Bosentan in Digital Ulcers (RAPIDS 2 OL)

This study has been completed.

Sponsor:

Information provided by (Responsible Party):

Actelion

ClinicalTrials.gov Identifier:

NCT00319696

First received: April 27, 2006

Last updated: September 27, 2012

Last verified: September 2012

History of Changes

Results First Received: June 29, 2012

Study Type:	Interventional
Study Design:	Allocation: Non-Randomized; Endpoint Classification: Safety/Efficacy Study; Intervention Model: Single Group Assignment; Masking: Open Label; Primary Purpose: Treatment
Conditions:	Systemic Sclerosis Digital Ulcers
Intervention:	Drug: bosentan

Participant Flow

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Recruitment Details

Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
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

Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
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.

Reporting Groups

	Description
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

Participant Flow: Overall Study

	Bosentan
STARTED	116
COMPLETED	56
NOT COMPLETED	60
Adverse Event	36
withdrawal of consent	14
administrative	7
Lost to Follow-up	3

Baseline Characteristics

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Reporting Groups

	Description
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

Baseline Measures

	Bosentan
Number of Participants [units: participants]	116
Age [units: years] Mean ± Standard Deviation	49.3 ± 12.0
Age, Customized [units: participants]
Between 24 and 79 years	116
Gender [units: participants]
Female	87
Male	29
Region of Enrollment [units: participants]
Austria	0
Canada	11
France	10
Germany	9
Italy	9
Switzerland	4
United Kingdom	6
United States	67
Scleroderma Health Assessment Questionnaire (SHAQ) Individual Domain Score ^[1] [units: score on a scale] Mean ± Standard Deviation
Dressing	1.3 ± 0.9
Arising	0.5 ± 0.8
Eating	1.5 ± 1.0
Walking	0.5 ± 0.7
Hygiene	0.9 ± 1.0
Reach	1.1 ± 0.9
Grip	1.1 ± 0.8
Activity	1.0 ± 0.9
Overall hand pain ^[2] [units: mm] Mean ± Standard Deviation	58.62 ± 29.80
United Kingdom Scleroderma Functional Score (UKFS) ^[3] [units: score on a scale] Mean ± Standard Deviation	11.06 ± 7.50

[1]	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.
[2]	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.
[3]	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.

Outcome Measures

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1. Primary:

Total Number of New Digital Ulcers (DUs) Per Patient Observed by the Investigator at Planned Visits [ Time Frame: At planned visits up to week 80 ]

Show Outcome Measure 1

2. Primary:

Time to Complete Healing of Each Baseline DU [ Time Frame: Baseline to healing ]

Show Outcome Measure 2

3. Primary:

Time to Complete Healing of Each New DU [ Time Frame: New DU occurence to healing ]

Show Outcome Measure 3

4. Primary:

Mean Change From Baseline at Each 16 Week Interval up to Week 80 in Scleroderma Health Assessment Questionnaire (SHAQ) Individual Domain Score: Dressing [ Time Frame: 80 weeks ]

Show Outcome Measure 4

5. Primary:

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 ]

Show Outcome Measure 5

6. Primary:

Mean Change From Baseline at Each 16 Week Interval up to Week 80 in Scleroderma Health Assessment Questionnaire (SHAQ) Individual Domain Score: Eating [ Time Frame: 80 weeks ]

Show Outcome Measure 6

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 [ Time Frame: 80 weeks ]

Show Outcome Measure 7

8. Primary:

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 ]

Show Outcome Measure 8

9. Primary:

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 ]

Show Outcome Measure 9

10. Primary:

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 ]

Show Outcome Measure 10

11. Primary:

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 ]

Show Outcome Measure 11

12. Primary:

Mean Changes From Baseline at Each 16 Week Interval up to Week 80 in Overall Hand Pain Related to Finger Ulcers [ Time Frame: 80 weeks ]

Show Outcome Measure 12

13. Primary:

Mean Change From Baseline at Each 16 Week Interval up to Week 80 in the UK Systemic Sclerosis Functional Score (UKFS) [ Time Frame: 80 weeks ]

Show Outcome Measure 13

14. Secondary:

Adverse Events up to 24 Hours After Last Study Medication [ Time Frame: 80 weeks ]

