This study aims to evaluate the effect of AZD4831 on functional improvement and reduction of symptoms in participants with heart failure with left ventricular ejection fraction > 40%. Additionally, the PK and overall safety profile of AZD4831…
ID
Source
Brief title
Condition
- Heart failures
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Part A
KCCQ-TSS change from baseline at 16 weeks compared with placebo
6MWD change from baseline at 16 weeks compared with placebo
Part B
KCCQ-TSS,primary assessment at 24 weeks
6MWD, primary assessment at 24 weeks
Secondary outcome
Part A
• KCCQ-TSS change from baseline at 24 and 48 weeks compared with placebo
• 6MWD change from baseline at 24 and 48 weeks compared with placebo
• NT-proBNP change from baseline at 16, 24 and 48 weeks compared with placebo
• LV-GLS change from baseline at 16 and 24 weeks compared with placebo
• LAVI change from baseline at 16 and 24 weeks compared with placebo
• LVMI change from baseline at 16 and 24 weeks compared with placebo
Concentrations will be summarised by timepoint and dose level.
• hsCRP and IL-6 change from baseline at 16, 24, and 48 weeks compared with
placebo
Safety
Safety and tolerability will be evaluated in terms of AEs, Vital signs,
Clinical laboratory, and ECG.
Assessments related to AEs will cover:
• Occurrence/Frequency
• Seriousness
• Death
• AEs leading to discontinuation of IMP
• AEoSIs related to skin reactions, including maculopapular rash, and infection
Vital signs parameters include blood pressure, pulse
rate, and body temperature; assessments will cover:
• Observed value
• Absolute change from baseline values over time
• Orthostatic blood pressure
A complete list of laboratory parameters is presented
in Section 8.2.4; assessments will cover:
• Observed value
• Absolute change from baseline values over time
• Treatment-emergent changes in selected laboratory parameters
Electrocardiogram measurements assessments will cover:
• Investigator evaluation
Part B:
• NT-proBNP, primary assessment at 24 weeks
• hsCRP and IL-6, primary assessment at 24 weeks
Safety
• Occurrence and time to first occurrence of AE, SAE, SAE with outcome death,
AE leading to discontinuation of study intervention, possibly related AE as
assessed by investigator, possibly related SAE as assessed by investigator.
• Observed laboratory value, change from baseline and time to first treatment
emergent abnormality.
• Observed vital sign value, change from baseline, and time to first treatment
emergent abnormality.
• Observed ECG abnormalities, change from baseline, and time to first treatment
emergent abnormality.
• Occurrence and time to first occurrence of AEoSI categories: skin reactions,
including maculopapular rash, and infection.
Background summary
Chronic HF continues to be a major cause of mortality, hospitalisations, and
suboptimal quality of life. Even with the best possible treatment, the 5-year
survival rate for HF patients is worse than for most cancers. Heart failure
affects 2% of the Western
population, increases to 10% over the age of 65 years, and up to 20% over the
age of 75 years. The proportion of the Western population over the age of 65
years is expected to increase to over 30% by year 2050 and the costs of HF to
society are expected to triple between years 2010 and 2030. Heart failure is
currently broadly divided into three categories based on the systolic function
of the left ventricle: (1) HFrEF (LVEF < 40%), (2) HFmrEF (LVEF 40-49%), and
(3) HFpEF (LVEF >= 50%). Together, HFmrEF and HFpEF account for 55% of HF cases.
Heart failure with preserved ejection fraction is overrepresented in elderly
and in women. Mortality in the community approaches 25% at one year. In a
comparison of trial populations, the prognosis in HFpEF is 50-75 deaths and
40-75 HF hospitalisations per 1000 patient-years, whereas in stable coronary
disease it is 10-30 deaths and 5-10 hospitalisations per 1000 patient-years and
has improved further with modern therapy. Thus, novel interventions for
coronary artery disease have little potential, whereas for HFpEF, novel
treatment is both a critical unmet need and of great public health impact, if
successful.
