Trial Outcomes & Findings for Evaluate the Pharmacokinetics and Safety of MK-4448 in Participants With Nonvalvular Atrial Fibrillation or Atrial Flutter (NCT NCT01229254)

NCT ID: NCT01229254

Last Updated: 2023-08-07

Results Overview

Betrixaban PK concentration at 12 hr on Days 14, 18, and 21 in low and high weight groups

• Recruitment status: COMPLETED
• Study phase: PHASE2
• Target enrollment: 189 participants
• Primary outcome timeframe: Days 14, 18, and 21 of the PK period
• Results posted on: 2023-08-07

Participant Flow

Between 9Sep10 & 22Apr11, 189 patients were enrolled by 68 study centers in 2 countries (USA, Canada). Patients were enrolled to 1 of 3 treatment groups (betrixaban once daily 30, 60 or 90 mg) based on weight or use of amiodarone at screening. The study had an initial pharmacokinetics (PK) phase of 4 weeks and a safety extension phase of 20 weeks.

Patients weighing < 80 kg received daily betrixaban 60 mg, patients weighing ≥ 80 kg received daily betrixaban 90 mg, and patients on amiodarone at screening, regardless of weight, received daily betrixaban 30 mg. 241 patients were screened for study participation. Of these patients, 189 were enrolled and received at least 1 dose of study drug.

Participant milestones

Measure	Betrixaban 30 mg (+Amiodarone) Betrixaban 30 mg once daily for at least 4 weeks and up to 24 weeks for patients taking amiodarone	Betrixaban 60 mg (<80 kg) Betrixaban 60 mg once daily for at least 4 weeks and up to 24 weeks	Betrixaban 90 mg (≥80 kg) Betrixaban 90 mg once daily for at least 4 weeks and up to 24 weeks
Overall Study STARTED	42	74	73
Overall Study COMPLETED	27	58	61
Overall Study NOT COMPLETED	15	16	12

Reasons for withdrawal

Measure	Betrixaban 30 mg (+Amiodarone) Betrixaban 30 mg once daily for at least 4 weeks and up to 24 weeks for patients taking amiodarone	Betrixaban 60 mg (<80 kg) Betrixaban 60 mg once daily for at least 4 weeks and up to 24 weeks	Betrixaban 90 mg (≥80 kg) Betrixaban 90 mg once daily for at least 4 weeks and up to 24 weeks
Overall Study Not Continuing Into Safety Extension	3	1	1
Overall Study Adverse Event	4	5	3
Overall Study Lost to Follow-up	3	0	1
Overall Study Physician Decision	0	3	0
Overall Study Protocol Violation	4	6	5
Overall Study Withdrawal by Subject	1	0	1
Overall Study Non-compliance with Study Drug	0	1	1

Baseline Characteristics

Evaluate the Pharmacokinetics and Safety of MK-4448 in Participants With Nonvalvular Atrial Fibrillation or Atrial Flutter

Baseline characteristics by cohort

Measure	Betrixaban 30 mg (+Amiodarone) n=42 Participants Betrixaban 30 mg once daily for at least 4 weeks and up to 24 weeks for patients taking amiodarone	Betrixaban 60 mg (<80 kg) n=74 Participants Betrixaban 60 mg once daily for at least 4 weeks and up to 24 weeks	Betrixaban 90 mg (≥80 kg) n=73 Participants Betrixaban 90 mg once daily for at least 4 weeks and up to 24 weeks	Total n=189 Participants Total of all reporting groups
Age, Continuous	72.4 years STANDARD_DEVIATION 9.87 • n=5 Participants	77.1 years STANDARD_DEVIATION 7.12 • n=7 Participants	71.2 years STANDARD_DEVIATION 9.21 • n=5 Participants	73.8 years STANDARD_DEVIATION 8.98 • n=4 Participants
Age, Customized <75 years	23 Participants n=5 Participants	24 Participants n=7 Participants	46 Participants n=5 Participants	93 Participants n=4 Participants
Age, Customized >=75 years	19 Participants n=5 Participants	50 Participants n=7 Participants	27 Participants n=5 Participants	96 Participants n=4 Participants
Sex: Female, Male Female	19 Participants n=5 Participants	46 Participants n=7 Participants	16 Participants n=5 Participants	81 Participants n=4 Participants
Sex: Female, Male Male	23 Participants n=5 Participants	28 Participants n=7 Participants	57 Participants n=5 Participants	108 Participants n=4 Participants

