Clinical trial NCT05737940: A Study of AZD3427 in Participants With Heart Failure and Pulmonary Hypertension Group 2
Official title: A Phase IIb Randomised, Double-blind, Placebo-controlled, Multi-centre, Dose-ranging Study of AZD3427 in Participants With Heart Failure and Pulmonary Hypertension Due to Left Heart Disease (WHO Group 2)
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE2
Conditions: Pulmonary Hypertension (World Health Organization Group 2)
Heart Failure
Keywords: Pulmonary Hypertension
Heart Failure
Left Heart Disease
WHO Group 2
Dose-ranging Study
Pulmonary vascular resistance
Lead sponsor: AstraZeneca
Sponsor class: INDUSTRY
Collaborators: name: Parexel
First posted: 2023-02-21
Enrollment: 260
Sex: ALL
Minimum age (years): 18
Maximum age (years): 130
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This study is intended to assess the ability of AZD3427 to reduce pulmonary vascular resistance (PVR) after 24 weeks of treatment in participants with heart failure (HF) and pulmonary hypertension (PH) Group 2

Detailed description: This study is a randomized, placebo-controlled, multi-centre, dose-ranging study of AZD3427 in participants with heart failure and pulmonary hypertension due to left heart disease (World Health Organisation \[WHO\] Group 2).

Approximately 220 participants will be randomised to 4 treatment groups (in a 1:1:1:1 ratio) to receive a subcutaneous (SC) injection of AZD3427 or placebo every 2 weeks for 24 weeks.

This study will evaluate 3 dose levels of AZD3427: Dose A, Dose B, and Dose C. Dose modification is not applicable for this study.

The study will be conducted in approximately 60 study centres across an estimated 15 countries.

The study will include approximately 16 study visits: 2 visits during the Screening Period,13 visits during the Treatment Period, and one visit during the Follow-up Period.

The expected total duration of the study is 32 to 37 weeks, depending on the length of the Screening Period.

Eligibility criteria: Inclusion criteria:

1. Participant must be ≥ 18 years of age inclusive.
2. Participants must have a pre-existing diagnosis of HF, NYHA function class (FC) II to IV, and a pre-existing diagnosis of PH-LHD or likely or intermediate probability of Pulmonary hypertension due to left heart disease (PH-LHD) as per 2022 Pulmonary hypertension due to left heart disease European Society of Cardiology/European Respiratory Society (ESC/ERS) guidelines. Participants must be on stable HF standard of care medication, including diuretics.
3. Participants must have a combination of echocardiographic parameters that show intermediate or high probability of PH as per 2022 ESC/ERS guidelines.
4. Participants must have an on-study elevated pulmonary artery pressure from RHC performed as per RHC manual provided by the Sponsor, at Screening Visit 2:

   1. PAWP ≥ 15 mmHg
   2. mPAP ≥ 20 mmHg
5. Minimum body weight of 45 kg (inclusive).
6. Capable and willing of giving signed informed consent.

Exclusion Criteria

1. Diagnosis of PH in World Health Organization (WHO) Group 1, WHO Group 3, WHO Group 4, or WHO Group 5.
2. Historical or current evidence of a clinically significant disease or disorder.
3. Decompensated HF or hospitalisation due to decompensated HF.
4. Any contraindications to RHC.
5. History of hypersensitivity to SC injections or devices.
6. History of hypersensitivity to drugs with a similar chemical structure or class to AZD3427 or any component of AZD3427 drug product, or ongoing clinically important allergy/hypersensitivity.
7. Known lung disease with Forced expiratory volume in the first second (FEV1) \< 30% of predicted.
8. Congenital long QT syndrome.
9. Cardiac ventricular arrhythmia which requires treatment. Participants with atrial fibrillation or flutter and controlled ventricular rate are permitted.
10. History of or anticipated heart transplant or ventricular assist device implantation.
11. Any known planned (scheduled) highly invasive Cardiovascular (CV) procedure (eg, coronary revascularisation, ablation of atrial fibrillation/flutter, valve repair/replacement, aortic aneurysm surgery, etc).
12. Participants who have previously received AZD3427.