Show Outcome Measure 14

15. Secondary:

Serious Adverse Events up to 28 Days After Last Study Medication [ Time Frame: 80 weeks ]

Show Outcome Measure 15

16. Secondary:

Adverse Events Leading to Permanent Discontinuation of the Study Medication [ Time Frame: 80 weeks ]

Show Outcome Measure 16

Serious Adverse Events

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Time Frame	80 weeks
Additional Description	Treatment-emergent adverse events

Reporting Groups

	Description
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

Serious Adverse Events

	Bosentan
Total, serious adverse events
# participants affected / at risk	45/116 (38.79%)
Blood and lymphatic system disorders
ANAEMIA ^{† 1}
# participants affected / at risk	2/116 (1.72%)
IRON DEFICIENCY ANAEMIA ^{† 1}
# participants affected / at risk	1/116 (0.86%)
Cardiac disorders
CARDIAC FAILURE CONGESTIVE ^{† 1}
# participants affected / at risk	2/116 (1.72%)
ACUTE CORONARY SYNDROME ^{† 1}
# participants affected / at risk	1/116 (0.86%)
ATRIAL FIBRILLATION ^{† 1}
# participants affected / at risk	1/116 (0.86%)
CARDIAC ARREST ^{† 1}
# participants affected / at risk	1/116 (0.86%)
MYOCARDIAL INFARCTION ^{† 1}
# participants affected / at risk	1/116 (0.86%)
MYOCARDITIS ^{† 1}
# participants affected / at risk	1/116 (0.86%)
Gastrointestinal disorders
ABDOMINAL PAIN ^{† 1}
# participants affected / at risk	2/116 (1.72%)
ABDOMINAL PAIN LOWER ^{† 1}
# participants affected / at risk	1/116 (0.86%)
COLITIS ISCHAEMIC ^{† 1}
# participants affected / at risk	1/116 (0.86%)
DIVERTICULUM INTESTINAL ^{† 1}
# participants affected / at risk	1/116 (0.86%)
FAECALOMA ^{† 1}
# participants affected / at risk	1/116 (0.86%)
GASTRITIS ^{† 1}
# participants affected / at risk	1/116 (0.86%)
GASTROINTESTINAL MOTILITY DISORDER ^{† 1}
# participants affected / at risk	1/116 (0.86%)
ILEUS ^{† 1}
# participants affected / at risk	1/116 (0.86%)
INTESTINAL OBSTRUCTION ^{† 1}
# participants affected / at risk	1/116 (0.86%)
NAUSEA ^{† 1}
# participants affected / at risk	1/116 (0.86%)
OESOPHAGITIS HAEMORRHAGIC ^{† 1}
# participants affected / at risk	1/116 (0.86%)
VOMITING ^{† 1}
# participants affected / at risk	1/116 (0.86%)
General disorders
ADVERSE DRUG REACTION ^{† 1}
# participants affected / at risk	2/116 (1.72%)
CHEST PAIN ^{† 1}
# participants affected / at risk	2/116 (1.72%)
DEVICE DISLOCATION ^{† 1}
# participants affected / at risk	1/116 (0.86%)
DRUG WITHDRAWAL SYNDROME ^{† 1}
# participants affected / at risk	1/116 (0.86%)
IMPAIRED HEALING ^{† 1}
# participants affected / at risk	1/116 (0.86%)
PAIN ^{† 1}
# participants affected / at risk	1/116 (0.86%)
SUPRAPUBIC PAIN ^{† 1}
# participants affected / at risk	1/116 (0.86%)
Infections and infestations
PNEUMONIA ^{† 1}
# participants affected / at risk	6/116 (5.17%)
INFECTED SKIN ULCER ^{† 1}
# participants affected / at risk	4/116 (3.45%)
CELLULITIS ^{† 1}
# participants affected / at risk	2/116 (1.72%)
DEVICE RELATED INFECTION ^{† 1}
# participants affected / at risk	2/116 (1.72%)
SEPSIS ^{† 1}
# participants affected / at risk	2/116 (1.72%)
ABSCESS LIMB ^{† 1}
# participants affected / at risk	1/116 (0.86%)
APPENDICITIS ^{† 1}
# participants affected / at risk	1/116 (0.86%)
BRONCHITIS ^{† 1}