PRIMARY outcome

Timeframe: Days 14, 18, and 21 of the PK period

Population: Per protocol analysis set, which includes all allocated patients who received at least one dose of study treatment and who were ≥ 90% compliant with study treatment, took study treatment within 24 hours prior to steadystate blood sampling, had at least two post steady-state blood samples collected, and not on amiodarone.

Betrixaban PK concentration at 12 hr on Days 14, 18, and 21 in low and high weight groups

Outcome measures

Measure	Betrixaban 30 mg (+Amiodarone) Betrixaban 30 mg once daily for at least 4 weeks and up to 24 weeks for patients taking amiodarone	Betrixaban 60 mg (<80 kg) n=68 Participants Betrixaban 60 mg once daily for at least 4 weeks and up to 24 weeks	Betrixaban 90 mg (≥80 kg) n=69 Participants Betrixaban 90 mg once daily for at least 4 weeks and up to 24 weeks
Steady-state C12 hr on Days 14, 18, and 21 After Weight-based Dosing	—	7.870 ng/mL Interval 6.654 to 9.307	10.517 ng/mL Interval 8.903 to 12.423

SECONDARY outcome

Timeframe: Days 14, 18, and 21 of the PK period

Population: Full Analysis Set population, which includes all patients who received at least one dose of study treatment within 24 hours prior to steady-state (SS) blood sampling, were ≥ 90% compliant with treatment, and had at least one post SS sample. The endpoint was to summarize the SS C12 hr concentration across treatments and time points as a single arm.

Betrixaban PK concentration at 12 hr on Days 14, 18, and 21 in amiodarone, low and high weight groups

Outcome measures

Measure	Betrixaban 30 mg (+Amiodarone) n=172 Participants Betrixaban 30 mg once daily for at least 4 weeks and up to 24 weeks for patients taking amiodarone	Betrixaban 60 mg (<80 kg) Betrixaban 60 mg once daily for at least 4 weeks and up to 24 weeks	Betrixaban 90 mg (≥80 kg) Betrixaban 90 mg once daily for at least 4 weeks and up to 24 weeks
Steady-state C12 hr on Days 14, 18, and 21 After Weight and Amiodarone-based Dosing	9.498 ng/mL Interval 8.586 to 10.507	—	—

Adverse Events

Betrixaban 30 mg (+Amiodarone)

Serious events: 6 serious events

Other events: 18 other events

Deaths: 0 deaths

Betrixaban 60 mg (<80 kg)

Serious events: 13 serious events

Other events: 34 other events

Deaths: 0 deaths

Betrixaban 90 mg (≥80 kg)

