Clinical trial NCT03717961: Efficacy of Botulinum Toxin A in Adult Subjects With Raynaud Phenomenon Secondary to Systemic Sclerosis
Official title: Multicenter, Double-Blind, Randomized, Placebo-Controlled, Parallel Group, Study to Assess Efficacy of Botulinum Toxin A in Adult Subjects With Raynaud Phenomenon Secondary to Systemic Sclerosis
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Raynaud Phenomenon Secondary to Systemic Sclerosis
Keywords: Raynaud Phenomenon
Systemic Sclerosis
Botulinum toxin A
Lead sponsor: Assistance Publique - Hôpitaux de Paris
Sponsor class: OTHER
First posted: 2018-10-24
Enrollment: 91
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Multicenter, double-blind, randomized, placebo-controlled, parallel groups, phase III
Primary purpose: TREATMENT

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.

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

Primary outcomes:
measure: Absolute change from baseline in the number of RP attacks per week at 4 weeks
timeFrame: 4 weeks
Secondary outcomes:
measure: Absolute change from baseline in the number of RP attacks per week at 12 and 24 weeks
timeFrame: 24 weeks
measure: 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
timeFrame: 24 weeks
measure: Comparison between the 2 groups at 4, 12 and 24 weeks of follow-up after the treatment of the number of new digital ulcers.
timeFrame: 24 weeks
measure: 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.
timeFrame: 24 weeks
measure: 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.
timeFrame: 24 weeks
measure: 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
timeFrame: 24 weeks
measure: 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
timeFrame: 24 weeks
measure: 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
timeFrame: 24 weeks
measure: Frequency and severity of adverse drug events during treatment from baseline to weeks 4, 12 and 24.
timeFrame: 24 weeks
Other outcomes:
Locations:
city: Paris
country: France
facility: Hôpital Tenon
Study officials:
affiliation: Assistance Publique - Hôpitaux de Paris
name: Patricia Senet, MD
role: PRINCIPAL_INVESTIGATOR
References: