TABLE 1.
Overview of completed riociguat clinical trials
| Study design | Patients | PAH‐specific therapy at baseline | Riociguat dose | Primary endpoint | |
|---|---|---|---|---|---|
| 12‐wk study and LTE28 | PAH (n = 33) | Bosentan (n = 6) | 1–2.5 mg tid |
(n = 75) AEs were reported in 65 (87%) patients; 42 (56%) were study drug related; 3 (4%) patients discontinued due to AEs. 96% of study drug‐related AEs considered mild or moderate. Most common AEs reported were dyspepsia, headache and hypotension. |
|
| CTEPH (n = 42) | |||||
| 6MWD (m), mean ± SD | |||||
| 12‐wk, double‐blind study (PATENT‐1) and open‐label extension study (PATENT‐2)40, 41, 42 | PAH (n = 443) |
ERAs (n = 194) Prostanoids (n = 28) None (n = 221) |
1.5 mg (max) or 2.5 mg (max) tid |
Placebo (n = 126) BL: 368 ± 75 Week 12 change from BL: −6 ± 86 |
Riociguat 2.5 mg – maximum (n = 254) BL: 361 ± 68 Week 12 change from BL: 30 ± 66 |
| Placebo‐corrected LS mean difference (95% CI): 36 (20–52), P < .001 | |||||
| 6MWD (m), mean ± SD | |||||
| 16‐wk, double‐blind study (CHEST‐1) and open‐label extension study (CHEST‐2)43, 44, 45 | CTEPH (n = 261) | None | 2.5 mg (max) tid |
Placebo (n = 88) BL: 356 ± 75 Week 16 change from BL: −6 ± 84 |
Riociguat ≤2.5 mg (n = 173) BL: 342 ± 82 Week 16 change from BL: 39 ± 79 |
| Placebo‐corrected LS mean difference (95% CI): 46 (25–67), P < .001 | |||||
| Supine SBP (mmHg), mean ± SD | |||||
| 12‐wk study and LTE (PATENT PLUS)46 | PAH (n = 18) | Sildenafil (n = 18) | 2.5 mg (max) tid | Placebo (n = 6) | Riociguat (n = 12) |
| BL: −7.6 ± 3.9 | BL: −20.2 ± 15.3 | ||||
| Week 12: −20.2 ± 12.9 | Week 12: −20.7 ± 18.0 | ||||
| 6MWD (m), mean ± SD; exploratory | |||||
| 24‐wk study (RESPITE)47, 48 | PAH (n = 61) | ERAs (n = 50) | 1–2.5 mg |
BL (n = 61): 357 ± 81 Week 24 change from BL (n = 51): 31 ± 63 |
|
| 95% CI: 13–49, P = .001 | |||||
| mPAP (mmHg), mean ± SD | |||||
| 16‐wk study (LEPHT)49 | PH associated with HFrEF (n = 201) | None | 0.5 mg, 1 mg or 2 mg tid |
Placebo (n = 56) BL: 40.4 ± 1.2 Week 16: 36.4 ± 1.4 |
Riociguat 2 mg (n = 54) BL: 38.1 ± 1.3 Week 16: 32.0 ± 1.6 |
| Placebo‐corrected LS mean difference (95% CI): −2.7 (−6.0–0.6), P = .10 | |||||
| mPAP (mmHg), mean ± SD | |||||
| Single‐dose study (DILATE)50 | PH associated with HFpEF (n = 39) | None | 0.5 mg, 1 mg or 2 mg |
Placebo (n = 11) BL: 34.9 ± 8.0 Peak change from BL: −6.3 ± 4.2 |
Riociguat 2 mg (n = 10) BL: 35.1 ± 8.8 Peak change from BL: −5.1 ± 4.7 |
| Difference vs placebo (95% CI): 1.2 ± 4.4 (−2.9–5.2), P = .60 | |||||
| 12‐wk pilot study (with 12‐month LTE)51 | PH‐ILD (n = 22) | None | 2.5 mg (max) tid |
104 AEs were reported across 22 patients; 86 of these treatment‐emergent; 70% considered drug related. 3 patients discontinued due to study drug. Most common AEs were dyspnoea (n = 6), peripheral oedema (n = 6), dyspepsia (n = 3), headache (n = 3) and feeling hot (n = 3). 25 SAEs were experienced by 16 patients; 8 SAEs were considered possibly study drug related (syncope, dyspnoea, pancytopenia, respiratory disorder and respiratory failure). |
