Safety and tolerability study of AZD4831 in patients with heart failure. - SATELLITE

Study identifier:D6580C00003

ClinicalTrials.gov identifier:NCT03756285

EudraCT identifier:N/A

CTIS identifier:N/A

Terminated/Withdrawn

Official Title

A randomized, double blind, placebo-controlled, parallel group, multicentre, phase 2a study to assess target engagement, safety and tolerability of AZD4831 in patients with Heart Failure with preserved Ejection Fraction (HFpEF)

Medical condition

heart failure

Phase

Phase 2

Healthy volunteers

Study drug

AZD4831, Placebo

Sex

All

Actual Enrollment

Study type

Interventional

Age

45 Years - 85 Years

Date

Study Start Date: 11 Dec 2018

Primary Completion Date: 07 May 2020

Study Completion Date: 07 May 2020

Study design

Allocation: Randomized
Endpoint Classification: -
Intervention Model: Parallel Assignment
Masking: -
Primary Purpose: Treatment

Verification:

Verified 01 Jun 2021 by AstraZeneca

Collaborators

Inclusion and exclusion criteria

Inclusion Criteria

Informed consent
1. Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this CSP
2. Provision of signed and dated, written informed consent form prior to any mandatory study specific procedures, sampling, and analyses
Age
3. Patient must be 45 to 85 years of age inclusive, at the time of signing the informed consent form
Type of patient and disease characteristics
4. Signs and symptoms of HF in judgement of Investigator AND
a. Stable NYHA II-IV and
b. Ejection fraction (EF) ≥ 40 % and
c. Elevated NT-proBNP or BNP in the last 1 year defined as:
o Measured as out-patient: NT-proBNP ≥125 ng/L or BNP≥35 ng/L with sinus rhythm, NT-proBNP ≥750 ng/L or BNP ≥200 ng/L with atrial fibrillation (AF),
or
o Measured when hospitalized acutely: NT-proBNP ≥500 (ng/L) or BNP ≥125 ng/L with sinus rhythm, NT-proBNP ≥1250 (ng/L) or BNP ≥350 ng/L with AF
d. And at least one of the following:
• Hospitalization with HF as primary cause in last 12 months
• Structural heart disease on echo according to ESC guidelines i.e. either enlarged Left atrial volume index (LAVI > 34 ml/m2) or increased LVM (LVM index > 95 g/m2 in women and > 115 g/m2 in men)
• Pulmonary capillary wedge pressure (PCWP) at rest >15 mmHg or >25 mmHg at exercise
• Spectral tissue Doppler echocardiography - E/e’ ratio ≥13 at rest
Weight
5. Body Mass Index (BMI) range 18-40kg/m2
Sex
6. Male or female of nonchildbearing potential
Reproduction
7. Female patients must be 1 year post-menopausal or surgically sterile
8. Male patients must be surgically sterile or using an acceptable method of contraception (defined as barrier methods in conjunction with spermicides) for the duration of the study (from the time they sign consent) and for 3 months after the last dose of AZD4831/matching placebo to prevent pregnancy in a partner. Male patients must not donate or bank sperm during this same time period
Genetic sampling
9. For inclusion in this genetic research, patients must fulfil all of the inclusion criteria described above and provide informed consent for the genetic sampling and analysis

Exclusion Criteria

Creatinine clearance by Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) eGFR <30 ml/min/1.73m2 or dialysis
Life expectancy < 3 years due to other reasons than cardiovascular disease
Any ongoing skin disorder, history of or ongoing clinically significant allergy/hypersensitivity.
Current decompensated HF
Primary cardiomyopathy (e.g. constrictive, restrictive, infiltrative, toxic, hypertrophic, congenital or any primary cardiomyopathy) in judgment of investigator
Current hemodynamically significant valve disease in opinion of investigator
EF ever documented < 40%
Any current life-threatening dysrhythmia
Probable alternative primary reason for patient’s symptoms in judgment of investigator, including but not limited to:
a. Isolated pulmonary arterial hypertension or right ventricular (RV) failure; in the absence of left-sided HF
b. Anaemia: Hb <100 mg/L (10g/dL)
c. Severe chronic obstructive pulmonary disease (COPD) or lung disease (chronic O2, nebulizer or oral steroid therapy)
Cardiac surgery, acute coronary syndrome (ACS), or non-elective percutaneous coronary intervention (PCI) < 3 months
Known or clinically judged significant macrovascular coronary artery disease (CAD) that has not been revascularized
Heart transplantation or left ventricular assist device ever
Patients with uncontrolled or clinically significant thyroid disease as judged by the investigator.
Alanine transaminase (ALT) or aspartate aminotransferase (AST) ≥2 x upper limit of normal (ULN). Resampling will not be allowed during the same screening period if detected abnormal values do not have reasonable explanation and are not expected to return to normal level within few days.
Known positive HIV, hepatitis C antibody, hepatitis B virus surface antigen or hepatitis B virus core antibody, at screening

