Systemic Sclerosis, Scleroderma
Conditions
Keywords
Scleroderma, Diffuse, Scleroderma, Limited, Scleroderma, Systemic, Ulcer, prostacyclin
Brief summary
This study will evaluate the effect of treprostinil diethanolamine (UT-15C) sustained release tablets(compared to placebo) on digital ulcers in patients with scleroderma. Treprostinil diethanolamine is an analog of prostacyclin. Prostacyclin is a naturally occuring substance produced by the cells of blood vessels that inhibits platelet aggregation, induces vasodilation, and suppresses smooth muscle proliferation. Improvement in blood flow in lower limbs and fingers would be anticipated to result in a reduction in ischemic pain, Raynaud's phenomenon and promote healing of digital ulcers and other ischemic wounds.
Interventions
oral sustained release tablet. Maximum tolerable dose not exceeding 16 mg twice daily (BID)
DRUGplacebo
Sponsors
United Therapeutics
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Subject gave voluntary written informed consent to participate in the study * Diagnosis of systemic sclerosis (SSc) as defined by American College of Rheumatology (ACR) criteria * Males and females age greater than 18 years at Screening * Presence of at least one active digital ulcer (met protocol defined qualifications for active digital ulcer) at Baseline * Females of childbearing potential willing to use a reliable form of medically acceptable contraception and have a negative pregnancy test at Screening and Baseline * Able to communicate effectively with study personnel and willing to comply with protocol requirements
Exclusion criteria
* Diagnosis of pulmonary arterial hypertension (PAH) * Body weight less than 40 kg at Screening and confirmed at Baseline * History of postural hypotension, unexplained syncope, a blood pressure that is less than 90 mmHg systolic or 50 mmHg diastolic at Screening and Baseline * Hemoglobin concentration less than 75% of the lower limit of the normal range at Screening * Moderate to severe hepatic impairment, i.e., Child-Pugh Class B or C, or ALT greater than three times upper limit of normal * Intractable diarrhea, or severe malabsorption, defined as greater than 15% unintentional loss of body weight in the last 6 months prior to Screening; any severe organ failure (e.g., lung, kidney), bleeding diathesis or platelet disorder, or any life-threatening condition * Pregnant or breast-feeding * Simultaneously fulfilled criteria for a second connective tissue disease including systemic lupus erythermatosus, rheumatoid arthritis or inflammatory myopathy * Sympathectomy of the upper limb, involving the hand, performed within 12 months of Baseline. Sympathectomy performed on the non-target limb (hand not presenting with qualifying ulcers) or which did not include the hand, performed within 6 months of Baseline * Receipt of prostanoid treatment (epoprostenol, treprostinil sodium, or other prostacyclin analog) within the previous 3 months of Baseline for conditions including Raynaud's phenomenon, rest pain and / or digital ulcers * Required systemic antibiotics for infected digital ulcers within 2 weeks of Screening * Local injection of botulinum toxin in an affected finger within 1 month prior to Baseline * Treatment with endothelin receptor antagonists within 1 month prior to Baseline * Patients on phosphodiasterase inhibitors, such as sildenafil or tadalafil, who have received treatment for less than 6 months prior to Baseline (unless for intermittent treatment of male erectile dysfunction) * Treatment with statin within 1 month prior to Screening, unless for management of hyperlipidemia * Received an investigational product within 1 month preceding Screening * Known hypersensitivity to treprostinil diethanolamine or any of the excipients * Tobacco or nicotine use at any level within the past 6 months prior to Screening * Any condition or laboratory that in the opinion of the investigator might interfere with subject's participation, pose an additional risk for the subject, could prevent understanding the objectives, nature or consequences of the trial, compliance with the protocol, adherence to therapy, or that would interfere with interpretation of study assessments
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Net Ulcer Burden | Week 20 | Net ulcer burden was defined as the number of new or active digital ulcers (DU), plus the number of indeterminate DUs at that assessment that have previously been classified as either active or new at any earlier assessment during the study. A DU was defined as an area with visually discernable depth and a loss of continuity of epithelial coverage, which could be denuded or covered by a scab or necrotic tissue. If denuded, the DU was pronounced active. If denudation could not be judged because of the presence of scab or necrotic tissue, DU presenting with features, including underlying pain, based on Investigator clinical judgment to be consistent with loss of epithelialization, epidermis, or dermis, and requiring treatment were designated as active. Otherwise, the DU was pronounced indeterminate. Only DUs distal to the proximal interphalangeal joints, volar to the equator of the finger, not localized in creases and vascular in origin were assessed. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Patient Global Assessment of Digital Ulcer Severity VAS | Week 20 | Patients rated their global impression of digital ulcer severity on a 15-cm VAS from scaled 0 (no disease activity) to 100 (very severe disease). The term severity was used to measure the extent of disease activity and associated disability or discomfort the patient experienced during the indicated time period. |
| Physician Global Assessment of Digital Ulcer Severity VAS | Week 20 | Physicians rated their global impression of digital ulcer severity on a 15-cm VAS from scaled 0 (no disease activity) to 100 (very severe disease). The term severity was used to measure the extent of disease activity and associated disability or discomfort the patient experienced during the indicated time period. |
| Cochin Hand Function Scale (CHFS) | Week 20 | The CHFS has been demonstrated as a reliable and valid assessment of hand function at the activity level in persons with SSc. It is comprised of 18 questions with possible integer responses of 0 (without difficulty) to 5 (impossible). The CHFS Score is simply the sum of all 18 questions, divided by the number of questions actually answered, multiplied by 18. At least 10 of the 18 questions must have been answered in order for CHFS to be calculated. Therefore, CHFS Score values can range from 0 (least limitation) to 90 (most limitation). A higher score indicates more difficulty in hand function or greater disability. |
