# CADOR (Capsaicin in neuropathic-like pain in digital osteoarthritis) study protocol: a multicentre randomised parallel-group trial

Angelique Fan, Céline Lambert, Jeremie Sellam, Roland Chapurlat, Hubert Marotte, Bruno Pereira, Thierry Thomas, Anne Tournadre, Martin Soubrier, Sylvain Mathieu

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## To cite this version:

Angelique Fan, Céline Lambert, Jeremie Sellam, Roland Chapurlat, Hubert Marotte, et al., CADOR (Capsaicin in neuropathic-like pain in digital osteoarthritis) study protocol: a multicentre randomised parallel-group trial. BMJ Open, 2025, 15 (3), pp.e093409. 10.1136/bmjopen-2024-093409. hal-05101454

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# BMJ Open CADOR (Capsaicin in neuropathic-like pain in digital osteoarthritis) study protocol: a multicentre randomised parallel-group trial

Angelique Fan¹, Céline Lambert,² Jeremie Sellam,³,⁴ Roland Chapurlat,⁵,⁶
Hubert Marotte⁷,⁸ Bruno Pereira,² Thierry Thomas,⁷,⁸ Anne Tournadre,¹,⁹
Martin Soubrier,¹ Sylvain Mathieu¹,¹⁰

**To cite:** Fan A, Lambert C, Sellam J, et al. CADOR (Capsaicin in neuropathic-like pain in digital osteoarthritis) study protocol: a multicentre randomised parallel-group trial. *BMJ Open* 2025;15:e093409. doi:10.1136/bmjopen-2024-093409

► Prepublication history for this paper is available online. To view these files, please visit the journal online (https://doi.org/10.1136/bmjopen-2024-093409).

Received 06 September 2024

Accepted 14 February 2025

## ABSTRACT

**Introduction** It is common for finger pain in hand osteoarthritis (HOA) to display a neuropathic component. Non-steroidal anti-inflammatory drugs (NSAIDs) and conventional analgesics are not very effective in relieving this neuropathic-like pain. Capsaicin, a compound extracted from chilli peppers, is approved for the management of localised neuropathic pain. However, the effectiveness of an 8% capsaicin transdermal patch has never been tested in HOA patients with neuropathic-like pain in a randomised setting. In this study, we aimed to compare the 60-day (D60) efficacy of a transdermal application of capsaicin 8% versus a control (very low-dose capsaicin at 0.04%) on hand pain in patients with painful digital osteoarthritis with a neuropathic-like pain component.

**Methods and analysis** CADOR (CAPsaicin in neuropathic-like pain in Digital Osteoarthritis: a Randomised trial) is a multicentre, randomised, controlled, double-blind, two parallel group, phase 3 clinical trial. Eligible patients have HOA according to the American College of Rheumatology criteria and at least Kellgren-Lawrence grade≥2, with neuropathic-like pain ('Douleur neuropathique en 4 questions' (DN4) score≥4/10 and pain intensity≥40/100 mm). At Day 0, 120 patients will be randomised (1:1) to receive a single 30 min topical application of either capsaicin 8% transdermal patch (experimental group) or capsaicin 0.04% transdermal patch (control group). The primary outcome is pain intensity in the fingers over the past 48 hours at Day 60, measured with a Visual Analogue Scale (VAS) ranging from 0 to 100 mm. Secondary outcomes are functional disability, quality of life, anxiety and depression, the patient's global impression of improvement, use of analgesics and NSAIDs and the safety of capsaicin. At visit D60, patients who still have finger pain≥40/100 mm on the VAS will receive, if they wish a single 30 min topical application of capsaicin 8% transdermal patch (not blinded). The efficacy of two transdermal applications of capsaicin (either two applications of 8% patch in the experimental arm or one application of 0.04% and one application of 8% in the control arm) will be assessed on Day 120.

**Ethics and dissemination** Ethics approval was obtained from the French Health Authorities (Comité de protection des Personnes SUD EST V and Agence Nationale de

## STRENGTHS AND LIMITATIONS OF THIS STUDY

⇒ The patients included are those seen in hospital and are therefore relatively severe, which affects the generalisability of the results.

⇒ The use of a placebo with a low dose of capsaicin allows blinding to be maintained.

⇒ The analysis of the repeated efficacy of the patch application is exploratory only.

Sécurité du Médicament) on 23 May 2024 in accordance with European Regulation n°536/2014 of 16 April 2014 (ref: 2024-511159-16-00) before participant enrolment.

