Scleroderma, Raynaud's Syndrome
Conditions
Keywords
Scleroderma, Systemic, Raynaud Disease, Botulinum Toxins, Type A
Brief summary
This is a randomized, double-blinded, clinical trial assessing the therapeutic efficacy of Botulinum toxin A (Onabotulinumtoxin A) in treating scleroderma-associated Raynaud's syndrome. Each patient will undergo injection with a treatment dose of Botulinum toxin A in one randomly-selected hand, and the contralateral hand will be injected with sterile saline (placebo) to serve as a control. Study participants at the first study visit will complete study questionnaires, their hands will be assessed clinically for digital ulceration, and their hands will undergo non-invasive laser Doppler imaging to assess blood flow. After this initial assessment, the patients will undergo peri-arterial injection of Botulinum toxin A in one hand, and of sterile saline solution (placebo) in the other, in a randomized, blinded manner. Patient will report the severity of their Raynaud's symptoms weekly over the four month study period. At one month post-injection, the patient will complete study questionnaires, their hands will be assessed clinically for digital ulceration, and their hands will undergo non-invasive laser Doppler imaging. At four months post-injection, the patient will again complete study questionnaires, their hands will be assessed clinically for digital ulceration, and their hands will undergo non-invasive laser Doppler imaging. In addition, patient will be given the option of one week post-injection visit, at which point the same assessment will be performed. At the conclusion of the study, unblinding will occur.
Interventions
Sponsors
Allergan
Johns Hopkins University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Aged 18 years and older * Diagnosed with scleroderma. * Symptoms of Raynaud's syndrome affecting both hands (not necessarily to equal extents) * Ability to return/be available for follow-up evaluations * Able and willing to give informed consent * Able to speak and read in the English language.
Exclusion criteria
* A history of Myasthenia gravis. * Reported allergy or hypersensitivity to any Botulinum toxin preparation. * Active infection in either hand. * Patients who have ever received Botulinum toxin vaccine. * Pregnant or lactating women. * Females unable or unwilling to maintain abstinence or use contraception for 28 days following the injections. * Patients who have previously undergone any vascular surgery on the upper extremity, including surgical sympathectomies. * Current use of any aminoglycoside antibiotic
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Digital Blood Flow From Pre- to Post-injection. | Measured pre-injection and at one month post-injection. | The primary outcome measure is change in blood flow to the fingers, from a pre-injection baseline to post-injection follow-up visit as measured by non-invasive laser Doppler imaging. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Rate of Change in Raynaud's Phenomenon Symptoms Measured With the Raynaud's Condition Score. | Weekly rate of change over the four-month study period. | Raynaud's Condition Score is a patient-reported, validated outcomes scale that measures the severity of Raynaud's phenomenon on a scale of 0 (No difficulty) to 10 (Extreme difficulty), where higher values represent a worse outcome. Data from each weekly report were combined using a statistical model (generalized linear population-average model) to calculate a weekly rate of change for each participant's hand, where a negative value represents a improvement over time and a positive value represents worsening over time. |
| Number of Ulcers as Measure of Digital Ulcer Healing | Measured at one month post-injection. | A secondary outcome of this study is the number of digital ulcers as determined by clinical examination. Mean number of ulcers was calculated as total number of ulcers / total number of hands in each group. |
| Assessment of Raynaud's Symptoms Severity Using the Quick-DASH Score. | Measured at one month post-injection. | A secondary outcome of this study is severity of Raynaud's symptoms as measured by the self-reported Quick-DASH score. The Quick-DASH scores measures the degree of hand and upper extremity function on a scale of 0 (not limited) to 100 (severely limited) where a higher value represents a worse outcome. |
| Assessment of Raynaud's Symptom Severity Using the McCabe Cold Sensitivity Score. | Measured at one month post-injection. | A secondary outcome of this study is the patient-reported sensitivity to coldness as measured by the McCabe Cold Sensitivity score. Patients' answers on this validated instrument are scored on a scale from 0 (no sensitivity) to 400 (extreme sensitivity), where a higher number represents a worse outcome. |
| Assessment of Raynaud's Symptom Severity Using the VAS for Pain. | Measured at one month post-injection. | A secondary outcome of this study is pain as measured by the validated visual-analog scale (VAS) for pain. The VAS pain instrument measures pain on a scale from 0 cm (no pain) to 10 cm (extreme pain) |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Onabotulinumtoxin A One hand of each patient was be randomly selected for injection of Botulinum Toxin A (Onabotulinumtoxin A, 20 units/mL).