A novel paradigm for HFpEF pathophysiology states that co-morbidities (renal
disease, hypertension, obesity, and diabetes) lead to a global inflammatory
state, leading to immune cell recruitment and endothelial and coronary
microvascular dysfunction, with distinct pathophysiology different from
macrovascular coronary disease. This, in turn, can lead to both extracellular
fibrosis and myocardial stiffness and reduced
myocardial nitric oxide bioavailability and cyclic guanosine monophosphate
content and impaired myocyte relaxation. Numerous clinical data support this
hypothesis.
Multiple lines of evidence suggest that MPO may play a role in atherogenesis in
humans and MPO plasma levels predict outcome of cardiovascular disease. In
chronic HF, plasma levels of MPO are elevated and also associated with more
advanced HF. Additionally, elevated plasma MPO
levels can predict increased adverse clinical outcomes in HF patients.
Individuals with inherited low MPO activity were protected from leukocyte
activation induced deterioration of vascular function.
Overall, recent evidence suggests that MPO may provide a mechanistic link
between inflammation, oxidative stress, vascular dysfunction and impaired
cardiac remodelling. It is thus hypothesised that the MPO inhibitor AZD4831
will improve coronary microvascular status as well as systemic endothelial
function, leading to improved diastolic function and overall status of HFpEF
patients.
Study objective
This study aims to evaluate the effect of AZD4831 on functional improvement and
reduction of symptoms in participants with heart failure with left ventricular
ejection fraction > 40%. Additionally, the PK and overall safety profile of
AZD4831 will be evaluated.
Study design
This is a double-blind (participant, investigator, and sponsor blinded)
parallel group treatment study with 3 arms in Part A and 2 arms in Part B.
Intervention
In Part A, participants will undergo a screening period of up to 4 weeks,
followed by randomisation across 3 different treatment arms. Eligible
participants will be randomised at a 1:1:1 ratio and dosed orally daily. The
planned treatment arms are AZD4831 2.5 mg, AZD4831 5 mg, and placebo.
Participants will receive either AZD4831 or placebo for 16 weeks and then
continue into a safety extension, during which they will receive an additional
32 weeks of the intervention (AZD4831 or placebo, as per their assigned arm
during randomisation). A final follow-up visit will occur at 52 weeks from
randomisation. In the event that randomisation to the AZD4831 5 mg treatment
arm is stopped during the study in either the whole study or in a country or
specific ethnic population due to safety, the remaining participants in that
cohort would be randomised at a 2:1 ratio to AZD4831 2.5 mg
or matching placebo.
In Part B, participants will undergo a screening period of up to 2 weeks,
followed by randomisation across 2 treatment arms. Eligible participants will
be randomised at a 1:1 (AZD4831:placebo) ratio and dosed orally daily. The
planned treatment arms are AZD4831 at the dose selected based on Part A, and
placebo. Participants will be treated for 24, 36 or 48 weeks. A final follow-up
visit will occur 4 weeks after last treatment (week 24, 36 or 48) visit.
Participants can be randomised only once in the study; therefore, participants
who were randomised into Part A cannot be included in Part B.
Study burden and risks
On average, the patient will have to come to the hospital more often than if
the patient did not participate in the study. In addition, the following
investigations are carried out that sometimes would be performed less often or
never:
Physical examination, vital signs, height and weight are measured, orthostatic
blood pressure is measured in Part A, EKG, ultrasound, 6-minute walk test,
questionnaires, urine samples, blood samples, possibly a skin biopsy.
In previous studies completed in healthy volunteers, maculopapular rash
(reddish rash with flat and raised areas) was identified as a side effect of
AZD4831 seen in about 14% (8/59) healthy volunteers given AZD4831 in single and
repeated doses. These rashes were seen in healthy volunteers given single doses
of 45 mg and above, and at repeated doses of 15 mg and above. These rashes
started 7-10 days after starting drug, were considered mild to moderate in
severity and generalized (covering bigger portions of the body rather than just
a small area or a single body part), and resolved after stopping drug.
