Efficacy of Botulinum Toxin A in Adult Subjects With Raynaud Phenomenon Secondary to Systemic Sclerosis

NCT ID: NCT03717961

Last Updated: 2022-02-10

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 91 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2018-10-15
• Study Completion Date: 2020-07-31

Brief Summary

This study aims to assess whether or not a single injection schedule of botulinum toxin A (BTX-A) in both hands improves Raynaud phenomenon (RP) secondary to systemic sclerosis (SSc) better than a placebo at 4, 12 and 24 weeks after the treatment.

This study's hypothesis is that the number of RP attacks per week from baseline to 4 weeks after treatment is significantly lower in the group treated with BTX-A than in the control group treated by the placebo. Furthermore, BTX-A in both hands is expected to improve both symptomatic (attack frequency, digital ulcer healing) and functional (pain, hand function, quality of life) symptoms of RP secondary to SSc more than placebo.

Detailed Description

In SSc, RP is present in 95% of the patients. Despite cold avoidance, RP attacks are severe, painful, affecting the quality of life, with frequent severe ischemic symptoms such as digital ulcers. Treating patients with RP secondary to SSc is extremely challenging. Oral calcium channel blockers, the most commonly prescribed drugs, were shown to be minimally effective in reducing frequency and severity of RP attacks. There is limited evidence for the efficacy of alpha-1-adrenergic receptor antagonists, angiotensin receptor blockers, phosphodiesterase inhibitors and endothelin-1 receptor antagonists to treat RP. The intravenously administered prostacyclin analogue iloprost is considered a second-line therapy, after oral calcium channel blockers, but its administration requires a 5-days hospitalisation for progressive increase in dosage and close blood pressure monitoring. Side effects are almost constant: headache, flushing, malaise and hypotension. Between 2004 and 2015, a total of 145 patients underwent botulinum toxin-A (BTX-A) injections to treat RP in case reports, retrospective or open studies. Since 2016, only 1 randomized, controlled study was performed, including 40 patients but was underpowered, not designed for clinical outcomes, and treated the patient only in one hand. Symptomatic patients treated by BTX-A experienced, in the 3 to 6 following months, pain relief in 75-100% of the cases, as well as reduction in severity and frequency of attacks and increased ulcer healing rate, with minimal adverse effects. The most common complication was temporary hand weakness, related to the injected dose. When the total dose/hand was 50 UI or lower, the rate of hand weakness was 0 to 9%. The proposed study is the first randomized double blinded multicenter clinical trial designed to assess whether or not a single injection schedule of BTX-A in both hands improves RP secondary to SSc better than a placebo at 4, 12 and 24 weeks after the treatment.

Conditions

Raynaud Phenomenon Secondary to Systemic Sclerosis

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

" BTX-A" group

• BOTOX® solution
• Saline serum
• lidocaine/prilocaine cream
• Nitrous oxide/oxygen (50%/50%)

Intervention Description :

• BOTOX 100 UNITES (Allergan, Courbevoie, France, and São Paulo, Brazil) Single injection schedule of BOTOX® in both hands, diluted in 2 ml of sterile serum saline, with a dosage of 50 UI (1 ml) by hand. Injections will be performed at the level of the distal palmar crease, targeting the neurovascular bundles in the 4 web spaces (0.25 ml/injection site)
• between 2 to 3 hours before the procedure, application of lidocaine/prilocaine cream under an occlusive dressing (polyurethane film) in each palmar crease of the patients (1/2 tube/hand), according to the recommendations of the manufacturer
• inhaled nitrous oxide/oxygen (50% / 50%) may be used, if needed

Group Type: EXPERIMENTAL

BOTOX® solution

Intervention Type: DRUG

Botox solution + Saline serum + lidocaine/prilocaine cream + Nitrous oxide/oxygen (50%/50%)

Placebo group

• Saline serum
• lidocaine/prilocaine cream
• Nitrous oxide/oxygen (50%/50%)

Intervention Description :

• Sterile saline solution Single injection schedule of 2 ml (1 ml by hand) of serum saline, in both hands. Injections will be performed at the level of the distal palmar crease, targeting the neurovascular bundles in the 4 web spaces (0.25 ml/injection site).
• between 2 to 3 hours before the procedure, application of lidocaine/prilocaine cream under an occlusive dressing (polyurethane film) in each palmar crease of the patients (1/2 tube/hand), according to the recommendations of the manufacturer of the lidocaine cream.
• inhaled nitrous oxide/oxygen (50% / 50%) may be used, if needed

Group Type: PLACEBO_COMPARATOR

Placebo group

Intervention Type: DRUG

Placebo + lidocaine/prilocaine cream + Nitrous oxide/oxygen (50%/50%)

Interventions

BOTOX® solution

Botox solution + Saline serum + lidocaine/prilocaine cream + Nitrous oxide/oxygen (50%/50%)

Intervention Type: DRUG

Placebo group

Placebo + lidocaine/prilocaine cream + Nitrous oxide/oxygen (50%/50%)

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

• Aged 18 years and older
• Diagnosed with systemic sclerosis (EULAR/ACR 2013 criteria ; or Leroy and Metsger criteria).
• Symptoms of Raynaud's phenomenon affecting both hands (not necessarily to equal extents)
• Frequency of Raynaud's attacks ≥ 5/week during cold weather
• Stable dose of phosphodiesterase inhibitors (sildenafil, tadalafil or vardenafil), endothelin antagonists, or calcium channel blockers defined as 1-month with no change in dose
• Ability to return/be available for follow-up evaluations
• Ability to fill the diary
• Ability/willingness to give informed consent
• Affiliation to any French social security regime

Exclusion Criteria

• History of myasthenia gravis or Eaton Lambert syndrome
• Inflammatory myositis <2 years or pre-existing motor neurone disease or upper limb motor neuropathy
• Reported allergy or hypersensitivity to any Botulinum toxin preparation or to lidocaine or other local anesthetic agent or to albumin or to inhaled nitrous oxide/oxygen.
• Active infection in either hand.
• Pregnant or lactating women (women of child bearing potential must undergo a urine pregnancy teste before inclusion and at treatment day).
• women of child bearing potential without medically accepted method of birth control
• Patients who have previously undergone any vascular surgery on the upper extremity, including surgical sympathectomy or ever received botulinum toxin or planned to receive botulinum toxin in the next 6 months
• Cognitive impairment
• Iloprost scheduled the month following injections

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Assistance Publique - Hôpitaux de Paris

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Patricia Senet, MD

Role: PRINCIPAL_INVESTIGATOR

Assistance Publique - Hôpitaux de Paris

Locations

Hôpital Tenon

Paris, , France

Countries

France

References

Senet P, Maillard H, Diot E, Lazareth I, Blaise S, Arnault JP, Pistorius MA, Boulon C, Cogrel O, Warzocha U, Riviere S, Malloizel-Delaunay J, Servettaz A, Sassolas B, Viguier M, Monfort JB, Janique S, Vicaut E; BRASS collaborators. Efficacy and Safety of Botulinum Toxin in Adults with Raynaud's Phenomenon Secondary to Systemic Sclerosis: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Study. Arthritis Rheumatol. 2023 Mar;75(3):459-467. doi: 10.1002/art.42342. Epub 2022 Dec 14.

Reference Type: DERIVED

PMID: 36066501 (View on PubMed)

Other Identifiers

P170904J

Identifier Type: -

Identifier Source: org_study_id