SATELLITE: Safety and Tolerability Study of AZD4831 in Patients With Heart Failure.

• Sponsor: AstraZeneca (Industry)
• Overall Status: Terminated
• CT.gov ID: NCT03756285
• Collaborator: (none)
• Enrollment: 41
• Locations: 13
• Arms: 2
• Actual Duration (Months): 16.9
• Patients Per Site: 3.2
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

A randomized, double-blind, placebo-controlled, parallel group, multicentre study in patients with Heart Failure with preserved Ejection Fraction (HFpEF). The study will be conducted at approximately 15 sites in 5 countries. Approximately 96 patients will be randomized to AZD4831 or placebo (treatment duration 90 days).

Condition or Disease	Intervention/Treatment	Phase
Heart Failure	Drug: AZD4831; Drug: Placebo	Phase 2

Detailed Description

This is a randomized, double-blind, placebo controlled, parallel group, multicentre study in patients with Heart Failure with preserved Ejection Fraction (HFpEF) and mid-range Ejection Fraction (HRmrEF). The study will be conducted at approximately 15 sites in 5 countries (USA, Sweden, Denmark, Finland, Netherlands). Patients suitable for the study will be checked for eligibility, signing the informed consent and enrolled to the study at visit 1. The study will be divided into two parts, Part A and Part B. In part A 37 patients will be randomized at visit 2 in a 2:1 ratio to once daily dosing of AZD4831 or matching placebo for approximately 90 days. After approximately 30 days of treatment, an interim analysis will be done to analyse the safety, tolerability and target engagement. After the evaluation, the randomization to Part B may proceed. In Part B the approximate 59 remaining patients will be randomized and treated for approximately 90 days.

Study Design

• Study Type: Interventional
• Actual Enrollment: 41 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Care Provider, Investigator)
• Primary Purpose: Treatment
• 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)
• Actual Study Start Date: Dec 11, 2018
• Actual Primary Completion Date: May 7, 2020
• Actual Study Completion Date: May 7, 2020

Arms and Interventions

Arm	Intervention/Treatment
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.

Outcome Measures

Primary Outcome Measures

1. Change From Baseline in MPO Specific Activity [Measurements on day 0, 10, 30 and 90. Change reported from day 0 to day 90.]

   To compare the effect of AZD4831 to placebo on Target engagement, defined as ex vivo zymozan stimulated Myeloperoxidase (MPO) specific activity

Secondary Outcome Measures

1. 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). [Measurement on day 0 and 90.]

   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).

2. Change From Baseline in Walking Distance [Measurement on day 0, 30 and 90. Change reported from day 0 to day 90.]

   To compare the effect of AZD4831 to placebo on 6 minutes walking test (6MWT)

Eligibility Criteria

Criteria

• Ages Eligible for Study: 45 Years to 85 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

1. 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

1. Signs and symptoms of HF in judgement of Investigator AND

2. Stable NYHA II-IV and

3. Ejection fraction (EF) ≥ 40 % and

4. 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

1. 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

1. Body Mass Index (BMI) range 18-40kg/m2

Sex

1. Male or female of nonchildbearing potential

Reproduction

1. Female patients must be 1 year post-menopausal or surgically sterile

2. 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

1. 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:

1. Isolated pulmonary arterial hypertension or right ventricular (RV) failure; in the absence of left-sided HF

2. Anaemia: Hb <100 mg/L (10g/dL)

3. 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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Research Site	Chicago	Illinois	United States	60611
2	Research Site	Boston	Massachusetts	United States	02115
3	Research Site	Aarhus N		Denmark	8200
4	Research Site	Herlev		Denmark	2730
5	Research Site	Hvidovre		Denmark	2650
6	Research Site	Odense C		Denmark	5000
7	Research Site	Turku		Finland	20520
8	Research Site	Deventer		Netherlands	7416 SE
9	Research Site	Dordrecht		Netherlands	3318 AT
10	Research Site	Groningen		Netherlands	9713 GZ
11	Research Site	Göteborg		Sweden	41345
12	Research Site	Lund		Sweden	22242
13	Research Site	Stockholm		Sweden	171 76

Sponsors and Collaborators

• AstraZeneca

Investigators

None specified.

Study Documents (Full-Text)

• Study Protocol - Jan 9, 2020
• Statistical Analysis Plan - Nov 12, 2020

More Information

Additional Information:

• Redacted CSP
• Redacted SAP

Publications

None provided.

