Systemic Sclerosis
Conditions
Keywords
systemic sclerosis, scleroderma, digital ulcers, vasculopathy
Brief summary
This open label extension trial will allow ongoing treatment of subjects who participated in the randomized controlled trials, and will provide long term information about the safety of treprostinil diethanolamine SR in subjects with SSc and digital ulcers.
Interventions
sustained release tablet; BID dosing; up to 16 mg BID
Sponsors
United Therapeutics
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Eligible subjects who completed assessments for the final visit of the previous TDE-DU-201 controlled trial and who signed appropriate informed consent were eligible to enroll in this extension study. * If a female of childbearing potential, the subject must have agreed to continue practicing an acceptable method of birth control (i.e., surgical sterilization, approved hormonal contraceptives, barrier methods \[such as a condom or diaphragm\] used with a spermicide, or an intrauterine device).
Exclusion criteria
* Have had any change in clinical status that, in the opinion of the Investigator, would pose a safety risk for participation in this extension study; * Have been found to be unable to complete study assessments in the previous controlled trial; * Have prematurely discontinued study drug during the previous study due to clinical worsening or treatment related adverse events.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Net Ulcer Burden- Mean Change From Time of Study Entry for Each Scheduled Visit Assessment | Baseline and Months 1, 3, 6, 9, 12, and 18 | Net ulcer burden at any given assessment was defined as the number of new or active ulcers at that assessment, plus the number of indeterminate ulcers at that assessment that had previously been classified as either active or new at any earlier assessment during the study. The mean change in net ulcer burden from time of study entry was summarized for each scheduled visit assessment. |
| Total Ulcer Number- Mean Change From Time of Study Entry for Each Scheduled Visit Assessment | Baseline and Months 1, 3, 6, 9, 12, and 18 | The total ulcer number includes all ulcers designated as active, indeterminate, or new for a given visit. The mean change in the total number of ulcers present from time of study entry was summarized for each scheduled visit assessment. |
| Formation of New Ulcers | 18 months (or last study visit) | The number and percentage of subjects who developed new ulcers during the study were summarized. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Patient Function and QOL Measure: Scleroderma Health Assessments Questionnaire (SHAQ)- Mean Change From Study Entry in SHAQ Component Scores at Each Scheduled Assessment | Baseline and Months 1, 3, 6, and 12 | The SHAQ consists of 20 health assessment questionnaire questions with integer responses of 0 (without any difficulty) to 3 (unable to do), and five scleroderma-specific visual analog scale (VAS) domains (Overall Disease Activity, Raynaud's Phenomenon, Finger Ulcers, Breathing, and Intestinal Problems) with values ranging from 0.0 to 15.0 centimeters. The questions are divided into eight component domains: Dressing & Grooming, Arising, Eating, Walking, Hygiene, Reach, Grip, and Activities. Each domain score is calculated by summing the domain responses and dividing by the number of questions in that domain. Each VAS domain score is calculated by dividing the value in centimeters by 5. SHAQ component and VAS domain score ranges from 0 (least limitation) to 3 (most limitation). The aggregate SHAQ score is calculated by dividing the sum of all domain scores by 13, with a score ranging from 0 (least limitation) to 3 (most limitation). |
| Patient Function and Quality of Life Measure: Cochin Hand Function Scale (CHFS)-Mean Change From Study Entry in CHFS Score at Each Scheduled Assessment | Baseline and Months 1, 3, 6, and 12 | The CHFS score is derived from 18 validated questions that assess functional disability and handicap due to hand involvement in rheumatoid arthritis. Each answer is scored on a scale 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), with improvements in function or reduction of limitation indicated a decreased score value. The mean change from study entry in CHFS scores at each scheduled assessment are summarized. |
Countries
Canada, United Kingdom, United States
Participant flow
Recruitment details
Subjects were recruited to enroll in 26 centers in the US, Canada, and the UK in this open-label trial within 14 days of completion of TDE-DU-201. Subjects who prematurely terminated the previous controlled trial were not eligible. Data from the final study visit of the previous trial served as Baseline data and subject blinding was maintained.
Pre-assignment details
Eligible subjects who completed assessments for the final visit of the previous controlled trial, TDE-DU-201, were eligible to enroll in this extension study. Data from this final study visit served as Baseline data. A total of 115 subjects were enrolled, with 115 subjects receiving study medication at an initial dose of 0.25 mg twice daily (BID).
