Digital Ulcers
Conditions
Keywords
digital ulcers, systemic sclerosis, finger ulcers, bosentan, open label
Brief summary
The aim of the study is to collect long-term efficacy, tolerability and safety data of bosentan in Systemic Sclerosis (SSc) patients suffering from ischemic digital ulcers (DUs).
Interventions
DRUGBosentan 62.5 mg
Bosentan 62.5-mg oral tablets twice daily (b.i.d.) for 4 weeks (initial dose)
DRUGBosentan 125 mg
Bosentan 125-mg oral tablets administered b.i.d. (target dose)
Sponsors
Actelion
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Patients with SSc according to the classification criteria of the American College of Rheumatology 2. SSc patients with at least one DU at baseline qualifying as a CU (see definition section 3.2.2) 3. CU occurred \< 3 months and \> 1 week prior to randomization. The subset of patients with SSc felt to be at high risk for DUs will be identified in the screening period but will not be eligible for enrollment until a CU has developed 4. Male or female patients \>/= 18 years of age 5. Women of childbearing potential must have a negative pre-treatment pregnancy test and use a reliable method of contraception during study treatment and for at least 3 months after study treatment termination 6. Women not of childbearing potential are defined as postmenopausal (i.e., amenorrhea for at least 1 year), or surgically or naturally sterile 7. Signed informed consent.
Exclusion criteria
1. DUs due to condition other than SSc 2. Severe PAH (WHO class III and IV) 3. Systolic blood pressure \< 85 mmHg 4. Hemoglobin concentration \< 75% of the lower limit of the normal range 5. AST and/or ALT values greater than 3 times the upper limit of normal 6. Moderate to severe hepatic impairment, i.e., Child-Pugh Class B or C 7. Severe malabsorption or any severe organ failure (e.g., lung, kidney) or any life-threatening condition 8. Pregnancy or breast-feeding 9. Previous treatment with bosentan 10. Treatment with any of the following: glibenclamide (glyburide), fluconazole, cyclosporine A, tacrolimus and any other calcineurin inhibitor 1 week prior to randomization 11. Local injection of botulinum toxin in an affected finger 1 month prior to randomization 12. Treatment with parenteral prostanoids (prostaglandin E, epoprostenol, treprostinil sodium or other prostacyclin analogs) 3 months prior to randomization 13. Treatment with inhaled or oral prostanoids one month prior to randomization 14. Systemic antibiotics to treat infection of DUs 2 weeks prior to randomization 15. Treatment with phosphodiesterase inhibitors such as sildenafil, except for intermittent treatment of male erectile dysfunction 16. Body weight \< 40 kg 17. Patient with conditions that prevent compliance with the protocol or adhering to therapy 18. Patient who received an investigational product within 1 month preceding screening 19. Known hypersensitivity to bosentan or any of the excipients.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Total Number of New Digital Ulcers (DUs) Per Patient Observed by the Investigator at Planned Visits | At planned visits up to week 80 | The total number of new DUs per patient observed by the investigator at planned visits and new transient DUs recorded in the patient diary (a patient diary was used to record DUs that might appear and disappear between two planned visits) were assessed at each clinic visit |
| Mean Change From Baseline at Each 16 Week Interval up to Week 80 in Scleroderma Health Assessment Questionnaire (SHAQ) Individual Domain Score: Activity | 80 weeks | SHAQ evaluates physical disability. Patients were instructed to rate their capacity to perform activities of daily living within the previous 7 days by checking one of the following descriptors: without any difficulty, with some difficulty, with much difficulty, or unable to do, equivalent to scores of 0, 1, 2, and 3, respectively. Items were categorized into 8 domains: dressing/grooming, arising, eating, walking, hygiene, reach, grip, and activities. |
| Mean Changes From Baseline at Each 16 Week Interval up to Week 80 in Overall Hand Pain Related to Finger Ulcers | 80 weeks | Overall hand pain related to finger ulcers was assessed by the patient using a Visual Analogue Scale. Patients were instructed to score their pain by marking on the continuous 10-cm scale, where 0 (left) was no pain and 100 (right) very severe pain, in response to the question, How much pain have you had because of your finger ulcers in the past week? The investigator measured the distance in millimeters between 0 and the patient mark with the ruler provided and recorded the distance. |
| Mean Change From Baseline at Each 16 Week Interval up to Week 80 in the UK Systemic Sclerosis Functional Score (UKFS) | 80 weeks | UKFS relates to upper and lower extremity function and muscle weakness. For each item, the patient indicated the responses that best described their current ability: able to perform in a normal manner, able to perform with alteration in style, can only manage with difficulty, and impossible to achieve. Each response was given an integer from 0 (able to perform in a normal manner) to 3 (impossible to achieve), and the sum of individual responses provided an overall score of 0 to 33. Missing values were replaced with the worst value the patient reported on the other items at that visit. |
| Time to Complete Healing of Each Baseline DU | Baseline to healing | — |
| Time to Complete Healing of Each New DU | New DU occurence to healing | — |
| Mean Change From Baseline at Each 16 Week Interval up to Week 80 in Scleroderma Health Assessment Questionnaire (SHAQ) Individual Domain Score: Dressing | 80 weeks | SHAQ evaluates physical disability. Patients were instructed to rate their capacity to perform activities of daily living within the previous 7 days by checking one of the following descriptors: without any difficulty, with some difficulty, with much difficulty, or unable to do, equivalent to scores of 0, 1, 2, and 3, respectively. Items were categorized into 8 domains: dressing/grooming, arising, eating, walking, hygiene, reach, grip, and activities. |
| Mean Change From Baseline at Each 16 Week Interval up to Week 80 in Scleroderma Health Assessment Questionnaire (SHAQ) Individual Domain Score: Arising | 80 weeks | SHAQ evaluates physical disability. Patients were instructed to rate their capacity to perform activities of daily living within the previous 7 days by checking one of the following descriptors: without any difficulty, with some difficulty, with much difficulty, or unable to do, equivalent to scores of 0, 1, 2, and 3, respectively. Items were categorized into 8 domains: dressing/grooming, arising, eating, walking, hygiene, reach, grip, and activities. |
| Mean Change From Baseline at Each 16 Week Interval up to Week 80 in Scleroderma Health Assessment Questionnaire (SHAQ) Individual Domain Score: Eating | 80 weeks | SHAQ evaluates physical disability. Patients were instructed to rate their capacity to perform activities of daily living within the previous 7 days by checking one of the following descriptors: without any difficulty, with some difficulty, with much difficulty, or unable to do, equivalent to scores of 0, 1, 2, and 3, respectively. Items were categorized into 8 domains: dressing/grooming, arising, eating, walking, hygiene, reach, grip, and activities. |
