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.
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.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
QUADRUPLE
Enrollment
91
Botox solution + Saline serum + lidocaine/prilocaine cream + Nitrous oxide/oxygen (50%/50%)
Placebo + lidocaine/prilocaine cream + Nitrous oxide/oxygen (50%/50%)
Hôpital Tenon
Paris, France
Absolute change from baseline in the number of RP attacks per week at 4 weeks
Comparison between the 2 groups of the change (absolute) from baseline in the number of RP attacks per week at 4 weeks. An attack is defined as an episode of pallor or cyanosis (with or without pain, tingling or numbness). Subjects will keep a daily record of the number of RP attacks they experienced per day and the duration of each attack, from Day -14 to Day 0 (+/- 4 days) and from Day 14 to Day 28 ( +/- 4 days)
Time frame: 4 weeks
Absolute change from baseline in the number of RP attacks per week at 12 and 24 weeks
Comparison between the 2 groups of the change (absolute) from baseline in the number of RP attacks per week at 12 and 24 weeks. Subjects kept a daily record of the number of RP attacks they experienced per day and the duration of each attack, over a 14-day +/- 4 days period before each assessment visit at 12 and 24 weeks
Time frame: 24 weeks
Comparison between the 2 groups at 4, 12 and 24 weeks of follow-up after the treatment of the percentage of digital ulcers with complete healing
Comparison between the 2 groups at 4, 12 and 24 weeks of follow-up after the treatment of the percentage of digital ulcers with complete healing
Time frame: 24 weeks
Comparison between the 2 groups at 4, 12 and 24 weeks of follow-up after the treatment of the number of new digital ulcers.
Comparison between the 2 groups at 4, 12 and 24 weeks of follow-up after the treatment of the number of new digital ulcers.
Time frame: 24 weeks
Comparison between the 2 groups at 4, 12 and 24 weeks of follow-up after the treatment of the change in Raynaud's pain score.
Comparison between the 2 groups at 4, 12 and 24 weeks of follow-up after the treatment of the change in Raynaud's pain score. Pain associated with each attack is self-reported on a 10-point scale, and averaged over 14-day +/- 4 days period before each assessment visit
Time frame: 24 weeks
Comparison between the 2 groups at 4, 12 and 24 weeks of follow-up after the treatment of the change in Raynaud's Condition Score.
Comparison at 4, 12 and 24 weeks of follow-up after the treatment of the change in Raynaud's Condition Score. Raynaud Condition Score is a daily self-assessment of RP activity using a 0-10 ordinal scale and averaged over 14-day +/- 4 days period before each assessment visit. The RCS incorporates the cumulative daily frequency, duration, severity and impact of RP attacks.
Time frame: 24 weeks
Comparison between the 2 groups at 4, 12 and 24 weeks of follow-up after the treatment of the change in quality of life from baseline to weeks 4, 12 and 24
Comparison between the 2 groups at 4, 12 and 24 weeks of follow-up after the treatment of the change in quality of life from baseline to weeks 4, 12 and 24. QOL is assessed by the Health Assessment Questionnaire (HAQ)
Time frame: 24 weeks
Comparison between the 2 groups at 4, 12 and 24 weeks of follow-up after the treatment of the change in hand function from baseline to weeks 4, 12 and 24
Comparison between the 2 groups from baseline to 4, 12 and 24 weeks of follow-up after the treatment of the change in hand function measured by Quick-DASH (Disabilities of the Arm, Shoulder and Hand)
Time frame: 24 weeks
Comparison between the 2 groups at 4, 12 and 24 weeks of follow-up after the treatment of the change in hand function from baseline to weeks 4, 12 and 24
Comparison between the 2 groups from baseline to at 4, 12 and 24 weeks of follow-up after the treatment of the change in hand function measured by the Hand Function Scale of Cochin
Time frame: 24 weeks
Frequency and severity of adverse drug events during treatment from baseline to weeks 4, 12 and 24.
Frequency and severity of adverse drug events during treatment from baseline to weeks 4, 12 and 24.
Time frame: 24 weeks
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