# participants affected / at risk	1/116 (0.86%)
CATHETER SITE INFECTION ^{† 1}
# participants affected / at risk	1/116 (0.86%)
DIVERTICULITIS ^{† 1}
# participants affected / at risk	1/116 (0.86%)
GANGRENE ^{† 1}
# participants affected / at risk	1/116 (0.86%)
GASTROENTERITIS ^{† 1}
# participants affected / at risk	1/116 (0.86%)
HEPATITIS B ^{† 1}
# participants affected / at risk	1/116 (0.86%)
HERPES ZOSTER ^{† 1}
# participants affected / at risk	1/116 (0.86%)
INFLUENZA ^{† 1}
# participants affected / at risk	1/116 (0.86%)
LOBAR PNEUMONIA ^{† 1}
# participants affected / at risk	1/116 (0.86%)
LOCALISED INFECTION ^{† 1}
# participants affected / at risk	1/116 (0.86%)
OSTEOMYELITIS ^{† 1}
# participants affected / at risk	1/116 (0.86%)
VIRAL PERICARDITIS ^{† 1}
# participants affected / at risk	1/116 (0.86%)
VIRAL UPPER RESPIRATORY TRACT INFECTION ^{† 1}
# participants affected / at risk	1/116 (0.86%)
Injury, poisoning and procedural complications
ASBESTOSIS ^{† 1}
# participants affected / at risk	1/116 (0.86%)
JOINT INJURY ^{† 1}
# participants affected / at risk	1/116 (0.86%)
PROCEDURAL PAIN ^{† 1}
# participants affected / at risk	1/116 (0.86%)
VASCULAR GRAFT OCCLUSION ^{† 1}
# participants affected / at risk	1/116 (0.86%)
Investigations
HEPATIC ENZYME INCREASED ^{† 1}
# participants affected / at risk	1/116 (0.86%)
Metabolism and nutrition disorders
DEHYDRATION ^{† 1}
# participants affected / at risk	1/116 (0.86%)
MALNUTRITION ^{† 1}
# participants affected / at risk	1/116 (0.86%)
Musculoskeletal and connective tissue disorders
INTERVERTEBRAL DISC PROTRUSION ^{† 1}
# participants affected / at risk	2/116 (1.72%)
SCLERODERMA ^{† 1}
# participants affected / at risk	2/116 (1.72%)
MUSCULAR WEAKNESS ^{† 1}
# participants affected / at risk	1/116 (0.86%)
MYOSITIS ^{† 1}
# participants affected / at risk	1/116 (0.86%)
OSTEOARTHRITIS ^{† 1}
# participants affected / at risk	1/116 (0.86%)
PAIN IN EXTREMITY ^{† 1}
# participants affected / at risk	1/116 (0.86%)
RHEUMATOID ARTHRITIS ^{† 1}
# participants affected / at risk	1/116 (0.86%)
ROTATOR CUFF SYNDROME ^{† 1}
# participants affected / at risk	1/116 (0.86%)
SYSTEMIC SCLEROSIS ^{† 1}
# participants affected / at risk	1/116 (0.86%)
TENOSYNOVITIS ^{† 1}
# participants affected / at risk	1/116 (0.86%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
CHRONIC LYMPHOCYTIC LEUKAEMIA ^{† 1}
# participants affected / at risk	1/116 (0.86%)
Nervous system disorders
CAROTID ARTERY STENOSIS ^{† 1}
# participants affected / at risk	1/116 (0.86%)
CEREBROVASCULAR ACCIDENT ^{† 1}
# participants affected / at risk	1/116 (0.86%)
DIZZINESS POSTURAL ^{† 1}
# participants affected / at risk	1/116 (0.86%)
HYPOAESTHESIA ^{† 1}
# participants affected / at risk	1/116 (0.86%)
LUMBAR RADICULOPATHY ^{† 1}
# participants affected / at risk	1/116 (0.86%)
PARAESTHESIA ^{† 1}
# participants affected / at risk	1/116 (0.86%)
Psychiatric disorders
ALCOHOLIC PSYCHOSIS ^{† 1}
# participants affected / at risk	1/116 (0.86%)
DEPRESSION ^{† 1}
# participants affected / at risk	1/116 (0.86%)
Renal and urinary disorders
SCLERODERMA RENAL CRISIS ^{† 1}
# participants affected / at risk	2/116 (1.72%)
RENAL FAILURE ACUTE ^{† 1}