Primary outcomes:
measure: Change from baseline in Pulmonary Vascular Resistance (PVR)
timeFrame: Baseline to Week 25
Secondary outcomes:
measure: Change from baseline in Mean pulmonary arterial pressure (mPAP)
timeFrame: Baseline to Week 25
measure: Change from baseline in Pulmonary artery wedge pressure (PAWP)
timeFrame: Baseline to Week 25
measure: Change from baseline in cardiac output
timeFrame: Baseline to Week 25
measure: Change from baseline in Stroke Volume (SV)
timeFrame: Baseline to Week 25
measure: Change from baseline in Ejection fraction (EF)
timeFrame: Baseline to Week 25
measure: Change from baseline in left ventricular global longitudinal strain (LVGLS)
timeFrame: Baseline to Week 25
measure: Change from baseline in pulmonary arterial systolic pressure (PASP)
timeFrame: Baseline to Week 25
measure: Change from baseline in right ventricle/left ventricle (RV/LV) ratio
timeFrame: Baseline to Week 25
measure: Change from baseline in right ventricular outflow tract acceleration time (RVOT AT)
timeFrame: Baseline to Week 25
measure: Change from baseline in Tricuspid regurgitation velocity (TRV)
timeFrame: Baseline to Week 25
measure: Change from baseline in TAPSE/PASP [Tricuspid annular plane systolic excursion/ Pulmonary arterial systolic pressure]
timeFrame: Baseline to Week 25
measure: Change from baseline in systemic vascular resistance
timeFrame: Baseline to Week 25
measure: Change from baseline in 6-minute walking distance (6MWD)
timeFrame: Baseline to Week 25
measure: Change from baseline in Kansas City Cardiomyopathy Questionnaire total symptom score (KCCQ TSS)
timeFrame: Baseline to Week 25
measure: Change from baseline in New York Heart Association Functional Class (NYHA FC)
timeFrame: Baseline to Week 25
measure: Change from baseline in serum creatinine
timeFrame: Baseline to Week 13 and Week 25
measure: Change from baseline in N-terminal prohormone of brain natriuretic peptide (NT-proBNP)
timeFrame: Baseline to Week 13 and Week 25
measure: Change from baseline in cystatin C
timeFrame: Baseline to Week 13 and Week 25
measure: Change from baseline in eGFR (estimated glomerular filtration rate)
timeFrame: Baseline to Week 13 and Week 25
measure: Pharmacokinetics (AZD3427 serum exposure)
timeFrame: On Day 15, Day 29, Day 85, Day 127, Day 169, and Day 211
measure: Number of participants with presence of Anti-drug antibodies (ADAs)
timeFrame: On Day 1, Day 15, Day 29, Day 85, Day 169, and Day 211
measure: Evaluation of positive ADA titer
timeFrame: On Day 1, Day 15, Day 29, Day 85, Day 169, and Day 211
Other outcomes:
measure: Number of participants with adverse events and serious adverse events
timeFrame: From Randomization (Day 1) up to Follow-up Visit (Day 211)
Locations:
city: Beverly Hills
country: United States
facility: Research Site
state: California
city: La Jolla
country: United States
facility: Research Site
state: California
city: New Haven
country: United States
facility: Research Site
state: Connecticut
city: Jacksonville
country: United States
facility: Research Site
state: Florida
city: Baltimore
country: United States
facility: Research Site
state: Maryland
city: Saint Louis
country: United States
facility: Research Site
state: Missouri
city: Omaha
country: United States
facility: Research Site
state: Nebraska
city: Rock Hill
country: United States
facility: Research Site
state: South Carolina
city: Linz
country: Austria
facility: Research Site
city: Wien
country: Austria
facility: Research Site
city: Edmonton
country: Canada
facility: Research Site
state: Alberta
city: Vancouver
country: Canada
facility: Research Site
state: British Columbia
city: Halifax
country: Canada
facility: Research Site
state: Nova Scotia
city: London
country: Canada
facility: Research Site
state: Ontario
city: Ottawa
country: Canada
facility: Research Site
state: Ontario
city: Toronto
country: Canada
facility: Research Site
state: Ontario
city: Montreal
country: Canada
facility: Research Site
state: Quebec
city: Beijing
country: China
facility: Research Site
city: Changsha
country: China
facility: Research Site
city: Guangzhou
country: China
facility: Research Site
city: Kunming
country: China
facility: Research Site
city: Praha 10
country: Czechia
facility: Research Site
city: Praha 2
country: Czechia
facility: Research Site
city: Praha 4
country: Czechia
facility: Research Site
city: Aarhus
country: Denmark
facility: Research Site
city: Copenhagen
country: Denmark
facility: Research Site
city: Berlin
country: Germany
facility: Research Site
city: Cologne
country: Germany
facility: Research Site
city: Frankfurt
country: Germany
facility: Research Site
city: Jena
country: Germany
facility: Research Site
city: Brescia
country: Italy
facility: Research Site
city: Genoa
country: Italy
facility: Research Site
city: Marche
country: Italy
facility: Research Site
city: Milano
country: Italy
facility: Research Site
city: Milan
country: Italy
facility: Research Site
city: Trieste
country: Italy
facility: Research Site
city: Bunkyo-ku
country: Japan
facility: Research Site
city: Kasugai-shi
country: Japan
facility: Research Site
city: Kure-shi
country: Japan
facility: Research Site
city: Nagoya-shi
country: Japan
facility: Research Site
city: Sapporo-shi
country: Japan
facility: Research Site
city: Sunto-gun
country: Japan
facility: Research Site
city: Toyama-shi
country: Japan
facility: Research Site
city: Deventer
country: Netherlands
facility: Research Site
city: Heerlen
country: Netherlands
facility: Research Site
city: Tilburg
country: Netherlands
facility: Research Site
city: Białystok
country: Poland
facility: Research Site
city: Gdansk
country: Poland
facility: Research Site
city: Krakow
country: Poland
facility: Research Site
city: Warszawa
country: Poland
facility: Research Site
city: Warszawa
country: Poland
facility: Research Site
city: Wrocław
country: Poland
facility: Research Site
city: Majadahonda
country: Spain
facility: Research Site
city: Sevilla
country: Spain
facility: Research Site
city: Toledo
country: Spain
facility: Research Site
city: Valencia
country: Spain
facility: Research Site
city: Göteborg
country: Sweden
facility: Research Site
city: Huddinge
country: Sweden
facility: Research Site
city: Cambridge
country: United Kingdom
facility: Research Site
city: Clydebank
country: United Kingdom
facility: Research Site
city: London
country: United Kingdom
facility: Research Site
Study officials:
References: