A Study to Investigate the Safety and Efficacy of KER-012 in Combination With Background Therapy in Adult Participants With Pulmonary Arterial Hypertension (PAH) (TROPOS).
Study Details
Study Description
Brief Summary
Study KER-012-A201 is Phase 2, double-blind, randomized, placebo-controlled study to determine the efficacy and safety of KER-012 compared to Placebo in adults with PAH (WHO Group 1 PH) on stable background PAH therapy. The study is divided into the Screening Period, Treatment Period, Extension Period, and Follow-Up Period.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 2 |
Detailed Description
This is a randomized, phase 2, double-blind, placebo-controlled study of KER-012 in combination with background therapy in participants with PAH of World Health Organization (WHO) Group 1, functional class II-III. Participants will be randomly assigned in a 2:2:2:3 ratio to receive KER-012 (Dose A), KER-012 (Dose B), KER-012 (Dose C), or placebo by subcutaneous injection (SC) every 4 weeks for a period of 24 weeks in the placebo-controlled treatment period of the study while on background therapy. Evaluations will include changes in pulmonary vascular resistance (PVR), 6-minute walk distance (6MWD), and safety parameters. Participants who have not discontinued early from the placebo-controlled treatment period and have had their post-treatment period PVR assessment will be able to continue into the 72-week extension period in which KER-012 treated participants will continue to receive their same assigned dose level from the treatment period every 4 weeks and placebo treated participants will receive KER-012 (Dose B) every 4 weeks while on background therapy.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Arm 1 (N=20) KER-012 (Dose A) subcutaneously (SC) (every 4 weeks [Q4W]) Treatment Period: Dose A for 24 weeks; Extension Period: Dose A for another 72 weeks |
Biological: Dose A KER-012
Dose A KER-012 (Q4W);
|
| Experimental: Arm 2 (N=20) KER-012 (Dose B) SC (Q4W) Treatment Period: Dose B for 24 weeks; Extension Period: Dose B for another 72 weeks |
Biological: Dose B KER-012
Dose B KER-012 (Q4W);
|
| Experimental: Arm 3 (N=20) KER-012 (Dose C) SC (Q4W) Treatment Period: Dose C for 24 weeks; Extension Period: Dose C for another 72 weeks |
Biological: Dose C KER-012
Dose C KER-012 (Q4W);
|
| Placebo Comparator: Arm 4 (N=30) Treatment Period: Placebo for 24 weeks; Extension Period: Dose B for another 72 weeks |
Biological: Dose B KER-012
Dose B KER-012 (Q4W);
Biological: Placebo for 24 Weeks followed by Dose B KER-012 for 72 weeks
Treatment Period (24 weeks): Placebo SC (Q4W) Extension Period (72 weeks after Placebo treatment): KER-012 (Dose B) SC (Q4W)
|
Outcome Measures
Primary Outcome Measures
- Change from Baseline in PVR (Pulmonary Vascular Resistance) [Baseline and Week 24]
Evaluate the effect of KER-012 on pulmonary hemodynamics compared to Placebo in participants on background pulmonary arterial hypertension (PAH) therapy
Secondary Outcome Measures
- Change from Baseline in the 6MWD [Through week 24 (primary treatment period) and Through week 96 (extension period)]
Evaluate the effect of KER-012 on exercise capacity compared to Placebo in participants on background PAH therapy
- Incidence of treatment-emergent adverse events (TEAEs) [Through week 24 (primary treatment period) and Through week 96 (extension period)]
A TEAE is any untoward medical occurrence in a study participant occurring after the initiation of a study treatment that does not necessarily have to have a causal relationship with this treatment. A TEAE can therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product, whether or not related to the medicinal product.
- Number of treatment-related TEAEs [Through week 24 (primary treatment period) and Through week 96 (extension period)]
A treatment-related TEAE is any untoward medical occurrence in a study participant occurring after the initiation of a study treatment that has a causal relationship with this treatment.
- Number of discontinuations due to TEAEs [Through week 24 (primary treatment period) and Through week 96 (extension period)]
A treatment-related TEAE is any untoward medical occurrence in a study participant occurring after the initiation of a study treatment that has a causal relationship with this treatment. A TEAE can therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product, whether or not related to the medicinal product.
