TABLE 3.
Ongoing interventional clinical trials of PDE5Is beyond ED and PH
| Drug(s) tested | Sponsor | Target group | Stage of development (status; clinical identifier) | Results of clinical trial/reason for termination |
|---|---|---|---|---|
| Hypertension | ||||
| Sildenafil | University of Edinburgh, UK; Pfizer, USA | Primary hypertension | Phase IV (completed 2005; NCT00479908) | Significant ambulatory BP reduction compared to placebo (Oliver, Melville, & Webb, 2006). |
| PF‐00489791 | Pfizer, USA | Primary hypertension | Phase II (completed 2008; NCT00422461) | Significant ambulatory BP reduction compared to placebo (Wolk, Smith et al., 2009). |
| Sildenafil | University of Campinas, Brazil | RHTN | Not applicable (completed 2012; NCT01392638) | Significant improvement in diastolic function and BP compared to placebo (Quinaglia, de Faria et al., 2013). |
| Tadalafil | University of Campinas, Brazil | Left ventricular function in RHTN | Not applicable (completed 2012; NCT01743911) | Significant improvement in diastolic function compared to placebo. No significant change in BP (Santos, de Faria et al., 2014). |
| Cardiac | ||||
| Tadalafil | New England Research Institutes; NHLBI; Massachusetts General Hospital, USA | HFrEF | Phase III (terminated 2015; NCT01910389) | Terminated by funding agency. |
| Udenafil | Seoul National University Hospital; Dong‐A Pharm, South Korea | HFrEF | Phase III (terminated 2014; NCT01646515) | Substantial benefit was observed in the active treatment group. |
| Sildenafil | Massachusetts General Hospital, USA | HFrEF | Phase III (completed 2006; NCT00309790) | Improved cardiac indices (Malhotra, Dhakal et al., 2016). |
| Sildenafil | University of Milan, Italy | HFpEF | Phase II/III (completed 2009; NCT00781508 and NCT01156636) | Improved cardiac indices and clinical status (Guazzi, Vicenzi et al., 2011). |
| Sildenafil | University of Milan, Italy | HFrEF | Phase II (completed 2010; NCT01185925) | Not reported. |
| Vardenafil | McGuire Research Institute, USA | IRI after cardiac surgery | Phase I (completed 2011; NCT01260285) | Not reported. |
| Sildenafil | Duke University; NHLBI; Pfizer, USA | HFpEF | Phase III (completed 2012; NCT00763867) | No effect on exercise capacity or clinical status (Redfield, Chen et al., 2013). |
| Sildenafil | Rigshospitalet, Denmark | HFpEF after MI | Phase IV (completed 2012; NCT01046838) | No improvement in filling pressure. Significant improvements in cardiac indices, exercise capacity and diastolic BP (Andersen, Ersbøll et al., 2013). |
| Udenafil | Seoul National University Hospital; Dong‐A Pharm, South Korea | HFpEF | Phase III (completed 2013; NCT01599117) | Not reported. |
| Sildenafil | Hospital Ana Nery, Brazil | Unspecified HF | Phase II/III (completed 2013; NCT01936350) | No effect on cardiac indices (Fernandes, Andrade et al., 2015). |
| Tadalafil ± Nesiritide | Mayo Clinic; NCRR; NHLBI, USA | Preclinical HF, expected renal function improvement | Phase I/II (completed 2014; NCT01544998) | Not reported. |
| Sildenafil | University Medical Center Groningen, Netherlands; Pfizer, USA | HFpEF | Phase III (completed 2014; NCT01726049) | No effect on cardiac indices or clinical status (Liu, Hummel et al., 2017). |
| Sildenafil | Pfizer, USA | HFrEF | Phase III (ongoing; NCT01616381 and NCT03460470) | Ongoing. |
| Udenafil | Mezzion Pharma Co. Ltd, South Korea; NHLBI, USA | Congenital heart defects | Phase III (ongoing; NCT02741115) | Ongoing. |
| Sildenafil | University of Calgary, Canada; Pfizer, USA | RHF | Phase III (ongoing; NCT03356353) | Ongoing. |
| Stroke | ||||
