A Dose-range Finding Study of MAA868 in Patients With Atrial Fibrillation

• Sponsor: Anthos Therapeutics, Inc. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT04213807
• Collaborator: Covance (Industry)
• Enrollment: 28
• Locations: 6
• Arms: 2
• Actual Duration (Months): 14.9
• Patients Per Site: 4.7
• Patients Per Site Per Month: 0.3

Study Details

Study Description

Brief Summary

This study is a multicenter, randomized, subject and Investigator-blinded, placebo-controlled, parallel-group, multiple ascending dose-ranging study to evaluate the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) effects of MAA868 in patients with atrial fibrillation (AF) or flutter at low risk of thromboembolic stroke or peripheral embolism.

Condition or Disease	Intervention/Treatment	Phase
Atrial Fibrillation	Biological: MAA868 Cohort 1; Biological: MAA868 Cohort 2; Biological: MAA868 Cohort 3; Other: Placebo	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 28 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Prevention
• Official Title: A Randomized, Placebo-controlled, Dose-range Finding Study to Assess the Pharmacokinetic and Pharmacodynamic Parameters, Safety, Tolerability, and Immunogenicity of MAA868 in Patients With Atrial Fibrillation
• Actual Study Start Date: Dec 11, 2019
• Actual Primary Completion Date: Dec 29, 2020
• Actual Study Completion Date: Mar 8, 2021

Arms and Interventions

Arm	Intervention/Treatment
Experimental: MAA868 Subcutaneous injection on Day 1 with two subsequent monthly injections	Biological: MAA868 Cohort 1; Subcutaneous injection: low dose; Biological: MAA868 Cohort 2; Subcutaneous injection: high dose; Biological: MAA868 Cohort 3; Subcutaneous injection: Dose to be determined.
Placebo Comparator: Placebo Subcutaneous injection: Placebo on Day 1 with two subsequent monthly injections	Other: Placebo; Subcutaneous injection: Placebo

Outcome Measures

Primary Outcome Measures

1. Number of Participants That Achieved More Than or Equal to 50%, 80%, and 90% Factor XI Inhibition at Trough After the Third Dose (Day 91) at Different Dose Levels of MAA868 [Day 91]

   Number of participants achieving more than or equal to 50%, 80%, and 90% inhibition of factor XI (less than 50%, 20%, or 10% free factor XI) at trough after the third dose on Day 91 at different dose levels of MAA868

Secondary Outcome Measures

1. Number of Participants Achieving More Than or Equal to 50%, 80%, and 90% Factor XI Inhibition at Trough After First (Day 31) and Second Doses (Day 61) at Different Dose Levels of MAA868 [Day 31 and Day 61]

   Number of participants achieving more than or equal to 50%, 80%, and 90% inhibition of factor XI (less than 50%, 20%, or 10% free factor XI) at trough on Day 31 (after first dose) and Day 61 (after second dose) at different dose levels of MAA868

2. Overall Number of Participants Who Experienced Adverse Events, Including Serious Adverse Events, During the Treatment Period and Through End of Study [Day 1 through end of study, up to 170 days]

   Overall number of participants who experienced adverse events following multiple subcutaneous administration of MAA868 compared to placebo in participants with atrial fibrillation or atrial flutter

3. Incidence of Major Bleeding Events, Clinically Relevant Non-major Bleeding Events and Total Bleeding With MAA868 Relative to Placebo [Day 1 through end of study, up to 170 days]

   Occurrence of confirmed major bleeding events, clinically relevant non-major bleeding events and total bleeding events during the treatment period

4. Immunogenicity of MAA868 [Days 1, 31, 61, 71, 91, 121 and 170]

   Number of participants with anti-drug (MAA868) antibodies for all participants who received MAA868 120 mg or MAA868 180 mg. "Non-evaluable observation" refers to participants who had no sample collected (due to no visit or remote visit) or for whom the sample was not frozen.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 85 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Male and female patients ≥ 18 and < 85 years old with paroxysmal atrial fibrillation (PAF) or atrial flutter on 12 lead electrocardiography at Screening Or

• Patients with a history of PAF or atrial flutter, as documented by (telemetry, 12 lead electrocardiography or ambulatory [e.g. Holter] monitor) and not due to a reversible condition (e.g. alcohol binge drinking) can be entered even if they do not have PAF at Screening. There is not time-limit for this.