- Change from baseline in Systolic and Diastolic Blood Pressure [Through week 24 (primary treatment period) and Through week 96 (extension period)]
Systolic and Diastolic blood pressure measured in mmHg
- Change from baseline in QTcF intervals [Through week 24 (primary treatment period) and Through week 96 (extension period)]
QTcF intervals measured in msec via ECGs
- Incidence of Antidrug Antibodies (ADA) [Through week 24 (primary treatment period) and Through week 96 (extension period)]
The amount of ADA measured in serum
- Evaluate the changes from baseline in the concentration of the PAH biomarker, NT-proBNP in blood samples [Up to week 24 (primary treatment period) and up to Week 96 (extension period)]
Change from Baseline in NT-proBNP by visit
- Evaluate the effect of KER-012 on pulmonary hemodynamics compared to Placebo in participants on background PAH therapy- mPAP [Up to week 24 (primary treatment period) and up to Week 96 (extension period)]
Change from Baseline in mean pulmonary artery pressure (mPAP)
- Evaluate the effect of KER-012 on pulmonary hemodynamics compared to Placebo in participants on background PAH therapy- CO [Up to week 24 (primary treatment period) and up to Week 96 (extension period)]
Change from Baseline in cardiac output (CO)
- Evaluate the effect of KER-012 on pulmonary hemodynamics compared to Placebo in participants on background PAH therapy- PAWP [Up to week 24 (primary treatment period) and up to Week 96 (extension period)]
Change from Baseline in pulmonary artery wedge pressure (PAWP)
- Evaluate improvement in functional assessment of KER-012 compared to Placebo in participants on background PAH therapy [Up to week 24 (primary treatment period) and up to Week 96 (extension period)]
Proportion of participants who achieved improvement from Baseline in NYHA FC/WHO by visit
- Number of participants who experienced events indicative of clinical worsening of pulmonary arterial hypertension (PAH) [Up to week 24 (primary treatment period) and up to Week 96 (extension period)]
Events that indicate clinical worsening of PAH include death, non-elective PAH-related hospitalization and/or right heart failure inclusive of lung or heart/lung transplant, or atrial septostomy, need to initiate an approved PAH SOC rescue therapy, or functional deterioration (worsened WHO Functional Class AND 15% decrease in 6MWD).
- Population PK predicted maximum concentration (Cmax) of KER-012 [Through week 24 (primary treatment period) and Through week 96 (extension period)]
Cmax is a measure of the maximum concentration of a drug in the serum after the dose is given.
- Population PK predicted Area under concentration curve (AUC) of KER-012 [Through week 24 (primary treatment period) and Through week 96 (extension period)]
AUC is a measure of the area under the serum concentration curve after dose is given.
- Evaluate improvement in risk stratifications of KER-012 in participants on background PAH therapy [Up to week 24 (primary treatment period) and up to Week 96 (extension period)]
Proportion of participants who achieve improvement/or maintain low risk in ESC/ ERC 4-strata risk category assessment
Eligibility Criteria
Criteria
Inclusion Criteria:
-
Adult participants ≥ 18 years of age
-
Symptomatic World Health Organization (WHO) Group 1 Pulmonary Hypertension (PH)(PAH) classified by one of the following subgroups:
-
Idiopathic pulmonary arterial hypertension (IPAH);
-
Heritable pulmonary arterial hypertension (HPAH);
-
Associated with drugs and toxins;
-
PAH associated with:
-
Connective tissue disease
-
Congenital systemic-pulmonary intracardiac shunt
-
Has the following hemodynamic parameters that are consistent with the diagnosis of
PAH:
-
Mean pulmonary arterial pressure (mPAP) > 20 mmHg at rest, AND
-
Pulmonary artery wedge pressure (PAWP) ≤ 15 mmHg, AND
-
PVR ≥ 5 Wood Units (400 dyn·sec·cm-5)
-
Has WHO/New York Heart Association (NYHA) Functional Class (FC) II or III symptoms as assessed by the Investigator
-
Must be on a stable PAH background therapy with either an endothelin-receptor antagonist (ERA) and/or a phosphodiesterase-5 inhibitor (PDE5-I) or soluble guanylate cyclase (sGC) stimulator and/or prostacyclin analogue or receptor agonist (oral/inhaled/SC/intravenous)
-
6MWD ≥ 150 and ≤ 500 meters at screening
-
Provide written (signed and dated) informed consent form before the initiation of any Screening tests or procedures
Exclusion Criteria:
-
Evidence or history of left ventricular dysfunction and/or clinically significant cardiac disease
-
Has pulmonary function tests (PFTs) with evidence of significant obstructive or parenchymal lung disease
-
Evidence of thromboembolic disease assessed by ventilation perfusion (V/Q) lung scan or other local standard of care diagnostic evaluation at the time of PAH diagnosis or after
-
Has uncontrolled systemic hypertension
-
Hemoglobin < 9 g/dL at Screening
-
Prior heart or heart-lung transplants, active on the lung transplant list, or life expectancy of < 12 months per Investigator assessment
-
Diagnosis of pulmonary veno-occlusive disease or pulmonary capillary hemangiomatosis
-
Initiation or discontinuation of an exercise program for cardiopulmonary rehabilitation within 90 days prior to Baseline or planned initiation during the study
-
Prior participation in a KER-012 study or prior treatment with a therapy targeting TGF-β superfamily (e.g. sotatercept)
-
Prior participation in another interventional clinical study with medicinal products within 30 days or 5 half-lives prior to Screening, whichever is longer
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Macquarie University | Sydney | Australia | 2095 |
Sponsors and Collaborators
- Keros Therapeutics, Inc.
Investigators
None specified.Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- KER-012-A201