# participants affected / at risk	1/116 (0.86%)
Respiratory, thoracic and mediastinal disorders
DYSPNOEA ^{† 1}
# participants affected / at risk	6/116 (5.17%)
PULMONARY FIBROSIS ^{† 1}
# participants affected / at risk	2/116 (1.72%)
PULMONARY HYPERTENSION ^{† 1}
# participants affected / at risk	2/116 (1.72%)
ACUTE RESPIRATORY FAILURE ^{† 1}
# participants affected / at risk	1/116 (0.86%)
CHRONIC OBSTRUCTIVE PULMONARY DISEASE ^{† 1}
# participants affected / at risk	1/116 (0.86%)
PLEURAL EFFUSION ^{† 1}
# participants affected / at risk	1/116 (0.86%)
PNEUMONITIS ^{† 1}
# participants affected / at risk	1/116 (0.86%)
PNEUMOTHORAX ^{† 1}
# participants affected / at risk	1/116 (0.86%)
PULMONARY ARTERIAL HYPERTENSION ^{† 1}
# participants affected / at risk	1/116 (0.86%)
Skin and subcutaneous tissue disorders
SKIN ULCER ^{† 1}
# participants affected / at risk	5/116 (4.31%)
PYODERMA GANGRENOSUM ^{† 1}
# participants affected / at risk	1/116 (0.86%)
SKIN DISCOLOURATION ^{† 1}
# participants affected / at risk	1/116 (0.86%)
SKIN NECROSIS ^{† 1}
# participants affected / at risk	1/116 (0.86%)
Surgical and medical procedures
ARTHRODESIS ^{† 1}
# participants affected / at risk	1/116 (0.86%)
FINGER AMPUTATION ^{† 1}
# participants affected / at risk	1/116 (0.86%)
FOOT AMPUTATION ^{† 1}
# participants affected / at risk	1/116 (0.86%)
HIP ARTHROPLASTY ^{† 1}
# participants affected / at risk	1/116 (0.86%)
LUNG TRANSPLANT ^{† 1}
# participants affected / at risk	1/116 (0.86%)
REVISION OF INTERNAL FIXATION ^{† 1}
# participants affected / at risk	1/116 (0.86%)
Vascular disorders
PERIPHERAL ISCHAEMIA ^{† 1}
# participants affected / at risk	4/116 (3.45%)
EXTREMITY NECROSIS ^{† 1}
# participants affected / at risk	1/116 (0.86%)
FEMORAL ARTERY OCCLUSION ^{† 1}
# participants affected / at risk	1/116 (0.86%)
HYPOTENSION ^{† 1}
# participants affected / at risk	1/116 (0.86%)

†	Events were collected by systematic assessment
1	Term from vocabulary, MedDRA (13.0)

Other Adverse Events

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More Information

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Certain Agreements:

Principal Investigators are NOT employed by the organization sponsoring the study.

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

The agreement is:

	The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.
	The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.
	Other disclosure agreement that restricts the right of the PI to discuss or publish trial results after the trial is completed. Restriction Description: No text entered.

Limitations and Caveats

Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterpretable data
No text entered.

Results Point of Contact:

Name/Title: Andjela Kusic-Pajic, MD/Clinical Project Team Leader
Organization: Actelion Pharmaceuticals Ltd
phone: +41 61 565 64 17

No publications provided

Responsible Party:	Actelion
ClinicalTrials.gov Identifier:	NCT00319696 History of Changes
Other Study ID Numbers:	AC-052-333, RAPIDS-2 OL
Study First Received:	April 27, 2006
Results First Received:	June 29, 2012
Last Updated:	September 27, 2012
Health Authority:	United States: Food and Drug Administration

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