| Scleroderma Health Assessment Questionnaire (SHAQ) | Week 20 | The SHAQ is a patient self-administered instrument which has been previously validated in SSc and demonstrates meaningful clinical changes in the course of the disease over time. It is comprised of a 20 question instrument pertaining to specific activities with possible integer responses of 0 (without any difficulty) to 3 (unable to do), and five additional scleroderma-specific visual analog scale (VAS) domains (Overall Disease Activity, Raynaud's Phenomenon, Finger Ulcers, Breathing, and Intestinal Problems) with possible values ranging from 0.0 to 15.0. The 20 questions are divided into eight domains. A mean score is calculated for each domain ranging from 0 to 3. A composite HAQ DI score is calculated by dividing the summed domain scores by the number of domains answered. The composite score is reported, falling between 0 and 3 on an ordinal scale. The scores are interpreted as 0 (no impairment in function) to 3 (maximal impairment of function). |
| Modified Rodnan Skin Score (mRSS) | Week 20 | The skin thickening was assessed by the Investigator in 17 body areas: fingers, hands, forearms, arms, feet, legs, and thighs (bilaterally) and face, chest, and abdomen (singly). Each area was scored 0-3; 0 representing normal skin and 3 being severe thickening. The mRSS was the sum of the individual skin assessment scores: possible range of 0-51; 0 (no thickening) to 51 (severe thickening in all 17 areas) . |
| Digital Ulcer Pain VAS | Week 20 | Digital ulcer pain was rated on a 100-mm VAS on which subjects were asked to rate their average overall hand pain during the last week. The recorded value was divided by 10, with values ranging from 0.0 (no pain) to 10.0 (unbearable pain), expressed to one decimal. |
| Patient Impression of Change (PIC) Questionnaire | Week 20 | The PIC questionnaire consisted of three Likert items that asked the subject to rate changes in their digital ulcer, Raynaud's phenomenon and disease status since their last visit on a seven-level scale (very much improved, much improved, somewhat improved, same, somewhat worse, much worse and very much worse). |
| Short Form 36 | Week 20 | Change in patient quality of life was measured by the Medical Outcomes Study 36-Item Short Form Health Survey (SF-36), a self-administered questionnaire covering eight areas: physical function, physical role, bodily pain, general health, vitality, social function, emotional role, and mental health. For each area, the score range from 0 (poorer health status) to 100 (better health status). The SF-36 is one of the most widely used and validated instruments to assess quality of life in patients with systemic illnesses. A decrease (negative change) in a domain score corresponds to deterioration. |
| Time to Ulcer Healing- Percentage of Subjects With Complete Healing | Week 20 | A subject was counted as having all ulcers completely healed at the earliest assessment for which all ulcers are designated as healed and no new ulcers appeared for the remainder of the trial. |
| Time to Ulcer Healing | Week 20 | A subject was counted as having all ulcers completely healed at the earliest assessment for which all ulcers are designated as healed and no new ulcers appeared for the remainder of the trial. The time to complete healing of all ulcers were calculated as the number of days from randomization to the date of these respective assessments, provided that complete healing was achieved during the study. |
| Short-Form McGill Pain Questionnaire | Week 20 | The SF-MPQ assessment has three component scores: the pain rating index (PRI), a pain visual analogue numerical scale (Pain VAS) and the present pain intensity (PPI). PRI is calculated by summing the responses (0=None to 3=Severe) to the 15 questions describing pain during the previous week and rated on an intensity scale as 0= none, 1= mild, 2= moderate or 3= severe and has possible values ranging from 0 to 45. The Pain VAS is a 100 mm VAS on which subjects were asked to rate pain during the previous week with values ranging from no pain (0.0) to worst possible pain (10.0). The PPI rated pain on a 6-point category scale from 0 (no pain) to 5 (excruciating pain). |
Countries
Canada, United Kingdom, United States
Participant flow
Recruitment details
Subjects were recruited across 32 clinical trial sites in the US, Canada and UK experienced in the treatment of systemic sclerosis (SSc) and capable of conducting the trial according to ICH GCP guidance. Subjects were recruited between April 2009 and October 2010.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Matching placebo sustained release tablet initiated at 0.25 mg BID and titrated up to a maximum dose of 16 mg BID or the individual's maximum tolerated dose. | 76 |
| Treprostinil Diethanolamine Treprostinil diethanolamine sustained release tablet initiated at 0.25 mg BID and titrated up to a maximum dose of 16 mg BID or the individual's maximum tolerated dose. | 71 |
| Total | 147 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 7 | 9 |
| Overall Study | Lack of Efficacy | 1 | 1 |
| Overall Study | Lost to Follow-up | 1 | 0 |
| Overall Study | Protocol Violation | 2 | 2 |
| Overall Study | Withdrawal by Subject | 0 | 1 |
Baseline characteristics
| Characteristic | Treprostinil Diethanolamine | Total | Placebo |
|---|---|---|---|
| Age, Continuous | 49.8 years | 48.8 years | 47.8 years |
| Race/Ethnicity, Customized Asian | 4 participants | 7 participants | 3 participants |
| Race/Ethnicity, Customized Black or African American | 7 participants | 17 participants | 10 participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander | 1 participants | 1 participants | 0 participants |
| Race/Ethnicity, Customized Unknown or Not Reported | 1 participants | 2 participants | 1 participants |
| Race/Ethnicity, Customized White | 59 participants | 121 participants | 62 participants |
| Sex: Female, Male Female | 54 Participants | 109 Participants | 55 Participants |
| Sex: Female, Male Male | 17 Participants | 38 Participants | 21 Participants |
| SSc Classification Diffuse | 31 participants | 52 participants | 21 participants |
| SSc Classification Limited | 40 participants | 95 participants | 55 participants |
| Years since SSc diagnosis | 10.3 years | 10.5 years | 10.7 years |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 76 | 0 / 71 |
| other Total, other adverse events | 74 / 76 | 71 / 71 |
| serious Total, serious adverse events | 4 / 76 | 9 / 71 |
Outcome results
Primary
Net Ulcer Burden
Net ulcer burden was defined as the number of new or active digital ulcers (DU), plus the number of indeterminate DUs at that assessment that have previously been classified as either active or new at any earlier assessment during the study. A DU was defined as an area with visually discernable depth and a loss of continuity of epithelial coverage, which could be denuded or covered by a scab or necrotic tissue. If denuded, the DU was pronounced active. If denudation could not be judged because of the presence of scab or necrotic tissue, DU presenting with features, including underlying pain, based on Investigator clinical judgment to be consistent with loss of epithelialization, epidermis, or dermis, and requiring treatment were designated as active. Otherwise, the DU was pronounced indeterminate. Only DUs distal to the proximal interphalangeal joints, volar to the equator of the finger, not localized in creases and vascular in origin were assessed.
