Bosentan in Digital Ulcers

Phase 3CompletedNCT00319696

Actelion116 enrolled

Overview

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).

Study Type

INTERVENTIONAL

Allocation

Purpose

TREATMENT

Masking

NONE

Enrollment

116

Conditions

Digital Ulcers

Interventions

Bosentan 62.5 mgDRUG

Bosentan 62.5-mg oral tablets twice daily (b.i.d.) for 4 weeks (initial dose)

Bosentan 125 mgDRUG

Bosentan 125-mg oral tablets administered b.i.d. (target dose)

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

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.

Outcomes

Primary Outcomes

Time to Complete Healing of Each Baseline DU

Time frame: Baseline to healing

Time to Complete Healing of Each New DU

Time frame: 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.

Time frame: 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

Time frame: 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

Data from ClinicalTrials.gov

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Time frame: 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

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: 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.

Time frame: 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.

Time frame: 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

Time frame: At planned visits up to week 80

Secondary Outcomes

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

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

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