| Mean Change From Baseline at Each 16 Week Interval up to Week 80 in Scleroderma Health Assessment Questionnaire (SHAQ) Individual Domain Score: Walking | 80 weeks | SHAQ evaluates physical disability. Patients were instructed to rate their capacity to perform activities of daily living within the previous 7 days by checking one of the following descriptors: without any difficulty, with some difficulty, with much difficulty, or unable to do, equivalent to scores of 0, 1, 2, and 3, respectively. Items were categorized into 8 domains: dressing/grooming, arising, eating, walking, hygiene, reach, grip, and activities. |
| Mean Change From Baseline at Each 16 Week Interval up to Week 80 in Scleroderma Health Assessment Questionnaire (SHAQ) Individual Domain Score: Hygiene | 80 weeks | SHAQ evaluates physical disability. Patients were instructed to rate their capacity to perform activities of daily living within the previous 7 days by checking one of the following descriptors: without any difficulty, with some difficulty, with much difficulty, or unable to do, equivalent to scores of 0, 1, 2, and 3, respectively. Items were categorized into 8 domains: dressing/grooming, arising, eating, walking, hygiene, reach, grip, and activities. |
| Mean Change From Baseline at Each 16 Week Interval up to Week 80 in Scleroderma Health Assessment Questionnaire (SHAQ) Individual Domain Score: Reach | 80 weeks | SHAQ evaluates physical disability. Patients were instructed to rate their capacity to perform activities of daily living within the previous 7 days by checking one of the following descriptors: without any difficulty, with some difficulty, with much difficulty, or unable to do, equivalent to scores of 0, 1, 2, and 3, respectively. Items were categorized into 8 domains: dressing/grooming, arising, eating, walking, hygiene, reach, grip, and activities. |
| Mean Change From Baseline at Each 16 Week Interval up to Week 80 in Scleroderma Health Assessment Questionnaire (SHAQ) Individual Domain Score: Grip | 80 weeks | SHAQ evaluates physical disability. Patients were instructed to rate their capacity to perform activities of daily living within the previous 7 days by checking one of the following descriptors: without any difficulty, with some difficulty, with much difficulty, or unable to do, equivalent to scores of 0, 1, 2, and 3, respectively. Items were categorized into 8 domains: dressing/grooming, arising, eating, walking, hygiene, reach, grip, and activities. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Adverse Events Leading to Permanent Discontinuation of the Study Medication | 80 weeks | Number of patients with an adverse event leading to permanent discontinuation of the study treatment |
| Serious Adverse Events up to 28 Days After Last Study Medication | 80 weeks | Number of patients with at least one treatment-emergent serious adverse event (TESAE) were reported. TESAEs are serious AEs that occurred after study drug initiation and up to 28 days after study drug discontinuation. More details on the SAEs are provided in the specific Adverse Events Section |
| Adverse Events up to 24 Hours After Last Study Medication | 80 weeks | Number of patients with at least one treatment-emergent adverse event. All adverse events that occurred after study drug initiation and up to 24 hours after study drug discontinuation were to be recorded. |
Participant flow
Recruitment details
Patients were enrolled at 33 centers in 7 countries (Canada, France, Germany, Italy, Switzerland, UK, and USA. The first patient enrolled and started treatment on 8 July 2004 and the last patient enrolled and started treatment on 20 October 2005.
Pre-assignment details
Patients who completed RAPIDS-2 and who still had digital ulcers (DUs) or developed a new digital ulcer (DU) after the last follow-up visit were eligible. After release of the RAPIDS-2 results, patients who were prematurely discontinued from RAPIDS-2 for treatment failure or, if on placebo, for an adverse event and had DUs were also eligible.
Participants by arm
| Arm | Count |
|---|---|
| Bosentan Initial dose: bosentan 62.5 mg twice daily (b.i.d.) for the first 4 weeks. Target dose: bosentan 125 mg b.i.d. thereafter | 116 |
| Total | 116 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | administrative | 7 |
| Overall Study | Adverse Event | 36 |
| Overall Study | Lost to Follow-up | 3 |
| Overall Study | withdrawal of consent | 14 |
Baseline characteristics
| Characteristic | Bosentan |
|---|---|
| Age, Continuous | 49.3 years STANDARD_DEVIATION 12 |
| Age, Customized Between 24 and 79 years | 116 Participants |
| Overall hand pain | 58.62 mm STANDARD_DEVIATION 29.8 |
| Region of Enrollment Canada | 11 Participants |
| Region of Enrollment France | 10 Participants |
| Region of Enrollment Germany | 9 Participants |
| Region of Enrollment Italy | 9 Participants |
| Region of Enrollment Switzerland | 4 Participants |
| Region of Enrollment United Kingdom | 6 Participants |
| Region of Enrollment United States | 67 Participants |
| Scleroderma Health Assessment Questionnaire (SHAQ) Individual Domain Score Activity | 1.0 score on a scale STANDARD_DEVIATION 0.9 |
| Scleroderma Health Assessment Questionnaire (SHAQ) Individual Domain Score Arising | 0.5 score on a scale STANDARD_DEVIATION 0.8 |
| Scleroderma Health Assessment Questionnaire (SHAQ) Individual Domain Score Dressing | 1.3 score on a scale STANDARD_DEVIATION 0.9 |
| Scleroderma Health Assessment Questionnaire (SHAQ) Individual Domain Score Eating | 1.5 score on a scale STANDARD_DEVIATION 1 |
| Scleroderma Health Assessment Questionnaire (SHAQ) Individual Domain Score Grip | 1.1 score on a scale STANDARD_DEVIATION 0.8 |
| Scleroderma Health Assessment Questionnaire (SHAQ) Individual Domain Score Hygiene | 0.9 score on a scale STANDARD_DEVIATION 1 |
| Scleroderma Health Assessment Questionnaire (SHAQ) Individual Domain Score Reach | 1.1 score on a scale STANDARD_DEVIATION 0.9 |
| Scleroderma Health Assessment Questionnaire (SHAQ) Individual Domain Score Walking | 0.5 score on a scale STANDARD_DEVIATION 0.7 |
| Sex: Female, Male Female | 87 Participants |
| Sex: Female, Male Male | 29 Participants |
| United Kingdom Scleroderma Functional Score (UKFS) | 11.06 score on a scale STANDARD_DEVIATION 7.5 |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 6 / 116 |
| other Total, other adverse events | 111 / 116 |
| serious Total, serious adverse events | 45 / 116 |
Outcome results
Primary
Mean Change From Baseline at Each 16 Week Interval up to Week 80 in Scleroderma Health Assessment Questionnaire (SHAQ) Individual Domain Score: Activity
SHAQ evaluates physical disability. Patients were instructed to rate their capacity to perform activities of daily living within the previous 7 days by checking one of the following descriptors: without any difficulty, with some difficulty, with much difficulty, or unable to do, equivalent to scores of 0, 1, 2, and 3, respectively. Items were categorized into 8 domains: dressing/grooming, arising, eating, walking, hygiene, reach, grip, and activities.