**Trial registration number** ClinicalTrials.gov: NCT06444919.

## INTRODUCTION

Osteoarthritis (OA) is the most common osteoarticular disease, affecting 7.6% of the world's population. Hand osteoarthritis (HOA) is the second most common site after the knee (2226 cases/100 000). Its incidence varies considerably, with a peak in Central Asian countries.¹ It is characterised by degradation of the cartilage and subchondral bone and manifests as pain and morning stiffness, which can cause significant functional disability.²

It is common for pain in OA to take on a neuropathic-like component in the form of burning, tingling, electrical discharge and itching. This is reported to affect 20–30% of patients with knee OA³ and up to 41.2% of patients with erosive HOA, according to studies using the ‘Douleur neuropathique en 4 questions’ (DN4) questionnaire.⁴ The presence of pain with a neuropathic-like component may explain the failure of conventional analgesic treatments, NSAIDs and corticoids to relieve these patients, as they have been proven ineffective for such pain.⁵ ⁶

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**Correspondence to**
Dr Sylvain Mathieu;
smathieu@chu-clermont ferrand.fr
Antidepressants and antiepileptics are the recommended and most effective treatments for neuropathic pain;⁷ ⁸ however, their use is hindered by adverse effects.⁹ ¹⁰ Other options include transdermal application of a patch containing a local anaesthetic (lidocaine 5%) or capsaicin; however, these two specialties are often reimbursed for specific indications, which do not include HOA.

Capsaicin, a compound found in chilli peppers, selectively activates the vanilloid compound receptor, inducing desensitisation of a small diameter of sensitive afferent fibres, thus reducing pain. It is available as a cream or a transdermal patch.¹¹ A cream containing a very low dose of capsaicin is available and has been tested in HOA. However, it is not recommended as there is insufficient evidence of its efficacy.¹² ¹³ A recent systematic review including eight randomised controlled trials concluded that topical capsaicin may reduce pain intensity in OA patients.¹⁴ But this review concerned only topical capsaicin in gel, cream, ointment and solution and not in transdermal patch. Indeed, capsaicin is also available as a high-dose transdermal patch (QUTENZA) at a concentration of 179 mg (8% weight per weight) for the treatment of localised peripheral neuropathic pain. However, no robust study has evaluated this specialty for neuropathic-like pain associated with HOA. A small feasibility study was carried out in our centre on eight HOA patients with neuropathic-like pain, who applied a capsaicin patch to their proximal and distal interphalangeal (PIP/DIP) joints for 30 min. Six of the eight patients reported a reduction in pain intensity, and the average pain Visual Analogue Scale (VAS) was 40.0±14.1 mm 2 weeks after the application of an 8% capsaicin transdermal patch. The patch was well tolerated. This small study showed that capsaicin patches could provide a short-term reduction in pain intensity with a good tolerance profile.¹⁵ Such a study confirmed the feasibility of using capsaicin patches in HOA patients with neuropathic-like pain and prompted us to launch a randomised controlled trial to demonstrate the efficacy of cutaneous capsaicin patches in patients with painful HOA with neuropathic-like pain. The main objective of this study is to compare the D60 efficacy of a transdermal application of capsaicin 8% versus a control (very low-dose capsaicin at 0.04%) on hand pain in patients with painful digital OA with a neuropathic-like pain component (first double-blinded part of the study). The key secondary objectives are to compare the D60 efficacy regarding functional disability, quality of life, anxiety and depression, disease activity, painful OA symptoms, the patient's global impression of improvement, use of analgesics and NSAIDs and the safety of capsaicin. There is a second exploratory part in this study up to D120. The efficacy of two transdermal applications of capsaicin (either two applications of 8% patch in the experimental arm, or one application of 0.04% and one application of 8% in the control arm) will be assessed on Day 120. An 8% capsaicin patch can currently be applied every 2 months. But no study compared the systematic 8% capsaicin retreatment every 2 months and

an on-demand application in HOA patients. In the same way, two applications of 8% capsaicin have never been compared with one application for long-term efficacy at 4 months, for example. With the second part of the trial, we will have data to explore these two questions. First, we will be able to compare the patients with one 8% capsaicin application (0.04% capsaicin and then 8% capsaicin) to those with two 8% capsaicin applications. Second, some patients will have only one 8% capsaicin application at D0 and no other application because of a sufficient pain decrease at D60, and we will be able to compare them to those with two 8% capsaicin applications (one at D0 and another one at D60 for patients always painful).