In addition, one patient out of 27 on 5mg AZD4831 in a study in patients with
heart failure experienced maculopapular rash that was considered severe and
generalized. It resolved after treatment with antihistamine (allergy medicine)
and steroids (medicine used to decrease inflammation).
There are also potential (possible) risks with AZD4831 that have been
identified based on animal studies and how the drug might work:
• Low blood pressure and increased heart rate
• Abnormalities in thyroid function
• Anemia (low red blood cells in the blood)
• Increased incidence of infections
• Agranulocytosis (severely decreased white blood cell count)
These potential risks have been monitored for in previous studies, and safety
concerns have not been seen in humans.
Prinses Beatrixlaan 582
Den Haag 2595BM
NL
Prinses Beatrixlaan 582
Den Haag 2595BM
NL
Listed location countries
Age
Inclusion criteria
Part A:
1. >= 40 to <= 85 years of age, at the time of signing the informed consent.
2. Documented stable symptomatic HF (New York Heart Association Class II-IV)
for at least 1 month at Screening (Visit 1) (transient HF in the setting of an
MI does not qualify), with a medical history of typical symptoms of HF and
receiving optimal therapy for HF as determined by the health-care physician.
3. LVEF >40% at Screening (Visit 1). All participants will undergo a local
echocardiogram at the Screening (Visit 1) with central reading to confirm the
LVEF >40% eligibility criteria before randomisation.
4. 6MWD >= 30 meters and <= 400 meters at Screening (Visit 1) and Randomisation
(Visit 3). Difference in 6MWD between Screening and Randomisation must be < 50
meters.
5. KCCQ-TSS <= 90 points at Screening (Visit 1) and Randomisation (Visit 3)
6.NT-proBNP >= 250 pg/mL (sinus rhythm) or >= 500 pg/mL (atrial
fibrillation/flutter) at Screening (Visit 1) for patients with BMI <=30 kg/m2.
NT-proBNP >= 200 pg/mL (sinus rhythm) or >= 400 pg/mL (atrial
fibrillation/flutter) at Screening (Visit 1) for patients with BMI > 30 kg/m2.
The ECG performed at Screening should be used for heart rhythm evaluation.
7.At least one of the following:
(a) Structural heart disease, ie, LA enlargement and/or left ventricular
hypertrophy at the echocardiogram performed at Screening (Visit 1). Left atrial
enlargement is defined by at least 1 of the following: LA width (diameter) >=
3.8 cm or LA length >= 5.0 cm, or LA area >= 20 cm2 or LA volume >= 55 mL or LAVI
> 34 mL/m2. Left ventricular hypertrophy is defined by septal thickness or
posterior wall thickness >= 1.1 cm or LVMI > 95 g/m2 in women and > 115 g/m2 in
men.
(b) Spectral tissue Doppler echocardiography - E/e* ratio (average of septal
and lateral) >= 13 at rest at the echocardiogram performed at Screening (Visit
1).
(c) Indirectly estimated elevation of PASP by TRmax velocity > 2.8 m/s (280
cm/s) (PASP >35 mmHg) at the echocardiogram performed at Screening (Visit 1) OR
directly measured pulmonary capillary wedge pressure > 15 mmHg at rest within
the past 12 months or > 25 mmHg at exercise documented by right heart
catheterisation within 12 months prior to Screening (Visit 1).
(d) HF decompensation within 6 months before Randomisation (Visit 3), defined
as hospitalisation for HF or IV diuretic treatment for HF during an urgent,
unscheduled visit without hospitalisation.
8.Body mass index >= 18.0 kg/m2 and <= 45.0 kg/m2
9.Male or female of non-childbearing potential.
Part B:
1 Participant must be >= 40 to <= 85 years of age, at the time of signing the
informed consent.