Serious events: 6 serious events

Other events: 35 other events

Deaths: 0 deaths

Serious adverse events

Measure	Betrixaban 30 mg (+Amiodarone) n=42 participants at risk Betrixaban 30 mg once daily for at least 4 weeks and up to 24 weeks for patients taking amiodarone	Betrixaban 60 mg (<80 kg) n=74 participants at risk Betrixaban 60 mg once daily for at least 4 weeks and up to 24 weeks	Betrixaban 90 mg (≥80 kg) n=73 participants at risk Betrixaban 90 mg once daily for at least 4 weeks and up to 24 weeks
Blood and lymphatic system disorders Anaemia	2.4% 1/42 • Maximum of 24 weeks Incidence of serious adverse events by system organ class	0.00% 0/74 • Maximum of 24 weeks Incidence of serious adverse events by system organ class	0.00% 0/73 • Maximum of 24 weeks Incidence of serious adverse events by system organ class
Blood and lymphatic system disorders Thrombocytopenia	2.4% 1/42 • Maximum of 24 weeks Incidence of serious adverse events by system organ class	0.00% 0/74 • Maximum of 24 weeks Incidence of serious adverse events by system organ class	0.00% 0/73 • Maximum of 24 weeks Incidence of serious adverse events by system organ class
Cardiac disorders Atrial fibrillation	2.4% 1/42 • Maximum of 24 weeks Incidence of serious adverse events by system organ class	1.4% 1/74 • Maximum of 24 weeks Incidence of serious adverse events by system organ class	0.00% 0/73 • Maximum of 24 weeks Incidence of serious adverse events by system organ class
Cardiac disorders Cardiac failure congestive	0.00% 0/42 • Maximum of 24 weeks Incidence of serious adverse events by system organ class	1.4% 1/74 • Maximum of 24 weeks Incidence of serious adverse events by system organ class	0.00% 0/73 • Maximum of 24 weeks Incidence of serious adverse events by system organ class
Cardiac disorders Coronary artery stenosis	0.00% 0/42 • Maximum of 24 weeks Incidence of serious adverse events by system organ class	1.4% 1/74 • Maximum of 24 weeks Incidence of serious adverse events by system organ class	0.00% 0/73 • Maximum of 24 weeks Incidence of serious adverse events by system organ class
Ear and labyrinth disorders Vertigo	0.00% 0/42 • Maximum of 24 weeks Incidence of serious adverse events by system organ class	1.4% 1/74 • Maximum of 24 weeks Incidence of serious adverse events by system organ class	0.00% 0/73 • Maximum of 24 weeks Incidence of serious adverse events by system organ class
Gastrointestinal disorders Gastrointestinal haemorrhage	2.4% 1/42 • Maximum of 24 weeks Incidence of serious adverse events by system organ class	0.00% 0/74 • Maximum of 24 weeks Incidence of serious adverse events by system organ class	0.00% 0/73 • Maximum of 24 weeks Incidence of serious adverse events by system organ class
Gastrointestinal disorders Small intestinal obstruction	0.00% 0/42 • Maximum of 24 weeks Incidence of serious adverse events by system organ class	1.4% 1/74 • Maximum of 24 weeks Incidence of serious adverse events by system organ class	0.00% 0/73 • Maximum of 24 weeks Incidence of serious adverse events by system organ class
General disorders Chest pain	2.4% 1/42 • Maximum of 24 weeks Incidence of serious adverse events by system organ class	2.7% 2/74 • Maximum of 24 weeks Incidence of serious adverse events by system organ class	0.00% 0/73 • Maximum of 24 weeks Incidence of serious adverse events by system organ class
Infections and infestations Bronchitis	0.00% 0/42 • Maximum of 24 weeks Incidence of serious adverse events by system organ class	1.4% 1/74 • Maximum of 24 weeks Incidence of serious adverse events by system organ class	0.00% 0/73 • Maximum of 24 weeks Incidence of serious adverse events by system organ class
