Bosentan in Digital Ulcers (RAPIDS 2 OL)

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

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 Overview

• Status: Completed
• Conditions: Digital Ulcers
• Intervention / Treatment: Drug: Bosentan 62.5 mg; Drug: Bosentan 125 mg

• Study Type: Interventional
• Enrollment (Actual): 116
• Phase: Phase 3

Contacts and Locations

Study Locations

• Austria
  • Innsbruck, Austria
    • Universitätsklinik
  • Wien, Austria
    • AKH Universitatsklinik
• Canada
  • Ontario
    • London, Ontario, Canada, N6A 4V2
      • Janet Pope, MD
    • Toronto, Ontario, Canada, M5G 1X5
      • Peter Lee, MD
  • Quebec
    • Montreal, Quebec, Canada, H2L 4M1
      • Eric Rich, MD
    • Montreal, Quebec, Canada, H3T1E2
      • Murray Baron, MD
• France
  • Grenoble, France
    • Centre Hospitalier Universitaire
  • Lille, France
    • CHRU Claude Huriez
• Germany
  • Dresden, Germany
    • Universitätsklinikum
  • Erlangen, Germany
    • Universitätsklinikum
  • Freiburg, Germany
    • Universitätsklinik
  • Koln, Germany
    • Universitätsklinik
• Italy
  • Firenze, Italy
    • Instituto di Clinica, Villa Monna Tessa
  • Milano, Italy
    • Ospedale Maggiore
  • Roma, Italy
    • Policlinico Umberto 1
• Switzerland
  • Bern, Switzerland
    • Inselspital, Universitatspital Bern
• United Kingdom
  • Birmingham, United Kingdom
    • Selly Oak Hospital
  • London, United Kingdom
    • Royal Free Hospital
  • Newcastle, United Kingdom
    • Freeman Hospital
• United States
  • Alabama
    • Birmingham, Alabama, United States, 35249-7201
      • Barri Fessler, MD
  • California
    • Los Angeles, California, United States, 90095-1670
      • Daniel Furst, MD
  • Colorado
    • Aurora, Colorado, United States, 80010
      • David Collier, MD
  • Connecticut
    • Farmington, Connecticut, United States, 06030-1310
      • Naomi Rothfield, MD
  • Illinois
    • Chicago, Illinois, United States, 60637
      • Nadera Sweiss, MD
  • Louisiana
    • New Orleans, Louisiana, United States, 70112
      • Mittie Doyle, MD
  • Maryland
    • Baltimore, Maryland, United States, 21224
      • Frederick Wigley, MD
  • Massachusetts
    • Boston, Massachusetts, United States, 02118-2394
      • Peter Merkel, MD
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Thomas Osborn, MD
  • New Jersey
    • New Brunswick, New Jersey, United States, 08903
      • Vivien Hsu, MD - UMDNJ
  • New York
    • Manhasset, New York, United States, 11042
      • Avram Goldberg, MD
  • Ohio
    • Toledo, Ohio, United States, 43614
      • Bashar Kahaleh, MD
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15261
      • Thomas Medsger, MD
  • South Carolina
    • Charleston, South Carolina, United States, 29425
      • Edwin Smith, MD
    • Charleston, South Carolina, United States, 29425
      • Medical Universtiy of South Carolina
  • Texas
    • Houston, Texas, United States, 77030
      • Maureen Mayes, MD
  • Washington
    • Seattle, Washington, United States, 98101
      • Jerry Molitor, MD
    • Spokane, Washington, United States, 99204
      • Howard Kenney, MD
  • Wisconsin
    • Milwaukee, Wisconsin, United States, 53211
      • Mary Ellen Csuka, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Bosentan; 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; Bosentan 62.5-mg oral tablets twice daily (b.i.d.) for 4 weeks (initial dose); Drug: Bosentan 125 mg; Bosentan 125-mg oral tablets administered b.i.d. (target dose)

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Actelion

Study record dates

Study Major Dates

• Study Start (Actual): July 8, 2004
• Primary Completion (Actual): January 22, 2009
• Study Completion (Actual): January 22, 2009

Study Registration Dates

• First Submitted: April 27, 2006
• First Submitted That Met QC Criteria: April 27, 2006
• First Posted (Estimate): April 27, 2006

Study Record Updates

• Last Update Posted (Actual): January 8, 2019
• Last Update Submitted That Met QC Criteria: December 18, 2018
• Last Verified: December 1, 2018

More Information

Terms related to this study

• Keywords: systemic sclerosis; open label; digital ulcers; bosentan; finger ulcers
• Additional Relevant MeSH Terms: Pathologic Processes; Skin Diseases; Ulcer; Skin Ulcer; Molecular Mechanisms of Pharmacological Action; Antihypertensive Agents; Endothelin Receptor Antagonists; Bosentan
• Other Study ID Numbers: AC-052-333