Time frame: 80 weeks
Population: number of participants at baseline, week 16, week 32, week 48, week 64, and week 80 was 116, 99, 93, 85, 82, and 78, respectively
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Bosentan | Mean Change From Baseline at Each 16 Week Interval up to Week 80 in Scleroderma Health Assessment Questionnaire (SHAQ) Individual Domain Score: Activity | change from baseline to week 16 | -0.2 scores on a scale | Standard Deviation 0.5 |
| Bosentan | Mean Change From Baseline at Each 16 Week Interval up to Week 80 in Scleroderma Health Assessment Questionnaire (SHAQ) Individual Domain Score: Activity | change from baseline to week 32 | -0.1 scores on a scale | Standard Deviation 0.7 |
| Bosentan | Mean Change From Baseline at Each 16 Week Interval up to Week 80 in Scleroderma Health Assessment Questionnaire (SHAQ) Individual Domain Score: Activity | change from baseline to week 48 | -0.1 scores on a scale | Standard Deviation 0.7 |
| Bosentan | Mean Change From Baseline at Each 16 Week Interval up to Week 80 in Scleroderma Health Assessment Questionnaire (SHAQ) Individual Domain Score: Activity | change from baseline to week 64 | -0.1 scores on a scale | Standard Deviation 0.7 |
| Bosentan | Mean Change From Baseline at Each 16 Week Interval up to Week 80 in Scleroderma Health Assessment Questionnaire (SHAQ) Individual Domain Score: Activity | change from baseline to week 80 | -0.1 scores on a scale | Standard Deviation 0.6 |
Primary
Mean Change From Baseline at Each 16 Week Interval up to Week 80 in Scleroderma Health Assessment Questionnaire (SHAQ) Individual Domain Score: Arising
SHAQ evaluates physical disability. Patients were instructed to rate their capacity to perform activities of daily living within the previous 7 days by checking one of the following descriptors: without any difficulty, with some difficulty, with much difficulty, or unable to do, equivalent to scores of 0, 1, 2, and 3, respectively. Items were categorized into 8 domains: dressing/grooming, arising, eating, walking, hygiene, reach, grip, and activities.
Time frame: 80 weeks
Population: number of participants at baseline, week 16, week 32, week 48, week 64, and week 80 was 116, 99, 93, 85, 82, and 78, respectively
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Bosentan | Mean Change From Baseline at Each 16 Week Interval up to Week 80 in Scleroderma Health Assessment Questionnaire (SHAQ) Individual Domain Score: Arising | change from baseline to week 16 | 0.0 scores on a scale | Standard Deviation 0.6 |
| Bosentan | Mean Change From Baseline at Each 16 Week Interval up to Week 80 in Scleroderma Health Assessment Questionnaire (SHAQ) Individual Domain Score: Arising | change from baseline to week 32 | -0.0 scores on a scale | Standard Deviation 0.6 |
| Bosentan | Mean Change From Baseline at Each 16 Week Interval up to Week 80 in Scleroderma Health Assessment Questionnaire (SHAQ) Individual Domain Score: Arising | change from baseline to week 48 | 0.1 scores on a scale | Standard Deviation 0.6 |
| Bosentan | Mean Change From Baseline at Each 16 Week Interval up to Week 80 in Scleroderma Health Assessment Questionnaire (SHAQ) Individual Domain Score: Arising | change from baseline to week 64 | 0.1 scores on a scale | Standard Deviation 0.7 |
| Bosentan | Mean Change From Baseline at Each 16 Week Interval up to Week 80 in Scleroderma Health Assessment Questionnaire (SHAQ) Individual Domain Score: Arising | change from baseline to week 80 | 0.1 scores on a scale | Standard Deviation 0.6 |
Primary
Mean Change From Baseline at Each 16 Week Interval up to Week 80 in Scleroderma Health Assessment Questionnaire (SHAQ) Individual Domain Score: Dressing
SHAQ evaluates physical disability. Patients were instructed to rate their capacity to perform activities of daily living within the previous 7 days by checking one of the following descriptors: without any difficulty, with some difficulty, with much difficulty, or unable to do, equivalent to scores of 0, 1, 2, and 3, respectively. Items were categorized into 8 domains: dressing/grooming, arising, eating, walking, hygiene, reach, grip, and activities.
