Scleroderma, Systemic
Conditions
Brief summary
To investigate if Riociguat is effective in the treatment of systemic sclerosis
Interventions
DRUGRiociguat (Adempas, BAY63-2521)
Starting dose 0.5 mg TID, increase by 0.5 mg every 2 weeks until highest possible dose of 2.5 mg TID
DRUGPlacebo
Sham-titration
Sponsors
Bayer
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
* Men or women aged 18 years and older * Systemic sclerosis, as defined by ACR/EULAR (American College of Rheumatology/European League Against Rheumatism) 2013 criteria * dcSSc (diffuse cutaneous systemic sclerosis) according to the LeRoy criteria, ie, skin fibrosis proximal to the elbows and knees in addition to acral fibrosis * Disease duration of ≤ 18 months (defined as time from the first non-Raynaud's phenomenon manifestation) * ≥ 10 and ≤ 22 mRSS (modified Rodnan skin score) units at the screening visit * FVC (forced vital capacity) ≥ 45% of predicted at screening * DLCO (diffusion capacity of the lung for carbon monoxide) ≥ 40% of predicted (hemoglobin-corrected) at screening * Negative serum pregnancy test in a woman of childbearing potential at the screening visit * Women of childbearing potential must agree to use adequate contraception when sexually active. Adequate contraception is defined as any combination of at least 2 effective methods of birth control, of which at least 1 is a physical barrier (e.g. condom with hormonal contraception like implants or combined oral contraceptives, condom with intrauterine devices). This applies since signing of the informed consent form until 30 (+5) days after the last study drug administration.
Exclusion criteria
* Limited cutaneous SSc (systemic sclerosis) at screening * Major surgery (including joint surgery) within 8 weeks prior to screening * Hepatic insufficiency classified as Child-Pugh C * Patients with isolated AST or ALT \>3xULN or bilirubin \>2xULN can be included in the trial under the condition of additional monitoring during the trial * Estimated glomerular filtration rate (eGFR) \< 15 mL/min/1.73 m\^2 (Modification of Diet in Renal Disease formula) or on dialysis at the screening visit. Patients entering the trial with eGFR 15-29 mL/min/1.73 m\^2 will be undergo additional monitoring of renal function * Any prior history of renal crisis * Sitting SBP (systolic blood pressure) \< 95 mmHg at the screening visit * Sitting heart rate \< 50 beats per minute (BPM) at the screening visit * Left ventricular ejection fraction \< 40% prior to screening * Any form of pulmonary hypertension as determined by right heart catheterization * Pulmonary disease with FVC \< 45% of predicted or DLCO (hemoglobin-corrected) \< 40% of predicted at screening * Active state of hemoptysis or pulmonary hemorrhage, including those events managed by bronchial artery embolization * Not permitted prior and concomitant medication * Pregnant or breast feeding women * Women of childbearing potential not willing to use adequate contraception and not willing to agree to 4-weekly pregnancy testing from Visit 1 (first administration of study drug) onwards until 30 (+5) days after last study drug intake.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Modified Rodnan Skin Score (mRSS) to Week 52 | Baseline to week 52 | The mRSS is a validated physical examination method for estimating skin thickness. It correlates with biopsy measures of collagen in the dermis and reflects prognosis and visceral involvement, especially in early disease. It is scored on 0 (normal) to 3+ (severe induration) ordinal scales over 17 body areas, with a maximum score of 51 (higher score means worse situation) and is used to categorize severity of SSc. A decrease in the mean change of mRSS shows mRSS improved. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| CRISS (American College of Rheumatology Composite Response Index for Clinical Trials) at Week 52 Reported as Number of Participants With a CRISS Probability >=0.60 or <0.60 From Baseline to Week 52 | Week 52 | CRISS forms a composite response index consisting of SSc-related organ involvement and the following five variables: mRSS, FVC percent predicted, physician's and patient's global assessments, and HAQ-DI score (from SHAQ patient-reported outcome). The resulting index is a 2-step process that captures clinically meaningful worsening of internal organ involvement and the core variables that show change. Patients for whom the predicted CRISS probability was ≥ 0.60 were considered improved, while patients for whom the predicted probability was \< 0.60 were considered not improved. |