Infections and infestations Bronchopneumonia	0.00% 0/42 • Maximum of 24 weeks Incidence of serious adverse events by system organ class	0.00% 0/74 • Maximum of 24 weeks Incidence of serious adverse events by system organ class	1.4% 1/73 • Maximum of 24 weeks Incidence of serious adverse events by system organ class
Infections and infestations Pneumonia	2.4% 1/42 • Maximum of 24 weeks Incidence of serious adverse events by system organ class	0.00% 0/74 • Maximum of 24 weeks Incidence of serious adverse events by system organ class	0.00% 0/73 • Maximum of 24 weeks Incidence of serious adverse events by system organ class
Infections and infestations Sepsis	2.4% 1/42 • Maximum of 24 weeks Incidence of serious adverse events by system organ class	1.4% 1/74 • Maximum of 24 weeks Incidence of serious adverse events by system organ class	0.00% 0/73 • Maximum of 24 weeks Incidence of serious adverse events by system organ class
Infections and infestations Viral infection	0.00% 0/42 • Maximum of 24 weeks Incidence of serious adverse events by system organ class	0.00% 0/74 • Maximum of 24 weeks Incidence of serious adverse events by system organ class	1.4% 1/73 • Maximum of 24 weeks Incidence of serious adverse events by system organ class
Injury, poisoning and procedural complications Thoracic vertebral fracture	0.00% 0/42 • Maximum of 24 weeks Incidence of serious adverse events by system organ class	0.00% 0/74 • Maximum of 24 weeks Incidence of serious adverse events by system organ class	1.4% 1/73 • Maximum of 24 weeks Incidence of serious adverse events by system organ class
Metabolism and nutrition disorders Electrolyte imbalance	0.00% 0/42 • Maximum of 24 weeks Incidence of serious adverse events by system organ class	1.4% 1/74 • Maximum of 24 weeks Incidence of serious adverse events by system organ class	0.00% 0/73 • Maximum of 24 weeks Incidence of serious adverse events by system organ class
Musculoskeletal and connective tissue disorders Neck pain	0.00% 0/42 • Maximum of 24 weeks Incidence of serious adverse events by system organ class	1.4% 1/74 • Maximum of 24 weeks Incidence of serious adverse events by system organ class	0.00% 0/73 • Maximum of 24 weeks Incidence of serious adverse events by system organ class
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Basal cell carcinoma	0.00% 0/42 • Maximum of 24 weeks Incidence of serious adverse events by system organ class	2.7% 2/74 • Maximum of 24 weeks Incidence of serious adverse events by system organ class	2.7% 2/73 • Maximum of 24 weeks Incidence of serious adverse events by system organ class
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Squamous cell carcinoma	2.4% 1/42 • Maximum of 24 weeks Incidence of serious adverse events by system organ class	1.4% 1/74 • Maximum of 24 weeks Incidence of serious adverse events by system organ class	0.00% 0/73 • Maximum of 24 weeks Incidence of serious adverse events by system organ class
Nervous system disorders Cerebrovascular accident	0.00% 0/42 • Maximum of 24 weeks Incidence of serious adverse events by system organ class	1.4% 1/74 • Maximum of 24 weeks Incidence of serious adverse events by system organ class	0.00% 0/73 • Maximum of 24 weeks Incidence of serious adverse events by system organ class
Respiratory, thoracic and mediastinal disorders Epistaxis	0.00% 0/42 • Maximum of 24 weeks Incidence of serious adverse events by system organ class	0.00% 0/74 • Maximum of 24 weeks Incidence of serious adverse events by system organ class	1.4% 1/73 • Maximum of 24 weeks Incidence of serious adverse events by system organ class
Vascular disorders Orthostatic hypotension	0.00% 0/42 • Maximum of 24 weeks Incidence of serious adverse events by system organ class	1.4% 1/74 • Maximum of 24 weeks Incidence of serious adverse events by system organ class	0.00% 0/73 • Maximum of 24 weeks Incidence of serious adverse events by system organ class