2 Documented diagnosis of symptomatic HF (NYHA class II-IV) at Screening (Visit
1), and a medical history of typical symptoms/signs of heart failure >=6 weeks
before Screening (Visit 1), and receiving optimal therapy for HF as determined
by the health-care physician, with at least intermittent need for diuretic
treatment. Symptoms and signs are defined in Appendix G.
3 LVEF >40% and evidence of structural heart disease (ie, left ventricular
hypertrophy or left atrial enlargement [1]) documented by the most recent
echocardiogram, or cardiac magnetic resonance imaging within the last 12 months
prior to Screening (Visit 1). If no echocardiogram is available, it can be
performed at Screening (Visit 1).
[1] Structural heart disease, ie, LA enlargement and/or left ventricular
hypertrophy at the echocardiogram performed at Screening (Visit 1). Left atrial
enlargement is defined by at least 1 of the following: LA width (diameter) >=
3.8 cm or LA length >= 5.0 cm, or LA area >= 20 cm2 or LA volume >= 55 mL or LAVI
> 34 mL/m2. Left ventricular hypertrophy is defined by septal thickness or
posterior wall thickness >= 1.1 cm or LVMI > 95 g/m2 in women and > 115 g/m2 in
men.
4 6MWD >= 30 meters and <= 400 meters at Screening (Visit 1) and Randomisation
(Visit 2). Difference in 6MWD between Screening and Randomisation must be < 50
meters.
5 KCCQ-TSS <= 90 points at Screening (Visit 1) and Randomisation (Visit 2).
6 NT-proBNP >= 250 pg/mL (sinus rhythm) or >= 500 pg/mL (atrial
fibrillation/flutter) at Screening (Visit 1) for patients with BMI <= 30 kg/m2.
NT-proBNP >= 200 pg/mL (sinus rhythm) or >= 400 pg/mL (atrial
fibrillation/flutter) at Screening (Visit 1) for patients with BMI > 30 kg/m2.
The ECG performed at Screening should be used for heart rhythm evaluation.
7 Body mass index >= 18.0 kg/m2 and <= 45.0 kg/m2 (without rounding the values).
8 Male or female of non-childbearing potential.
Exclusion criteria
Part A:
1 eGFR < 30 mL/min/1.73m2 (Chronic Kidney Disease-Epidemiology Collaboration
formula) at Screening (Visit 1).
2. Systolic blood pressure < 90 mmHg or >= 160 mmHg if not on treatment with >= 3
blood pressure lowering medications or >= 180 mmHg irrespective of treatments at
Randomisation
3. Heart rate > 110 bpm or < 50 bpm at Randomisation
4. Life expectancy < 3 years due to other reasons than cardiovascular disease.
5. History or ongoing allergy/hypersensitivity reactions to drugs (including
but not limited to rash, angioedema, acute urticaria).
6. Presence of any disease or condition rather than HF constituting the main
reason for limiting the ability to exercise/reduced exercise capacity
7. Current decompensated HF and/or NT-proBNP > 5000 pg/mL at Screening (Visit 1)
8. Documented history of ejection fraction <= 40%.i.e. HF with recovered
ejection fraction. Transient ejection fraction decrease e.g. in the setting of
an MI does not apply
9. Any planned cardiovascular procedure (eg, coronary revascularisation,
ablation of atrial fibrillation/flutter, valve repair/replacement, aortic
aneurysm surgery, etc).
10. Any cardiac event (eg, myocardial infarction, unstable angina), coronary
revascularisation (percutaneous coronary intervention or coronary artery bypass
grafting), ablation of atrial fibrillation/flutter, valve repair/replacement,
implantation of a cardiac resynchronisation therapy device within 12 weeks
prior to Screening (Visit 1) or between Screening and Randomisation (Visit 3).
Patients who underwent a successful atrial fibrillation/flutter cardioversion,
can be enrolled in the study after 4 weeks.