Time frame: Week 20
Population: The intent to treat population is all subjects that received at least one dose of study drug. Subjects were counted in the assigned group regardless of the actual treatment given. Missing values imputed by carrying last observation forward or assigning value equalling overall poorest relative change.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Placebo | Net Ulcer Burden | Baseline | 1.0 ulcers |
| Placebo | Net Ulcer Burden | Change at Week 20 | 0.0 ulcers |
| Treprostinil Diethanolamine | Net Ulcer Burden | Baseline | 2.0 ulcers |
| Treprostinil Diethanolamine | Net Ulcer Burden | Change at Week 20 | -1.0 ulcers |
Comparison: A Cochran-Mantel Haenszel mean score test was used on the standardized reverse mid-ranks (overall reverse ranks divided by the number of ranks +1, or modified ridit scores; largely negative changes had ranks near 1 and largely positive changes had ranks near 0)of the residuals from an ordinary least squares regression with change in net ulcer burden at Week 20 as a linear function of Baseline PDEI or prostacyclin use (binary variable:Yes/No) and net ulcer burden at Baseline(continuous variable).p-value: 0.295% CI: [-1, 0]Cochran-Mantel-Haenszel
Secondary
Cochin Hand Function Scale (CHFS)
The CHFS has been demonstrated as a reliable and valid assessment of hand function at the activity level in persons with SSc. It is comprised of 18 questions with possible integer responses of 0 (without difficulty) to 5 (impossible). The CHFS Score is simply the sum of all 18 questions, divided by the number of questions actually answered, multiplied by 18. At least 10 of the 18 questions must have been answered in order for CHFS to be calculated. Therefore, CHFS Score values can range from 0 (least limitation) to 90 (most limitation). A higher score indicates more difficulty in hand function or greater disability.
Time frame: Week 20
Population: The intent to treat population is all subjects that received at least one dose of study drug. Subjects were counted in the assigned group regardless of the actual treatment given. Missing values imputed by carrying last observation forward or assigning value equalling overall poorest relative change. Excluded subjects without a Baseline observation
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Placebo | Cochin Hand Function Scale (CHFS) | Baseline | 18.5 units on a scale |
| Placebo | Cochin Hand Function Scale (CHFS) | Week 20 | 19.0 units on a scale |
| Treprostinil Diethanolamine | Cochin Hand Function Scale (CHFS) | Baseline | 24.0 units on a scale |
| Treprostinil Diethanolamine | Cochin Hand Function Scale (CHFS) | Week 20 | 21.0 units on a scale |
Comparison: The difference between treatment groups for the change from Baseline in CHFS Score were tested using the Wilcoxon rank-sum test.p-value: 0.4795% CI: [-4, 2]Wilcoxon (Mann-Whitney)
Secondary
Digital Ulcer Pain VAS
Digital ulcer pain was rated on a 100-mm VAS on which subjects were asked to rate their average overall hand pain during the last week. The recorded value was divided by 10, with values ranging from 0.0 (no pain) to 10.0 (unbearable pain), expressed to one decimal.
Time frame: Week 20
Population: The intent to treat population is all subjects that received at least one dose of study drug. Subjects were counted in the assigned group regardless of the actual treatment given. Missing values imputed by carrying last observation forward or assigning value equalling overall poorest relative change. Excluded subjects without a Baseline observation
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Placebo | Digital Ulcer Pain VAS | Baseline | 4.85 units on a scale |
| Placebo | Digital Ulcer Pain VAS | Change at Week 20 | -1.05 units on a scale |
| Treprostinil Diethanolamine | Digital Ulcer Pain VAS | Baseline | 6.00 units on a scale |
| Treprostinil Diethanolamine | Digital Ulcer Pain VAS | Change at Week 20 | -1.45 units on a scale |
Comparison: The difference between treatment groups for the change from Baseline was tested using the Wilcoxon rank-sum test.p-value: 0.3195% CI: [-1.4, 0.4]Wilcoxon (Mann-Whitney)
Secondary
Modified Rodnan Skin Score (mRSS)
The skin thickening was assessed by the Investigator in 17 body areas: fingers, hands, forearms, arms, feet, legs, and thighs (bilaterally) and face, chest, and abdomen (singly). Each area was scored 0-3; 0 representing normal skin and 3 being severe thickening. The mRSS was the sum of the individual skin assessment scores: possible range of 0-51; 0 (no thickening) to 51 (severe thickening in all 17 areas) .
Time frame: Week 20
Population: The intent to treat population is all subjects that received at least one dose of study drug. Subjects were counted in the assigned group regardless of the actual treatment given. Missing values imputed by carrying last observation forward or assigning value equalling overall poorest relative change. Excluded subjects without a Baseline observation
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Placebo | Modified Rodnan Skin Score (mRSS) | Baseline | 6.0 units on a scale |
| Placebo | Modified Rodnan Skin Score (mRSS) | Week 20 | 6.0 units on a scale |
| Treprostinil Diethanolamine | Modified Rodnan Skin Score (mRSS) | Baseline | 8.0 units on a scale |
| Treprostinil Diethanolamine | Modified Rodnan Skin Score (mRSS) | Week 20 | 6.0 units on a scale |
Comparison: he difference between treatment groups for the change from Baseline and at Week 20 in the mRSS was tested using the Wilcoxon rank-sum test.p-value: 0.6895% CI: [0, 1]Wilcoxon (Mann-Whitney)
Secondary
Patient Global Assessment of Digital Ulcer Severity VAS
Patients rated their global impression of digital ulcer severity on a 15-cm VAS from scaled 0 (no disease activity) to 100 (very severe disease). The term severity was used to measure the extent of disease activity and associated disability or discomfort the patient experienced during the indicated time period.