• Responsible Party: AstraZeneca
• ClinicalTrials.gov Identifier: NCT03756285
• Other Study ID Numbers: D6580C00003
• First Posted: Nov 28, 2018
• Last Update Posted: Jul 19, 2021
• Last Verified: Jun 1, 2021

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No
• Keywords provided by AstraZeneca: Heart Failure with Ejection Fraction
• Additional relevant MeSH terms: Heart Failure

Study Results

Participant Flow

Arm/Group Title	AZD4831	Placebo
Arm/Group Description	AZD4831 tablets taken orally for for 90 days.	Placebo tablets taken orally for 90 days.
Period Title: Overall Study
STARTED	27	14
COMPLETED	24	9
NOT COMPLETED	3	5

Baseline Characteristics

Arm/Group Title	AZD4831	Placebo	Total
Arm/Group Description	AZD4831 tablets taken orally for for 90 days.	Placebo tablets taken orally for 90 days.	Total of all reporting groups
Overall Participants	27	14	41
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	74.8 (6.61)	73.5 (6.99)	74.3 (6.68)
Sex: Female, Male (Count of Participants)
Female	12 44.4%	7 50%	19 46.3%
Male	15 55.6%	7 50%	22 53.7%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%	0 0%	0 0%
Not Hispanic or Latino	27 100%	14 100%	41 100%
Unknown or Not Reported	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	0 0%	1 7.1%	1 2.4%
White	27 100%	13 92.9%	40 97.6%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%
Country (Count of Participants)
Denmark	3 11.1%	2 14.3%	5 12.2%
Netherlands	2 7.4%	1 7.1%	3 7.3%
USA	0 0%	1 7.1%	1 2.4%
Finland	5 18.5%	3 21.4%	8 19.5%
Sweden	17 63%	7 50%	24 58.5%

Outcome Measures

1. Primary Outcome

Title	Change From Baseline in MPO Specific Activity
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.

Outcome Measure Data

Analysis Population Description

20 of 27 patients in AZD4831 and 14 of 14 patients in placebo with evaluable measurements for analysis

Arm/Group Title	AZD4831	Placebo
Arm/Group Description	AZD4831 tablets taken orally for 90 days.	Placebo tablets taken orally for 90 days.
Measure Participants	20	14
Geometric Least Squares Mean (95% Confidence Interval) [Ratio]	0.547	2.177

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	AZD4831, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mixed Models Analysis
	Comments	Covariates: atrial fibrillation status at randomization, baseline value, treatment, visit, and treatment*visit.
Method of Estimation	Estimation Parameter	Least Square Means Ratio
	Estimated Value	0.25
	Confidence Interval	(2-Sided) 95%; 0.12 to 0.52
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	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).
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.

Outcome Measure Data

Analysis Population Description

18 of 27 patients in AZD4831 and 5 of 14 patients in placebo with evaluable measurements for analysis

Arm/Group Title	AZD4831	Placebo
Arm/Group Description	AZD4831 tablets taken orally for for 90 days.	Placebo tablets taken orally for 90 days.
Measure Participants	18	5
Geometric Least Squares Mean (95% Confidence Interval) [Ratio]	0.975	1.002

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	AZD4831, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.568
	Comments
	Method	ANCOVA
	Comments	Covariates: atrial fibrillation status at randomization, baseline value, treatment
Method of Estimation	Estimation Parameter	Least Square Means Ratio
	Estimated Value	0.97
	Confidence Interval	(1-Sided) 95%; 0.74 to
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Change From Baseline in Walking Distance
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.

Outcome Measure Data

Analysis Population Description

23 of 27 patients in AZD4831 and 11 of 14 patients in placebo with evaluable measurements for analysis

Arm/Group Title	AZD4831	Placebo
Arm/Group Description	AZD4831 tablets taken orally for for 90 days.	Placebo tablets taken orally for 90 days.
Measure Participants	23	11
Least Squares Mean (95% Confidence Interval) [Meters]	47.4	25.6

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	AZD4831, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.407
	Comments
	Method	Mixed Models Analysis
	Comments	Covariates: atrial fibrillation status at randomization, baseline value, treatment, visit, and treatment*visit.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	21.8
	Confidence Interval	(2-Sided) 95%; -30.5 to 74.1
	Parameter Dispersion	Type: Value:
	Estimation Comments