| Change From Baseline in Health Assessment Questionnaire Disability Index (HAQ-DI) Score to Week 52 | Baseline to week 52 | The HAQ-DI is a composite measure from which a 'Standard Disability Index' score can be computed to assess a patient's disability level. Generally, a score of 0-1 represents mild to moderate difficulty, 1-2 moderate to severe disability and 2-3 severe to very severe disability. The HAQ-DI comprises 20 items that assess patient abilities across 8 functional activities: dressing, rising, eating, walking, hygiene, reach, grip, and usual activities. Each item is rated on a 4-point scale: 0=Without ANY difficulty, 1=With SOME difficulty, 2=With MUCH difficulty, 3=UNABLE to do. The 8 scores of the 8 sections are summed and divided by 8. In the event that one section is not completed by a subject then the summed score would be divided by 7. The final overall HAQ-DI score ranges from 0 to 3 and positive change indicates worse health-related quality of life (HRQoL). |
| Change From Baseline in Patient's Global Assessment Score to Week 52 | Baseline to week 52 | The patient's global assessments (a self-report) quantified the overall disease activity or severity of SSc, with scores ranging from 0 (good) to 10 (worse). Positive change in the patient's global assessments score indicates worsening. |
| Change From Baseline in Physician's Global Assessment Score to Week 52 | Baseline to week 52 | The physician's global assessments (reported by the physician) quantified the overall disease activity or severity of SSc, with scores ranging from 0 (good) to 10 (worse). Positive change in the physician's global assessments score indicates worsening. |
| Change From Baseline in Forced Vital Capacity (FVC) Percent Predicted to Week 52 | Baseline to week 52 | Negative change in FVC percent predicted indicates worsening. |
Countries
Australia, Belgium, Canada, Czechia, France, Germany, Hungary, Italy, Japan, Netherlands, New Zealand, Switzerland, Turkey (Türkiye), United Kingdom, United States
Participant flow
Recruitment details
The study was conducted between 15 January 2015 (first patient first visit) and 28 March 2019 (last patient last visit). The Main Treatment Phase has been conducted between 15 Jan 2015 (first subject first visit) and 03 Jan 2018 (last subject last visit for the main treatment phase).
Pre-assignment details
139 patients were screened in 60 study centers in 15 countries worldwide. 121 patients of 139 patients were randomized and treated with at least one dose of study medication. 88 of the 121 randomized patients completed the treatment phase, of whom 87 entered the long term extension (LTE) phase.
Participants by arm
| Arm | Count |
|---|---|
| Riociguat (Adempas, BAY63-2521) Main treatment phase of 52 weeks: participants received increasing doses of riociguat by 0.5 mg every 2 weeks up to 2.5 mg 3 times a day (TID) in a-titration period of up to 10 weeks and a maintenance period of up to 42 weeks. Long-term extension phase: starting after the completion of the Main Treatment Phase in Week 52, participants received sham-titration in a dose-titration period of up to 10 weeks followed by a maintenance period. | 60 |
| Placebo Main treatment phase of 52 weeks: participants received matching placebo tablets to riociguat as sham-titration in a dose-titration period up to 10 weeks and a maintenance period of up to 42 weeks. Long-term extension phase: starting after the completion of the Main Treatment Phase in Week 52, participants received increasing doses of riociguat by 0.5 mg every 2 weeks up to 2.5 mg 3 times a day (TID) in a dose-titration period of up to 10 weeks followed by a maintenance period. | 61 |
| Total | 121 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Long-term Extension Phase (LTE) | Adverse Event | 2 | 6 |
| Long-term Extension Phase (LTE) | Lack of Efficacy | 1 | 1 |
| Long-term Extension Phase (LTE) | Lost to Follow-up | 0 | 1 |
| Long-term Extension Phase (LTE) | Physician Decision | 1 | 2 |
| Long-term Extension Phase (LTE) | Protocol Violation | 1 | 1 |
| Long-term Extension Phase (LTE) | Study terminated at site | 1 | 0 |
| Long-term Extension Phase (LTE) | Withdrawal by Subject | 4 | 3 |
| Main Treatment Phase (MT) | Adverse Event | 9 | 9 |
| Main Treatment Phase (MT) | Lack of Efficacy | 1 | 0 |
| Main Treatment Phase (MT) | Physician Decision | 1 | 1 |
| Main Treatment Phase (MT) | Pregnancy | 0 | 1 |
| Main Treatment Phase (MT) | Withdrawal by Subject | 7 | 4 |
Baseline characteristics
| Characteristic | Riociguat (Adempas, BAY63-2521) | Placebo | Total |
|---|---|---|---|
| Age, Continuous | 51.9 years STANDARD_DEVIATION 11.5 | 49.5 years STANDARD_DEVIATION 12.9 | 50.7 years STANDARD_DEVIATION 12.2 |
| Forced vital capacity (FVC) percent predicted | 90.743 FVC percent predicted STANDARD_DEVIATION 18.523 | 94.823 FVC percent predicted STANDARD_DEVIATION 17.034 | 92.800 FVC percent predicted STANDARD_DEVIATION 17.832 |
| Modified Rodnan skin score (mRSS) | 16.9 score on a scale STANDARD_DEVIATION 3.4 | 16.7 score on a scale STANDARD_DEVIATION 4.1 | 16.8 score on a scale STANDARD_DEVIATION 3.7 |
| Race/Ethnicity, Customized Asian | 12 Participants | 12 Participants | 24 Participants |