| PF‐03049423 | Pfizer, USA | Acute ischaemic stroke | Phase II (terminated 2016; NCT01208233) | Interim analysis demonstrated futility. No reported safety concerns (Di Cesare, Mancuso et al., 2016). |
| Sildenafil | University of Utah, USA | Subacute ischaemic stroke | Phase I (terminated 2017; NCT02628847) | Recruitment failure. |
| Sildenafil | Henry Ford Hospital, USA | Subacute ischaemic stroke | Phase I (terminated 2011; NCT00452582) | Recruitment failure. |
| Tadalafil | Herlev Hospital, Denmark | Cerebral small vessel disease | Phase II (completed 2017; NCT02801032) | Not reported. |
| Sildenafil | University of Oxford, UK | Cerebral small vessel disease | Phase II (ongoing; NCT03855332) | Ongoing. |
| Peripheral circulation | ||||
| Vardenafil | University of Cologne, Germany | Mixed RP | Phase II/III (completed 2010; NCT01291199) | Significant improvement in digital blood flow and clinical symptoms compared to placebo (Caglayan, Axmann et al., 2012). |
| Tadalafil | Sanjay Gandhi Postgraduate Institute of Medical Sciences, India | Treatment‐resistant secondary RP | Phase III (completed 2010; NCT00626665 and NCT01117298) | Significant improvement in clinical symptoms, quality of life, digital ulcer frequency, and healing with add‐on PDE5I therapy compared to placebo (Shenoy, Kumar et al., 2010). |
| PF‐00489791 | Pfizer, USA | Mixed RP | Phase II (completed 2011; NCT01090492) | Not reported. Trials discontinued. |
| Udenafil | Seoul National University Hospital, South Korea | Secondary RP | Phase II/III (completed 2011; NCT01280266) | Significant improvement in digital blood flow compared to amlodipine. Similar efficacy in reducing RP attacks (Lee, Park et al., 2013). |
| Sildenafil | Lille University Hospital, France | Secondary RP | Phase III (completed 2013; NCT01295736) | Frequent sildenafil use for 12 weeks significantly improved healing of digital ulcers secondary to systemic sclerosis compared to placebo (Hachulla, Hatron et al., 2016). |
| Tadalafil | Northwestern University; Eli Lilly and Company, USA | Secondary RP | Not applicable (completed 2014; NCT00822354) | Not reported. |
| Sildenafil | Federal University of São Paulo, Brazil | Secondary RP | Phase III (completed 2016; NCT01347008) | Significant improvement in digital blood flow and symptoms after 8 weeks of treatment compared to placebo (Andrigueti, Ebbing et al., 2017). |
| Sildenafil | Grenoble University Hospital, France; Pfizer, USA | Mixed RP | Phase II/III (completed 2016; NCT02050360) | Non‐significant improvement in clinical symptoms compared to placebo, with substantial heterogeneity in patient response (Roustit, Giai et al., 2018). |
| Sildenafil (topical) | Pontifical Catholic University of Chile, Chile | Secondary RP | Phase I (completed 2016; NCT03027674) | Significant improvement in digital blood flow compared to topical nifedipine cream (Wortsman, Del Barrio‐Díaz et al., 2018). |
| Sildenafil | Angers University Hospital, France | PAD | Phase III (completed 2017; NCT02832570) | Significant improvement in maximal walking time but no significant effects on pain‐free walking time and oxygenation parameters (Omarjee, Le Pabic et al., 2019). |
| Sildenafil | Angers University Hospital, France | PAD | Phase II/III (not yet recruiting; NCT02387450) | Not yet recruiting. |
| Sildenafil | Rennes University Hospital, France | PAD | Phase III (ongoing; NCT03686306) | Ongoing. |
| Chronic kidney disease | ||||
| Sildenafil | University of Guadalajara, Mexico | Diabetic nephropathy | Not applicable. | Significant reduction in microalbuminuria compared to placebo (Grover‐Páez, Rivera et al., 2007). |