• Patients with a Congestive heart failure, Hypertension, Age ( > 65 = 1 point, > 75 = 2 points), Diabetes, previous Stroke/transient ischemic attack (2 points) (CHA2DS2-VASc) risk score (tool as a predictor for estimating the risk of stroke in patients with atrial fibrillation (AF); Lip et al 2010) of 0-1 for men and 1-2 for women and in whom, in the investigator's judgment, the use of an anticoagulant for stroke prevention is not indicated

Exclusion Criteria:

• History of stroke, transient ischemic attack or systemic embolism

• History of major bleeding during treatment with an anticoagulant or antiplatelet therapy. (Patients who have had major bleeding on anticoagulants or antiplatelet therapy more than a year ago can be enrolled only if the bleeding was due to a reversible cause, e.g. gastro-duodenal ulcer that was successfully treated.)

• History of traumatic or non-traumatic intracranial, intraspinal or intraocular bleeding

• Known bleeding diathesis or any known active bleeding site at screening or baseline

• Family history of bleeding disorder

• Known active GI lesions predisposing to bleeding events

• Myocardial infarction, unstable angina pectoris or coronary artery bypass graft (CABG) surgery within 12 months prior to the Screening period

• Known clinically significant valvular heart disease including moderate or severe mitral stenosis (valve area <1.5 cm2)

• Patients with a prosthetic heart valve

Other protocol defined Inclusion/Exclusion criteria may apply

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Anthos Investigative Site	Beverly Hills	California	United States	90211
2	Anthos Investigative Site	Wichita	Kansas	United States	67207
3	Anthos Investigative Site	Alexandria	Louisiana	United States	71301
4	Anthos Investigative Site	Lansing	Michigan	United States	48912
5	Anthos Investigative Site	Wynnewood	Pennsylvania	United States	19096
6	Anthos Investigative Site	McKinney	Texas	United States	75069

Sponsors and Collaborators

• Anthos Therapeutics, Inc.
• Covance

Investigators

• Principal Investigator: Norman E Lepor, MD FACC FAHA FSCAI, Westside Medical Associates of Los Angeles

Study Documents (Full-Text)

• Study Protocol - May 10, 2020
• Statistical Analysis Plan - Mar 18, 2021

More Information

Publications

None provided.

• Responsible Party: Anthos Therapeutics, Inc.
• ClinicalTrials.gov Identifier: NCT04213807
• Other Study ID Numbers: ANT-004
• First Posted: Dec 30, 2019
• Last Update Posted: Jan 11, 2022
• Last Verified: Dec 1, 2021

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Anthos Therapeutics, Inc.: atrial fibrillation; flutter; paroxysmal atrial fibrillation; stroke; cardiac arrhythmia
• Additional relevant MeSH terms: Atrial Fibrillation

Study Results

Participant Flow

Recruitment Details	No subjects were enrolled in the optional Cohort 3.
Pre-assignment Detail	28 participants were screened. 5 participants did not meet inclusion/exclusion criteria; 5 eligible participants failed randomization.

Arm/Group Title	Placebo	MAA868 120 mg	MAA868 180 mg
Arm/Group Description	Subcutaneous injection of placebo on Day 1, Day 31, and Day 61	Subcutaneous injection of 120 mg MAA868 on Day 1, Day 31, and Day 61	Subcutaneous injection of 180 mg MAA868 on Day 1, Day 31, and Day 61
Period Title: Overall Study
STARTED	5	6	7
COMPLETED	5	6	6
NOT COMPLETED	0	0	1

