Ignite Creation Date:
2024-05-05 @ 10:09 PM
Last Modification Date:
2024-10-26 @ 10:14 AM
Study NCT ID:
NCT01042158
Status:
COMPLETED
Last Update Posted:
2017-09-12
First Post:
2010-01-04
Brief Title:
A Clinical Trial of Ambrisentan and Tadalafil in Pulmonary Arterial Hypertension Associated With Systemic Sclerosis
Sponsor:
Johns Hopkins University
Organization:
Johns Hopkins University
Study Overview
Official Title:
A Clinical Trial of Ambrisentan and Tadalafil in Pulmonary Arterial Hypertension Associated With Systemic Sclerosis
Status:
COMPLETED
Status Verified Date:
2017-08
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
ATPAHSS
Brief Summary:
This will be a 36-week single group open label study assessing the effects of Tadalafil plus Ambrisentan combination therapy in patients with pulmonary arterial hypertension associated with the scleroderma spectrum of disease PAH-SSD Standard outcome measures such as six-minute walk distance 6MWD New York heart Association NYHA classification and hemodynamic measurements will be assessed as well as novel functional measures of RV-PV function including the transthoracic echocardiogram parameter tricuspid annular plane systolic ejection TAPSE contrast-enhanced cardiac MRI and heart rate variability assessed by Holter monitoring This design excluding a placebo arm was selected for ethical concerns and to provide optimal efficiency and active therapy to all study subjects It also allows for comparisons between the two monotherapies and with combination therapy
Detailed Description:
Pulmonary Arterial Hypertension PAH includes a heterogeneous group of clinical entities sharing similar clinical and pathological features that have been subcategorized as idiopathic PAH IPAH formerly known as primary pulmonary hypertension or PPH familial PAH pulmonary hypertension related to connective tissue diseases such as systemic sclerosis portopulmonary hypertension and pulmonary hypertension related to HIV infection drugs and toxins 10 PAH is clinically defined by a resting mean pulmonary artery pressure 25 mmHg and pulmonary artery wedge pressure 15 mmHg in the absence of left heart disease underlying parenchymal lung disease thromboembolic disease or other causes of pulmonary hypertension
PAH is characterized by increased pulmonary vascular resistance due to remodeling and occlusion of the pulmonary arterioles Left untreated PAH leads irremediably to right ventricular RV hypertrophy pressure overload and dilation resulting in death within 2-3 years 11 For the past two decades it has been appreciated that the integrity of the RV function rather than the degree of pulmonary vascular injury is the major determinant of symptoms and mortality in patients with PAH RV dysfunction at time of presentation as reflected by an elevation in right atrial pressure RAP the presence of pericardial effusion or depressed cardiac output CO is a powerful prognosticator of death 12
Current PAH therapies consist of prostacyclin analogues endothelin receptor antagonists ETRA and phosphodiesterase type V PDE V inhibitors 13 All have been shown to be effective in improving exercise capacity as measured by the 6 MWD in short term 12 - 16 week randomized placebo-controlled clinical trials However the clinical response is highly variable and mortality remains high 14 Moreover the majority of subjects enrolled in these trials have had IPAH Over the past 10 years the Johns Hopkins Pulmonary Hypertension Program and Scleroderma Center have worked closely to address the daunting clinical challenge of PAH associated with scleroderma or systemic sclerosis PAH-SSc Previous work from our group 1516 and others 17-19 has clearly demonstrated a markedly worse prognosis in PAH-SSc compared with IPAH despite similar treatments An intriguing and consistent finding when comparing these two groups is that whereas mPAP is on average lower in PAH-SSc markers of RV dysfunction eg CO and RAP are similar raising the possibility of maladaptive RV response to pressure overload andor intrinsic myocardial disease Current PAH therapies target pathways that have been implicated in the remodeling of the pulmonary vasculature PV However there is no clear evidence that these therapies have altered PV andor RV remodeling or offered significant beneficial effects in patients with PAH-SSc in whom mortality remains exceedingly high In addition their effects on RV dysfunction and RV-PV interaction remain poorly characterized
We hypothesize that improvement in PAH-SSc will only be achieved with therapy directly targeted at RV-PV dysfunction Sildenafil and tadalafil inhibit phosphodiesterase type 5 PDE5 which is abundant in the lung and is the main enzyme responsible for cyclic Guanosine MonoPhosphate cGMP hydrolysis The resulting increase in cGMP probably mediates the relaxant and anti-hypertrophic actions of nitric oxide and natriuretic peptides in vascular tissues and exerts a direct anti-hypertrophic action on cardiac muscle as demonstrated in compelling preliminary experiments by investigators of the NHLBI-funded Hopkins Scientific Center of Clinically Oriented Research SCCOR in Pulmonary Vascular Disease In these experiments sildenafil was capable of preventing and reversing RV hypertrophy and dysfunction in a model of pulmonary artery banding similar to its effects on the left ventricle with aortic banding 20 indicating a direct beneficial action on RV remodeling