Time frame: 80 weeks
Population: number of participants at baseline, week 16, week 32, week 48, week 64, and week 80 was 116, 99, 93, 85, 82, and 78, respectively
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Bosentan | Mean Change From Baseline at Each 16 Week Interval up to Week 80 in Scleroderma Health Assessment Questionnaire (SHAQ) Individual Domain Score: Dressing | change from baseline to week 16 | -0.3 scores on a scale | Standard Deviation 0.6 |
| Bosentan | Mean Change From Baseline at Each 16 Week Interval up to Week 80 in Scleroderma Health Assessment Questionnaire (SHAQ) Individual Domain Score: Dressing | change from baseline to week 32 | -0.2 scores on a scale | Standard Deviation 0.7 |
| Bosentan | Mean Change From Baseline at Each 16 Week Interval up to Week 80 in Scleroderma Health Assessment Questionnaire (SHAQ) Individual Domain Score: Dressing | change from baseline to week 48 | -0.1 scores on a scale | Standard Deviation 0.7 |
| Bosentan | Mean Change From Baseline at Each 16 Week Interval up to Week 80 in Scleroderma Health Assessment Questionnaire (SHAQ) Individual Domain Score: Dressing | change from baseline to week 64 | -0.1 scores on a scale | Standard Deviation 0.7 |
| Bosentan | Mean Change From Baseline at Each 16 Week Interval up to Week 80 in Scleroderma Health Assessment Questionnaire (SHAQ) Individual Domain Score: Dressing | change from baseline to week 80 | -0.1 scores on a scale | Standard Deviation 0.7 |
Primary
Mean Change From Baseline at Each 16 Week Interval up to Week 80 in Scleroderma Health Assessment Questionnaire (SHAQ) Individual Domain Score: Eating
SHAQ evaluates physical disability. Patients were instructed to rate their capacity to perform activities of daily living within the previous 7 days by checking one of the following descriptors: without any difficulty, with some difficulty, with much difficulty, or unable to do, equivalent to scores of 0, 1, 2, and 3, respectively. Items were categorized into 8 domains: dressing/grooming, arising, eating, walking, hygiene, reach, grip, and activities.
Time frame: 80 weeks
Population: number of participants at baseline, week 16, week 32, week 48, week 64, and week 80 was 116, 99, 93, 85, 82, and 78, respectively
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Bosentan | Mean Change From Baseline at Each 16 Week Interval up to Week 80 in Scleroderma Health Assessment Questionnaire (SHAQ) Individual Domain Score: Eating | change from baseline to week 16 | -0.2 scores on a scale | Standard Deviation 0.6 |
| Bosentan | Mean Change From Baseline at Each 16 Week Interval up to Week 80 in Scleroderma Health Assessment Questionnaire (SHAQ) Individual Domain Score: Eating | change from baseline to week 32 | -0.1 scores on a scale | Standard Deviation 0.7 |
| Bosentan | Mean Change From Baseline at Each 16 Week Interval up to Week 80 in Scleroderma Health Assessment Questionnaire (SHAQ) Individual Domain Score: Eating | change from baseline to week 48 | -0.2 scores on a scale | Standard Deviation 0.7 |
| Bosentan | Mean Change From Baseline at Each 16 Week Interval up to Week 80 in Scleroderma Health Assessment Questionnaire (SHAQ) Individual Domain Score: Eating | change from baseline to week 64 | -0.1 scores on a scale | Standard Deviation 0.6 |
| Bosentan | Mean Change From Baseline at Each 16 Week Interval up to Week 80 in Scleroderma Health Assessment Questionnaire (SHAQ) Individual Domain Score: Eating | change from baseline to week 80 | -0.1 scores on a scale | Standard Deviation 0.7 |
Primary
Mean Change From Baseline at Each 16 Week Interval up to Week 80 in Scleroderma Health Assessment Questionnaire (SHAQ) Individual Domain Score: Grip
SHAQ evaluates physical disability. Patients were instructed to rate their capacity to perform activities of daily living within the previous 7 days by checking one of the following descriptors: without any difficulty, with some difficulty, with much difficulty, or unable to do, equivalent to scores of 0, 1, 2, and 3, respectively. Items were categorized into 8 domains: dressing/grooming, arising, eating, walking, hygiene, reach, grip, and activities.
Time frame: 80 weeks
Population: number of participants at baseline, week 16, week 32, week 48, week 64, and week 80 was 116, 99, 93, 85, 82, and 78, respectively
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Bosentan | Mean Change From Baseline at Each 16 Week Interval up to Week 80 in Scleroderma Health Assessment Questionnaire (SHAQ) Individual Domain Score: Grip | change from baseline to week 16 | -0.1 scores on a scale | Standard Deviation 0.7 |
| Bosentan | Mean Change From Baseline at Each 16 Week Interval up to Week 80 in Scleroderma Health Assessment Questionnaire (SHAQ) Individual Domain Score: Grip | change from baseline to week 32 | -0.2 scores on a scale | Standard Deviation 0.7 |
| Bosentan | Mean Change From Baseline at Each 16 Week Interval up to Week 80 in Scleroderma Health Assessment Questionnaire (SHAQ) Individual Domain Score: Grip | change from baseline to week 48 | -0.1 scores on a scale | Standard Deviation 0.7 |
| Bosentan | Mean Change From Baseline at Each 16 Week Interval up to Week 80 in Scleroderma Health Assessment Questionnaire (SHAQ) Individual Domain Score: Grip | change from baseline to week 64 | -0.1 scores on a scale | Standard Deviation 0.7 |
| Bosentan | Mean Change From Baseline at Each 16 Week Interval up to Week 80 in Scleroderma Health Assessment Questionnaire (SHAQ) Individual Domain Score: Grip | change from baseline to week 80 | -0.1 scores on a scale | Standard Deviation 0.7 |
Primary
Mean Change From Baseline at Each 16 Week Interval up to Week 80 in Scleroderma Health Assessment Questionnaire (SHAQ) Individual Domain Score: Hygiene
SHAQ evaluates physical disability. Patients were instructed to rate their capacity to perform activities of daily living within the previous 7 days by checking one of the following descriptors: without any difficulty, with some difficulty, with much difficulty, or unable to do, equivalent to scores of 0, 1, 2, and 3, respectively. Items were categorized into 8 domains: dressing/grooming, arising, eating, walking, hygiene, reach, grip, and activities.