## METHODS

### Study design

CADOR (CAPsaicin in neuropathic-like pain in Digital Osteoarthritis: a Randomised trial) is a multicentre, randomised, parallel-group, double-blind, placebo-controlled, phase 3 study. Four rheumatology departments of French academic hospitals: Assistance Publique des Hôpitaux de Paris (AP-HP), Clermont-Ferrand, Lyon and Saint-Etienne teaching hospitals will participate in this study.

### Assignment of intervention

All patients who give consent for participation and fulfil the inclusion criteria will be randomised. Randomisation will be performed by the assessor investigators or the study coordinator using a computer-generated allocation sequence accessible from each centre via a secure, dedicated website (Ennov Clinical). The investigator in charge of the randomisation is blinded to the randomisation group and selects the intervention according to the code number provided by the web-based electronic case report form. A unique randomisation number will be generated for each allocation. The allocation sequence will be generated by the biostatistics unit of the sponsor applying a permuted blocks design with random block size and stratified by study centre and sex.

All study participants (participant, nurse, rheumatologist) will be blinded to allocation until the end of the study, when the follow-up of the last patient and statistical analyses have been performed. The study drug will be labelled and identified with a study code in such a manner that neither the patient nor the study staff will be able to determine which treatment arm the patient is assigned to from the dispensed packaging. The success of blinding will be tested by asking the participant to guess their study group allocation. Unblinding is not planned except in case of serious side effects.

### Interventions

Within 30 days of the preselection visit, at the inclusion visit (D0), eligible patients will be randomly assigned in a 1:1 ratio to receive a single 30 min application of either capsaicin 8% transdermal patch (experimental group) or
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capsaicin 0.04% transdermal patch (control group). The patch is applied only to painful fingers identified by the rheumatologist at the metacarpophalangeal (MCP), PIP and DIP joints.

A very low-dose patch (0.04%) has been chosen as the blind control as it produces the same local adverse effects (burning, pain, pruritus) as the 8% patch. Adverse effects are mild to moderate in intensity, transient and not serious, even in the oldest patients.¹⁶

At visit D60, patients who still have finger pain≥40/100 mm on the VAS will receive, if they wish, a single 30-min application of an 8% capsaicin patch. The patches (8% and 0.04% capsaicin patch) were graciously provided by the laboratory Grünenthal marketing the 8% capsaicin patch and repackaged in neutral packaging by the sponsor's coordinating hospital pharmacy. The two patches will look exactly the same, and there will be no way of identifying them. The patches will be applied under the responsibility of nurses, who will be specially trained in the precautions to be taken when using the patches and who will be blinded to the outcome of the randomisation. A standard procedure and a training video for applying the patches will be distributed to each centre.

## Participant timeline

At the screening visit, the rheumatologist investigators will present and explain the protocol in detail. After a cooling-off period and having obtained written informed consent (supplemental material 1), patients will be invited to Day 0 (inclusion) within 30 days of the screening visit and follow-up visits at day 60 (D60) and day 120 (D120) (figure 1).

On D0, eligibility criteria will be double-checked before randomisation. Sociodemographic characteristics (age, sex, smoking status, height, weight), HOA characteristics and current treatment will be extracted directly from the patient's medical records. At each visit (D0, D60 and D120), patients undergo hand and

general clinical examination (number of painful and swollen joints, blood pressure in mmHg) by a rheumatologist, complete in paper and pen self-questionnaires (Assessment of activity, fatigue and pain using a VAS, Cochin scale, Functional Index for Hand Osteoarthritis (FIHOA), Hospital Anxiety and Depression Scale (HADS), Osteoarthritis Symptom Inventory Scale 9 (OASIS9) and EuroQol 5-dimension (EQ-5D)) and take a blood sample for the ultrasensitive C-reactive protein measurement (table 1).

Blood samples of 8mL will be collected at D0 and D60, centrifuged and frozen at -80°C in the biobank in order to explore change in serum levels of inflammatory or pain-related markers (interleukin (IL)-6, IL-8, TNF, nerve growth factor) and serum markers (cartilage degradation (cartilage oligomeric matrix protein), collagen 2-1 (Col2-1) level, a marker of type II collagen denaturation) and Col2-1-NO2, cartilage-based biomarkers. Other serum biomarkers will be measured according to the state-of-the-art OA-related biomarkers at the end of the study.

