Efficacy and Safety of Upfront Combination of ΒΟsentan and ΤΑdalafil in Pulmonary Arterial Hypertension

Elpen Pharmaceutical Co. Inc.

Overview

The development of disease-targeted drugs for the treatment of pulmonary arterial hypertension (PAH) has significantly improved within the last years. Combining drug products with different mechanisms of action such as Endothelin-Receptor-Antagonists (ERAs) and Phosphodiesterase-Type-5-inhibitors (PDE-5-Inhibitors) has become increasingly important for the treatment of PAH. Recently, the results of the AMBITION study reported that an upfront combination treatment of ambrisentan and tadalafil immediately after diagnosis leads to a delayed disease progression. On the other hand, the sequential combination of bosentan and sildenafil did not show a similar positive clinical effect and this was attributed to a negative clinically relevant pharmacodynamic drug-drug interaction. Although, recent guidelines have extrapolated that initial upfront combination treatment follows a class effect in terms of efficacy and safety, there is an imperative need to support this notion with other combinations of ERAs and PDE-5-Inhibitors.

The primary objective of BOTA study is to compare the change in clinical and hemodynamic measures of PAH after the initiation of first line combination therapy with bosentan and tadalafil in adult patients with PAH. The safety and tolerability of first line combination therapy will also be evaluated. In patients with PAH initial upfront combination treatment with bosentan and tadalafil 1. Improves * Exercise capacity as expressed by distance walked in six minute walk test and WHO functional class * Hemodynamics in terms of pulmonary vascular resistance (PVR), mean pulmonary artery pressure (mPAP) reduction and cardiac index (CI) elevation * Quality of life * NTproBNP serum levels * Echocardiographic prognostic parameters such as right atrial area and presence of pericardial effusion. 2. Is safe as assessed by * Liver function markers such as serum SGOT and SGPT levels * Hemoglobin levels

Study Type

OBSERVATIONAL

Conditions

Pulmonary Hypertension

Eligibility

Medical Language ↔ Plain English

Inclusion Criteria: Male or females between 18 to 75 years of age at inclusion Diagnosis of PAH due to the following: * Idiopathic Primary Pulmonary Arterial Hypertension (IPAH) * Hereditary PAH * PAH secondary to connective tissue disease * PAH diagnosis confirmed by right heart catheterization performed within 3 months prior to study enrolment Subjects must weigh at least 40 kg at inclusion Subject must have a current diagnosis of being in World Health Organisation (WHO) Functional Class II or III. Treatment PAH naïve subjects PAH documented by * mPAP ≥25mmHg, * pulmonary capillary wedge pressure (PCWP) or * left ventricular end-diastolic pressure (LVEDP) ≤15mmHg and * PVR ≥3 Wood Units. Subject must walk a distance of ≥125m and ≤500m at the screening visit Exclusion Criteria: * History of pulmonary embolism * No prior treatment with PDE-5 inhibitors * History of chronic lung disease / restrictive lung disease (eg, chronic obstructive pulmonary disease (COPD) or scleroderma) with impairment of lung function * Current treatment with nitrates or nitric oxide * Significant (ie, \>2+) valvular disease other than tricuspid regurgitation or pulmonary regurgitation * History of cardiac arrest, respiratory arrest, hemodynamic collapse, CPR, ventricular tachycardia, ventricular fibrillation, or uncontrolled atrial fibrillation

Outcomes

Primary Outcomes

Change From Baseline in the N-Terminal Pro-B-Type Natriuretic Peptide at Month 6

N-Terminal Pro-B-Type Natriuretic Peptide (NT-proBNP) is a surrogate marker of heart failure. The geometric mean ratio will be calculated as the ratio between the month 6 value and the Baseline value and presented as percent change = 100 \* (geometric mean ratio - 1). The Baseline value is the last value prior to administration of study drug; this may be prior to or on the day of study drug initiation.

Time frame: 6 months

Secondary Outcomes

Number of Participants With First Adjudicated Clinical Failure (CF) Event

Hospitalisation for Worsening PAH, Disease Progression, Unsatisfactory Clinical Response

Time frame: 6 months

Time to first clinical worsening (TTCW) event

TTCW defined as the number of days between first dose of study drug and the occurrence of a predefined clinical worsening event.

Time frame: 6 months

Percentage of Participants With a Satisfactory Clinical Response at Month 6

A satisfactory clinical response at month 6 is defined as a participant who meets all of the following criteria: 10% improvement in 6MWD compared with Baseline;

Time frame: 6 months

Change From Baseline in the World Health Organization Functional Class at month 6

Change From Baseline in the World Health Organization Functional Class Time Frame: Baseline and Month 6 The WHO Functional Class (FC) indicates the severity of PAH and is an adaptation of the New York Heart Association classification.

Time frame: 6 months

Change From Baseline in the 6 Minute Walk Distance (6MWD) Test at month 6

Change From Baseline in the 6 Minute Walk Distance (6MWD) Test at month 6 MWD is the distance a participant can walk in 6 minutes. The 6-minute walk distance (6MWD) test measures the distance that a participant can walk in a period of 6 minutes.

Time frame: 6 months

Change From Baseline in Borg Dyspnea Index at month 6

Borg Dyspnea Index (BDI) indicates the degree of breathlessness after completion of the 6 minute walk test.

Time frame: 6 months

Quality of Life

Change in emPHasis-10 questionnaire score

Time frame: 6 moths