Location

Research Site

Groningen, Netherlands, 9713 GZ

Location

Research Site

DEVENTER, Netherlands, 7416 SE

Arms	Assigned Interventions
Experimental: AZD4831 AZD4831 tablets taken orally for for 90 days.	Drug: AZD4831 AZD4831 tablet taken orally for 90 days.
Placebo Comparator: Placebo Placebo tablets taken orally for 90 days.	Drug: Placebo Placebo tablet taken orally for 90 days.

Participant Flow

Recruitment Details

Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
No text entered.

Pre-Assignment Details

Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
No text entered.

Reporting Groups

	Description
AZD4831	AZD4831 tablets taken orally for for 90 days.
Placebo	Placebo tablets taken orally for 90 days.

Participant Flow: Overall Study

	AZD4831	Placebo
STARTED	27	14
COMPLETED	24	9
NOT COMPLETED	3	5
Lost to Follow-up	0	1
Study discontinued due to Other (Protocol deviation:subject meets exclusion criteria 20.)	0	1
Study discontinued due to Other (Dosing discontinued due to COVID-19)	3	3

Baseline Characteristics

Analysis Population Description -- Explanation of how the number of participants for analysis was determined.

Reporting Groups

	Description
AZD4831	AZD4831 tablets taken orally for for 90 days.
Placebo	Placebo tablets taken orally for 90 days.

Baseline Measures

	AZD4831	Placebo	Total
Number of Participants [units: Participants]	27	14	41
Age Continuous [units: years] Mean ± Standard Deviation	74.8 ± 6.61	73.5 ± 6.99	74.3 ± 6.68
Sex: Female, Male [units: participants]
Female	12	7	19
Male	15	7	22
Race (NIH/OMB) [units: ]
American Indian or Alaska Native	0	0	0
Asian	0	0	0
Native Hawaiian or Other Pacific Islander	0	0	0
Black or African American	0	1	1
White	27	13	40
More than one race	0	0	0
Unknown or Not Reported	0	0	0
Ethnicity (NIH/OMB) [units: ]
Hispanic or Latino	0	0	0
Not Hispanic or Latino	27	14	41
Unknown or Not Reported	0	0	0
Country [units: ]
Denmark	3	2	5
Netherlands	2	1	3
USA	0	1	1
Finland	5	3	8
Sweden	17	7	24

Outcome Measures

1. Primary Outcome Measure: Change from baseline in MPO specific activity [ Time Frame: Measurements on day 0, 10, 30 and 90. Change reported from day 0 to day 90. ]

Measure Type	Primary
Measure Name	Change from baseline in MPO specific activity
Measure Description	To compare the effect of AZD4831 to placebo on Target engagement, defined as ex vivo zymozan stimulated Myeloperoxidase (MPO) specific activity
Time Frame	Measurements on day 0, 10, 30 and 90. Change reported from day 0 to day 90.
Safety Issue?

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
20 of 27 patients in AZD4831 and 14 of 14 patients in placebo with evaluable measurements for analysis

Reporting Groups

	Description
AZD4831	AZD4831 tablets taken orally for 90 days.
Placebo	Placebo tablets taken orally for 90 days.

Measured Values

	AZD4831	Placebo
Number of Participants Analyzed [units:participants]	20	14
Change from baseline in MPO specific activity [units: Ratio] Geometric Least Squares Mean (95% Confidence Interval)	0.547 (0.379 to 0.790)	2.177 (1.168 to 4.058)

Statistical Analysis 1 for Change from baseline in MPO specific activity

Groups^[1]	All groups
Method^[3]	Mixed Models Analysis
P-Value^[4]	<0.001
Other^[5]	0.25
95% Confidence Interval	( 0.12 to 0.52 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	Covariates: atrial fibrillation status at randomization, baseline value, treatment, visit, and treatment*visit.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No text entered.
[5]	Other relevant estimation information:
	No text entered.