Participants by arm
| Arm | Count |
|---|---|
| Oral Treprostinil Diethanolamine Oral Treprostinil Diethanolamine initiated at 0.25 mg and titrated up to a maximum dose of 16 mg BID or the individual's maximum tolerated dose (MTD). | 115 |
| Total | 115 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 9 |
| Overall Study | Death | 1 |
| Overall Study | Lost to Follow-up | 2 |
| Overall Study | Pregnancy | 1 |
| Overall Study | Withdrawal by Subject | 8 |
Baseline characteristics
| Characteristic | Oral Treprostinil Diethanolamine |
|---|---|
| Age, Continuous | 50 years |
| Race/Ethnicity, Customized African-American | 13 participants |
| Race/Ethnicity, Customized Asian | 4 participants |
| Race/Ethnicity, Customized Caucasian | 97 participants |
| Race/Ethnicity, Customized Native American | 1 participants |
| Race/Ethnicity, Customized Not provided | 1 participants |
| Scleroderma Classification Diffuse | 33 participants |
| Scleroderma Classification Limited | 82 participants |
| Sex: Female, Male Female | 88 Participants |
| Sex: Female, Male Male | 27 Participants |
| Years since scleroderma diagnosis | 10.9 years |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 113 / 115 |
| serious Total, serious adverse events | 17 / 115 |
Outcome results
Primary
Formation of New Ulcers
The number and percentage of subjects who developed new ulcers during the study were summarized.
Time frame: 18 months (or last study visit)
Population: Efficacy was assessed by the change in net ulcer burden and in the total ulcer number from Baseline at each of the follow-up visits and the percentage of subjects with formation of new ulcers during the study. Assessments performed after discontinuation of study drug were excluded from the summaries.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Oral Treprostinil Diethanolamine | Formation of New Ulcers | No new ulcers | 48 participants |
| Oral Treprostinil Diethanolamine | Formation of New Ulcers | At least one new ulcer formed | 63 participants |
| Oral Treprostinil Diethanolamine | Formation of New Ulcers | Indeterminate / missing data | 4 participants |
Primary
Net Ulcer Burden- Mean Change From Time of Study Entry for Each Scheduled Visit Assessment
Net ulcer burden at any given assessment was defined as the number of new or active ulcers at that assessment, plus the number of indeterminate ulcers at that assessment that had previously been classified as either active or new at any earlier assessment during the study. The mean change in net ulcer burden from time of study entry was summarized for each scheduled visit assessment.
Time frame: Baseline and Months 1, 3, 6, 9, 12, and 18
Population: Efficacy was assessed using data obtained at each visit, if available, from all subjects enrolled in this study. Assessments performed after discontinuation of study drug were excluded from the summaries.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Oral Treprostinil Diethanolamine | Net Ulcer Burden- Mean Change From Time of Study Entry for Each Scheduled Visit Assessment | Month 1 | -0.77 ulcers | Standard Deviation 1.61 |
| Oral Treprostinil Diethanolamine | Net Ulcer Burden- Mean Change From Time of Study Entry for Each Scheduled Visit Assessment | Month 3 | -0.52 ulcers | Standard Deviation 2.02 |
| Oral Treprostinil Diethanolamine | Net Ulcer Burden- Mean Change From Time of Study Entry for Each Scheduled Visit Assessment | Month 6 | -0.32 ulcers | Standard Deviation 1.19 |
| Oral Treprostinil Diethanolamine | Net Ulcer Burden- Mean Change From Time of Study Entry for Each Scheduled Visit Assessment | Month 9 | -0.52 ulcers | Standard Deviation 1.53 |
| Oral Treprostinil Diethanolamine | Net Ulcer Burden- Mean Change From Time of Study Entry for Each Scheduled Visit Assessment | Month 12 | -0.64 ulcers | Standard Deviation 1.2 |
| Oral Treprostinil Diethanolamine | Net Ulcer Burden- Mean Change From Time of Study Entry for Each Scheduled Visit Assessment | Month 18 | -1.67 ulcers | Standard Deviation 0.58 |
Primary
Total Ulcer Number- Mean Change From Time of Study Entry for Each Scheduled Visit Assessment
The total ulcer number includes all ulcers designated as active, indeterminate, or new for a given visit. The mean change in the total number of ulcers present from time of study entry was summarized for each scheduled visit assessment.