The patient global impression of change and the percentage improvement of the most painful finger will be assessed at D60 and D120.

Pain and consumption of analgesics, NSAIDs and corticoids will be recorded daily in a patient diary and reported at each visit. Immediate capsaicin-induced adverse events will be collected by the nurse at the end of patching on D0 and, if applicable, D60. Serious and non-serious adverse events will be collected in accordance with Good Clinical Practice-International Conference on Harmonisation (GCP-ICH) throughout the study in the patient diary, reported to the investigator at each study visit and reported to the relevant authorities in a timely manner. Efficacy and tolerance criteria will be assessed at D60. No visit is scheduled between D0 and D60, but VAS pain and use of analgesics, NSAIDs and corticosteroids are recorded daily in a diary by the patient.

<figure><img src="image_4.png" /><figcaption>**Figure 1** The planned flow chart of the multicentre, randomised, controlled, double-blind, two parallel group, CADOR study. CADOR, CApsaicin in neuropathic-like pain in digital osteoarthritis: a randomised trial; mm, millimetres; n, number of patients; VAS, Visual Analogue Scale.</figcaption></figure>
<table><caption>**Table 1 Schedule of enrolment, interventions and assessments of the CADOR study**</caption><thead><tr><th rowspan="2">Timepoint</th><th colspan="2">Days 0-30</th><th>Day 60</th><th colspan="2">Day 120</th></tr><tr><th>Screening</th><th>Allocation</th><th>Efficacy assessment</th><th>End of study</th></tr></thead><tbody><tr><td>Enrolment</td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Eligibility screen</td><td>x</td><td>x</td><td></td><td></td><td></td></tr><tr><td>Informed consent</td><td></td><td>x</td><td></td><td></td><td></td></tr><tr><td>Urinary β-human chorionic gonadotropin test</td><td></td><td>x*</td><td></td><td></td><td></td></tr><tr><td>Randomisation</td><td></td><td>x</td><td></td><td></td><td></td></tr><tr><td>Interventions</td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Blinded 8% capsaicin</td><td></td><td>x</td><td></td><td></td><td></td></tr><tr><td>Blinded 0.04% capsaicin</td><td></td><td>x</td><td></td><td></td><td></td></tr><tr><td>Open 8% capsaicin</td><td></td><td></td><td>x*</td><td></td><td></td></tr><tr><td>Assessments</td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Medical history</td><td></td><td>x</td><td></td><td></td><td></td></tr><tr><td>Sociodemographic characteristics (age, tobacco use)</td><td></td><td>x</td><td></td><td></td><td></td></tr><tr><td>DN-4 questionnaire</td><td></td><td>x</td><td></td><td></td><td></td></tr><tr><td>Clinical general examination (blood pressure, height, weight)</td><td></td><td>x</td><td>x</td><td>x</td><td></td></tr><tr><td>Hand clinical examination</td><td></td><td>x</td><td>x</td><td>x</td><td></td></tr><tr><td>Current pain treatment</td><td></td><td>x</td><td>x</td><td>x</td><td></td></tr><tr><td>VAS hand pain in the previous 48 hours</td><td></td><td>x</td><td>x</td><td>x</td><td></td></tr><tr><td>VAS pain in the most painful finger</td><td></td><td>x</td><td>x</td><td>x</td><td></td></tr><tr><td>VAS patient disease activity</td><td></td><td>x</td><td>x</td><td>x</td><td></td></tr><tr><td>VAS fatigue</td><td></td><td>x</td><td>x</td><td>x</td><td></td></tr><tr><td>FIHOA index</td><td></td><td>x</td><td>x</td><td>x</td><td></td></tr><tr><td>Cochin scale</td><td></td><td>x</td><td>x</td><td>x</td><td></td></tr><tr><td>EuroQol EQ-5D</td><td></td><td>x</td><td>x</td><td>x</td><td></td></tr><tr><td>OASIS9</td><td></td><td>x</td><td>x</td><td>x</td><td></td></tr><tr><td>HADS</td><td></td><td>x</td><td>x</td><td>x</td><td></td></tr><tr><td>Average weekly hand pain</td><td></td><td></td><td>x</td><td>x</td><td></td></tr><tr><td>Percentage improvement in pain of the most painful finger</td><td></td><td></td><td>x</td><td>x</td><td></td></tr><tr><td>Patient's global impression of change</td><td></td><td></td><td>x</td><td>x</td><td></td></tr><tr><td>Ultrasensitive C-reactive protein</td><td></td><td>x</td><td>x</td><td></td><td></td></tr><tr><td>Blood collection</td><td></td><td>x</td><td>x</td><td></td><td></td></tr><tr><td>Adverse events</td><td></td><td>x</td><td>x</td><td>x</td><td></td></tr><tr><td>Patient's impression of treatment received on Day 0</td><td></td><td></td><td>x</td><td></td><td></td></tr></tbody></table>

*As required.