2. Secondary Outcome Measure: Change from baseline in CFVR measured in the mid-distal segment of the left anterior descending (LAD) coronary artery under adenosine infusion measured by Transthoracic Doppler Echocardiography (TDE). [ Time Frame: Measurement on day 0 and 90. ]

Measure Type	Secondary
Measure Name	Change from baseline in CFVR measured in the mid-distal segment of the left anterior descending (LAD) coronary artery under adenosine infusion measured by Transthoracic Doppler Echocardiography (TDE).
Measure Description	To compare the effect of AZD4831 to placebo on coronary flow velocity reserve (CFVR) measured in the mid-distal segment of the left anterior descending (LAD) coronary artery under adenosine infusion measured by Transthoracic Doppler Echocardiography (TDE).
Time Frame	Measurement on day 0 and 90.
Safety Issue?

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
18 of 27 patients in AZD4831 and 5 of 14 patients in placebo with evaluable measurements for analysis

Reporting Groups

	Description
AZD4831	AZD4831 tablets taken orally for for 90 days.
Placebo	Placebo tablets taken orally for 90 days.

Measured Values

	AZD4831	Placebo
Number of Participants Analyzed [units:participants]	18	5
Change from baseline in CFVR measured in the mid-distal segment of the left anterior descending (LAD) coronary artery under adenosine infusion measured by Transthoracic Doppler Echocardiography (TDE). [units: Ratio] Geometric Least Squares Mean (95% Confidence Interval)	0.975 (0.835 to 1.138)	1.002 (0.747 to 1.344)

Statistical Analysis 1 for Change from baseline in CFVR measured in the mid-distal segment of the left anterior descending (LAD) coronary artery under adenosine infusion measured by Transthoracic Doppler Echocardiography (TDE).

Groups^[1]	All groups
Method^[3]	ANCOVA
P-Value^[4]	0.568
Other^[5]	0.97
95% Confidence Interval	( 0.74 to --- )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	Covariates: atrial fibrillation status at randomization, baseline value, treatment
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No text entered.
[5]	Other relevant estimation information:
	No text entered.

3. Secondary Outcome Measure: Change from baseline in Walking distance [ Time Frame: Measurement on day 0, 30 and 90. Change reported from day 0 to day 90. ]

Measure Type	Secondary
Measure Name	Change from baseline in Walking distance
Measure Description	To compare the effect of AZD4831 to placebo on 6 minutes walking test (6MWT)
Time Frame	Measurement on day 0, 30 and 90. Change reported from day 0 to day 90.
Safety Issue?

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
23 of 27 patients in AZD4831 and 11 of 14 patients in placebo with evaluable measurements for analysis

Reporting Groups

	Description
AZD4831	AZD4831 tablets taken orally for for 90 days.
Placebo	Placebo tablets taken orally for 90 days.

Measured Values

	AZD4831	Placebo
Number of Participants Analyzed [units:participants]	23	11
Change from baseline in Walking distance [units: Meters] Least Squares Mean (95% Confidence Interval)	47.4 (20.3 to 74.5)	25.6 (-19.8 to 71.1)

Statistical Analysis 1 for Change from baseline in Walking distance

Groups^[1]	All groups
Method^[3]	Mixed Models Analysis
P-Value^[4]	0.407
Mean Difference (Final Values)^[5]	21.8
95% Confidence Interval	( -30.5 to 74.1 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	Covariates: atrial fibrillation status at randomization, baseline value, treatment, visit, and treatment*visit.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No text entered.
[5]	Other relevant estimation information:
	No text entered.

Serious Adverse Events

Time Frame	Adverse Events will be collected from the time of the first dose throughout the treatment period and including the follow-up period, up to 124 days. Serious Adverse Events will be recorded from the time of signing the informed consent form through follow-up period, up to 124 days.
Additional Description	No text entered.

Reporting Groups

	Description
AZD4831	AZD4831 tablets taken orally for for 90 days.
Placebo	Placebo tablets taken orally for 90 days.

