Efficacy of A Non-Invasive Botulinum Toxin Microneedle Pad for the Treatment of Secondary Raynaud's Phenomenon (Botox SSc-RP)
Efficacy of A Non-Invasive Botulinum Toxin Microneedle Pad for the Treatment of Secondary Raynaud's Phenomenon and Digital Ulcers in Systemic Sclerosis: A Randomized Placebo-Controlled Trial
Study Overview
Status
Intervention / Treatment
Detailed Description
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.
Study Type
Enrollment (Estimated)
Phase
- Phase 3
Contacts and Locations
Study Contact
- Name: Chingching Foocharoen, MD
- Phone Number: 66906784212
- Email: fching@kku.ac.th
Study Contact Backup
- Name: Sasithorn Sriyotee, BSc.
- Phone Number: 66946539656
- Email: shrimm2@hotmail.com
Participation Criteria
Eligibility Criteria
Ages Eligible for Study
- Adult
- Older Adult
Accepts Healthy Volunteers
Description
Inclusion Criteria:
- SSc patients aged between 18 and 70 years
- Diagnosed according to ACR/EULAR 2013 classification criteria20
- Having RP with/without DU on fingers or toes
- Understand and able to read and write Thai language
- Stable steroid, immunosuppressant, and vasodilator including CCB, PDE5i for at least 4 weeks before enrollment
Exclusion Criteria:
- History of allergy or hypersensitivity to Botulinum toxin or ISDN
- Overlap with other connective tissue diseases
- Documented having peripheral arterial disease or vasculitis that affected vascular supply of fingers or toes
- Current use of 2% ISDN cream for treatment of RP
- Current use vasoconstrictor or medication that has vasoconstrictor effect such as ergotamine sulfate, beta-blocker
- Pregnancy and lactating patients
- Bedridden and confined to no self-care
- Evidence of active malignant disease
- Active infection or sepsis
- Localized infection of hand
- Impaired of intrinsic muscle hand function
- Active smoker
- Prior upper extremity vascular surgery, including surgical sympathectomy within 1 month before enrollment
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: Randomized
- Interventional Model: Parallel Assignment
- Masking: Triple
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
|---|---|
|
Experimental: Intervention group
Group A: Botulinum toxin A with placebo cream
|
Botulinum toxin A plus cream placebo
|
|
Placebo Comparator: Control group
Group B: Placebo botulinum A with isosorbide dinitrate cream
|
Normal saline via microneedles plus isosorbide dinitrate cream
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
|---|---|---|
|
Change from baseline in distal digit temperature at 4 Weeks
Time Frame: Baseline and 4 weeks after treatment
|
The change in distal digit temperature is evaluated using an infrared thermometer from baseline to 4 weeks after treatment.
|
Baseline and 4 weeks after treatment
|
Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
|---|---|---|
|
Change from baseline in Raynaud's Phenomenon pain severity score on the Visual Analogue Scale (VAS)
Time Frame: Baseline to 1 week, baseline to 4 weeks, and baseline to 12 weeks after treatment
|
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).
|
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
Time Frame: 1 week, 4 weeks, and 12 weeks after treatment
|
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.
|
1 week, 4 weeks, and 12 weeks after treatment
|
|
Change from baseline in Raynaud's Condition Score (RCS)
Time Frame: Baseline to 1 week, baseline to 4 weeks, and baseline to 12 weeks after treatment
|
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.
|
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)
Time Frame: 1, 4, and 12 weeks
|
The progression of RP to DU using numbers of DU at 1, 4 , and 12 weeks after treatment
|
1, 4, and 12 weeks
|
|
The progression of Raynaud's phenomenon (RP) to digital ulcer (DU)
Time Frame: 1, 4 , and 12 weeks after treatment
|
The progression of RP to DU using size in mm of DU at 1, 4 , and 12 weeks after treatment
|
1, 4 , and 12 weeks after treatment
|
|
The clinical benefit and safety of microneedle pad
Time Frame: 1, 4, and 12 weeks
|
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.
|
1, 4, and 12 weeks
|
|
The progression of Raynaud's phenomenon (RP) to digital ulcers (DUs)
Time Frame: 1, 4 , and 12 weeks after treatment
|
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
|
1, 4 , and 12 weeks after treatment
|
|
The clinical benefit and safety of microneedle pad
Time Frame: 1, 4, and 12 weeks after treatment
|
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. |
1, 4, and 12 weeks after treatment
|
Collaborators and Investigators
Study record dates
Study Major Dates
Study Start (Estimated)
Primary Completion (Estimated)
Study Completion (Estimated)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Actual)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Keywords
Additional Relevant MeSH Terms
Other Study ID Numbers
- Botox for scleroderma-Raynaud
- Khon Kaen University (Other Identifier: Khon Kaen University)
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
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