CADOR, CAPSAICIN IN NEUROPATHIC-LIKE PAIN IN DIGITAL OSTEOARTHRITIS: A RANDOMISED TRIAL; DN-4, DOULEUR NEUROPATHIQUE EN 4 QUESTIONS; EQ-5D-3L, EUROQOL 5-DIMENSIONS 3-LEVELS QUALITY OF LIFE QUESTIONNAIRE; FIHOA, FUNCTIONAL INDEX FOR HAND OSTEOARTHRITIS; HADS, HOSPITAL ANXIETY AND DEPRESSION SCALE; HOA, HAND OSTEOARTHRITIS; mg, MILLIGRAMS; OASIS9, OSTEOARTHRITIS SYMPTOM INVENTORY SCALE 9; VAS, VISUAL ANALOGUE SCALE.

At visit D60, patients who still have finger pain ≥40/100 mm on the VAS will receive, if they wish, an 8% capsaicin patch in open. Patients, nurses and assessors will be aware that this is a capsaicin 8% patch.

The strict D60 period between two patch applications must be respected to comply with the minimum interval before retreatment recommended by the summary of product characteristics.

The final assessment will be carried out at D120 for all enrolled patients, whether they had a single patch or two patches applied. The assessment at D120 will be the same as at D60, except that no patch application will be performed at D120. Efficacy and tolerability criteria will also be assessed at D120. No visit is planned between D60 and D120, but VAS pain and use of analgesics, NSAIDs and corticosteroids will be recorded daily by the patient
in the same diary. This diary is used to calculate average weekly hand pain between D0 and D60 and between D60 and D120.

Regarding safety, adverse events during patch application and all adverse events occurring during the study will be collected. At each study visit, participants will be questioned about any adverse events they have experienced since the last study visit

## Outcomes and measures

- The primary outcome is the intensity of finger pain experienced in the previous 48 hours and will be assessed by the patient at D60 using a 100 mm VAS pain scale. (0: no pain; 100: worst pain).

- The following secondary outcomes will be assessed:

- Number of painful and swollen joints in the two hands (0-28): 10 MCP, 8 PIP and 10 DIP.

- Patient's global disease activity (VAS 0-100 mm).

- Fatigue intensity (VAS 0-100 mm).

- Pain in the most painful finger (VAS 0-100 mm).

- Functional disability using the Cochin hand functional disability scale. A self-report questionnaire consisting of 18 items. Items are scored on a 7-point scale from 0 (no difficulty) to 5 (impossible). The total score ranges from 0 to 90. A higher score indicates greater disability or difficulty.¹⁷

- Hand function using the Functional Index for Hand Osteoarthritis. A 10-item self-report questionnaire. Items are scored on a 4-point scale from 0 (possible without difficulty) to 3 (impossible). The scores for each item are summed to give a total score, which ranges from 0 to 30. Low scores indicate better hand function.¹⁸

- Anxiety and Depression using the Hospital Anxiety and Depression Scale.¹⁹ Seven questions relate to anxiety and seven to depression, resulting in two scores (maximum score for each=21). A higher score indicates more anxious or depressive symptoms.

- Assessment of OA symptoms using the Osteoarthritis Symptom Inventory Scale 9 score.²⁰ A 9-item self-administered questionnaire. Each item was quantified on a numerical scale from 0 to 10 and the total score ranges from 0 to 90. A higher score indicates greater pain symptoms.

- Quality of life using the EuroQol 5-dimension 3-level (EQ-5D-3L) score.²¹ Five questions on mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension has three levels: no problems, some problems and extreme problems. The total score ranges from 5 to 15 points. The lower the score, the better the quality of life.

- Overall patient improvement in the most painful finger as reported by the patient using a VAS between 0 and 100%, where 0% is no improvement and 100% is complete improvement.

