Bosentan in Digital Ulcers

Study Overview
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Brief Summary
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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).

Official Title
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Long-term Bosentan Open Label Extension of the AC-052-331 Study in Systemic Sclerosis Patients With Ischemic Digital Ulcers

Conditions
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Digital Ulcers

Intervention / Treatment
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* Drug: Bosentan 62.5 mg
* Drug: Bosentan 125 mg


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with SSc according to the classification criteria of the American College of Rheumatology SSc patients with at least one DU at baseline qualifying as a CU (see definition section 3.2.2) 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 Male or female patients >/= 18 years of age 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 Women not of childbearing potential are defined as postmenopausal (i.e., amenorrhea for at least 1 year), or surgically or naturally sterile Signed informed consent. Exclusion Criteria: DUs due to condition other than SSc Severe PAH (WHO class III and IV) Systolic blood pressure < 85 mmHg Hemoglobin concentration < 75% of the lower limit of the normal range AST and/or ALT values greater than 3 times the upper limit of normal Moderate to severe hepatic impairment, i.e., Child-Pugh Class B or C Severe malabsorption or any severe organ failure (e.g., lung, kidney) or any life-threatening condition Pregnancy or breast-feeding Previous treatment with bosentan Treatment with any of the following: glibenclamide (glyburide), fluconazole, cyclosporine A, tacrolimus and any other calcineurin inhibitor 1 week prior to randomization Local injection of botulinum toxin in an affected finger 1 month prior to randomization Treatment with parenteral prostanoids (prostaglandin E, epoprostenol, treprostinil sodium or other prostacyclin analogs) 3 months prior to randomization Treatment with inhaled or oral prostanoids one month prior to randomization Systemic antibiotics to treat infection of DUs 2 weeks prior to randomization Treatment with phosphodiesterase inhibitors such as sildenafil, except for intermittent treatment of male erectile dysfunction Body weight < 40 kg Patient with conditions that prevent compliance with the protocol or adhering to therapy Patient who received an investigational product within 1 month preceding screening Known hypersensitivity to bosentan or any of the excipients.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Bosentan<br>Bosentan 62.5 mg tablets b.i.d. for the first 4 weeks followed by bosentan 125 mg b.i.d. thereafter | Drug: Bosentan 62.5 mg<br>* Bosentan 62.5-mg oral tablets twice daily (b.i.d.) for 4 weeks (initial dose)<br>Drug: Bosentan 125 mg<br>* Bosentan 125-mg oral tablets administered b.i.d. (target dose)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 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. | 80 weeks | 
| 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. | 80 weeks | 
| 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. | 80 weeks | 
| 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. | 80 weeks | 
| 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. | 80 weeks | 
| 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. | 80 weeks | 
| 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. | 80 weeks | 
| 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. | 80 weeks | 
| 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. | 80 weeks | 
| 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. | 80 weeks | 
| 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 | At planned visits up to week 80 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 80 weeks | 
| 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 | 80 weeks | 
| 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 | 80 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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digital ulcers, systemic sclerosis, finger ulcers, bosentan, open label