| Race/Ethnicity, Customized Black | 2 Participants | 3 Participants | 5 Participants |
| Race/Ethnicity, Customized Native Hawaiian or other pacific islander | 1 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Not Hispanic or Latino | 59 Participants | 58 Participants | 117 Participants |
| Race/Ethnicity, Customized White | 43 Participants | 46 Participants | 89 Participants |
| Sex: Female, Male Female | 47 Participants | 45 Participants | 92 Participants |
| Sex: Female, Male Male | 13 Participants | 16 Participants | 29 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 42 | 0 / 45 | 1 / 60 | 1 / 61 |
| other Total, other adverse events | 38 / 42 | 39 / 45 | 55 / 60 | 49 / 61 |
| serious Total, serious adverse events | 10 / 42 | 11 / 45 | 9 / 60 | 15 / 61 |
Outcome results
Primary
Change From Baseline in Modified Rodnan Skin Score (mRSS) to Week 52
The mRSS is a validated physical examination method for estimating skin thickness. It correlates with biopsy measures of collagen in the dermis and reflects prognosis and visceral involvement, especially in early disease. It is scored on 0 (normal) to 3+ (severe induration) ordinal scales over 17 body areas, with a maximum score of 51 (higher score means worse situation) and is used to categorize severity of SSc. A decrease in the mean change of mRSS shows mRSS improved.
Time frame: Baseline to week 52
Population: Full analysis set (FAS: all participants randomized and treated with study medication) with evaluable data for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Riociguat (Adempas, BAY63-2521) | Change From Baseline in Modified Rodnan Skin Score (mRSS) to Week 52 | -2.088 score on a scale | Standard Deviation 5.658 |
| Placebo | Change From Baseline in Modified Rodnan Skin Score (mRSS) to Week 52 | -0.769 score on a scale | Standard Deviation 8.243 |
p-value: 0.081595% CI: [-4.99, 0.3]MMRM (Method 1)
Secondary
Change From Baseline in Forced Vital Capacity (FVC) Percent Predicted to Week 52
Negative change in FVC percent predicted indicates worsening.
Time frame: Baseline to week 52
Population: FAS with evaluable data for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Riociguat (Adempas, BAY63-2521) | Change From Baseline in Forced Vital Capacity (FVC) Percent Predicted to Week 52 | -2.376 FVC percent predicted | Standard Deviation 7.515 |
| Placebo | Change From Baseline in Forced Vital Capacity (FVC) Percent Predicted to Week 52 | -2.945 FVC percent predicted | Standard Deviation 9.727 |
Comparison: change from baselinep-value: 0.90195% CI: [-3.4, 3]MMRM (Method 1)
Secondary
Change From Baseline in Health Assessment Questionnaire Disability Index (HAQ-DI) Score to Week 52
The HAQ-DI is a composite measure from which a 'Standard Disability Index' score can be computed to assess a patient's disability level. Generally, a score of 0-1 represents mild to moderate difficulty, 1-2 moderate to severe disability and 2-3 severe to very severe disability. The HAQ-DI comprises 20 items that assess patient abilities across 8 functional activities: dressing, rising, eating, walking, hygiene, reach, grip, and usual activities. Each item is rated on a 4-point scale: 0=Without ANY difficulty, 1=With SOME difficulty, 2=With MUCH difficulty, 3=UNABLE to do. The 8 scores of the 8 sections are summed and divided by 8. In the event that one section is not completed by a subject then the summed score would be divided by 7. The final overall HAQ-DI score ranges from 0 to 3 and positive change indicates worse health-related quality of life (HRQoL).
Time frame: Baseline to week 52
Population: FAS with evaluable data for this outcome measure.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Riociguat (Adempas, BAY63-2521) | Change From Baseline in Health Assessment Questionnaire Disability Index (HAQ-DI) Score to Week 52 | Baseline | 0.888 score on a scale | Standard Deviation 0.665 |
| Riociguat (Adempas, BAY63-2521) | Change From Baseline in Health Assessment Questionnaire Disability Index (HAQ-DI) Score to Week 52 | Change from baseline | 0.054 score on a scale | Standard Deviation 0.381 |
| Placebo | Change From Baseline in Health Assessment Questionnaire Disability Index (HAQ-DI) Score to Week 52 | Baseline | 0.693 score on a scale | Standard Deviation 0.688 |
| Placebo | Change From Baseline in Health Assessment Questionnaire Disability Index (HAQ-DI) Score to Week 52 | Change from baseline | 0.127 score on a scale | Standard Deviation 0.418 |
Comparison: change from baselinep-value: 0.352995% CI: [-0.23, 0.08]MMRM (Method 1)
Secondary
Change From Baseline in Patient's Global Assessment Score to Week 52
The patient's global assessments (a self-report) quantified the overall disease activity or severity of SSc, with scores ranging from 0 (good) to 10 (worse). Positive change in the patient's global assessments score indicates worsening.