Time frame: 80 weeks
Population: number of participants at baseline, week 16, week 32, week 48, week 64, and week 80 was 116, 99, 93, 85, 82, and 78, respectively
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Bosentan | Mean Change From Baseline at Each 16 Week Interval up to Week 80 in Scleroderma Health Assessment Questionnaire (SHAQ) Individual Domain Score: Hygiene | change from baseline to week 16 | -0.0 scores on a scale | Standard Deviation 0.7 |
| Bosentan | Mean Change From Baseline at Each 16 Week Interval up to Week 80 in Scleroderma Health Assessment Questionnaire (SHAQ) Individual Domain Score: Hygiene | change from baseline to week 32 | -0.0 scores on a scale | Standard Deviation 0.8 |
| Bosentan | Mean Change From Baseline at Each 16 Week Interval up to Week 80 in Scleroderma Health Assessment Questionnaire (SHAQ) Individual Domain Score: Hygiene | change from baseline to week 48 | -0.0 scores on a scale | Standard Deviation 0.8 |
| Bosentan | Mean Change From Baseline at Each 16 Week Interval up to Week 80 in Scleroderma Health Assessment Questionnaire (SHAQ) Individual Domain Score: Hygiene | change from baseline to week 64 | 0.1 scores on a scale | Standard Deviation 0.7 |
| Bosentan | Mean Change From Baseline at Each 16 Week Interval up to Week 80 in Scleroderma Health Assessment Questionnaire (SHAQ) Individual Domain Score: Hygiene | change from baseline to week 80 | 0.2 scores on a scale | Standard Deviation 0.8 |
Primary
Mean Change From Baseline at Each 16 Week Interval up to Week 80 in Scleroderma Health Assessment Questionnaire (SHAQ) Individual Domain Score: Reach
SHAQ evaluates physical disability. Patients were instructed to rate their capacity to perform activities of daily living within the previous 7 days by checking one of the following descriptors: without any difficulty, with some difficulty, with much difficulty, or unable to do, equivalent to scores of 0, 1, 2, and 3, respectively. Items were categorized into 8 domains: dressing/grooming, arising, eating, walking, hygiene, reach, grip, and activities.
Time frame: 80 weeks
Population: number of participants at baseline, week 16, week 32, week 48, week 64, and week 80 was 116, 99, 93, 85, 82, and 78, respectively
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Bosentan | Mean Change From Baseline at Each 16 Week Interval up to Week 80 in Scleroderma Health Assessment Questionnaire (SHAQ) Individual Domain Score: Reach | change from baseline to week 16 | -0.1 scores on a scale | Standard Deviation 0.7 |
| Bosentan | Mean Change From Baseline at Each 16 Week Interval up to Week 80 in Scleroderma Health Assessment Questionnaire (SHAQ) Individual Domain Score: Reach | change from baseline to week 32 | 0.0 scores on a scale | Standard Deviation 0.7 |
| Bosentan | Mean Change From Baseline at Each 16 Week Interval up to Week 80 in Scleroderma Health Assessment Questionnaire (SHAQ) Individual Domain Score: Reach | change from baseline to week 48 | 0.0 scores on a scale | Standard Deviation 0.8 |
| Bosentan | Mean Change From Baseline at Each 16 Week Interval up to Week 80 in Scleroderma Health Assessment Questionnaire (SHAQ) Individual Domain Score: Reach | change from baseline to week 64 | 0.1 scores on a scale | Standard Deviation 0.8 |
| Bosentan | Mean Change From Baseline at Each 16 Week Interval up to Week 80 in Scleroderma Health Assessment Questionnaire (SHAQ) Individual Domain Score: Reach | change from baseline to week 80 | 0.0 scores on a scale | Standard Deviation 0.7 |
Primary
Mean Change From Baseline at Each 16 Week Interval up to Week 80 in Scleroderma Health Assessment Questionnaire (SHAQ) Individual Domain Score: Walking
SHAQ evaluates physical disability. Patients were instructed to rate their capacity to perform activities of daily living within the previous 7 days by checking one of the following descriptors: without any difficulty, with some difficulty, with much difficulty, or unable to do, equivalent to scores of 0, 1, 2, and 3, respectively. Items were categorized into 8 domains: dressing/grooming, arising, eating, walking, hygiene, reach, grip, and activities.
Time frame: 80 weeks
Population: number of participants at baseline, week 16, week 32, week 48, week 64, and week 80 was 116, 99, 93, 85, 82, and 78, respectively
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Bosentan | Mean Change From Baseline at Each 16 Week Interval up to Week 80 in Scleroderma Health Assessment Questionnaire (SHAQ) Individual Domain Score: Walking | change from baseline to week 16 | -0.1 scores on a scale | Standard Deviation 0.6 |
| Bosentan | Mean Change From Baseline at Each 16 Week Interval up to Week 80 in Scleroderma Health Assessment Questionnaire (SHAQ) Individual Domain Score: Walking | change from baseline to week 32 | 0.0 scores on a scale | Standard Deviation 0.7 |
| Bosentan | Mean Change From Baseline at Each 16 Week Interval up to Week 80 in Scleroderma Health Assessment Questionnaire (SHAQ) Individual Domain Score: Walking | change from baseline to week 48 | 0.1 scores on a scale | Standard Deviation 0.7 |
| Bosentan | Mean Change From Baseline at Each 16 Week Interval up to Week 80 in Scleroderma Health Assessment Questionnaire (SHAQ) Individual Domain Score: Walking | change from baseline to week 64 | 0.1 scores on a scale | Standard Deviation 0.8 |
| Bosentan | Mean Change From Baseline at Each 16 Week Interval up to Week 80 in Scleroderma Health Assessment Questionnaire (SHAQ) Individual Domain Score: Walking | change from baseline to week 80 | 0.1 scores on a scale | Standard Deviation 0.8 |
Primary
Mean Change From Baseline at Each 16 Week Interval up to Week 80 in the UK Systemic Sclerosis Functional Score (UKFS)
UKFS relates to upper and lower extremity function and muscle weakness. For each item, the patient indicated the responses that best described their current ability: able to perform in a normal manner, able to perform with alteration in style, can only manage with difficulty, and impossible to achieve. Each response was given an integer from 0 (able to perform in a normal manner) to 3 (impossible to achieve), and the sum of individual responses provided an overall score of 0 to 33. Missing values were replaced with the worst value the patient reported on the other items at that visit.