Time frame: Baseline and Months 1, 3, 6, 9, 12, and 18
Population: Efficacy was assessed by the change in net ulcer burden and in the total ulcer number from Baseline at each of the follow-up visits and the percentage of subjects with formation of new ulcers during the study. Assessments performed after discontinuation of study drug were excluded from the summaries.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Oral Treprostinil Diethanolamine | Total Ulcer Number- Mean Change From Time of Study Entry for Each Scheduled Visit Assessment | Month 1 | -0.23 number of ulcers | Standard Deviation 1.36 |
| Oral Treprostinil Diethanolamine | Total Ulcer Number- Mean Change From Time of Study Entry for Each Scheduled Visit Assessment | Month 3 | -0.24 number of ulcers | Standard Deviation 1.99 |
| Oral Treprostinil Diethanolamine | Total Ulcer Number- Mean Change From Time of Study Entry for Each Scheduled Visit Assessment | Month 6 | -0.21 number of ulcers | Standard Deviation 1.21 |
| Oral Treprostinil Diethanolamine | Total Ulcer Number- Mean Change From Time of Study Entry for Each Scheduled Visit Assessment | Month 9 | -0.46 number of ulcers | Standard Deviation 1.57 |
| Oral Treprostinil Diethanolamine | Total Ulcer Number- Mean Change From Time of Study Entry for Each Scheduled Visit Assessment | Month 12 | -0.61 number of ulcers | Standard Deviation 1.2 |
| Oral Treprostinil Diethanolamine | Total Ulcer Number- Mean Change From Time of Study Entry for Each Scheduled Visit Assessment | Month 18 | -1.67 number of ulcers | Standard Deviation 0.58 |
Secondary
Patient Function and QOL Measure: Scleroderma Health Assessments Questionnaire (SHAQ)- Mean Change From Study Entry in SHAQ Component Scores at Each Scheduled Assessment
The SHAQ consists of 20 health assessment questionnaire questions with integer responses of 0 (without any difficulty) to 3 (unable to do), and five scleroderma-specific visual analog scale (VAS) domains (Overall Disease Activity, Raynaud's Phenomenon, Finger Ulcers, Breathing, and Intestinal Problems) with values ranging from 0.0 to 15.0 centimeters. The questions are divided into eight component domains: Dressing & Grooming, Arising, Eating, Walking, Hygiene, Reach, Grip, and Activities. Each domain score is calculated by summing the domain responses and dividing by the number of questions in that domain. Each VAS domain score is calculated by dividing the value in centimeters by 5. SHAQ component and VAS domain score ranges from 0 (least limitation) to 3 (most limitation). The aggregate SHAQ score is calculated by dividing the sum of all domain scores by 13, with a score ranging from 0 (least limitation) to 3 (most limitation).
Time frame: Baseline and Months 1, 3, 6, and 12
Population: Efficacy was assessed by the change in net ulcer burden and in the total ulcer number from Baseline at each of the follow-up visits and the percentage of subjects with formation of new ulcers during the study. Assessments performed after discontinuation of study drug were excluded from the summaries.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Oral Treprostinil Diethanolamine | Patient Function and QOL Measure: Scleroderma Health Assessments Questionnaire (SHAQ)- Mean Change From Study Entry in SHAQ Component Scores at Each Scheduled Assessment | Month 1 | -0.01 units on a scale | Standard Deviation 0.21 |
| Oral Treprostinil Diethanolamine | Patient Function and QOL Measure: Scleroderma Health Assessments Questionnaire (SHAQ)- Mean Change From Study Entry in SHAQ Component Scores at Each Scheduled Assessment | Month 3 | 0.02 units on a scale | Standard Deviation 0.23 |
| Oral Treprostinil Diethanolamine | Patient Function and QOL Measure: Scleroderma Health Assessments Questionnaire (SHAQ)- Mean Change From Study Entry in SHAQ Component Scores at Each Scheduled Assessment | Month 6 | 0.02 units on a scale | Standard Deviation 0.28 |
| Oral Treprostinil Diethanolamine | Patient Function and QOL Measure: Scleroderma Health Assessments Questionnaire (SHAQ)- Mean Change From Study Entry in SHAQ Component Scores at Each Scheduled Assessment | Month 12 | -0.04 units on a scale | Standard Deviation 0.27 |
Secondary
Patient Function and Quality of Life Measure: Cochin Hand Function Scale (CHFS)-Mean Change From Study Entry in CHFS Score at Each Scheduled Assessment
The CHFS score is derived from 18 validated questions that assess functional disability and handicap due to hand involvement in rheumatoid arthritis. Each answer is scored on a scale 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), with improvements in function or reduction of limitation indicated a decreased score value. The mean change from study entry in CHFS scores at each scheduled assessment are summarized.
Time frame: Baseline and Months 1, 3, 6, and 12
Population: Efficacy was assessed by the change in net ulcer burden and in the total ulcer number from Baseline at each of the follow-up visits and the percentage of subjects with formation of new ulcers during the study. Assessments performed after discontinuation of study drug were excluded from the summaries.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Oral Treprostinil Diethanolamine | Patient Function and Quality of Life Measure: Cochin Hand Function Scale (CHFS)-Mean Change From Study Entry in CHFS Score at Each Scheduled Assessment | Month 6 | -1.0 units on a scale | Standard Deviation 9.3 |
| Oral Treprostinil Diethanolamine | Patient Function and Quality of Life Measure: Cochin Hand Function Scale (CHFS)-Mean Change From Study Entry in CHFS Score at Each Scheduled Assessment | Month 3 | -1.2 units on a scale | Standard Deviation 8.7 |
| Oral Treprostinil Diethanolamine | Patient Function and Quality of Life Measure: Cochin Hand Function Scale (CHFS)-Mean Change From Study Entry in CHFS Score at Each Scheduled Assessment | Month 12 | -2.8 units on a scale | Standard Deviation 9.7 |
| Oral Treprostinil Diethanolamine | Patient Function and Quality of Life Measure: Cochin Hand Function Scale (CHFS)-Mean Change From Study Entry in CHFS Score at Each Scheduled Assessment | Month 1 | -1.1 units on a scale | Standard Deviation 9.7 |