Other adverse events

Measure	Betrixaban 30 mg (+Amiodarone) n=42 participants at risk Betrixaban 30 mg once daily for at least 4 weeks and up to 24 weeks for patients taking amiodarone	Betrixaban 60 mg (<80 kg) n=74 participants at risk Betrixaban 60 mg once daily for at least 4 weeks and up to 24 weeks	Betrixaban 90 mg (≥80 kg) n=73 participants at risk Betrixaban 90 mg once daily for at least 4 weeks and up to 24 weeks
Respiratory, thoracic and mediastinal disorders Epistaxis	4.8% 2/42 • Maximum of 24 weeks Incidence of serious adverse events by system organ class	4.1% 3/74 • Maximum of 24 weeks Incidence of serious adverse events by system organ class	8.2% 6/73 • Maximum of 24 weeks Incidence of serious adverse events by system organ class
Infections and infestations Upper respiratory tract infection	7.1% 3/42 • Maximum of 24 weeks Incidence of serious adverse events by system organ class	1.4% 1/74 • Maximum of 24 weeks Incidence of serious adverse events by system organ class	8.2% 6/73 • Maximum of 24 weeks Incidence of serious adverse events by system organ class
Nervous system disorders Dizziness	0.00% 0/42 • Maximum of 24 weeks Incidence of serious adverse events by system organ class	12.2% 9/74 • Maximum of 24 weeks Incidence of serious adverse events by system organ class	6.8% 5/73 • Maximum of 24 weeks Incidence of serious adverse events by system organ class
General disorders Fatigue	7.1% 3/42 • Maximum of 24 weeks Incidence of serious adverse events by system organ class	6.8% 5/74 • Maximum of 24 weeks Incidence of serious adverse events by system organ class	6.8% 5/73 • Maximum of 24 weeks Incidence of serious adverse events by system organ class
Gastrointestinal disorders Diarrhoea	4.8% 2/42 • Maximum of 24 weeks Incidence of serious adverse events by system organ class	5.4% 4/74 • Maximum of 24 weeks Incidence of serious adverse events by system organ class	6.8% 5/73 • Maximum of 24 weeks Incidence of serious adverse events by system organ class
General disorders Oedema peripheral	7.1% 3/42 • Maximum of 24 weeks Incidence of serious adverse events by system organ class	4.1% 3/74 • Maximum of 24 weeks Incidence of serious adverse events by system organ class	6.8% 5/73 • Maximum of 24 weeks Incidence of serious adverse events by system organ class
Gastrointestinal disorders Nausea	7.1% 3/42 • Maximum of 24 weeks Incidence of serious adverse events by system organ class	2.7% 2/74 • Maximum of 24 weeks Incidence of serious adverse events by system organ class	6.8% 5/73 • Maximum of 24 weeks Incidence of serious adverse events by system organ class
Respiratory, thoracic and mediastinal disorders Dyspnoea	4.8% 2/42 • Maximum of 24 weeks Incidence of serious adverse events by system organ class	2.7% 2/74 • Maximum of 24 weeks Incidence of serious adverse events by system organ class	5.5% 4/73 • Maximum of 24 weeks Incidence of serious adverse events by system organ class
Musculoskeletal and connective tissue disorders Arthralgia	0.00% 0/42 • Maximum of 24 weeks Incidence of serious adverse events by system organ class	2.7% 2/74 • Maximum of 24 weeks Incidence of serious adverse events by system organ class	5.5% 4/73 • Maximum of 24 weeks Incidence of serious adverse events by system organ class
Infections and infestations Nasopharyngitis	7.1% 3/42 • Maximum of 24 weeks Incidence of serious adverse events by system organ class	2.7% 2/74 • Maximum of 24 weeks Incidence of serious adverse events by system organ class	4.1% 3/73 • Maximum of 24 weeks Incidence of serious adverse events by system organ class
Injury, poisoning and procedural complications Contusion	9.5% 4/42 • Maximum of 24 weeks Incidence of serious adverse events by system organ class	9.5% 7/74 • Maximum of 24 weeks Incidence of serious adverse events by system organ class	2.7% 2/73 • Maximum of 24 weeks Incidence of serious adverse events by system organ class
Injury, poisoning and procedural complications Fall	9.5% 4/42 • Maximum of 24 weeks Incidence of serious adverse events by system organ class	4.1% 3/74 • Maximum of 24 weeks Incidence of serious adverse events by system organ class	1.4% 1/73 • Maximum of 24 weeks Incidence of serious adverse events by system organ class
Infections and infestations Urinary tract infection	4.8% 2/42 • Maximum of 24 weeks Incidence of serious adverse events by system organ class	12.2% 9/74 • Maximum of 24 weeks Incidence of serious adverse events by system organ class	0.00% 0/73 • Maximum of 24 weeks Incidence of serious adverse events by system organ class
Injury, poisoning and procedural complications Excoriation	4.8% 2/42 • Maximum of 24 weeks Incidence of serious adverse events by system organ class	5.4% 4/74 • Maximum of 24 weeks Incidence of serious adverse events by system organ class	0.00% 0/73 • Maximum of 24 weeks Incidence of serious adverse events by system organ class
Psychiatric disorders Insomnia	7.1% 3/42 • Maximum of 24 weeks Incidence of serious adverse events by system organ class	2.7% 2/74 • Maximum of 24 weeks Incidence of serious adverse events by system organ class	0.00% 0/73 • Maximum of 24 weeks Incidence of serious adverse events by system organ class

Additional Information

Head of Clinical Development

Portola Pharmaceuticals, Inc.

Phone: 650-246-7000

Results disclosure agreements

• Principal investigator is a sponsor employee Due to multiple studies, centers and countries this may vary.
• Publication restrictions are in place

Restriction type: OTHER