Time frame: 80 weeks
Population: number of participants at baseline, week 16, week 32, week 48, week 64, and week 80 was 116, 98, 93, 84, 82, and 78, respectively
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Bosentan | Mean Change From Baseline at Each 16 Week Interval up to Week 80 in the UK Systemic Sclerosis Functional Score (UKFS) | change from baseline to week 16 | -1.37 score on a scale | Standard Deviation 3.64 |
| Bosentan | Mean Change From Baseline at Each 16 Week Interval up to Week 80 in the UK Systemic Sclerosis Functional Score (UKFS) | change from baseline to week 32 | -1.25 score on a scale | Standard Deviation 4.01 |
| Bosentan | Mean Change From Baseline at Each 16 Week Interval up to Week 80 in the UK Systemic Sclerosis Functional Score (UKFS) | change from baseline to week 48 | -0.89 score on a scale | Standard Deviation 4.98 |
| Bosentan | Mean Change From Baseline at Each 16 Week Interval up to Week 80 in the UK Systemic Sclerosis Functional Score (UKFS) | change from baseline to week 64 | -1.17 score on a scale | Standard Deviation 4 |
| Bosentan | Mean Change From Baseline at Each 16 Week Interval up to Week 80 in the UK Systemic Sclerosis Functional Score (UKFS) | change from baseline to week 80 | -0.45 score on a scale | Standard Deviation 4.66 |
Primary
Mean Changes From Baseline at Each 16 Week Interval up to Week 80 in Overall Hand Pain Related to Finger Ulcers
Overall hand pain related to finger ulcers was assessed by the patient using a Visual Analogue Scale. Patients were instructed to score their pain by marking on the continuous 10-cm scale, where 0 (left) was no pain and 100 (right) very severe pain, in response to the question, How much pain have you had because of your finger ulcers in the past week? The investigator measured the distance in millimeters between 0 and the patient mark with the ruler provided and recorded the distance.
Time frame: 80 weeks
Population: number of participants at baseline, week 16, week 32, week 48, week 64, and week 80 was 110, 94, 89, 81, 76, and 73, respectively
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Bosentan | Mean Changes From Baseline at Each 16 Week Interval up to Week 80 in Overall Hand Pain Related to Finger Ulcers | change from baseline to week 16 | -21.59 mm | Standard Deviation 28.02 |
| Bosentan | Mean Changes From Baseline at Each 16 Week Interval up to Week 80 in Overall Hand Pain Related to Finger Ulcers | change from baseline to week 32 | -28.16 mm | Standard Deviation 32.64 |
| Bosentan | Mean Changes From Baseline at Each 16 Week Interval up to Week 80 in Overall Hand Pain Related to Finger Ulcers | change from baseline to week 48 | -21.90 mm | Standard Deviation 32.09 |
| Bosentan | Mean Changes From Baseline at Each 16 Week Interval up to Week 80 in Overall Hand Pain Related to Finger Ulcers | change from baseline to week 64 | -22.96 mm | Standard Deviation 33.27 |
| Bosentan | Mean Changes From Baseline at Each 16 Week Interval up to Week 80 in Overall Hand Pain Related to Finger Ulcers | change from baseline to week 80 | -24.29 mm | Standard Deviation 36.55 |
Primary
Time to Complete Healing of Each Baseline DU
Time frame: Baseline to healing
Population: Complete healing of each baseline was not calculated due to the lack of effect on healing variables seen in the previous placebo-controlled study (RAPIDS 2). In consequence, the endpoint on time to complete healing of baseline DUs was not evaluated.
Primary
Time to Complete Healing of Each New DU
Time frame: New DU occurence to healing
Population: Complete healing of each new DU was not calculated due to the lack of effect on healing variables seen in the previous placebo-controlled study (RAPIDS 2). In consequence, the endpoint on DU healing originally planned time to complete healing of new DUs was not evaluated.
Primary
Total Number of New Digital Ulcers (DUs) Per Patient Observed by the Investigator at Planned Visits
The total number of new DUs per patient observed by the investigator at planned visits and new transient DUs recorded in the patient diary (a patient diary was used to record DUs that might appear and disappear between two planned visits) were assessed at each clinic visit
Time frame: At planned visits up to week 80
Population: One patient did not have a DU at baseline (number of patients assessed at Weeks 0-4,4-8,8-16,16-24,24-32,32-40,40-48,48-56,56-64,64-72, and 72-80 were 114, 107, 103, 100, 97, 94, 88, 87, 86, 86, and 83, respectively.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Bosentan | Total Number of New Digital Ulcers (DUs) Per Patient Observed by the Investigator at Planned Visits | Week 16-24 | 64 number of new digital ulcers |
| Bosentan | Total Number of New Digital Ulcers (DUs) Per Patient Observed by the Investigator at Planned Visits | Week 32-40 | 59 number of new digital ulcers |
| Bosentan | Total Number of New Digital Ulcers (DUs) Per Patient Observed by the Investigator at Planned Visits | Week 24-32 | 56 number of new digital ulcers |
| Bosentan | Total Number of New Digital Ulcers (DUs) Per Patient Observed by the Investigator at Planned Visits | Week 64-72 | 51 number of new digital ulcers |
| Bosentan | Total Number of New Digital Ulcers (DUs) Per Patient Observed by the Investigator at Planned Visits | Week 4-8 | 73 number of new digital ulcers |
| Bosentan | Total Number of New Digital Ulcers (DUs) Per Patient Observed by the Investigator at Planned Visits | Week 72-80 | 51 number of new digital ulcers |
| Bosentan | Total Number of New Digital Ulcers (DUs) Per Patient Observed by the Investigator at Planned Visits | Week 56-64 | 48 number of new digital ulcers |