- Patient's global impression of change (0, no change or very much worse to 7, considerable improvement).²²

- Consumption of analgesics, NSAIDs and corticoids.

- Ultrasensitive C-reactive protein.

- Serum levels of inflammatory, pain-related and cartilage degradation markers.

- Safety and tolerability.

- Patients' beliefs about whether the patient had received the active or control capsaicin patch.

## Patients recruitment and eligibility criteria

Patient recruitment will start in February 2025 for a 3-year period in the four rheumatology departments of French academic hospitals. However, as patients with HOA are often followed up in outpatient clinics, patients are also recruited from hospital outpatient departments and from rheumatologists in private practice who work with the trial centres. To achieve the target sample size, all HOA patients with digital neuropathic-like pain will be invited to participate. If a patient is interested, an initial evaluation will be carried out by the investigator to assess the eligibility criteria during a screening visit. Neuropathic pain (NP) in the hand was assessed using the DN4. This diagnostic tool measures the presence of symptoms and signs commonly associated with neuropathic pain (burning, painful cold, electric shocks, tingling, pins and needles, numbness, itching). 10 questions are based on patient interview and clinical examination (hypoesthesia and allodynia). Each positive item is given a score of 1 and each negative item a score of 0. The total score is the sum of the 10 items and the cut-off for the diagnosis of NP ((neuropathic pain) is 4/10. All examiners have been trained, and the same equipment is used for standardised screening for hypoesthesia and allodynia localised to the hand.

## Inclusion criteria

Patients eligible for the trial must comply with all the following criteria at randomisation:

- 18 years or older.

- Patient with HOA according to the American College of Rheumatology criteria with ≥2 symptomatic joints among PIP/DIP joints including also the first interphalangeal joint with Kellgren-Lawrence≥2.²³ Patients with radiographic evidence of HOA can be screened on the basis of a previous routine radiograph of both hands.

- Patient with chronic pain (> 3 months) in the hands or digits.

- Baseline hand pain intensity≥40/100 mm on a VAS, with 0 representing no pain and 100 representing the worst pain imaginable.

- Pain with a neuropathic-like component localised to the hand as assessed by the DN4 questionnaire with a score≥4/10.²⁴
* Inadequate response, adverse reactions and/or contraindications to conventional analgesics and NSAIDs.

* Women of childbearing potential may be enrolled, provided they use effective contraception (contraceptive pill, contraceptive implant, intrauterine device, condom or tubal ligation) throughout the trial.

* Agree to sign the Informed Consent Form.

* Be affiliated with a social security system.

## Exclusion criteria

* Isolated rhizarthrosis.

* Joint diseases, other than OA, affecting the fingers: gout, chondrocalcinosis, rheumatoid arthritis, spondyloarthritis and psoriatic arthritis.

* Upper extremity pain syndrome that may interfere with the assessment of finger pain.

* Skin lesions on the fingers: psoriasis, wounds, chronic ulcers, eczema, shingles and dermatitis.

* Uncontrolled blood hypertension.

* Known hypersensitivity to capsaicin.

* Fibromyalgia.

* Other pathologies responsible for neuropathic hand pain: carpal tunnel syndrome, diabetic neuropathy, Guyon's canal syndrome, cervicobrachial neuralgia and brachial plexitis.

* Use of an 8% capsaicin patch in the year before inclusion and wearing of a wrist or finger orthosis in the previous month.

* Intramuscular, intra-articular or intravenous corticosteroid injections and conventional antirheumatic treatments (methotrexate and hydroxychloroquine) in the 3 months prior to enrolment.

* Pregnant or breastfeeding woman (a urine pregnancy test will be performed in women of childbearing potential before randomisation).

* Patients under guardianship or curatorship or deprived of liberty or judicial protection.

## Concomitant and excluded medications and care

NSAIDs, corticosteroid and analgesic treatments, as well as treatment for neuropathic pain, can be continued. However, the dosage of neuropathic pain treatments should remain constant throughout the study period. The following drugs and procedures are prohibited during the study: topical therapies on the finger, joint injection of the fingers, mesotherapy sessions, acupuncture on the hands and hand or wrist orthoses. Patients should not undergo finger surgery during the study, except in the case of emergency surgery.

