The purpose of this study is to explore the efficacy and safety of LTP001 in participants with WHO Group 1 pulmonary hypertension (PH), also referred to as Pulmonary Arterial Hypertension (PAH).This proof of concept study will be executed as the…
ID
Source
Brief title
Condition
- Pulmonary vascular disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
PVR, pulmonaire vasculaire resistance at week 25 in participants treated with
LTP001 compared to placebo.
Secondary outcome
To evaluate the effect of LTP001 on:
* Six Minute Walk Distance (6MWD)
* Hemodynamic parameters other than PVR
* Measurements of right ventricular function
To assess the impact of LTP001 on:
* patient reported outcomes (PRO).
* Time to Clinical Worsening (TTCW)
* The N-terminal fragment of the prohormone B-type natriuetic peptide
(NT-proBNP)
To assess the safety and tolerability of LTP001
* To investigate the pharmacokinetics (PK) of LTP001
Background summary
PAH is an orphan disease characterized by chronic elevation in pulmonary
arterial pressure,which eventually leads to remodeling of the pulmonary
vasculature, followed by right-sided heart failure.
SMURF1 is upregulated in vascular cells from patients with PAH.The role of
SMURF1 is to target proteins in the BMP pathway for ubiquitination, thereby
triggering degradation of the BMP pathway signal, resulting in vascular smooth
muscle cell proliferation and remodeling.
LTP001 is a highly selective and potent, orally administered, small molecule
designed to inhibit the SMAD-specific E3 ubiquitin protein ligase 1 (SMURF1).
SMURF1 is upregulated in vascular cells from patients with pulmonary arterial
hypertension (PAH)
Increased activity of this ligase is expected to result in impaired bone
morphogenic protein (BMP) signaling by degradation of mediators of the pathway
activity.
Therapies that specifically target remodeling of the pulmonary vasculature
would be expected
to provide significant benefit as add-on to the available standard of care.
Study objective
The purpose of this study is to explore the efficacy and safety of LTP001 in
participants with WHO Group 1 pulmonary hypertension (PH), also referred to as
Pulmonary Arterial Hypertension (PAH).
This proof of concept study will be executed as the efficacy of SMURF1
inhibition has not yet been established in the PAH population. This study will
provide insights to whether SMURF1 inhibition is effective in reducing the
pulmonary vascular resistance, improves patient symptom burden and increases
the time to clinical worsening.
Study design
This is a non-confirmatory, randomized, subject- and investigator-blinded,
placebo controlled study of LTP001 in PAH participants. 44 participants will
be randomized in a 3:1 ratio of LTP001 6 mg to placebo. Participants will be
screened for up to 8 weeks followed by 24 weeks of daily dosing with
visits approximately every 4 weeks. One follow up visit will also be the end of
study visit and occurs approximately 30 days after the end of treatment.
Total study duration is approximately 37 weeks from start of screening to end
of study visit. If a participant continues into the open-label extension
study, then the follow-up visit may be skipped.
Intervention
LTP001
Study burden and risks
Minimum of 9 visits, duration vary from xxx hours per visit, total study time
29 weeks.
Physical examination: 3 times
ECG: 1 time
Right heart catheterization: 2 times
Echocardiography: 4 times
6 min walking test: 4 times
Questionnaires: 8 times
Blood samples taken: 9 times
Lung function testing: Only to be conducted if historical lung function testing
within 24 months of screening is not available.
Optional: Multi Sensor Activity monitoring ( Day -7 to Week 25 for as much time
as possible including non-visit days)
optional : genetic research
Haaksbergweg 16
Amsterdam 1101 BX
NL
Haaksbergweg 16
Amsterdam 1101 BX
NL
Listed location countries
Age
Inclusion criteria
History of PAH belonging to one of the following subgroups of the Clinical
Classification Group 1 (WHO):
- Participants with idiopathic pulmonary arterial hypertension (IPAH)
- Hereditary pulmonary arterial hypertension
- Congenital heart disease (surgically repaired at least 12 months prior to
screening)
- drug or toxin induced (for example, anorexigen, or methamphetamine use).
-Resting mean pulmonary arterial pressure (mPAP) > 25 mmHg; pulmonary capillary
wedge pressure (PCWP) or left ventricular end diastolic pressure < 15 mmHg, as
determined by right
heart catheterization within 20 days of randomization.
- Pulmonary Vascular Resistance > 6 Wood units (480 dynes s/cm-5), as
determined by right heart catheterization within 20 days of randomization.
- WHO Functional Class II-III
- 6MWD must be between 150 and 550 m (inclusive). The qualifying test needs to
be within 20 days of randomization. To meet the above criterion additional six
minute walk test (6MWT) may be performed up to a maximum of 3 tests in total
prior to dosing; the minimal time difference between two tests should be at
least 4 h.
- Standard of care therapy which is stable at least 6 weeks prior to RHC and
qualifying 6MWT assessment within 20 days of randomization.
Exclusion criteria
- Participants with pulmonary hypertension (PH) in the Clinical Classification
Groups 2-5 (WHO), and any PAH Group 1 subgroups not covered by Inclusion
Criterion #4.
- Participants with a history of left sided heart disease, chronic left sided
heart failure, congenital or acquired valvular disease compromising left
ventricular function and/or pulmonary venous hypertension or symptomatic
coronary disease
- Participants with obstructive lung disease defined as: FEV1/FVC < 60% and
FEV1 < 60% of predicted value after bronchodilator administration as well as
participants with moderate or severe
restrictive lung disease: Total Lung Capacity < 70% of predicted value.
- Acute or chronic impairment (other than dyspnea), which would limit the
ability to comply with study requirements, including interference with physical
activity and execution of study procedures such as 6MWT (e.g., angina pectoris,
claudication, musculoskeletal disorder, multiple
sclerosis, need for walking aids).
Design
Recruitment
Medical products/devices used
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 |
|---|---|
| EudraCT | EUCTR2021-000670-28-NL |
| CCMO | NL79478.029.21 |