Time frame: Week 20
Population: The intent to treat population is all subjects that received at least one dose of study drug. Subjects were counted in the assigned group regardless of the actual treatment given. Missing values imputed by carrying last observation forward or assigning value equalling overall poorest relative change. Excluded subjects without a Baseline observation
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Placebo | Patient Global Assessment of Digital Ulcer Severity VAS | Baseline | 57.0 units on a scale |
| Placebo | Patient Global Assessment of Digital Ulcer Severity VAS | Change at Week 20 | -24.0 units on a scale |
| Treprostinil Diethanolamine | Patient Global Assessment of Digital Ulcer Severity VAS | Baseline | 67.0 units on a scale |
| Treprostinil Diethanolamine | Patient Global Assessment of Digital Ulcer Severity VAS | Change at Week 20 | -24.3 units on a scale |
Comparison: The VAS-global assessments were recorded in centimeters, with possible values ranging from 0.0 to 15.0. The recorded value was divided by 15, then multiplied by 100 to convert it to the VAS-Global scale, with values ranging from 0 (no disease activity) to 100 (very severe disease). The difference between treatment groups for the change from Baseline was tested using the Wilcoxon rank-sum test.p-value: 0.1295% CI: [-21.3, 2.7]Wilcoxon (Mann-Whitney)
Secondary
Patient Impression of Change (PIC) Questionnaire
The PIC questionnaire consisted of three Likert items that asked the subject to rate changes in their digital ulcer, Raynaud's phenomenon and disease status since their last visit on a seven-level scale (very much improved, much improved, somewhat improved, same, somewhat worse, much worse and very much worse).
Time frame: Week 20
Population: The intent to treat population is all subjects that received at least one dose of study drug. Subjects were counted in the assigned group regardless of the actual treatment given. Missing values imputed by carrying last observation forward or assigning value equalling overall poorest relative change. Excluded subjects without a Baseline observation
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | Patient Impression of Change (PIC) Questionnaire | Somewhat Improved | 20 participants |
| Placebo | Patient Impression of Change (PIC) Questionnaire | Same | 24 participants |
| Placebo | Patient Impression of Change (PIC) Questionnaire | Very Much Worse | 1 participants |
| Placebo | Patient Impression of Change (PIC) Questionnaire | Much Worse | 1 participants |
| Placebo | Patient Impression of Change (PIC) Questionnaire | Much Improved | 11 participants |
| Placebo | Patient Impression of Change (PIC) Questionnaire | Very Much Improved | 5 participants |
| Placebo | Patient Impression of Change (PIC) Questionnaire | Somewhat Worse | 14 participants |
| Treprostinil Diethanolamine | Patient Impression of Change (PIC) Questionnaire | Somewhat Worse | 8 participants |
| Treprostinil Diethanolamine | Patient Impression of Change (PIC) Questionnaire | Somewhat Improved | 14 participants |
| Treprostinil Diethanolamine | Patient Impression of Change (PIC) Questionnaire | Very Much Improved | 9 participants |
| Treprostinil Diethanolamine | Patient Impression of Change (PIC) Questionnaire | Same | 21 participants |
| Treprostinil Diethanolamine | Patient Impression of Change (PIC) Questionnaire | Very Much Worse | 1 participants |
| Treprostinil Diethanolamine | Patient Impression of Change (PIC) Questionnaire | Much Improved | 15 participants |
| Treprostinil Diethanolamine | Patient Impression of Change (PIC) Questionnaire | Much Worse | 3 participants |
| Placebo- Raynaud's Phenomenon Response | Patient Impression of Change (PIC) Questionnaire | Somewhat Worse | 17 participants |
| Placebo- Raynaud's Phenomenon Response | Patient Impression of Change (PIC) Questionnaire | Very Much Improved | 0 participants |
| Placebo- Raynaud's Phenomenon Response | Patient Impression of Change (PIC) Questionnaire | Much Improved | 4 participants |
| Placebo- Raynaud's Phenomenon Response | Patient Impression of Change (PIC) Questionnaire | Somewhat Improved | 12 participants |
| Placebo- Raynaud's Phenomenon Response | Patient Impression of Change (PIC) Questionnaire | Same | 40 participants |
| Placebo- Raynaud's Phenomenon Response | Patient Impression of Change (PIC) Questionnaire | Much Worse | 1 participants |
| Placebo- Raynaud's Phenomenon Response | Patient Impression of Change (PIC) Questionnaire | Very Much Worse | 2 participants |
| Treprostinil Diethanolamine- Raynaud's Phenomenon Response | Patient Impression of Change (PIC) Questionnaire | Very Much Worse | 1 participants |
| Treprostinil Diethanolamine- Raynaud's Phenomenon Response | Patient Impression of Change (PIC) Questionnaire | Somewhat Improved | 20 participants |
| Treprostinil Diethanolamine- Raynaud's Phenomenon Response | Patient Impression of Change (PIC) Questionnaire | Very Much Improved | 3 participants |
| Treprostinil Diethanolamine- Raynaud's Phenomenon Response | Patient Impression of Change (PIC) Questionnaire | Much Worse | 1 participants |
| Treprostinil Diethanolamine- Raynaud's Phenomenon Response | Patient Impression of Change (PIC) Questionnaire | Same | 30 participants |
| Treprostinil Diethanolamine- Raynaud's Phenomenon Response | Patient Impression of Change (PIC) Questionnaire | Much Improved | 12 participants |
| Treprostinil Diethanolamine- Raynaud's Phenomenon Response | Patient Impression of Change (PIC) Questionnaire | Somewhat Worse | 4 participants |
| Placebo- Overall Disease Status Response | Patient Impression of Change (PIC) Questionnaire | Very Much Improved | 0 participants |
| Placebo- Overall Disease Status Response | Patient Impression of Change (PIC) Questionnaire | Same | 30 participants |
| Placebo- Overall Disease Status Response | Patient Impression of Change (PIC) Questionnaire | Much Improved | 5 participants |
| Placebo- Overall Disease Status Response | Patient Impression of Change (PIC) Questionnaire | Somewhat Worse | 18 participants |
| Placebo- Overall Disease Status Response | Patient Impression of Change (PIC) Questionnaire | Very Much Worse | 1 participants |
| Placebo- Overall Disease Status Response | Patient Impression of Change (PIC) Questionnaire | Much Worse | 0 participants |
| Placebo- Overall Disease Status Response | Patient Impression of Change (PIC) Questionnaire | Somewhat Improved | 22 participants |
| Treprostinil Diethanolamine- Overall Disease Status Response | Patient Impression of Change (PIC) Questionnaire | Much Worse | 0 participants |
| Treprostinil Diethanolamine- Overall Disease Status Response | Patient Impression of Change (PIC) Questionnaire | Very Much Improved | 3 participants |
| Treprostinil Diethanolamine- Overall Disease Status Response | Patient Impression of Change (PIC) Questionnaire | Same | 27 participants |
| Treprostinil Diethanolamine- Overall Disease Status Response | Patient Impression of Change (PIC) Questionnaire | Very Much Worse | 1 participants |
| Treprostinil Diethanolamine- Overall Disease Status Response | Patient Impression of Change (PIC) Questionnaire | Somewhat Worse | 10 participants |
| Treprostinil Diethanolamine- Overall Disease Status Response | Patient Impression of Change (PIC) Questionnaire | Much Improved | 17 participants |
| Treprostinil Diethanolamine- Overall Disease Status Response | Patient Impression of Change (PIC) Questionnaire | Somewhat Improved | 13 participants |
Secondary
Physician Global Assessment of Digital Ulcer Severity VAS
Physicians rated their global impression of digital ulcer severity on a 15-cm VAS from scaled 0 (no disease activity) to 100 (very severe disease). The term severity was used to measure the extent of disease activity and associated disability or discomfort the patient experienced during the indicated time period.