## Sample size

The sample size was calculated based on the preliminary study carried out by Mathieu *et al* on eight patients, in which the average pain VAS was 40.0±14.1 mm 2 weeks after the application of an 8% capsaicin transdermal patch. Considering an SD of 14.1 and a two-sided type I error of 5%, 42 patients per arm will be required to detect

a minimum clinically relevant difference of 10 mm,²⁵ with 90% statistical power. Ultimately, it is planned to include 60 patients per arm to compensate for more than 20% of patients lost to follow-up and to guarantee sufficient statistical power for the analysis of secondary outcomes. No interim analysis is planned.

## Data collection and management

All study personnel (investigators, study coordinators, nurses and pharmacists) will be trained in standardised procedures established by the coordinating investigator. All questionnaires used are validated in French for administration to patients with digital osteoarthritis. All data required by the protocol are entered into an electronic case report form (Ennov Clinical) by the investigators or the clinical research technician. All patient data are pseudonymised, with only initials and a number recorded. The study documents will be kept for 25 years after the end of the study.

## Statistical analysis

All analyses will be performed using Stata software (V.15; StataCorp, College Station, Texas, USA) before the breaking of the randomisation code, according to the GCP-ICH guidelines. All tests will be two-sided, with an alpha level set at 0.05. No correction for multiple testing will be applied in the analysis of secondary outcomes or in subgroup analyses.²⁶ Findings from these analyses will be interpreted as exploratory. The primary analysis will be conducted on the intention-to-treat (ITT) population, after the imputation of missing data. The quantity and nature of missing data will be studied to propose the most appropriate imputation method. In particular, if data are missing at random, multiple imputation will be implemented, considering the following prespecified parameters: sex, age, baseline hand pain and FIHOA. Analyses will also be conducted on the per-protocol population. The criteria for including patients in the ITT and per-protocol populations are provided below (study populations section).

The comparison between the two arms for the primary endpoint (pain VAS at D60) will be performed by an analysis of covariance (linear regression, considering an adjustment for pain VAS at D0). If appropriate (non-normality of the residuals), a logarithmic transformation of the dependent variable will be proposed. An effect size and its 95% CI will be calculated and interpreted according to Cohen's recommendations²⁷: 0.2=low, 0.5=moderate, 0.8=large. The primary analysis could be completed by a multivariable analysis (multiple linear regression) by considering covariates (measured at D0) determined regarding clinical relevance (age, number of painful joints, number of clinical palpable synovitis, FIHOA, HADS, initial pain in the most painful finger, EQ-5D and analgesic and NSAIDs consumption), in addition to stratification variables (sex). Attention will be paid to the centre effect, which can be considered (random
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effect) in a linear mixed model. The results will be expressed as regression coefficients and 95% CIs.

Subgroup analyses for the primary endpoint, according to patients' sex and pain VAS at D0, will be proposed. The "group × subgroup" interaction, resulting from the linear mixed model described for the main multivariable analysis, will be studied. The results will be expressed as regression coefficients and 95% CIs associated with this interaction. Analyses of quantitative secondary endpoints will be identical to those described for the primary endpoint. Categorical secondary endpoints will be compared between the two arms using a $\chi^2$ or Fisher's exact test. The results will be expressed as absolute differences and 95% CIs.

An exploratory study will evaluate the efficacy of two transdermal applications of capsaicin (either two 8% applications in the experimental arm, or one application at 0.04% and one at 8% in the control arm). The change in pain intensity between D0 and D120 and between D60 and D120 will be described in each arm separately for patients who received two applications.

## Study populations

The ITT population includes all patients, except those who withdrew their consent to the use of their data, and those who did not receive any transdermal application of capsaicin (neither 8% nor 0.04%). The per-protocol population includes all patients evaluable in ITT, except those who did not meet the inclusion and exclusion criteria, and those who did not receive the treatment defined by randomisation.

## ETHICS AND DISSEMINATION

Ethics approval was obtained from the French Health Authorities (Comité de protection des Personnes SUD EST V and Agence Nationale de Sécurité du Médicament) on 23 May 2024 in accordance with European Regulation n°536/2014 of 16 April 2014 (ref: 2024-511159-16-00) before participant enrolment. This protocol follows the Standard Protocol Items: Recommendations for Interven- tional Trials (SPIRIT) reporting guidelines. Any protocol changes will be communicated to ethics boards and participating districts. The study principal investigator, co-investigators, clinical research coordinator, research assistants and statistician will have access to the collected data. Trial results will be presented at national and inter- national congresses and published in a peer-reviewed journal.

