REPLACE: A prospective, randomized trial of riociguat replacing phosphodiesterase 5 inhibitor therapy in patients with pulmonary arterial hypertension who are not at treatment goal
Bibliographic record
Abstract
Many patients with pulmonary arterial hypertension (PAH) have an insufficient response to PDE5i therapy, possibly due to impairment of the NO–sGC–cGMP pathway. Data from the RESPITE study indicate that such patients may benefit from switching from PDE5i to the sGC stimulator riociguat. REPLACE (NCT02891850) will evaluate the efficacy and safety of switching to riociguat vs continuing treatment with PDE5i in PAH patients not at treatment goal (WHO FC III, 6MWD 165–440 m) despite receiving stable doses of PDE5i with or without ERA. REPLACE is a prospective, randomized, multicenter, double-arm, 24-week, controlled, open-label study with planned enrolment of 218 subjects. Patients will be randomized to continue PDE5i therapy or switch to riociguat (up to 2.5 mg tid). The composite primary efficacy endpoint is satisfactory clinical response at Week 24, defined as fulfilment of at least 2 out of 3 efficacy parameters (≥10% or ≥30 m increase from baseline (BL) in 6MWD, WHO FC I/II or ≥30% reduction from BL in NT-proBNP) in the absence of clinical worsening (independent central adjudication). Secondary outcomes include change from BL in 6MWD and WHO FC (blinded assessment), NT-proBNP and clinical worsening. Exploratory endpoints include quality of life (Living with Pulmonary Hypertension), REVEAL risk score and MRI parameters of right heart function. Safety will be assessed by adverse events and all-cause mortality. The results of REPLACE will help determine whether switching PAH patients with an inadequate response to PDE5i to riociguat is an effective and safe strategy to improve clinical outcomes.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.002 | 0.002 |
| Meta-epidemiology (narrow) | 0.002 | 0.001 |
| Meta-epidemiology (broad) | 0.003 | 0.002 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.001 | 0.001 |
| Research integrity | 0.003 | 0.003 |
| Insufficient payload (model declined to judge) | 0.008 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".