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.
Arm/Group Title	AZD4831		Placebo
Arm/Group Description	AZD4831 tablets taken orally for for 90 days.		Placebo tablets taken orally for 90 days.
All Cause Mortality
	AZD4831		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/27 (0%)		0/14 (0%)
Serious Adverse Events
	AZD4831		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/27 (7.4%)		2/14 (14.3%)
Infections and infestations
Pyelonephritis	0/27 (0%)	0	1/14 (7.1%)	1
Nervous system disorders
Syncope	1/27 (3.7%)	1	1/14 (7.1%)	1
Transient ischaemic attack	1/27 (3.7%)	1	0/14 (0%)	0
Surgical and medical procedures
Hospitalisation	0/27 (0%)	0	1/14 (7.1%)	1
Other (Not Including Serious) Adverse Events
	AZD4831		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	21/27 (77.8%)		9/14 (64.3%)
Cardiac disorders
Bradycardia	1/27 (3.7%)		0/14 (0%)
Cardiac failure	1/27 (3.7%)		0/14 (0%)
Ear and labyrinth disorders
Vertigo	1/27 (3.7%)		0/14 (0%)
Eye disorders
Blindness	1/27 (3.7%)		0/14 (0%)
Gastrointestinal disorders
Diarrhoea	2/27 (7.4%)		0/14 (0%)
Dyspepsia	0/27 (0%)		1/14 (7.1%)
Nausea	2/27 (7.4%)		0/14 (0%)
Plicated tongue	1/27 (3.7%)		0/14 (0%)
Vomiting	1/27 (3.7%)		0/14 (0%)
General disorders
Chest pain	1/27 (3.7%)		0/14 (0%)
Fatigue	2/27 (7.4%)		0/14 (0%)
Infusion site oedema	1/27 (3.7%)		0/14 (0%)
Pyrexia	2/27 (7.4%)		0/14 (0%)
Infections and infestations
Gingivitis	0/27 (0%)		1/14 (7.1%)
Influenza	1/27 (3.7%)		1/14 (7.1%)
Nasopharyngitis	2/27 (7.4%)		0/14 (0%)
Pyelonephritis	0/27 (0%)		1/14 (7.1%)
Respiratory tract infection	1/27 (3.7%)		0/14 (0%)
Urinary tract infection	1/27 (3.7%)		0/14 (0%)
Injury, poisoning and procedural complications
Contusion	1/27 (3.7%)		0/14 (0%)
Head injury	1/27 (3.7%)		0/14 (0%)
Scratch	1/27 (3.7%)		0/14 (0%)
Subcutaneous haematoma	1/27 (3.7%)		0/14 (0%)
Investigations
Blood urea increased	0/27 (0%)		1/14 (7.1%)
Prostatic specific antigen increased	0/27 (0%)		1/14 (7.1%)
Troponin T increased	0/27 (0%)		1/14 (7.1%)
Metabolism and nutrition disorders
Gout	2/27 (7.4%)		0/14 (0%)
Musculoskeletal and connective tissue disorders
Arthralgia	0/27 (0%)		1/14 (7.1%)
Bursitis	1/27 (3.7%)		0/14 (0%)
Musculoskeletal stiffness	0/27 (0%)		1/14 (7.1%)
Nervous system disorders
Dizziness	3/27 (11.1%)		1/14 (7.1%)
Headache	1/27 (3.7%)		0/14 (0%)
Syncope	1/27 (3.7%)		1/14 (7.1%)
Transient ischaemic attack	1/27 (3.7%)		0/14 (0%)
Respiratory, thoracic and mediastinal disorders
Cough	1/27 (3.7%)		1/14 (7.1%)
Dyspnoea	0/27 (0%)		1/14 (7.1%)
Epistaxis	1/27 (3.7%)		0/14 (0%)
Oropharyngeal pain	1/27 (3.7%)		0/14 (0%)
Rhinorrhoea	0/27 (0%)		1/14 (7.1%)
Skin and subcutaneous tissue disorders
Dermatitis allergic	1/27 (3.7%)		0/14 (0%)
Hyperhidrosis	1/27 (3.7%)		0/14 (0%)
Pruritus	3/27 (11.1%)		1/14 (7.1%)
Surgical and medical procedures
Hospitalisation	0/27 (0%)		1/14 (7.1%)
Vascular disorders
Bleeding varicose vein	1/27 (3.7%)		0/14 (0%)
Peripheral coldness	0/27 (0%)		1/14 (7.1%)

Limitations/Caveats

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.

More Information

Certain Agreements

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

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.