## Strengths and limitations

The most important strength of this study is that it is the first randomised, double-blind and controlled trial to evaluate an 8% capsaicin patch for the treatment of neuropathic-like pain in HOA. Efficient treatments are lacking to improve pain in HOA patients, especially neuropathic pain that is not really improved by tradi- tional analgesics or NSAIDs. This study is based on the

phenotyping of osteoarthritis pain beyond its intensity, evaluating capsaicin, a drug with a targeted mode of action and known safety in the treatment of neuropathic- like pain. The demonstration of an effective treatment (8% capsaicin patch) for neuropathic pain in HOA would be welcome. This treatment could benefit many patients and could be administered into a wider clinical setting. For now, capsaicin patches are only used in hospitals by trained teams, which is a limitation. By the same way, the patients included in this study are those seen in hospital and have therefore a relatively more severe disease, which can affect the generalisability of the results. However, if we find positive results in patients with severe disease, we can reasonably suppose that an 8% capsaicin patch would also be effective in decreasing pain in the other patients.

This study also makes it possible to evaluate the efficacy of using repeated 8% capsaicin patch. This is an explor- atory analysis which does not allow us to draw conclusions. However, in case of interesting results, this could lead to future clinical trials whose main objective will be to eval- uate the strategy for using the 8% capsaicin patches.

## Author affiliations

**Acknowledgements** Editorial assistance, in the form of language editing and correction, was provided by XpertScientific Editing and Consulting Services.

**Contributors** All authors were involved in the drafting of this manuscript or critically revising it for important intellectual content, and all authors approved the final version to be submitted for publication. Conceptualisation: SM, AT. Study design/methodology: SM, AF, CL, BP. Writing original draft preparation: SM, AF, CL, BP. Writing, review and editing: AF, SM, AT, JS, MS, RC, HM, TT, CL, BP. SM is responsible for the overall content as the guarantor.

**Funding** Financial support was received from the Direction Générale de l'offre de soins (PHRC IR MATHIEU 2022) and material support from Grünenthal laboratories. They will supply both types of capsaicin patch (8% and 0.04%). The funders had no role in the design or conduct of the study and will have no role in the analysis and reporting of the study results.

**Competing interests** None declared.

**Patient and public involvement** Patients and/or the public were involved in the design, conduct, reporting or dissemination plans of this research. Refer to the Methods section for further details.

**Patient consent for publication** Not applicable.

**Provenance and peer review** Not commissioned; externally peer reviewed.

**Open access** This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is

<footnote n="1">¹Department of Rheumatology, CHU Clermont-Ferrand, Clermont-Ferrand, France</footnote>

<footnote n="2">²Biostatistics Unit, CHU Clermont-Ferrand, Clermont-Ferrand, France</footnote>

<footnote n="3">³Department of Rheumatology, Saint-Antoine Hospital, Assistance Publique - Hôpitaux de Paris, Paris, Île-de-France, France</footnote>

<footnote n="4">⁴INSERM UMRS_938, Sorbonne Université, Paris, Île-de-France, France</footnote>

<footnote n="5">⁵Department of Rheumatology, CHU Lyon, Lyon, Auvergne-Rhône-Alpes, France</footnote>

<footnote n="6">⁶INSERM UMR 1033, Université Claude Bernard Lyon 1, Lyon, Auvergne-Rhône- Alpes, France</footnote>

<footnote n="7">⁷Department of Rheumatology, Centre Hospitalier Universitaire de Saint-Étienne Hopital Nord, Saint-Priest-en-Jarez, Auvergne-Rhône-Alpes, France</footnote>

<footnote n="8">⁸SAINBIOSE, INSERM U1059, Université Jean Monnet Saint-Étienne, Saint-Étienne, Auvergne-Rhône-Alpes, France</footnote>

<footnote n="9">⁹UNH, INRA UMR 1019, Université Clermont Auvergne, Clermont-Ferrand, Auvergne- Rhône-Alpes, France</footnote>

<footnote n="10">¹⁰INSERM, Neurodol, Université Clermont Auvergne, Clermont-Ferrand, Auvergne- Rhône-Alpes, France</footnote>
properly cited, appropriate credit is given, any changes made indicated, and the use
is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.

ORCID iDs

Angelique Fan http://orcid.org/0000-0003-4822-0582
Hubert Marotte http://orcid.org/0000-0003-1177-9497
Sylvain Mathieu http://orcid.org/0000-0003-2017-3227

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