Time frame: Week 20
Population: The intent to treat population is all subjects that received at least one dose of study drug. Subjects were counted in the assigned group regardless of the actual treatment given. Missing values imputed by carrying last observation forward or assigning value equalling overall poorest relative change. Excluded subjects without a Baseline observation
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Placebo | Physician Global Assessment of Digital Ulcer Severity VAS | Baseline | 44.7 units on a scale |
| Placebo | Physician Global Assessment of Digital Ulcer Severity VAS | Change at Week 20 | -13.3 units on a scale |
| Treprostinil Diethanolamine | Physician Global Assessment of Digital Ulcer Severity VAS | Baseline | 47.3 units on a scale |
| Treprostinil Diethanolamine | Physician Global Assessment of Digital Ulcer Severity VAS | Change at Week 20 | -26.7 units on a scale |
Comparison: The VAS-global assessments were recorded in centimeters, with possible values ranging from 0.0 to 15.0. The recorded value was divided by 15, then multiplied by 100 to convert it to the VAS-Global scale, with values ranging from 0 (no disease activity) to 100 (very severe disease). The difference between treatment groups for the change from Baseline was tested using the Wilcoxon rank-sum test.p-value: 0.0495% CI: [-18, 0]Wilcoxon (Mann-Whitney)
Secondary
Scleroderma Health Assessment Questionnaire (SHAQ)
The SHAQ is a patient self-administered instrument which has been previously validated in SSc and demonstrates meaningful clinical changes in the course of the disease over time. It is comprised of a 20 question instrument pertaining to specific activities with possible integer responses of 0 (without any difficulty) to 3 (unable to do), and five additional scleroderma-specific visual analog scale (VAS) domains (Overall Disease Activity, Raynaud's Phenomenon, Finger Ulcers, Breathing, and Intestinal Problems) with possible values ranging from 0.0 to 15.0. The 20 questions are divided into eight domains. A mean score is calculated for each domain ranging from 0 to 3. A composite HAQ DI score is calculated by dividing the summed domain scores by the number of domains answered. The composite score is reported, falling between 0 and 3 on an ordinal scale. The scores are interpreted as 0 (no impairment in function) to 3 (maximal impairment of function).
Time frame: Week 20
Population: The intent to treat population is all subjects that received at least one dose of study drug. Subjects were counted in the assigned group regardless of the actual treatment given. Missing values imputed by carrying last observation forward or assigning value equalling overall poorest relative change. Excluded subjects without a Baseline observation
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Placebo | Scleroderma Health Assessment Questionnaire (SHAQ) | Hygiene Score: Baseline (76/68) | 0.00 units on a scale |
| Placebo | Scleroderma Health Assessment Questionnaire (SHAQ) | Dressing & Grooming Score: Baseline (76/71) | 0.50 units on a scale |
| Placebo | Scleroderma Health Assessment Questionnaire (SHAQ) | Dressing&Grooming Score:Change at Week 20 | 0.00 units on a scale |
| Placebo | Scleroderma Health Assessment Questionnaire (SHAQ) | Arising Score: Baseline (76/71) | 0.00 units on a scale |
| Placebo | Scleroderma Health Assessment Questionnaire (SHAQ) | Arising Score: Change at Week 20 | 0.00 units on a scale |
| Placebo | Scleroderma Health Assessment Questionnaire (SHAQ) | Eating Score: Baseline (76/71) | 0.67 units on a scale |
| Placebo | Scleroderma Health Assessment Questionnaire (SHAQ) | Eating Score: Change at Week 20 | 0.00 units on a scale |
| Placebo | Scleroderma Health Assessment Questionnaire (SHAQ) | Walking Score: Baseline (76/71) | 0.00 units on a scale |
| Placebo | Scleroderma Health Assessment Questionnaire (SHAQ) | Walking Score: Change at Week 20 | 0.00 units on a scale |
| Placebo | Scleroderma Health Assessment Questionnaire (SHAQ) | Hygiene Score: Change at Week 20 | 0.00 units on a scale |
| Placebo | Scleroderma Health Assessment Questionnaire (SHAQ) | Reach Score: Baseline (76/68) | 0.00 units on a scale |
| Placebo | Scleroderma Health Assessment Questionnaire (SHAQ) | Reach Score: Change at Week 20 | 0.00 units on a scale |
| Placebo | Scleroderma Health Assessment Questionnaire (SHAQ) | Grip Score: Baseline (76/68) | 0.33 units on a scale |
| Placebo | Scleroderma Health Assessment Questionnaire (SHAQ) | Grip Score: Change at Week 20 | 0.00 units on a scale |
| Placebo | Scleroderma Health Assessment Questionnaire (SHAQ) | Activity Score: Baseline (76/68) | 0.33 units on a scale |
| Placebo | Scleroderma Health Assessment Questionnaire (SHAQ) | Activity Score: Change at Week 20 | 0.00 units on a scale |
| Placebo | Scleroderma Health Assessment Questionnaire (SHAQ) | HAQ Aggregate Score: Baseline (76/68) | 0.34 units on a scale |
| Placebo | Scleroderma Health Assessment Questionnaire (SHAQ) | HAQ Aggregate Score: Change at Week 20 | 0.00 units on a scale |
| Placebo | Scleroderma Health Assessment Questionnaire (SHAQ) | Hand Function Aggregate Score: Baseline (76/68) | 0.39 units on a scale |