| Bosentan | Total Number of New Digital Ulcers (DUs) Per Patient Observed by the Investigator at Planned Visits | Week 48-56 | 50 number of new digital ulcers |
| Bosentan | Total Number of New Digital Ulcers (DUs) Per Patient Observed by the Investigator at Planned Visits | Week 8-16 | 63 number of new digital ulcers |
| Bosentan | Total Number of New Digital Ulcers (DUs) Per Patient Observed by the Investigator at Planned Visits | Week 0-4 | 85 number of new digital ulcers |
| Bosentan | Total Number of New Digital Ulcers (DUs) Per Patient Observed by the Investigator at Planned Visits | Week 40-48 | 52 number of new digital ulcers |
| At Least 1 New Ulcer | Total Number of New Digital Ulcers (DUs) Per Patient Observed by the Investigator at Planned Visits | Week 8-16 | 40 number of new digital ulcers |
| At Least 1 New Ulcer | Total Number of New Digital Ulcers (DUs) Per Patient Observed by the Investigator at Planned Visits | Week 0-4 | 29 number of new digital ulcers |
| At Least 1 New Ulcer | Total Number of New Digital Ulcers (DUs) Per Patient Observed by the Investigator at Planned Visits | Week 32-40 | 35 number of new digital ulcers |
| At Least 1 New Ulcer | Total Number of New Digital Ulcers (DUs) Per Patient Observed by the Investigator at Planned Visits | Week 24-32 | 41 number of new digital ulcers |
| At Least 1 New Ulcer | Total Number of New Digital Ulcers (DUs) Per Patient Observed by the Investigator at Planned Visits | Week 48-56 | 37 number of new digital ulcers |
| At Least 1 New Ulcer | Total Number of New Digital Ulcers (DUs) Per Patient Observed by the Investigator at Planned Visits | Week 72-80 | 32 number of new digital ulcers |
| At Least 1 New Ulcer | Total Number of New Digital Ulcers (DUs) Per Patient Observed by the Investigator at Planned Visits | Week 64-72 | 35 number of new digital ulcers |
| At Least 1 New Ulcer | Total Number of New Digital Ulcers (DUs) Per Patient Observed by the Investigator at Planned Visits | Week 40-48 | 36 number of new digital ulcers |
| At Least 1 New Ulcer | Total Number of New Digital Ulcers (DUs) Per Patient Observed by the Investigator at Planned Visits | Week 56-64 | 38 number of new digital ulcers |
| At Least 1 New Ulcer | Total Number of New Digital Ulcers (DUs) Per Patient Observed by the Investigator at Planned Visits | Week 16-24 | 36 number of new digital ulcers |
| At Least 1 New Ulcer | Total Number of New Digital Ulcers (DUs) Per Patient Observed by the Investigator at Planned Visits | Week 4-8 | 34 number of new digital ulcers |
| At Least 2 New Ulcers | Total Number of New Digital Ulcers (DUs) Per Patient Observed by the Investigator at Planned Visits | Week 64-72 | 24 number of new digital ulcers |
| At Least 2 New Ulcers | Total Number of New Digital Ulcers (DUs) Per Patient Observed by the Investigator at Planned Visits | Week 0-4 | 17 number of new digital ulcers |
| At Least 2 New Ulcers | Total Number of New Digital Ulcers (DUs) Per Patient Observed by the Investigator at Planned Visits | Week 4-8 | 15 number of new digital ulcers |
| At Least 2 New Ulcers | Total Number of New Digital Ulcers (DUs) Per Patient Observed by the Investigator at Planned Visits | Week 8-16 | 22 number of new digital ulcers |
| At Least 2 New Ulcers | Total Number of New Digital Ulcers (DUs) Per Patient Observed by the Investigator at Planned Visits | Week 16-24 | 17 number of new digital ulcers |
| At Least 2 New Ulcers | Total Number of New Digital Ulcers (DUs) Per Patient Observed by the Investigator at Planned Visits | Week 24-32 | 22 number of new digital ulcers |
| At Least 2 New Ulcers | Total Number of New Digital Ulcers (DUs) Per Patient Observed by the Investigator at Planned Visits | Week 32-40 | 15 number of new digital ulcers |
| At Least 2 New Ulcers | Total Number of New Digital Ulcers (DUs) Per Patient Observed by the Investigator at Planned Visits | Week 40-48 | 20 number of new digital ulcers |
| At Least 2 New Ulcers | Total Number of New Digital Ulcers (DUs) Per Patient Observed by the Investigator at Planned Visits | Week 48-56 | 18 number of new digital ulcers |
| At Least 2 New Ulcers | Total Number of New Digital Ulcers (DUs) Per Patient Observed by the Investigator at Planned Visits | Week 56-64 | 14 number of new digital ulcers |
| At Least 2 New Ulcers | Total Number of New Digital Ulcers (DUs) Per Patient Observed by the Investigator at Planned Visits | Week 72-80 | 18 number of new digital ulcers |
| At Least 3 New Ulcers | Total Number of New Digital Ulcers (DUs) Per Patient Observed by the Investigator at Planned Visits | Week 4-8 | 6 number of new digital ulcers |
| At Least 3 New Ulcers | Total Number of New Digital Ulcers (DUs) Per Patient Observed by the Investigator at Planned Visits | Week 16-24 | 11 number of new digital ulcers |
| At Least 3 New Ulcers | Total Number of New Digital Ulcers (DUs) Per Patient Observed by the Investigator at Planned Visits | Week 24-32 | 12 number of new digital ulcers |
| At Least 3 New Ulcers | Total Number of New Digital Ulcers (DUs) Per Patient Observed by the Investigator at Planned Visits | Week 72-80 | 9 number of new digital ulcers |
| At Least 3 New Ulcers | Total Number of New Digital Ulcers (DUs) Per Patient Observed by the Investigator at Planned Visits | Week 48-56 | 13 number of new digital ulcers |
| At Least 3 New Ulcers | Total Number of New Digital Ulcers (DUs) Per Patient Observed by the Investigator at Planned Visits | Week 0-4 | 6 number of new digital ulcers |
| At Least 3 New Ulcers | Total Number of New Digital Ulcers (DUs) Per Patient Observed by the Investigator at Planned Visits | Week 64-72 | 15 number of new digital ulcers |
| At Least 3 New Ulcers | Total Number of New Digital Ulcers (DUs) Per Patient Observed by the Investigator at Planned Visits | Week 8-16 | 9 number of new digital ulcers |