Both sildenafil 21 and tadalafil 22 have been demonstrated to be effective in PAH and are FDA approved for this indication The endothelin-receptor antagonists bosentan 23 and ambrisentan 24 are also FDA-labeled for this indication and represent alternative options for oral therapy of PAH 25 A small randomized study comparing sildenafil with bosentan suggested that sildenafil was superior in reducing RV mass and improving exercise capacity in patients with PAH 26 Recently the results of a large multi-center randomized controlled trial of tadalafil therapy for PAH have been presented The data indicate that similar to sildenafil tadalafil at doses of 20 and 40 mg per day improved exercise capacity In addition tadalafil 40 mg per day improved pulmonary hemodynamics quality of life and reduced the incidence of clinical worsening
This study aims to compare the effects of upfront combination therapy with tadalafil and ambrisentan in PAH-SSc on PVR and RV mass It will also assess novel markers of RV function by cardiac MRI and echocardiography as well as the conventional endpoints including 6 MWD and functional class The trial is unique in that it will enroll only PAH-SSc patients the PAH subgroup with the poorest outcomes and will be considerably longer in duration 36 weeks than previous studies
PAH is characterized by increased pulmonary vascular resistance due to remodeling and occlusion of the pulmonary arterioles Left untreated PAH leads irremediably to right ventricular RV hypertrophy pressure overload and dilation resulting in death within 2-3 years 11 For the past two decades it has been appreciated that the integrity of the RV function rather than the degree of pulmonary vascular injury is the major determinant of symptoms and mortality in patients with PAH RV dysfunction at time of presentation as reflected by an elevation in right atrial pressure RAP the presence of pericardial effusion or depressed cardiac output CO is a powerful prognosticator of death 12
Current PAH therapies consist of prostacyclin analogues endothelin receptor antagonists ETRA and phosphodiesterase type V PDE V inhibitors 13 All have been shown to be effective in improving exercise capacity as measured by the 6 MWD in short term 12 - 16 week randomized placebo-controlled clinical trials However the clinical response is highly variable and mortality remains high 14 Moreover the majority of subjects enrolled in these trials have had IPAH Over the past 10 years the Johns Hopkins Pulmonary Hypertension Program and Scleroderma Center have worked closely to address the daunting clinical challenge of PAH associated with scleroderma or systemic sclerosis PAH-SSc Previous work from our group 1516 and others 17-19 has clearly demonstrated a markedly worse prognosis in PAH-SSc compared with IPAH despite similar treatments An intriguing and consistent finding when comparing these two groups is that whereas mPAP is on average lower in PAH-SSc markers of RV dysfunction eg CO and RAP are similar raising the possibility of maladaptive RV response to pressure overload andor intrinsic myocardial disease Current PAH therapies target pathways that have been implicated in the remodeling of the pulmonary vasculature PV However there is no clear evidence that these therapies have altered PV andor RV remodeling or offered significant beneficial effects in patients with PAH-SSc in whom mortality remains exceedingly high In addition their effects on RV dysfunction and RV-PV interaction remain poorly characterized
We hypothesize that improvement in PAH-SSc will only be achieved with therapy directly targeted at RV-PV dysfunction Sildenafil and tadalafil inhibit phosphodiesterase type 5 PDE5 which is abundant in the lung and is the main enzyme responsible for cyclic Guanosine MonoPhosphate cGMP hydrolysis The resulting increase in cGMP probably mediates the relaxant and anti-hypertrophic actions of nitric oxide and natriuretic peptides in vascular tissues and exerts a direct anti-hypertrophic action on cardiac muscle as demonstrated in compelling preliminary experiments by investigators of the NHLBI-funded Hopkins Scientific Center of Clinically Oriented Research SCCOR in Pulmonary Vascular Disease In these experiments sildenafil was capable of preventing and reversing RV hypertrophy and dysfunction in a model of pulmonary artery banding similar to its effects on the left ventricle with aortic banding 20 indicating a direct beneficial action on RV remodeling
Both sildenafil 21 and tadalafil 22 have been demonstrated to be effective in PAH and are FDA approved for this indication The endothelin-receptor antagonists bosentan 23 and ambrisentan 24 are also FDA-labeled for this indication and represent alternative options for oral therapy of PAH 25 A small randomized study comparing sildenafil with bosentan suggested that sildenafil was superior in reducing RV mass and improving exercise capacity in patients with PAH 26 Recently the results of a large multi-center randomized controlled trial of tadalafil therapy for PAH have been presented The data indicate that similar to sildenafil tadalafil at doses of 20 and 40 mg per day improved exercise capacity In addition tadalafil 40 mg per day improved pulmonary hemodynamics quality of life and reduced the incidence of clinical worsening
This study aims to compare the effects of upfront combination therapy with tadalafil and ambrisentan in PAH-SSc on PVR and RV mass It will also assess novel markers of RV function by cardiac MRI and echocardiography as well as the conventional endpoints including 6 MWD and functional class The trial is unique in that it will enroll only PAH-SSc patients the PAH subgroup with the poorest outcomes and will be considerably longer in duration 36 weeks than previous studies
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None
Secondary IDs
| Secondary ID | Type | Domain | Link |
|---|---|---|---|
| P50HL084946 | NIH | None | httpsreporternihgovquickSearchP50HL084946 |