| Placebo | Scleroderma Health Assessment Questionnaire (SHAQ) | Hand Function Aggregate Score: Change at Week 20 | 0.00 units on a scale |
| Placebo | Scleroderma Health Assessment Questionnaire (SHAQ) | Raynaud's Phenomenon VAS Score: Baseline (75/71) | 0.12 units on a scale |
| Placebo | Scleroderma Health Assessment Questionnaire (SHAQ) | Raynaud's Phenomenon VAS Score: Change at Week 20 | 0.00 units on a scale |
| Placebo | Scleroderma Health Assessment Questionnaire (SHAQ) | Intestinal Problems VAS Score: Baseline (75/70) | 0.20 units on a scale |
| Placebo | Scleroderma Health Assessment Questionnaire (SHAQ) | Intestinal Problems VAS Score: Change at Week 20 | 0.00 units on a scale |
| Placebo | Scleroderma Health Assessment Questionnaire (SHAQ) | Digital Ulcer VAS Score: Baseline (76/71) | 1.43 units on a scale |
| Placebo | Scleroderma Health Assessment Questionnaire (SHAQ) | Digital Ulcer VAS Score: Change at Week 20 | -0.34 units on a scale |
| Placebo | Scleroderma Health Assessment Questionnaire (SHAQ) | Breathing Problems VAS Score: Baseline (76/71) | 1.54 units on a scale |
| Placebo | Scleroderma Health Assessment Questionnaire (SHAQ) | Breathing Problems VAS Score: Change at Week 20 | -0.50 units on a scale |
| Placebo | Scleroderma Health Assessment Questionnaire (SHAQ) | Pain VAS Score: Baseline (76/69) | 1.27 units on a scale |
| Placebo | Scleroderma Health Assessment Questionnaire (SHAQ) | Pain VAS Score: Change at Week 20 | -0.26 units on a scale |
| Placebo | Scleroderma Health Assessment Questionnaire (SHAQ) | Overall Disease VAS Score: Baseline (76/71) | 1.22 units on a scale |
| Placebo | Scleroderma Health Assessment Questionnaire (SHAQ) | Overall Disease VAS Score: Change at Week 20 | -0.18 units on a scale |
| Treprostinil Diethanolamine | Scleroderma Health Assessment Questionnaire (SHAQ) | Overall Disease VAS Score: Change at Week 20 | -0.32 units on a scale |
| Treprostinil Diethanolamine | Scleroderma Health Assessment Questionnaire (SHAQ) | HAQ Aggregate Score: Baseline (76/68) | 0.53 units on a scale |
| Treprostinil Diethanolamine | Scleroderma Health Assessment Questionnaire (SHAQ) | Dressing & Grooming Score: Baseline (76/71) | 1.00 units on a scale |
| Treprostinil Diethanolamine | Scleroderma Health Assessment Questionnaire (SHAQ) | Digital Ulcer VAS Score: Baseline (76/71) | 1.50 units on a scale |
| Treprostinil Diethanolamine | Scleroderma Health Assessment Questionnaire (SHAQ) | Dressing&Grooming Score:Change at Week 20 | 0.00 units on a scale |
| Treprostinil Diethanolamine | Scleroderma Health Assessment Questionnaire (SHAQ) | HAQ Aggregate Score: Change at Week 20 | -0.03 units on a scale |
| Treprostinil Diethanolamine | Scleroderma Health Assessment Questionnaire (SHAQ) | Arising Score: Baseline (76/71) | 0.00 units on a scale |
| Treprostinil Diethanolamine | Scleroderma Health Assessment Questionnaire (SHAQ) | Pain VAS Score: Baseline (76/69) | 1.54 units on a scale |
| Treprostinil Diethanolamine | Scleroderma Health Assessment Questionnaire (SHAQ) | Hand Function Aggregate Score: Baseline (76/68) | 0.56 units on a scale |
| Treprostinil Diethanolamine | Scleroderma Health Assessment Questionnaire (SHAQ) | Eating Score: Baseline (76/71) | 0.67 units on a scale |
| Treprostinil Diethanolamine | Scleroderma Health Assessment Questionnaire (SHAQ) | Digital Ulcer VAS Score: Change at Week 20 | -0.56 units on a scale |
| Treprostinil Diethanolamine | Scleroderma Health Assessment Questionnaire (SHAQ) | Eating Score: Change at Week 20 | 0.00 units on a scale |
| Treprostinil Diethanolamine | Scleroderma Health Assessment Questionnaire (SHAQ) | Hand Function Aggregate Score: Change at Week 20 | 0.00 units on a scale |
| Treprostinil Diethanolamine | Scleroderma Health Assessment Questionnaire (SHAQ) | Walking Score: Baseline (76/71) | 0.00 units on a scale |
| Treprostinil Diethanolamine | Scleroderma Health Assessment Questionnaire (SHAQ) | Overall Disease VAS Score: Baseline (76/71) | 1.52 units on a scale |
| Treprostinil Diethanolamine | Scleroderma Health Assessment Questionnaire (SHAQ) | Walking Score: Change at Week 20 | 0.00 units on a scale |
| Treprostinil Diethanolamine | Scleroderma Health Assessment Questionnaire (SHAQ) | Arising Score: Change at Week 20 | 0.00 units on a scale |
| Treprostinil Diethanolamine | Scleroderma Health Assessment Questionnaire (SHAQ) | Hygiene Score: Baseline (76/68) | 0.33 units on a scale |
| Treprostinil Diethanolamine | Scleroderma Health Assessment Questionnaire (SHAQ) | Raynaud's Phenomenon VAS Score: Baseline (75/71) | 0.18 units on a scale |
| Treprostinil Diethanolamine | Scleroderma Health Assessment Questionnaire (SHAQ) | Hygiene Score: Change at Week 20 | 0.00 units on a scale |
| Treprostinil Diethanolamine | Scleroderma Health Assessment Questionnaire (SHAQ) | Breathing Problems VAS Score: Baseline (76/71) | 2.16 units on a scale |
| Treprostinil Diethanolamine | Scleroderma Health Assessment Questionnaire (SHAQ) | Reach Score: Baseline (76/68) | 0.50 units on a scale |