Time frame: Baseline to week 52
Population: FAS with evaluable data for this outcome measure.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Riociguat (Adempas, BAY63-2521) | Change From Baseline in Patient's Global Assessment Score to Week 52 | Baseline | 3.933 score on a scale | Standard Deviation 2.497 |
| Riociguat (Adempas, BAY63-2521) | Change From Baseline in Patient's Global Assessment Score to Week 52 | Change from baseline | 0.689 score on a scale | Standard Deviation 2.745 |
| Placebo | Change From Baseline in Patient's Global Assessment Score to Week 52 | Baseline | 3.770 score on a scale | Standard Deviation 2.341 |
| Placebo | Change From Baseline in Patient's Global Assessment Score to Week 52 | Change from baseline | -0.022 score on a scale | Standard Deviation 2.226 |
Comparison: Change from baselinep-value: 0.088795% CI: [-0.12, 1.69]MMRM (Method 1)
Secondary
Change From Baseline in Physician's Global Assessment Score to Week 52
The physician's global assessments (reported by the physician) quantified the overall disease activity or severity of SSc, with scores ranging from 0 (good) to 10 (worse). Positive change in the physician's global assessments score indicates worsening.
Time frame: Baseline to week 52
Population: FAS with evaluable data for this outcome measure.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Riociguat (Adempas, BAY63-2521) | Change From Baseline in Physician's Global Assessment Score to Week 52 | Baseline | 4.333 score on a scale | Standard Deviation 2.105 |
| Riociguat (Adempas, BAY63-2521) | Change From Baseline in Physician's Global Assessment Score to Week 52 | Change from baseline | -0.067 score on a scale | Standard Deviation 2.157 |
| Placebo | Change From Baseline in Physician's Global Assessment Score to Week 52 | Baseline | 4.016 score on a scale | Standard Deviation 2.004 |
| Placebo | Change From Baseline in Physician's Global Assessment Score to Week 52 | Change from baseline | -0.745 score on a scale | Standard Deviation 2.09 |
Comparison: Change from baselinep-value: 0.024195% CI: [0.11, 1.54]MMRM (Method 1)
Secondary
CRISS (American College of Rheumatology Composite Response Index for Clinical Trials) at Week 52 Reported as Number of Participants With a CRISS Probability >=0.60 or <0.60 From Baseline to Week 52
CRISS forms a composite response index consisting of SSc-related organ involvement and the following five variables: mRSS, FVC percent predicted, physician's and patient's global assessments, and HAQ-DI score (from SHAQ patient-reported outcome). The resulting index is a 2-step process that captures clinically meaningful worsening of internal organ involvement and the core variables that show change. Patients for whom the predicted CRISS probability was ≥ 0.60 were considered improved, while patients for whom the predicted probability was \< 0.60 were considered not improved.
Time frame: Week 52
Population: Full analysis set (FAS)
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Riociguat (Adempas, BAY63-2521) | CRISS (American College of Rheumatology Composite Response Index for Clinical Trials) at Week 52 Reported as Number of Participants With a CRISS Probability >=0.60 or <0.60 From Baseline to Week 52 | CRISS probability < 0.60 | 49 Participants |
| Riociguat (Adempas, BAY63-2521) | CRISS (American College of Rheumatology Composite Response Index for Clinical Trials) at Week 52 Reported as Number of Participants With a CRISS Probability >=0.60 or <0.60 From Baseline to Week 52 | CRISS probability ≥ 0.60 | 11 Participants |
| Placebo | CRISS (American College of Rheumatology Composite Response Index for Clinical Trials) at Week 52 Reported as Number of Participants With a CRISS Probability >=0.60 or <0.60 From Baseline to Week 52 | CRISS probability ≥ 0.60 | 11 Participants |
| Placebo | CRISS (American College of Rheumatology Composite Response Index for Clinical Trials) at Week 52 Reported as Number of Participants With a CRISS Probability >=0.60 or <0.60 From Baseline to Week 52 | CRISS probability < 0.60 | 50 Participants |
p-value: 0.97795% CI: [-13.68, 14.09]Mantel Haenszel