Ignite Creation Date:
2024-05-06 @ 1:29 PM
Last Modification Date:
2024-10-26 @ 1:15 PM
Study NCT ID:
NCT04039464
Status:
RECRUITING
Last Update Posted:
2023-10-31
First Post:
2019-07-01
Brief Title:
Mono vs Dual Therapy for Pediatric Pulmonary Arterial Hypertension
Sponsor:
Johns Hopkins University
Organization:
Johns Hopkins University
Study Overview
Official Title:
Kids MoD PAH Trial Mono- vs Duo-Therapy for Pediatric Pulmonary Arterial Hypertension
Status:
RECRUITING
Status Verified Date:
2024-10
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:
MoD
Brief Summary:
The investigators central hypothesis is that early combination therapy with two PAH-specific oral therapies that have been shown to be well tolerated in the pediatric population sildenafil and bosentan will result in better World Health Organization WHO functional class at 12 months after initiation of PAH treatment than therapy with sildenafil alone
Detailed Description:
A Phase III randomized open label pragmatic trial to compare the safety and efficacy of first-line combination therapy sildenafil and bosentan to first-line monotherapy sildenafil alone in pediatric subjects with WHO Functional Classes II or III and precapillary pulmonary hypertension of Group 1 PAH caused by idiopathic heritable drugs or toxins congenital heart disease or connective tissue disease or Group 3 PAH caused by lung disease or hypoxemia according to the WHO Nice classification system Precapillary pulmonary hypertension will be defined by standard criteria as mean pulmonary artery pressure over 25 mmHg andor pulmonary vascular resistance index PVRI 3 as well as pulmonary capillary wedge pressure or left ventricular end diastolic pressure 15 mmHg as determined by cardiac catheterization
For infants less than one year of age for whom cardiac catheterization is not considered as part of the clinical teams recommended approach enrollment will be possible without catheterization if the following four criteria i-iv are met
i Two separate echocardiograms clearly demonstrate pulmonary hypertension by at least three of the following metrics
1 Elevated MPA pressure early diastolic PR peak gradient 20 mmHg
2 Right ventricular hypertrophy qualitative as mild to severe
3 Right atrial enlargement scales for age will be provided
4 Elevated right ventricular systolic pressure 35mmHg on at least two at least two reliable spectral Doppler envelopes during the echocardiogram and in the setting of normal for age documented systolic blood pressure at least two reliable spectral Doppler envelopes during the echocardiogram
5 Flattening or R to L bowing of the interventricular septum qualitative or by elevated eccentricity index
6 Diminished RV function RV fractional area change 35 andor TAPSE below published normal range for age and weight
ii There is no clinical or imaging evidence of left heart dysfunction
iii Pulmonary venous stenosis and atresia are ruled out by CT angiography or MRI unless all four pulmonary veins are unequivocally normal on the two separate echocardiograms
iv There is no evidence of hemodynamically significant left-to-right shunting across an unrestricted systemic to pulmonary shunt
Study subjects will be followed with current standard of care assessments and diagnostics including longitudinal clinical evaluations determinations of functional class FC serial NT-pro-Brain Natriuretic Peptide NT-proBNP levels and echocardiography Data from these studies will be analyzed in central core facilities that will be used by all participating study sites
Clinical endpoints are the focus of this study However additional data collection is planned for exploratory aims to examine the potential role for future application of novel metrics of outcomes in children with PAH eg pediatric QOL and actigraphy as described below The investigators also plan to collect blood swab and urine samples to determine whether inherent genomic variations or novel proteomic biomarkers will associate with clinical responsiveness to interventions within the cohort Bio-specimens will be obtained to further test the hypothesis that therapeutic responders will have a different genomic or proteomic profile as compared to subjects who do not respond well to therapy
Bio-specimens will include the following
1 Blood for DNA peripheral blood mononuclear cells plasma and serum and
2 Paired Box Gene PAXgene tubes for RNA and miRNA studies and
3 Urine for biomarker analysis
Because sildenafil and bosentan have different mechanisms of action targeting different intracellular pathways combination therapy is a rational treatment strategy for pediatric patients with PAH Past work in adult PAH suggests that combination therapy with longer duration agents with the same mechanisms of action may cause greater and more sustained improvement in clinical course in comparison with monotherapy Whether children with PAH respond and tolerate combination therapy better than monotherapy has not been studied In addition despite a growing experience with sequential therapy additional medications are added only after clinical deterioration or failure to sustain responsiveness
