OT4 – Development and prevention of pulmonary hypertension
Observational Trial 4 (OT4) – Development and prevention of pulmonary hypertension
Several new treatment options have been developed within the last years and have increased the quality of life for Systemic Sclerosis patients affected by pulmonary hypertension. Unfortunately, pulmonary hypertension is still a severe complication of Systemic Sclerosis. For this reason, this study focuses on the time before the onset of pulmonary hypertension and looks at whether there are any medications that canprevent or delay the development of pulmonary hypertension.
The following protocol gives you a brief overview of observational trial 4:
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PI: Yannick ALLANORE, Jérôme AVOUAC (UPD) |
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Investigative objective |
Background: PH is a fatal disorder characterized by an increase in pulmonary vascular resistance, which leads to right ventricular failure. Despite being recently the object of greater attention and despite therapeutic advances, PH due to SSc remains associated with a dismal 47 - 67% 3-year survival [26]. Among SSc patients prospectively followed in the EUSTAR cohort, 26% of death was related to PH [4]. Although some previous data have suggested the protective effects of CCBs on the development of PH, the potential preventive effects of vasodilators for the prevention of PH have not been determined yet. This question is of importance, since a large number of SSc patients are treated with vasodilators for digital vasculopathy. Indeed, CCBs are recommended as the first line treatment for SSc- related digital vasculopathy [8]. In addition to be considered routinely for the treatment of SSc-related PH, prostanoids, ETRAs and PDE5i can also be used for this indication. Objective: To compare the outcomes of adult and juvenile SSc patients who are at high risk of developing PH and are receiving either different vasodilator treatments or no vasodilator treatment. |
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Primary endpoint(s) |
The number of patients with PH at 2 years |
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Secondary endpoint(s) |
The time to development of precapillary PH |
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Exploratory endpoints |
Identification other factors associated with the development of PH, in addition to treatments, such as autoantibodies (e.g. anti-centromere, anti-topoisomerase I, anti- RNA polymerase III, anti-angiotensin II type 1 receptor, anti-endothelin-1 type A receptor antibodies [57]) and vascular phenotype (occurrence and recurrence of DU), in order to improve the prediction model |
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Safety endpoints |
Incidence of drug-related adverse events, incidence of withdrawal from treatment due to drug-related adverse events |
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Participants Study population justification |
The study population are adult and juvenile SSc patients from the EUSTAR cohort (MEDSonline database) and the jSScWG cohort. Patients undergo a non-invasive screening for PH based on clinical evaluation, echocardiography and pulmonary function tests according to the standard of routine care. These assessments are performed at each visit (every 6 months) of the planned 24-month observational phase or in case of clinical worsening. Patients with a suspicion of PH according to these non-invasive investigations (unexplained dyspnea on clinical examination, or estimated systolic PAP ≥40 mmHg on echocardiography, or DLCO <50% predicted in the absence of pulmonary fibrosis [94,95]) will be offered to undergo RHC. Precapillary PH is defined at RHC as a mean resting PAP >25 mmHg in the presence of a PCWP ≤15 mmHg [25]. Patients with precapillary PH at inclusion or with venous / post-capillary PH at any time will be excluded. |
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Inclusion criteria |
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Exclusion criteria |
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Trial design |
Observational trial with 3 treatment arms. |
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Treatment arms |
Three different groups will be observed for analysis: (1) patients receiving no vasodilator (2) patients receiving a CCB for digital vasculopathy (3) patients treated with i.v. prostanoids or PDE5i or ETRAs regardless of whether a CCB is given in addition |
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Follow-up |
Patients with a suspicion of PH according to these non-invasive investigations (unexplained dyspnea on clinical examination, or estimated systolic PAP ≥40 mmHg on echocardiography, or DLCO <50% predicted in the absence of pulmonary fibrosis [91,95]) will be offered to undergo RHC. Precapillary PH is defined at RHC as a mean resting PAP >25 mmHg in the presence of a PCWP ≤15 mmHg [25]. Patients with precapillary PH at inclusion or with venous / post-capillary PH at any time will be excluded. Evaluations will be performed at baseline and every 6 months thereafter during a planned 24-month follow-up, or in case of clinical worsening. |
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Randomization |
No randomization (observational trial) |
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Justification of recruitment centres/ countries |
The OT will be performed based on the EUSTAR database MEDSonline, which includes approximately 9,600 patients, and the jSScWG taking care of approximately 100 – 120 children and adolescents |
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Pre-planned subgroup analyses (effect modification) |
The effects of the different treatment arms on the development of precapillary PH will be assessed by Cox proportional hazards models and will be summarized as hazard ratio and 95% confidence interval. This analysis will be stratified according to the occurrence/onset of ischemic DU, since several reports have reported the association between PH and ischemic DU. |
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Strengths |
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Limitations |
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| ClinicalTrials.gov Identifier: | NCT01840748 For further Information: http://clinicaltrials.gov/ct2/show/NCT01840748?term=desscipher&rank=4 |