Baseline Characteristics

Arm/Group Title	Placebo	MAA868 120 mg	MAA868 180 mg	Total
Arm/Group Description	Subcutaneous injection of placebo on Day 1, Day 31, and Day 61	Subcutaneous injection of 120 mg MAA868 on Day 1, Day 31, and Day 61	Subcutaneous injection of 180 mg MAA868 on Day 1, Day 31, and Day 61	Total of all reporting groups
Overall Participants	5	6	7	18
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	52.2 (18.79)	53.8 (9.24)	58.1 (8.34)	55.1 (11.81)
Age, Customized (years) [Number]
18 to 20	1	0	0	1
21 to 30	0	0	0	0
31 to 40	0	1	0	1
41 to 50	0	0	1	1
51 to 60	2	4	4	10
61 to 70	2	1	2	5
71 to 80	0	0	0	0
81 to 85	0	0	0	0
Sex: Female, Male (Count of Participants)
Female	0 0%	3 50%	2 28.6%	5 27.8%
Male	5 100%	3 50%	5 71.4%	13 72.2%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%	0 0%	0 0%	0 0%
Not Hispanic or Latino	5 100%	6 100%	7 100%	18 100%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%	0 0%
Black or African American	0 0%	0 0%	2 28.6%	2 11.1%
White	5 100%	6 100%	5 71.4%	16 88.9%
More than one race	0 0%	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%
Height (centimeters) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [centimeters]	182.01 (5.573)	174.60 (11.311)	175.74 (8.337)	177.10 (8.918)
Weight (kg) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg]	99.352 (13.1715)	91.667 (7.1102)	94.933 (23.2745)	95.072 (16.0115)
Body mass index (kg/m^2) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg/m^2]	30.022 (4.1647)	30.392 (4.7558)	30.887 (8.6754)	30.482 (6.1179)

Outcome Measures

1. Primary Outcome

Title	Number of Participants That Achieved More Than or Equal to 50%, 80%, and 90% Factor XI Inhibition at Trough After the Third Dose (Day 91) at Different Dose Levels of MAA868
Description	Number of participants achieving more than or equal to 50%, 80%, and 90% inhibition of factor XI (less than 50%, 20%, or 10% free factor XI) at trough after the third dose on Day 91 at different dose levels of MAA868
Time Frame	Day 91

Outcome Measure Data

Analysis Population Description

Pharmacokinetic/Pharmacodynamic Set

Arm/Group Title	Placebo	MAA868 120 mg	MAA868 180 mg
Arm/Group Description	Subcutaneous injection of placebo on Day 1, Day 31, and Day 61	Subcutaneous injection of 120 mg MAA868 on Day 1, Day 31, and Day 61	Subcutaneous injection of 180 mg MAA868 on Day 1, Day 31, and Day 61
Measure Participants	5	6	7
More than or equal to 50% inhibition of factor XI	0 0%	2 33.3%	4 57.1%
More than or equal to 80% inhibition of factor XI	0 0%	0 0%	1 14.3%
More than or equal to 90% inhibition of factor XI	0 0%	0 0%	0 0%

2. Secondary Outcome

Title	Number of Participants Achieving More Than or Equal to 50%, 80%, and 90% Factor XI Inhibition at Trough After First (Day 31) and Second Doses (Day 61) at Different Dose Levels of MAA868
Description	Number of participants achieving more than or equal to 50%, 80%, and 90% inhibition of factor XI (less than 50%, 20%, or 10% free factor XI) at trough on Day 31 (after first dose) and Day 61 (after second dose) at different dose levels of MAA868
Time Frame	Day 31 and Day 61

Outcome Measure Data

Analysis Population Description

Pharmacokinetic/Pharmacodynamic Set

Arm/Group Title	Placebo	MAA868 120 mg	MAA868 180 mg
Arm/Group Description	Subcutaneous injection of placebo on Day 1, Day 31, and Day 61	Subcutaneous injection of 120 mg MAA868 on Day 1, Day 31, and Day 61	Subcutaneous injection of 180 mg MAA868 on Day 1, Day 31, and Day 61
Measure Participants	5	6	7
More than or equal to 50% factor XI inhibition : Day 31	0 0%	1 16.7%	5 71.4%
More than or equal to 50% factor XI inhibition : Day 61	0 0%	2 33.3%	5 71.4%
More than or equal to 80% factor XI inhibition : Day 31	0 0%	1 16.7%	3 42.9%
More than or equal to 80% factor XI inhibition : Day 61	0 0%	0 0%	1 14.3%
More than or equal to 90% factor XI inhibition : Day 31	0 0%	0 0%	0 0%
More than or equal to 90% factor XI inhibition : Day 61	0 0%	0 0%	0 0%

3. Secondary Outcome

Title	Overall Number of Participants Who Experienced Adverse Events, Including Serious Adverse Events, During the Treatment Period and Through End of Study
Description	Overall number of participants who experienced adverse events following multiple subcutaneous administration of MAA868 compared to placebo in participants with atrial fibrillation or atrial flutter
Time Frame	Day 1 through end of study, up to 170 days