Pharmacokinetics will be assessed during this study in order to determine whether drug levels or compliance with therapy affect outcomes in this cohort In addition pharmacokinetics data and related clinical responses from mono- and dual therapy participants will be compared Interactions between these agents are well known whereby bosentan decreases sildenafil levels As a result sildenafil levels during mono- and combination therapy will be further defined by the planned pharmacokinetics in the current protocol In addition to strengthening this current study design such data will form a basis for optimizing the use of these agents and potential strategies for dose adjustments in the broader scope of clinical care in the future
For infants less than one year of age for whom cardiac catheterization is not considered as part of the clinical teams recommended approach enrollment will be possible without catheterization if the following four criteria i-iv are met
i Two separate echocardiograms clearly demonstrate pulmonary hypertension by at least three of the following metrics
1 Elevated MPA pressure early diastolic PR peak gradient 20 mmHg
2 Right ventricular hypertrophy qualitative as mild to severe
3 Right atrial enlargement scales for age will be provided
4 Elevated right ventricular systolic pressure 35mmHg on at least two at least two reliable spectral Doppler envelopes during the echocardiogram and in the setting of normal for age documented systolic blood pressure at least two reliable spectral Doppler envelopes during the echocardiogram
5 Flattening or R to L bowing of the interventricular septum qualitative or by elevated eccentricity index
6 Diminished RV function RV fractional area change 35 andor TAPSE below published normal range for age and weight
ii There is no clinical or imaging evidence of left heart dysfunction
iii Pulmonary venous stenosis and atresia are ruled out by CT angiography or MRI unless all four pulmonary veins are unequivocally normal on the two separate echocardiograms
iv There is no evidence of hemodynamically significant left-to-right shunting across an unrestricted systemic to pulmonary shunt
Study subjects will be followed with current standard of care assessments and diagnostics including longitudinal clinical evaluations determinations of functional class FC serial NT-pro-Brain Natriuretic Peptide NT-proBNP levels and echocardiography Data from these studies will be analyzed in central core facilities that will be used by all participating study sites
Clinical endpoints are the focus of this study However additional data collection is planned for exploratory aims to examine the potential role for future application of novel metrics of outcomes in children with PAH eg pediatric QOL and actigraphy as described below The investigators also plan to collect blood swab and urine samples to determine whether inherent genomic variations or novel proteomic biomarkers will associate with clinical responsiveness to interventions within the cohort Bio-specimens will be obtained to further test the hypothesis that therapeutic responders will have a different genomic or proteomic profile as compared to subjects who do not respond well to therapy
Bio-specimens will include the following
1 Blood for DNA peripheral blood mononuclear cells plasma and serum and
2 Paired Box Gene PAXgene tubes for RNA and miRNA studies and
3 Urine for biomarker analysis
Because sildenafil and bosentan have different mechanisms of action targeting different intracellular pathways combination therapy is a rational treatment strategy for pediatric patients with PAH Past work in adult PAH suggests that combination therapy with longer duration agents with the same mechanisms of action may cause greater and more sustained improvement in clinical course in comparison with monotherapy Whether children with PAH respond and tolerate combination therapy better than monotherapy has not been studied In addition despite a growing experience with sequential therapy additional medications are added only after clinical deterioration or failure to sustain responsiveness
Pharmacokinetics will be assessed during this study in order to determine whether drug levels or compliance with therapy affect outcomes in this cohort In addition pharmacokinetics data and related clinical responses from mono- and dual therapy participants will be compared Interactions between these agents are well known whereby bosentan decreases sildenafil levels As a result sildenafil levels during mono- and combination therapy will be further defined by the planned pharmacokinetics in the current protocol In addition to strengthening this current study design such data will form a basis for optimizing the use of these agents and potential strategies for dose adjustments in the broader scope of clinical care in the future
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
True
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
False
Is an FDA AA801 Violation?:
None
Secondary IDs
| Secondary ID | Type | Domain | Link |
|---|---|---|---|
| UG3HL151458 | NIH | None | None |
| UH3HL151458 | NIH | None | None |
| 1U24TR001609 | NIH | None | None |
| 1U24TR004440 | NIH | None | httpsreporternihgovquickSearch1U24TR004440 |