Serious Adverse Events

AZD4831

Placebo

Total, serious adverse events

# participants affected / at risk

2/27 (7.41%)

2/14 (14.29%)

Infections and infestations

Pyelonephritis¹,^†

# participants affected / at risk

0/27 (0.00%)

1/14 (7.14%)

# events

Nervous system disorders

Syncope¹,^†

# participants affected / at risk

1/27 (3.70%)

1/14 (7.14%)

# events

Nervous system disorders

Transient ischaemic attack¹,^†

# participants affected / at risk

1/27 (3.70%)

0/14 (0.00%)

# events

Surgical and medical procedures

Hospitalisation¹,^†

# participants affected / at risk

0/27 (0.00%)

1/14 (7.14%)

# events

†	Events were collected by systematic assessment
1	Term from vocabulary, MedDRA version 23.0

Other Adverse Events

Time Frame	Adverse Events will be collected from the time of the first dose throughout the treatment period and including the follow-up period, up to 124 days. Serious Adverse Events will be recorded from the time of signing the informed consent form through follow-up period, up to 124 days.
Additional Description	No text entered.

Frequency Threshold

Threshold above which other adverse events are reported	1%

Reporting Groups

	Description
AZD4831	AZD4831 tablets taken orally for for 90 days.
Placebo	Placebo tablets taken orally for 90 days.

Other Adverse Events

AZD4831

Placebo

Total, other (not including serious) adverse events

# participants affected / at risk

21/27 (77.78%)

9/14 (64.29%)

Infections and infestations

Gingivitis¹,^†

# participants affected / at risk

0/27 (0.00%)

1/14 (7.14%)

Infections and infestations

Influenza¹,^†

# participants affected / at risk

1/27 (3.70%)

1/14 (7.14%)

Infections and infestations

Nasopharyngitis¹,^†

# participants affected / at risk

2/27 (7.41%)

0/14 (0.00%)

Infections and infestations

Pyelonephritis¹,^†

# participants affected / at risk

0/27 (0.00%)

1/14 (7.14%)

Infections and infestations

Respiratory tract infection¹,^†

# participants affected / at risk

1/27 (3.70%)

0/14 (0.00%)

Metabolism and nutrition disorders

Gout¹,^†

# participants affected / at risk

2/27 (7.41%)

0/14 (0.00%)

Nervous system disorders

Dizziness¹,^†

# participants affected / at risk

3/27 (11.11%)

1/14 (7.14%)

Nervous system disorders

Headache¹,^†

# participants affected / at risk

1/27 (3.70%)

0/14 (0.00%)

Nervous system disorders

Syncope¹,^†

# participants affected / at risk

1/27 (3.70%)

1/14 (7.14%)

Nervous system disorders

Transient ischaemic attack¹,^†

# participants affected / at risk

1/27 (3.70%)

0/14 (0.00%)

Eye disorders

Blindness¹,^†

# participants affected / at risk

1/27 (3.70%)

0/14 (0.00%)

Ear and labyrinth disorders

Vertigo¹,^†

# participants affected / at risk

1/27 (3.70%)

0/14 (0.00%)

Cardiac disorders

Bradycardia¹,^†

# participants affected / at risk

1/27 (3.70%)

0/14 (0.00%)

Cardiac disorders

Cardiac failure¹,^†

# participants affected / at risk

1/27 (3.70%)

0/14 (0.00%)

Vascular disorders

Bleeding varicose vein¹,^†

# participants affected / at risk

1/27 (3.70%)

0/14 (0.00%)

Vascular disorders

Peripheral coldness¹,^†

# participants affected / at risk

0/27 (0.00%)

1/14 (7.14%)

Respiratory, thoracic and mediastinal disorders

Cough¹,^†

# participants affected / at risk

1/27 (3.70%)

1/14 (7.14%)

Respiratory, thoracic and mediastinal disorders

Dyspnoea¹,^†

# participants affected / at risk

0/27 (0.00%)

1/14 (7.14%)

Respiratory, thoracic and mediastinal disorders

Epistaxis¹,^†

# participants affected / at risk

1/27 (3.70%)

0/14 (0.00%)

Respiratory, thoracic and mediastinal disorders

Oropharyngeal pain¹,^†

# participants affected / at risk

1/27 (3.70%)

0/14 (0.00%)

Respiratory, thoracic and mediastinal disorders

Rhinorrhoea¹,^†

# participants affected / at risk

0/27 (0.00%)

1/14 (7.14%)

Gastrointestinal disorders

Diarrhoea¹,^†

# participants affected / at risk

2/27 (7.41%)

0/14 (0.00%)

Gastrointestinal disorders

Dyspepsia¹,^†

# participants affected / at risk

0/27 (0.00%)