| Treprostinil Diethanolamine | Scleroderma Health Assessment Questionnaire (SHAQ) | Raynaud's Phenomenon VAS Score: Change at Week 20 | 0.00 units on a scale |
| Treprostinil Diethanolamine | Scleroderma Health Assessment Questionnaire (SHAQ) | Reach Score: Change at Week 20 | 0.00 units on a scale |
| Treprostinil Diethanolamine | Scleroderma Health Assessment Questionnaire (SHAQ) | Pain VAS Score: Change at Week 20 | -0.34 units on a scale |
| Treprostinil Diethanolamine | Scleroderma Health Assessment Questionnaire (SHAQ) | Grip Score: Baseline (76/68) | 0.33 units on a scale |
| Treprostinil Diethanolamine | Scleroderma Health Assessment Questionnaire (SHAQ) | Intestinal Problems VAS Score: Baseline (75/70) | 0.11 units on a scale |
| Treprostinil Diethanolamine | Scleroderma Health Assessment Questionnaire (SHAQ) | Grip Score: Change at Week 20 | 0.00 units on a scale |
| Treprostinil Diethanolamine | Scleroderma Health Assessment Questionnaire (SHAQ) | Breathing Problems VAS Score: Change at Week 20 | -0.84 units on a scale |
| Treprostinil Diethanolamine | Scleroderma Health Assessment Questionnaire (SHAQ) | Activity Score: Baseline (76/68) | 0.67 units on a scale |
| Treprostinil Diethanolamine | Scleroderma Health Assessment Questionnaire (SHAQ) | Intestinal Problems VAS Score: Change at Week 20 | 0.11 units on a scale |
| Treprostinil Diethanolamine | Scleroderma Health Assessment Questionnaire (SHAQ) | Activity Score: Change at Week 20 | 0.00 units on a scale |
Secondary
Short Form 36
Change in patient quality of life was measured by the Medical Outcomes Study 36-Item Short Form Health Survey (SF-36), a self-administered questionnaire covering eight areas: physical function, physical role, bodily pain, general health, vitality, social function, emotional role, and mental health. For each area, the score range from 0 (poorer health status) to 100 (better health status). The SF-36 is one of the most widely used and validated instruments to assess quality of life in patients with systemic illnesses. A decrease (negative change) in a domain score corresponds to deterioration.
Time frame: Week 20
Population: The intent to treat population is all subjects that received at least one dose of study drug. Subjects were counted in the assigned group regardless of the actual treatment given. Missing values imputed by carrying last observation forward or assigning value equalling overall poorest relative change. Excluded subjects without a Baseline observation
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Placebo | Short Form 36 | Physical Component: Baseline | 55.0 units on a scale |
| Placebo | Short Form 36 | Physical Component: Change at Week 20 | 2.8 units on a scale |
| Placebo | Short Form 36 | Physical Functioning: Baseline | 62.5 units on a scale |
| Placebo | Short Form 36 | Physical Functioning: Change at Week 20 | 0.0 units on a scale |
| Placebo | Short Form 36 | Role-Physical: Baseline | 54.4 units on a scale |
| Placebo | Short Form 36 | Role-Physical: Change at Week 20 | 0.0 units on a scale |
| Placebo | Short Form 36 | Bodily Pain: Baseline | 57.5 units on a scale |
| Placebo | Short Form 36 | Bodily Pain: Change at Week 20 | 10.0 units on a scale |
| Placebo | Short Form 36 | General Health: Baseline | 42.0 units on a scale |
| Placebo | Short Form 36 | General Health: Change at Week 20 | 0.0 units on a scale |
| Placebo | Short Form 36 | Mental Component: Baseline | 68.3 units on a scale |
| Placebo | Short Form 36 | Mental Component: Change at Week 20 | 2.6 units on a scale |
| Placebo | Short Form 36 | Vitality: Baseline (75/71) | 50.0 units on a scale |
| Placebo | Short Form 36 | Vitality: Change at Week 20 | 0.0 units on a scale |
| Placebo | Short Form 36 | Social Functioning: Baseline | 72.5 units on a scale |
| Placebo | Short Form 36 | Social Functioning: Change at Week 20 | 0.0 units on a scale |
| Placebo | Short Form 36 | Role-Emotional: Baseline | 70.0 units on a scale |
| Placebo | Short Form 36 | Role-Emotional: Change at Week 20 | 0.0 units on a scale |
| Placebo | Short Form 36 | Mental Health: Baseline (75/71) | 69.0 units on a scale |
| Placebo | Short Form 36 | Mental Health: Change at Week 20 | 2.0 units on a scale |
| Treprostinil Diethanolamine | Short Form 36 | Role-Emotional: Change at Week 20 | 0.0 units on a scale |
| Treprostinil Diethanolamine | Short Form 36 | Physical Component: Baseline | 50.7 units on a scale |
| Treprostinil Diethanolamine | Short Form 36 | Mental Component: Baseline | 64.2 units on a scale |
| Treprostinil Diethanolamine | Short Form 36 | Physical Component: Change at Week 20 | 3.8 units on a scale |
| Treprostinil Diethanolamine | Short Form 36 | Social Functioning: Change at Week 20 | 10.0 units on a scale |
| Treprostinil Diethanolamine | Short Form 36 | Physical Functioning: Baseline | 60.0 units on a scale |
| Treprostinil Diethanolamine | Short Form 36 | Mental Component: Change at Week 20 | 4.0 units on a scale |
| Treprostinil Diethanolamine | Short Form 36 | Physical Functioning: Change at Week 20 | 0.0 units on a scale |
| Treprostinil Diethanolamine | Short Form 36 | Mental Health: Change at Week 20 | 3.0 units on a scale |