14. Hb <110 g/L (male) and <100 g/L (female) or iron-deficiency with/without
anaemia requiring ongoing or planned IV iron treatment.
15. Participants with hyperthyroidism, uncontrolled hypothyroidism (including
but not limited to TSH >=10 mIU/mL), or any clinically significant thyroid
disease as judged by the investigator.
18. ALT or AST >= 2 × ULN at Screening (Visit 1).
19. Pulmonary arterial hypertension, chronic pulmonary embolism, severe
pulmonary disease including COPD (ie, requiring home oxygen, chronic nebulizer
therapy or chronic oral steroid therapy, or hospitalization for exacerbation of
COPD requiring ventilatory support within 12 months prior to Screening (Visit
1).
20. Any active infection requiring oral, intravenous or intramuscular treatment
at Screening (Visit 1) and/or at Randomisation (Visit 3).
24. Any concomitant medications known to be a potent CYP3A4 inducers or
inhibitors, eg, itraconazole, rifampicin, clarithromycin, or propylthiouracil
Part B:
1 eGFR < 30 mL/min/1.73m2 by Chronic Kidney Disease-Epidemiology Collaboration
formula at Screening (Visit 1).
2 Systolic blood pressure < 90 mmHg or >= 160 mmHg if not on treatment with >= 3
BP lowering medications or >= 180 mmHg irrespective of treatments at
Randomisation (Visit 2).
3 Heart rate > 110 bpm or < 50 bpm at Randomisation (Visit 2).
4 Life expectancy < 2 years due to other reasons than cardiovascular disease.
5 History or ongoing allergy/hypersensitivity reactions to drugs (including but
not limited to rash, angioedema, acute urticaria).
6 Presence of any disease or condition rather than HF constituting the main
reason for limiting the ability to exercise/reduced exercise capacity.
7 Current decompensated HF and/or NT-proBNP > 5000 pg/mL at Screening (Visit 1).
8 Documented history of ejection fraction <= 40% (ie, HF with recovered ejection
fraction). Transient ejection fraction decrease (eg, in the setting of an MI
does not apply).
9 Any planned cardiovascular procedure (eg, coronary revascularisation,
ablation of atrial fibrillation/flutter, valve repair/replacement, aortic
aneurysm surgery etc).
10 Any cardiac event (eg, myocardial infarction, unstable angina), coronary
revascularisation (percutaneous coronary intervention or coronary artery bypass
grafting), ablation of atrial fibrillation/flutter, valve repair/replacement,
implantation of a cardiac resynchronisation therapy device within 12 weeks
prior to Screening (Visit 1) or between Screening (Visit 1) and Randomisation
(Visit 2). Patients who underwent a successful atrial fibrillation/flutter
cardioversion, can be enrolled in the study after 4 weeks.
13 Hb < 110 g/L (male) and < 100 g/L (female) or iron-deficiency with/without
anaemia requiring ongoing or planned IV iron treatment.
14 Participants with hyperthyroidism, uncontrolled hypothyroidism (including
but not limited to TSH >=10 mIU/mL), or any clinically significant thyroid
disease as judged by the investigator.
17 ALT or AST >= 2 × ULN at Screening (Visit 1).
18 Primary pulmonary hypertension, chronic pulmonary embolism, severe pulmonary
disease including COPD (ie, requiring home oxygen, chronic nebulizer therapy or
chronic oral steroid therapy, or hospitalization for exacerbation of COPD
requiring ventilatory support within 12 months prior to Screening [Visit 1]).
23 Any concomitant medications known to be a potent CYP3A4 inducers or
inhibitors, eg, itraconazole, rifampicin, clarithromycin, or propylthiouracil
(refer to Section 6.5 for a list of prohibited and/or restricted medications
and treatments).
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 | EUCTR2020-005844-47-NL |
| Other | IND 134026 |
| CCMO | NL81778.056.22 |