Injections were performed using a 30 gauge insulin syringe through the dorsal surface in seven locations: adjacent to the 2nd, 3rd, and 4th common digital arteries through the web spaces (10 units each=0.5mL each), and the radial side of the index finger metacarpal head, the ulnar side of the small finger metacarpal head, and each side of the thumb metacarpal head (5 units each= 0.25mL each). Total treatment dose of Botulinum Toxin A will not exceed 50 units per hand.
Onabotulinumtoxin A | 40 |
| Onabotulinumtoxin A One hand of each patient was be randomly selected for injection of Botulinum Toxin A (Onabotulinumtoxin A, 20 units/mL).
Injections were performed using a 30 gauge insulin syringe through the dorsal surface in seven locations: adjacent to the 2nd, 3rd, and 4th common digital arteries through the web spaces (10 units each=0.5mL each), and the radial side of the index finger metacarpal head, the ulnar side of the small finger metacarpal head, and each side of the thumb metacarpal head (5 units each= 0.25mL each). Total treatment dose of Botulinum Toxin A will not exceed 50 units per hand.
Onabotulinumtoxin A | 40 |
| Placebo One hand of each patient was randomly selected for injection of sterile saline solution (placebo).
Injections were performed using a 30 gauge insulin syringe through the dorsal surface in seven locations: adjacent to the 2nd, 3rd, and 4th common digital arteries through the web spaces (0.5 mL each), and the radial side of the index finger metacarpal head, the ulnar side of the small finger metacarpal head, and each side of the thumb metacarpal head (0.25 mL each).
sterile saline solution | 40 |
| Placebo One hand of each patient was randomly selected for injection of sterile saline solution (placebo).
Injections were performed using a 30 gauge insulin syringe through the dorsal surface in seven locations: adjacent to the 2nd, 3rd, and 4th common digital arteries through the web spaces (0.5 mL each), and the radial side of the index finger metacarpal head, the ulnar side of the small finger metacarpal head, and each side of the thumb metacarpal head (0.25 mL each).
sterile saline solution | 40 |
| Total | 160 |
Baseline characteristics
| Characteristic | Onabotulinumtoxin A | Placebo | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Hands | 0 Hands | 0 Hands |
| Age, Categorical >=65 years | 5 Hands | 5 Hands | 10 Hands |
| Age, Categorical Between 18 and 65 years | 35 Hands | 35 Hands | 70 Hands |
| Age, Continuous | 51.9 years STANDARD_DEVIATION 12.33 | 51.9 years STANDARD_DEVIATION 12.33 | 51.9 years STANDARD_DEVIATION 12.33 |
| Gender Female | 9 Hands | 9 Hands | 18 Hands |
| Gender Male | 31 Hands | 31 Hands | 62 Hands |
| Laser Doppler Imaging Blood Flow | 398.24 LDI flux units STANDARD_DEVIATION 190.27 | 395.65 LDI flux units STANDARD_DEVIATION 189.17 | 396.94 LDI flux units STANDARD_DEVIATION 188.52 |
| Region of Enrollment United States | 40 participants | 40 participants | 40 participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 2 / 40 | 0 / 40 |
| serious Total, serious adverse events | 0 / 40 | 0 / 40 |
Outcome results
Primary
Change in Digital Blood Flow From Pre- to Post-injection.
The primary outcome measure is change in blood flow to the fingers, from a pre-injection baseline to post-injection follow-up visit as measured by non-invasive laser Doppler imaging.