| Treprostinil Diethanolamine | Short Form 36 | Role-Physical: Baseline | 50.0 units on a scale |
| Treprostinil Diethanolamine | Short Form 36 | Vitality: Baseline (75/71) | 43.8 units on a scale |
| Treprostinil Diethanolamine | Short Form 36 | Role-Physical: Change at Week 20 | 0.0 units on a scale |
| Treprostinil Diethanolamine | Short Form 36 | Role-Emotional: Baseline | 80.0 units on a scale |
| Treprostinil Diethanolamine | Short Form 36 | Bodily Pain: Baseline | 45.0 units on a scale |
| Treprostinil Diethanolamine | Short Form 36 | Vitality: Change at Week 20 | 1.3 units on a scale |
| Treprostinil Diethanolamine | Short Form 36 | Bodily Pain: Change at Week 20 | 10.0 units on a scale |
| Treprostinil Diethanolamine | Short Form 36 | Mental Health: Baseline (75/71) | 64.0 units on a scale |
| Treprostinil Diethanolamine | Short Form 36 | General Health: Baseline | 45.0 units on a scale |
| Treprostinil Diethanolamine | Short Form 36 | Social Functioning: Baseline | 62.5 units on a scale |
| Treprostinil Diethanolamine | Short Form 36 | General Health: Change at Week 20 | 0.0 units on a scale |
Secondary
Short-Form McGill Pain Questionnaire
The SF-MPQ assessment has three component scores: the pain rating index (PRI), a pain visual analogue numerical scale (Pain VAS) and the present pain intensity (PPI). PRI is calculated by summing the responses (0=None to 3=Severe) to the 15 questions describing pain during the previous week and rated on an intensity scale as 0= none, 1= mild, 2= moderate or 3= severe and has possible values ranging from 0 to 45. The Pain VAS is a 100 mm VAS on which subjects were asked to rate pain during the previous week with values ranging from no pain (0.0) to worst possible pain (10.0). The PPI rated pain on a 6-point category scale from 0 (no pain) to 5 (excruciating pain).
Time frame: Week 20
Population: The intent to treat population is all subjects that received at least one dose of study drug. Subjects were counted in the assigned group regardless of the actual treatment given. Missing values imputed by carrying last observation forward or assigning value equalling overall poorest relative change. Excluded subjects without a Baseline observation
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Placebo | Short-Form McGill Pain Questionnaire | Total Pain Rating Index Score Change at Week 20 | -4.0 units on a scale |
| Placebo | Short-Form McGill Pain Questionnaire | Pain VAS Score Change at Week 20 | -0.6 units on a scale |
| Placebo | Short-Form McGill Pain Questionnaire | Present Pain Intensity Score Change at Week 20 | 0.0 units on a scale |
| Treprostinil Diethanolamine | Short-Form McGill Pain Questionnaire | Total Pain Rating Index Score Change at Week 20 | -3.0 units on a scale |
| Treprostinil Diethanolamine | Short-Form McGill Pain Questionnaire | Pain VAS Score Change at Week 20 | -1.1 units on a scale |
| Treprostinil Diethanolamine | Short-Form McGill Pain Questionnaire | Present Pain Intensity Score Change at Week 20 | -1.0 units on a scale |
Comparison: P value for Total Pain Rating Index Scorep-value: 0.5495% CI: [-3, 2]Wilcoxon (Mann-Whitney)
Comparison: P value for Pain VASp-value: 0.1895% CI: [-1.6, 0.3]Wilcoxon (Mann-Whitney)
Comparison: P value for Total Pain Rating Index Scorep-value: 0.195% CI: [-1, 0]Wilcoxon (Mann-Whitney)
Secondary
Time to Ulcer Healing
A subject was counted as having all ulcers completely healed at the earliest assessment for which all ulcers are designated as healed and no new ulcers appeared for the remainder of the trial. The time to complete healing of all ulcers were calculated as the number of days from randomization to the date of these respective assessments, provided that complete healing was achieved during the study.
Time frame: Week 20
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Time to Ulcer Healing | Time to Cardinal Ulcer Healing | 83.2 days | Standard Deviation 37.9 |
| Placebo | Time to Ulcer Healing | Time to All Ulcers Healed | 96.7 days | Standard Deviation 39.7 |
| Treprostinil Diethanolamine | Time to Ulcer Healing | Time to Cardinal Ulcer Healing | 76.3 days | Standard Deviation 35 |
| Treprostinil Diethanolamine | Time to Ulcer Healing | Time to All Ulcers Healed | 90.2 days | Standard Deviation 35.6 |
Secondary
Time to Ulcer Healing- Percentage of Subjects With Complete Healing
A subject was counted as having all ulcers completely healed at the earliest assessment for which all ulcers are designated as healed and no new ulcers appeared for the remainder of the trial.
Time frame: Week 20
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | Time to Ulcer Healing- Percentage of Subjects With Complete Healing | Cardinal Ulcer Healed | 61 percentage of participants |
| Placebo | Time to Ulcer Healing- Percentage of Subjects With Complete Healing | All Ulcers Healed | 41 percentage of participants |
| Treprostinil Diethanolamine | Time to Ulcer Healing- Percentage of Subjects With Complete Healing | Cardinal Ulcer Healed | 62 percentage of participants |
| Treprostinil Diethanolamine | Time to Ulcer Healing- Percentage of Subjects With Complete Healing | All Ulcers Healed | 49 percentage of participants |