Outcome Measure Data

Analysis Population Description

Safety Set

Arm/Group Title	Placebo	MAA868 120 mg	MAA868 180 mg
Arm/Group Description	Subcutaneous injection of placebo on Day 1, Day 31, and Day 61	Subcutaneous injection of 120 mg MAA868 on Day 1, Day 31, and Day 61	Subcutaneous injection of 180 mg MAA868 on Day 1, Day 31, and Day 61
Measure Participants	5	6	7
Count of Participants [Participants]	4 80%	5 83.3%	3 42.9%

4. Secondary Outcome

Title	Incidence of Major Bleeding Events, Clinically Relevant Non-major Bleeding Events and Total Bleeding With MAA868 Relative to Placebo
Description	Occurrence of confirmed major bleeding events, clinically relevant non-major bleeding events and total bleeding events during the treatment period
Time Frame	Day 1 through end of study, up to 170 days

Outcome Measure Data

Analysis Population Description

Safety Set

Arm/Group Title	Placebo	MAA868 120 mg	MAA868 180 mg
Arm/Group Description	Subcutaneous injection of placebo on Day 1, Day 31, and Day 61	Subcutaneous injection of 120 mg MAA868 on Day 1, Day 31, and Day 61	Subcutaneous injection of 180 mg MAA868 on Day 1, Day 31, and Day 61
Measure Participants	5	6	7
Major bleeding events	0	0	0
Clinically relevant non-major bleeding events	0	0	0
Nuisance (not clinically relevant) bleeding events	2	1	1
No bleeding events	0	1	0

5. Secondary Outcome

Title	Immunogenicity of MAA868
Description	Number of participants with anti-drug (MAA868) antibodies for all participants who received MAA868 120 mg or MAA868 180 mg. "Non-evaluable observation" refers to participants who had no sample collected (due to no visit or remote visit) or for whom the sample was not frozen.
Time Frame	Days 1, 31, 61, 71, 91, 121 and 170

Outcome Measure Data

Analysis Population Description

Safety Set

Arm/Group Title	MAA868 120 mg	MAA868 180 mg
Arm/Group Description	Subcutaneous injection of 120 mg MAA868 on Day 1, Day 31, and Day 61	Subcutaneous injection of 180 mg MAA868 on Day 1, Day 31, and Day 61
Measure Participants	6	7
Negative	6 120%	7 116.7%
Positive	0 0%	0 0%
Non-evaluable observation	0 0%	0 0%
Negative	6 120%	7 116.7%
Positive	0 0%	0 0%
Non-evaluable observation	0 0%	0 0%
Negative	6 120%	7 116.7%
Positive	0 0%	0 0%
Non-evaluable observation	0 0%	0 0%
Negative	3 60%	6 100%
Positive	0 0%	0 0%
Non-evaluable observation	3 60%	1 16.7%
Negative	4 80%	6 100%
Positive	0 0%	0 0%
Non-evaluable observation	2 40%	1 16.7%
Negative	5 100%	5 83.3%
Positive	0 0%	0 0%
Non-evaluable observation	1 20%	2 33.3%
Negative	5 100%	5 83.3%
Positive	0 0%	0 0%
Non-evaluable observation	1 20%	2 33.3%
Negative	6 120%	7 116.7%
Positive	0 0%	0 0%
Non-evaluable observation	0 0%	0 0%