1/14 (7.14%)

Gastrointestinal disorders

Nausea¹,^†

# participants affected / at risk

2/27 (7.41%)

0/14 (0.00%)

Skin and subcutaneous tissue disorders

Dermatitis allergic¹,^†

# participants affected / at risk

1/27 (3.70%)

0/14 (0.00%)

Skin and subcutaneous tissue disorders

Hyperhidrosis¹,^†

# participants affected / at risk

1/27 (3.70%)

0/14 (0.00%)

Skin and subcutaneous tissue disorders

Pruritus¹,^†

# participants affected / at risk

3/27 (11.11%)

1/14 (7.14%)

Musculoskeletal and connective tissue disorders

Arthralgia¹,^†

# participants affected / at risk

0/27 (0.00%)

1/14 (7.14%)

Musculoskeletal and connective tissue disorders

Bursitis¹,^†

# participants affected / at risk

1/27 (3.70%)

0/14 (0.00%)

Musculoskeletal and connective tissue disorders

Musculoskeletal stiffness¹,^†

# participants affected / at risk

0/27 (0.00%)

1/14 (7.14%)

General disorders

Chest pain¹,^†

# participants affected / at risk

1/27 (3.70%)

0/14 (0.00%)

General disorders

Fatigue¹,^†

# participants affected / at risk

2/27 (7.41%)

0/14 (0.00%)

General disorders

Infusion site oedema¹,^†

# participants affected / at risk

1/27 (3.70%)

0/14 (0.00%)

General disorders

Pyrexia¹,^†

# participants affected / at risk

2/27 (7.41%)

0/14 (0.00%)

Investigations

Blood urea increased¹,^†

# participants affected / at risk

0/27 (0.00%)

1/14 (7.14%)

Investigations

Prostatic specific antigen increased¹,^†

# participants affected / at risk

0/27 (0.00%)

1/14 (7.14%)

Investigations

Troponin T increased¹,^†

# participants affected / at risk

0/27 (0.00%)

1/14 (7.14%)

Injury, poisoning and procedural complications

Contusion¹,^†

# participants affected / at risk

1/27 (3.70%)

0/14 (0.00%)

Injury, poisoning and procedural complications

Head injury¹,^†

# participants affected / at risk

1/27 (3.70%)

0/14 (0.00%)

Injury, poisoning and procedural complications

Scratch¹,^†

# participants affected / at risk

1/27 (3.70%)

0/14 (0.00%)

Injury, poisoning and procedural complications

Subcutaneous haematoma¹,^†

# participants affected / at risk

1/27 (3.70%)

0/14 (0.00%)

Infections and infestations

Urinary tract infection¹,^†

# participants affected / at risk

1/27 (3.70%)

0/14 (0.00%)

Gastrointestinal disorders

Plicated tongue¹,^†

# participants affected / at risk

1/27 (3.70%)

0/14 (0.00%)

Gastrointestinal disorders

Vomiting¹,^†

# participants affected / at risk

1/27 (3.70%)

0/14 (0.00%)

Surgical and medical procedures

Hospitalisation¹,^†

# participants affected / at risk

0/27 (0.00%)

1/14 (7.14%)

†	Events were collected by systematic assessment
1	Term from vocabulary, MedDRA version 23.0

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

The agreement is:

	The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.
	The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days . The sponsor cannot require changes to the communication and cannot extend the embargo.
	Other disclosure agreement that restricts the right of the PI to discuss or publish trial results after the trial is completed. Restriction Description:

Limitations and Caveats

Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterpretable data
Due to premature study termination, the statistical assumptions for the study design according to the Clinical Study Protocol could not be fulfilled, therefore, no statistical conclusions can be made based on primary or secondary efficacy objectives. Statistical significance could not be evaluated for any efficacy objectives and the p-values presented are viewed as nominal.

Results Point of Contact

Name/Title:	Global Clinical Lead
Organization:	AstraZeneca
Phone	1-877-240-9479
E-mail:	[email protected]

Documents available

Redacted CSP
Download
Redacted SAP
Download
Trial Results Summaries
Available here

Contacts

Contact

AstraZeneca Clinical Study Information Center

1-877-240-9479

information.center@astrazeneca.com

Sponsors

Collaborators

Inclusion Criteria

Exclusion Criteria

Research Site

Research Site

Redacted CSP

Redacted SAP

Trial Results Summaries