Primary Objectives• To identify circulating micro RNA biomarkers associated with pulmonary hypertension in blood samples.• To develop signatures for detecting patients at high risk of pulmonary hypertension to assist in the diagnosis of pulmonary…
ID
Source
Brief title
Condition
- Pulmonary vascular disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Identification of potential miRNA biomarker signatures would help in the early
diagnosis of PAH. Patients at risk for PAH and CTEPH are especially likely to
benefit from earlier diagnosis, as these patients often experience symptoms for
years before a diagnosis is made.
Outcome: biomarker sample collection on Day 1
Time schedule of protocol, including follow-up duration: Screening period (max
60 days), Assessments on 1 day, additional assessment visit (if needed) up to
60 days after day 1.
Secondary outcome
NAP
Background summary
Relevance
PH (5 main groups) is a rare pathophysiological disorder formally defined as a
mean resting pulmonary artery pressure (that may involve multiple clinical
conditions and can complicate several cardiovascular and respiratory diseases.
Because all forms of PH are not diagnosed until the disease is severe, a
non-invasive test that helps detect PH and possibly stratifies patients based
on risk of PH, allowing for earlier diagnosis and intervention, is regarded as
an unmet need in the diagnosis of PH.
The proposed study is the first phase of Actelion*s development plan for
biomarkers, focusing on profiling the expression levels of 100-200 (and up to
600) miRNAs in serum or plasma samples to identify miRNA biomarkers associated
with PH
Scientific Rationale for Study Design
Increased or decreased levels of several circulating miRNAs have been shown to
be associated with PAH and PH clinical phenotypes (Miao 2018). Increasing
evidence suggests that many of these circulating miRNAs play a key role in
regulating the expressions of genes that are involved in the physiological and
pathological processes of PH and PAH. Some of these circulating miRNAs have
been also proposed as the master regulators that coordinate and regulate
multiple signaling pathways involved in the pathogenesis of PH and promote
PH-associated clinical phenotypes. It is therefore possible that a miRNA
biomarker signature could be developed for early detection of PH or
differentiating subtypes of PH, eg, PAH and CTEPH.
Study objective
Primary Objectives
• To identify circulating micro RNA biomarkers associated with pulmonary
hypertension in blood samples.
• To develop signatures for detecting patients at high risk of pulmonary
hypertension to assist in the diagnosis of pulmonary hypertension versus
non-pulmonary hypertension (as established by right heart catheterization) in
patients with atypical shortness of breath.
• To estimate the sensitivity, specificity, positive predictive value, and
negative predictive value of the biomarker signatures in identifying patients
with pulmonary hypertension by comparing the biomarker signatures to right
heart catheterization.
• To compare the sensitivity, specificity, positive predictive value, and
negative predictive value of the biomarker signatures with the sensitivity,
specificity, positive predictive value, and negative predictive value of
transthoracic echocardiogram in identifying patients with pulmonary
hypertension documented by right heart catheterization.
Secondary Objectives
• To analyze the performance of the various biomarkers in differentiating
groups of pulmonary hypertension; specifically, pulmonary arterial
hypertension, chronic thromboembolic pulmonary hypertension and isolated
pre-capillary versus post-capillary pulmonary hypertension.
• To assess the performance of the biomarker signatures in patients with
pulmonary hypertension who are receiving pulmonary arterial hypertension
specific drug therapies (as determined by their physician in accordance with
existing standard of care) versus patients with pulmonary hypertension who are
not receiving any drug therapy, and per class of pulmonary arterial
hypertension therapy.
Exploratory Objectives
• To assess the performance of the biomarker signatures for discriminating
non-pulmonary hypertension (mean pulmonary artery pressure <=20 mmHg), vs
patients with 20 mmHg < mean pulmonary artery pressure <25 mmHg vs patients
with mean pulmonary artery pressure >=25 mmHg.
• To assess the performance of the biomarker signatures in patients with
various subgroups of pulmonary arterial hypertension, including but not limited
to, heritable forms of pulmonary arterial hypertension and patients with
systemic diseases.
• To assess the performance of biomarker signatures in Functional Class II
patients versus
Study design
This is a prospective, multicenter study to discover, design and develop blood
biomarker signatures in patients with PH. A diagram of the study design is
provided in Figure 1. The study population will include prevalent (previously
diagnosed) and incident (newly diagnosed) patients who have undergone right
heart catheterization (RHC) grouped according to the following subgroups:
prevalent non-PH (RHC within 6 months), or incident non PH (RHC within 6
weeks), or incident PH (RHC within 6 weeks), or prevalent PH without or with
pulmonary arterial hypertension (PAH) therapy (RHC within 18 months). This will
provide adequate samples for biomarker signature discovery and validation of
the signature*s performance. The number of participants enrolled in each group
will ensure representation of the main PH groups of interest, ie, PAH and
chronic thromboembolic pulmonary hypertension (CTEPH).
At the time of enrollment in the study, blood samples will be taken and a
transthoracic echocardiogram (TTE) will be performed for each participant. All
TTE will be centrally read in a blinded manner. TTE readings will be used to
compare the diagnostic performance of the biomarker signature(s) to the current
best practice for non-invasive diagnosis of PH.
No genetic/genomic testing is planned in this protocol, however, blood samples
containing white blood cells will be collected to enable future analysis using
the most appropriate genomic analysis platform to allow for genomic research,
as necessary where local regulations permit. Participation in the genomic
research is optional.
Study burden and risks
NAP
Graaf Engelbertlaan 75
Breda 4837 DS
NL
Graaf Engelbertlaan 75
Breda 4837 DS
NL
Listed location countries
Age
Inclusion criteria
1. Male or female.
2. Age >=18 years of age inclusive.
3. Having undergone an RHC within 18 months (prevalent PH patients) or 6 months
(prevalent non-PH patients) or have undergone or planned RHC within 6 weeks
(incident patients). The results of the incident RHC (incident patients) or the
most recent RHC (prevalent patients) will be used to classify the participant
in one of the study population categories.
4. Medically stable on the basis of physical examination, medical history and
vital signs performed at screening. Any abnormalities must be consistent with
the underlying illness in the study population and this determination must be
recorded in the participant*s source documents and initialed by the
investigator.
5. Must sign an ICF (or their legally acceptable representative must sign)
indicating that he or she understands the purpose of, and procedures required
for, the study and is willing to participate in the study.
6. Must provide informed consent (or their legally-acceptable representative
must sign) if he or she agrees to provide an optional (DNA) sample for research
(where local regulations permit). Refusal to give consent for the optional
(DNA) research sample does not exclude a participant from participation in the
study.
Exclusion criteria
1. Participants requiring renal dialysis.
2. History of lung or heart transplant (waiting list status or consideration of
enlisting is allowed).
3. Severe left ventricular dysfunction: Left ventricular ejection function <35%.
4. Ongoing contagious respiratory disease.
5. Participants that have previously contributed blood samples for biomarker
analysis in the Actelion retrospective study of biomarkers for PH.
6. Participants unable to have at least 2 tubes of 10 mL blood drawn (i.e., one
10 mL plasma tube and one 10 mL serum tube).
7. For incident patients: treatment with any PAH specific drug prior to
collection of biomarker samples.
Design
Recruitment
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| ClinicalTrials.gov | NCT04193046 |
| CCMO | NL74376.029.20 |