Adverse Events

Time Frame	Adverse event information was collected at every study visit from providing written informed consent for participation in the study (on Days -28 to -3) until Day 170 (the end of study visit).
Adverse Event Reporting Description	The occurrence of adverse events was to be sought by non-directive questioning of the participants at each visit by the site staff during the study (e.g., "How are you feeling today?" or "How have you been feeling since your last visit") to elicit adverse event information from the participant. Adverse events might have been detected when they were volunteered by the participants during or between visits or through physical examination finding, laboratory test finding, or other assessments.
Arm/Group Title	Placebo		MAA868 120 mg		MAA868 180 mg
Arm/Group Description	Subcutaneous injection of placebo on Day 1, Day 31, and Day 61		Subcutaneous injection of 120 mg MAA868 on Day 1, Day 31, and Day 61		Subcutaneous injection of 180 mg MAA868 on Day 1, Day 31, and Day 61
All Cause Mortality
	Placebo		MAA868 120 mg		MAA868 180 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/5 (0%)		0/6 (0%)		0/7 (0%)
Serious Adverse Events
	Placebo		MAA868 120 mg		MAA868 180 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/5 (0%)		0/6 (0%)		0/7 (0%)
Other (Not Including Serious) Adverse Events
	Placebo		MAA868 120 mg		MAA868 180 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	4/5 (80%)		5/6 (83.3%)		3/7 (42.9%)
Blood and lymphatic system disorders
Leukocytosis	0/5 (0%)	0	0/6 (0%)	0	1/7 (14.3%)	1
Cardiac disorders
Atrial flutter	0/5 (0%)	0	1/6 (16.7%)	1	0/7 (0%)	0
Gastrointestinal disorders
Diarrhoea	1/5 (20%)	1	1/6 (16.7%)	1	0/7 (0%)	0
Abdominal pain	0/5 (0%)	0	1/6 (16.7%)	1	0/7 (0%)	0
Dental caries	0/5 (0%)	0	1/6 (16.7%)	1	0/7 (0%)	0
Gingival bleeding	0/5 (0%)	0	0/6 (0%)	0	1/7 (14.3%)	1
Infections and infestations
Gastroenteritis	0/5 (0%)	0	1/6 (16.7%)	1	0/7 (0%)	0
Herpes simplex	0/5 (0%)	0	1/6 (16.7%)	1	0/7 (0%)	0
Otitis media	0/5 (0%)	0	1/6 (16.7%)	1	0/7 (0%)	0
Sinusitis	0/5 (0%)	0	1/6 (16.7%)	1	0/7 (0%)	0
Injury, poisoning and procedural complications
Contusion	1/5 (20%)	1	0/6 (0%)	0	0/7 (0%)	0
Investigations
Blood pressure increased	1/5 (20%)	1	0/6 (0%)	0	0/7 (0%)	0
Coagulation test abnormal	0/5 (0%)	0	0/6 (0%)	0	1/7 (14.3%)	1
Eosinophil count increased	1/5 (20%)	1	0/6 (0%)	0	0/7 (0%)	0
Musculoskeletal and connective tissue disorders
Back pain	1/5 (20%)	1	0/6 (0%)	0	1/7 (14.3%)	2
Arthralgia	0/5 (0%)	0	1/6 (16.7%)	1	0/7 (0%)	0
Muscle spasms	1/5 (20%)	1	0/6 (0%)	0	0/7 (0%)	0
Musculoskeletal chest pain	0/5 (0%)	0	0/6 (0%)	0	1/7 (14.3%)	1
Pain in extremity	0/5 (0%)	0	1/6 (16.7%)	1	0/7 (0%)	0
Nervous system disorders
Syncope	0/5 (0%)	0	1/6 (16.7%)	1	0/7 (0%)	0
Renal and urinary disorders
Dysuria	0/5 (0%)	0	1/6 (16.7%)	1	0/7 (0%)	0
Haematuria	0/5 (0%)	0	1/6 (16.7%)	1	0/7 (0%)	0
Nephrolithiasis	0/5 (0%)	0	1/6 (16.7%)	1	0/7 (0%)	0
Renal impairment	1/5 (20%)	1	0/6 (0%)	0	0/7 (0%)	0
Reproductive system and breast disorders
Prostatitis	0/5 (0%)	0	0/6 (0%)	0	1/7 (14.3%)	1
Respiratory, thoracic and mediastinal disorders
Epistaxis	0/5 (0%)	0	1/6 (16.7%)	1	0/7 (0%)	0
Skin and subcutaneous tissue disorders
Skin lesion	0/5 (0%)	0	1/6 (16.7%)	1	0/7 (0%)	0
Vascular disorders
Haematoma	1/5 (20%)	1	0/6 (0%)	0	0/7 (0%)	0

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

Investigator agrees that no submission for publication or public disclosure by the Investigator will be made until after publication of the results of the Multicenter Trial, except as set forth in the clinical trial agreement. If, however, there is no multicenter publication within eighteen (18) months after completion or termination of the Study, Investigator may publish or publicly present the Study Data in accordance with the clinical trial agreement.