|
| Single‐dose study52 | PH‐COPD (n = 23) | None | 1 mg or 2.5 mg | mPAP (mmHg), peak postbaseline effect, mean ± SD; exploratory | |
|
iNO 20 ppm (n = 8) −3.88 ± 2.90 |
Riociguat 2.5 mg (n = 12) −4.8 ± 4.17 |
||||
| P = .002 | |||||
| PVR (dyn·s·cm −5 ), peak postbaseline effect, mean ± SD; exploratory | |||||
|
iNO 20 ppm (n = 7) −57.14 ± 78.64 |
Riociguat 2.5 mg (n = 11) −123.80 ± 73.53 |
||||
| P = .0002 | |||||
| Digital blood flow (mean ± SD) | |||||
| Single‐dose study (DIGIT)53 | Raynaud's phenomenon (n = 20) | None | 2 mg |
Room temperature Placebo (n = 20): −5% (59) Riociguat (n = 20): +41% (109) |
Cold exposure Placebo (n = 10): +25% (114) Riociguat (n = 10): +15% (51) |
| 26‐wk study (RISE‐IIP) and LTE54 | Idiopathic interstitial pneumonias (n = 147) | None | 2.5 mg (max) tid | Change in 6MWD from baseline to week 26 (m) | |
| Placebo‐corrected LS mean difference (95% CI): +21 m (−9 to +52), P = .2074 | |||||
| The study was terminated during the LTE due to increased SAEs and mortality and an unfavourable risk:benefit ratio. | |||||
| 52‐wk study (RISE‐SSc)55 | Diffuse cutaneous systemic sclerosis (n = 121) | None | 2.5 mg (max) tid | Change in mRSS from baseline to week 52 (mean ± SD) | |
|
Placebo (n = 61) BL: 16.71 ± 4.06 Week 52: 15.73 ± 10.48 |
Riociguat (n = 60) BL: 16.88 ± 3.38 Week 52: 14.63 ± 6.56 |
||||
| Placebo‐corrected LS mean treatment difference (95% CI): −2.34 (−4.99–0.30), P = .08 | |||||
| Two‐part study (Rio‐CF)56, 57, 58 | Phe508del homozygous CF (n = 21) | None | Part 1: 0.5 mg tid for 14 days, then 1.0 mg tid for 14 days | Change in sweat chloride content in part 1 (n = 16 available for this analysis) | |
|
Placebo (n = 7) Day 14 (0.5 mg): +8.7 ± 8.2 mmol/L Day 28 (1.0 mg): +9.0 ± 12.7 mmol/L |
Riociguat (n = 9) Day 14 (0.5 mg): +7.1 ± 10.3 mmol/L Day 28 (1.0 mg): 3.4 ± 11.0 mmol/L |
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6MWD, 6‐min walking distance; AE, adverse event; BL, baseline; CF, cystic fibrosis; CI, confidence interval; COPD, chronic obstructive pulmonary disease; CTEPH, chronic thromboembolic pulmonary hypertension; ERA, endothelin receptor antagonist; HFpEF, heart failure with a preserved ejection fraction; HFrEF, heart failure with a reduced ejection fraction; iNO, inhaled nitric oxide; ILD, interstitial lung disease; LS, least squares; LTE, long‐term extension; max, maximum; mPAP, mean pulmonary artery pressure; mRSS, modified Rodnan Skin Score; PAH, pulmonary arterial hypertension; PH, pulmonary hypertension; PVR, pulmonary vascular resistance; SAE, serious adverse event; SBP, systolic blood pressure; SD, standard deviation; tid, 3 times daily.