon attacks are evaluated using the Raynaud's Condition Score (RCS). The RCS is a self-assessment scale ranging from 0 to 10, where 0 represents no difficulty or severity and 10 represents extreme difficulty or severity. Higher numerical values indicate greater symptom severity and functional impairment.

Time frame: Baseline to 1 week, baseline to 4 weeks, and baseline to 12 weeks after treatment

The progression of Raynaud's phenomenon (RP) to digital ulcer (DU)

The progression of RP to DU using numbers of DU at 1, 4 , and 12 weeks after treatment

Time frame: 1, 4, and 12 weeks

The progression of Raynaud's phenomenon (RP) to digital ulcer (DU)

The progression of RP to DU using size in mm of DU at 1, 4 , and 12 weeks after treatment

Time frame: 1, 4 , and 12 weeks after treatment

The progression of Raynaud's phenomenon (RP) to digital ulcers (DUs)

The net ulcer burden of digital ulcers using Digital Ulcer Clinical Assessment Score (DUCAS) from 0-68 at 1, 4 , and 12 weeks after treatment. The higher Digital Ulcer Clinical Assessment Score values reflects a higher degree of symptom intensity

Time frame: 1, 4 , and 12 weeks after treatment

The clinical benefit and safety of microneedle pad

The clinical benefit and quality of life are evaluated using the EuroQol 5-Dimension 3-Level (EQ-5D-3L) questionnaire, which consists of two parts. The first part comprises five specific dimensions: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Each dimension has 3 levels: 1 (no problems), 2 (some problems), and 3 (extreme problems). Selecting a level for each dimension generates a 5-digit health state profile (e.g., 11223). This profile ranges from a minimum value of 11111 to a maximum value of 33333, where higher numerical profiles indicate a worse outcome. The second part features a standard 20-cm vertical Visual Analogue Scale where patients self-rate their overall health. The Visual Analogue Scale ranges from a minimum value of 0 ("the worst health you can imagine") to a maximum value of 100 ("the best health you can imagine"), where higher scores indicate a better outcome.

Time frame: 1, 4, and 12 weeks after treatment

The clinical benefit and safety of microneedle pad

The clinical benefit and safety of microneedle pad by healthy assessment using Scleroderma Health Assessment Questionnaire (SHAQ) at 1, 4, and 12 weeks after treatment. The scores range from 0 to 3 for each symptom, with higher numerical values reflecting a higher degree of symptom intensity.