Time frame: Measured pre-injection and at one month post-injection.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Onabotulinumtoxin A | Change in Digital Blood Flow From Pre- to Post-injection. | -36.19 Blood flow, measured in LDI flux units, |
| Placebo | Change in Digital Blood Flow From Pre- to Post-injection. | -6.10 Blood flow, measured in LDI flux units, |
Secondary
Assessment of Raynaud's Symptom Severity Using the McCabe Cold Sensitivity Score.
A secondary outcome of this study is the patient-reported sensitivity to coldness as measured by the McCabe Cold Sensitivity score. Patients' answers on this validated instrument are scored on a scale from 0 (no sensitivity) to 400 (extreme sensitivity), where a higher number represents a worse outcome.
Time frame: Measured at one month post-injection.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Onabotulinumtoxin A | Assessment of Raynaud's Symptom Severity Using the McCabe Cold Sensitivity Score. | 185.31 Units on a scale | Standard Deviation 74.19 |
| Placebo | Assessment of Raynaud's Symptom Severity Using the McCabe Cold Sensitivity Score. | 187.19 Units on a scale | Standard Deviation 86.76 |
Secondary
Assessment of Raynaud's Symptom Severity Using the VAS for Pain.
A secondary outcome of this study is pain as measured by the validated visual-analog scale (VAS) for pain. The VAS pain instrument measures pain on a scale from 0 cm (no pain) to 10 cm (extreme pain)
Time frame: Measured at one month post-injection.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Onabotulinumtoxin A | Assessment of Raynaud's Symptom Severity Using the VAS for Pain. | 2.68 centimeters measured on a visual scale | Standard Deviation 2.57 |
| Placebo | Assessment of Raynaud's Symptom Severity Using the VAS for Pain. | 3.05 centimeters measured on a visual scale | Standard Deviation 2.77 |
Secondary
Assessment of Raynaud's Symptoms Severity Using the Quick-DASH Score.
A secondary outcome of this study is severity of Raynaud's symptoms as measured by the self-reported Quick-DASH score. The Quick-DASH scores measures the degree of hand and upper extremity function on a scale of 0 (not limited) to 100 (severely limited) where a higher value represents a worse outcome.
Time frame: Measured at one month post-injection.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Onabotulinumtoxin A | Assessment of Raynaud's Symptoms Severity Using the Quick-DASH Score. | 26.96 Units on a scale | Standard Deviation 20.68 |
| Placebo | Assessment of Raynaud's Symptoms Severity Using the Quick-DASH Score. | 29.11 Units on a scale | Standard Deviation 23.8 |
Secondary
Number of Ulcers as Measure of Digital Ulcer Healing
A secondary outcome of this study is the number of digital ulcers as determined by clinical examination. Mean number of ulcers was calculated as total number of ulcers / total number of hands in each group.
Time frame: Measured at one month post-injection.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Onabotulinumtoxin A | Number of Ulcers as Measure of Digital Ulcer Healing | 0.45 Number of ulcers | Standard Deviation 0.9 |
| Placebo | Number of Ulcers as Measure of Digital Ulcer Healing | 0.53 Number of ulcers | Standard Deviation 0.93 |
Secondary
Rate of Change in Raynaud's Phenomenon Symptoms Measured With the Raynaud's Condition Score.
Raynaud's Condition Score is a patient-reported, validated outcomes scale that measures the severity of Raynaud's phenomenon on a scale of 0 (No difficulty) to 10 (Extreme difficulty), where higher values represent a worse outcome. Data from each weekly report were combined using a statistical model (generalized linear population-average model) to calculate a weekly rate of change for each participant's hand, where a negative value represents a improvement over time and a positive value represents worsening over time.
Time frame: Weekly rate of change over the four-month study period.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Onabotulinumtoxin A | Rate of Change in Raynaud's Phenomenon Symptoms Measured With the Raynaud's Condition Score. | -0.18 change in RCS/week |
| Placebo | Rate of Change in Raynaud's Phenomenon Symptoms Measured With the Raynaud's Condition Score. | -0.14 change in RCS/week |