| PF‐00489791 | Pfizer, USA | Diabetic nephropathy | Phase II (completed 2010; NCT01200394) | Significant reduction in macroalbuminuria compared to placebo (Scheele, Diamond et al., 2016). |
| Mirodenafil | Asan Medical Center; SK Chemicals, South Korea | CKD | Phase I (completed 2011; NCT01232010) | Not reported. |
| Sildenafil | University of Alabama at Birmingham, USA | Mixed CKD requiring arteriovenous fistula surgery | Not applicable (completed 2018; NCT02414204) | Not reported. |
| Tadalafil | New England Research Institutes; NHLBI; Massachusetts General Hospital, USA | CKD and AKI in HF | Phase III (completed 2018; NCT01960153) | Not reported. |
| Diabetes mellitus and metabolic syndrome | ||||
| Tadalafil | Sahlgrenska University Hospital, Sweden | Hyperglycaemia | Phase I (terminated 2015; NCT01238224) | Durability of study medications could not be guaranteed after the expiry date. |
| Sildenafil | University of Roma La Sapienza, Italy | Diabetic cardiomyopathy | Phase IV (completed 2009; NCT00692237) | Significant improvement in cardiac kinetic and metabolic indices compared to placebo (Giannetta, Isidori et al., 2012). |
| Sildenafil | Vanderbilt University; NHLBI; Pfizer, USA | Metabolic syndrome | Phase I/II (completed 2013; NCT01334554) | Not reported. |
| Tadalafil | Massachusetts General Hospital, USA | Metabolic syndrome | Phase III (completed 2013; NCT01444651) | No improvement in insulin resistance compared to placebo. Potential favourable effects on β‐cell compensation (Ho, Arora et al., 2014). |
| Vardenafil | Modena Local Health Unit, Italy | Endothelial dysfunction in T2DM | Phase II (completed 2014; NCT02219646) | Significant improvement in endothelial parameters and hypogonadism in men compared with placebo (Santi, Granata et al., 2016). |
| Tadalafil | University of Roma La Sapienza, Italy | Metabolic syndrome | Phase IV (completed 2015; NCT02554045) | Not reported. |
| Tadalafil | University of Guadalajara, Mexico | Metabolic syndrome | Phase IV (completed 2015; NCT02595684) | Not reported. |
| Sildenafil | Vanderbilt University, USA | Hyperglycaemia | Phase IV (completed 2016; NCT01409993 and NCT02129725) | Significant improvement in insulin sensitivity, endothelial parameters, and urine albuminuria after 3 months of PDE5I therapy. Sub‐study investigating insulin signalling in skeletal muscle not yet reported (Ramirez, Nian et al., 2015). |
| Sildenafil + leucine ± metformin | NuSirt Biopharma, USA | Metabolic syndrome | Phase II (completed 2018; NCT03364335) | Not reported. |
| Tadalafil | University of Roma La Sapienza, Italy | Diabetic cardiomyopathy | Phase IV (completed 2019; NCT01803828) | Not reported. |
| Tadalafil | Göteborg University, Sweden | Insulin resistance in T2DM | Phase II (ongoing; NCT02601989) | Ongoing. |
| Tadalafil | University Center for Health Science, Mexico | Metabolic syndrome | Phase III (ongoing; NCT03905018) | Ongoing. |
Note. Mode of drug administration is oral unless otherwise specified.
Abbreviations: AKI, acute kidney injury; CKD, chronic kidney disease; ED, erectile dysfunction; HF, heart failure; HFpEF, heart failure with preserved ejection fraction; HFrEF, heart failure with reduced ejection fraction; IRI, ischaemia reperfusion injury; MI, myocardial infarction; NCRR, National Center for Research Resources; NHLBI, National Heart, Lung, and Blood Institute; PAD, peripheral arterial disease; PDE5I, PDE type 5 inhibitor; PH, pulmonary hypertension; RHF, right heart failure; RHTN, treatment‐resistant hypertension; RP, Raynaud's phenomenon; T2DM, type 2 diabetes mellitus.