| At Least 3 New Ulcers | Total Number of New Digital Ulcers (DUs) Per Patient Observed by the Investigator at Planned Visits | Week 56-64 | 7 number of new digital ulcers |
| At Least 3 New Ulcers | Total Number of New Digital Ulcers (DUs) Per Patient Observed by the Investigator at Planned Visits | Week 40-48 | 11 number of new digital ulcers |
| At Least 3 New Ulcers | Total Number of New Digital Ulcers (DUs) Per Patient Observed by the Investigator at Planned Visits | Week 32-40 | 7 number of new digital ulcers |
| At Least 4 New Ulcers | Total Number of New Digital Ulcers (DUs) Per Patient Observed by the Investigator at Planned Visits | Week 48-56 | 7 number of new digital ulcers |
| At Least 4 New Ulcers | Total Number of New Digital Ulcers (DUs) Per Patient Observed by the Investigator at Planned Visits | Week 32-40 | 5 number of new digital ulcers |
| At Least 4 New Ulcers | Total Number of New Digital Ulcers (DUs) Per Patient Observed by the Investigator at Planned Visits | Week 8-16 | 7 number of new digital ulcers |
| At Least 4 New Ulcers | Total Number of New Digital Ulcers (DUs) Per Patient Observed by the Investigator at Planned Visits | Week 40-48 | 5 number of new digital ulcers |
| At Least 4 New Ulcers | Total Number of New Digital Ulcers (DUs) Per Patient Observed by the Investigator at Planned Visits | Week 4-8 | 4 number of new digital ulcers |
| At Least 4 New Ulcers | Total Number of New Digital Ulcers (DUs) Per Patient Observed by the Investigator at Planned Visits | Week 72-80 | 4 number of new digital ulcers |
| At Least 4 New Ulcers | Total Number of New Digital Ulcers (DUs) Per Patient Observed by the Investigator at Planned Visits | Week 56-64 | 4 number of new digital ulcers |
| At Least 4 New Ulcers | Total Number of New Digital Ulcers (DUs) Per Patient Observed by the Investigator at Planned Visits | Week 0-4 | 4 number of new digital ulcers |
| At Least 4 New Ulcers | Total Number of New Digital Ulcers (DUs) Per Patient Observed by the Investigator at Planned Visits | Week 16-24 | 4 number of new digital ulcers |
| At Least 4 New Ulcers | Total Number of New Digital Ulcers (DUs) Per Patient Observed by the Investigator at Planned Visits | Week 64-72 | 10 number of new digital ulcers |
| At Least 4 New Ulcers | Total Number of New Digital Ulcers (DUs) Per Patient Observed by the Investigator at Planned Visits | Week 24-32 | 8 number of new digital ulcers |
| At Least 5 New Ulcers | Total Number of New Digital Ulcers (DUs) Per Patient Observed by the Investigator at Planned Visits | Week 8-16 | 5 number of new digital ulcers |
| At Least 5 New Ulcers | Total Number of New Digital Ulcers (DUs) Per Patient Observed by the Investigator at Planned Visits | Week 56-64 | 3 number of new digital ulcers |
| At Least 5 New Ulcers | Total Number of New Digital Ulcers (DUs) Per Patient Observed by the Investigator at Planned Visits | Week 24-32 | 4 number of new digital ulcers |
| At Least 5 New Ulcers | Total Number of New Digital Ulcers (DUs) Per Patient Observed by the Investigator at Planned Visits | Week 32-40 | 4 number of new digital ulcers |
| At Least 5 New Ulcers | Total Number of New Digital Ulcers (DUs) Per Patient Observed by the Investigator at Planned Visits | Week 64-72 | 8 number of new digital ulcers |
| At Least 5 New Ulcers | Total Number of New Digital Ulcers (DUs) Per Patient Observed by the Investigator at Planned Visits | Week 4-8 | 3 number of new digital ulcers |
| At Least 5 New Ulcers | Total Number of New Digital Ulcers (DUs) Per Patient Observed by the Investigator at Planned Visits | Week 48-56 | 5 number of new digital ulcers |
| At Least 5 New Ulcers | Total Number of New Digital Ulcers (DUs) Per Patient Observed by the Investigator at Planned Visits | Week 40-48 | 3 number of new digital ulcers |
| At Least 5 New Ulcers | Total Number of New Digital Ulcers (DUs) Per Patient Observed by the Investigator at Planned Visits | Week 0-4 | 3 number of new digital ulcers |
| At Least 5 New Ulcers | Total Number of New Digital Ulcers (DUs) Per Patient Observed by the Investigator at Planned Visits | Week 16-24 | 2 number of new digital ulcers |
| At Least 5 New Ulcers | Total Number of New Digital Ulcers (DUs) Per Patient Observed by the Investigator at Planned Visits | Week 72-80 | 2 number of new digital ulcers |
Secondary
Adverse Events Leading to Permanent Discontinuation of the Study Medication
Number of patients with an adverse event leading to permanent discontinuation of the study treatment
Time frame: 80 weeks
Population: Study population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Bosentan | Adverse Events Leading to Permanent Discontinuation of the Study Medication | 36 participants |
Secondary
Adverse Events up to 24 Hours After Last Study Medication
Number of patients with at least one treatment-emergent adverse event. All adverse events that occurred after study drug initiation and up to 24 hours after study drug discontinuation were to be recorded.
Time frame: 80 weeks
Population: Study population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Bosentan | Adverse Events up to 24 Hours After Last Study Medication | 111 participants |
Secondary
Serious Adverse Events up to 28 Days After Last Study Medication
Number of patients with at least one treatment-emergent serious adverse event (TESAE) were reported. TESAEs are serious AEs that occurred after study drug initiation and up to 28 days after study drug discontinuation. More details on the SAEs are provided in the specific Adverse Events Section
Time frame: 80 weeks
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Bosentan | Serious Adverse Events up to 28 Days After Last Study Medication | 45 Participants |