Safety Evaluation of 3K3A-APC in Ischemic Stroke

A Multi-center, Phase 2 Study Using a Continual Reassessment Method to Determine the Safety and Tolerability of 3K3A-APC in Combination With tPA, Mechanical Thrombectomy or Both in Moderate to Severe Acute Ischemic Stroke

Status

Completed

Phases

Phase 2

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT02222714

Acronym

RHAPSODY

Enrollment

110

Registered

2014-08-21

Start date

2014-10-31

Completion date

2017-06-29

Last updated

2018-11-08

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Ischemic Stroke

Keywords

ischemic stroke, stroke, APC, 3K3A, 3K3A-APC, activated protein C, RHAPSODY

Brief summary

The purpose of this study was to evaluate the safety, pharmacokinetics (PK) and preliminary efficacy of multiple ascending intravenous doses of 3K3A-APC, a Recombinant Variant of Human activated protein C (APC), in in the treatment of acute ischemic stroke following treatment with recombinant tissue plasminogen activator (tPA), mechanical thrombectomy or both.

Detailed description

This was a multicenter, prospective, randomized, controlled, double-blinded Phase 2 study intended to evaluate the safety, PK and preliminary efficacy of 3K3A-APC following treatment with tPA, mechanical thrombectomy or both in subjects with moderate to severe acute ischemic stroke. Approximately 115 subjects were to be randomized, which included the planned 88 subjects in groups of 4 subjects to either 3K3A-APC or placebo (in a 3:1 ratio) and the additional placebo subjects who were enrolled during safety review pauses. This study used a modified version of the continual reassessment method (CRM) in order to establish a maximum tolerated dose (MTD). Eligible subjects received 3K3A-APC or placebo every 12 hours for up to 5 doses (approximately 3 days), or until discharge from the hospital, whichever occurred first. Subjects were monitored for safety evaluations through Day 7 (or discharge, if earlier) and were expected to be seen on Day 7, 14, 30, and 90 for safety and outcome evaluations.

Interventions

BIOLOGICAL3K3A-APC

3K3A-APC, diluted in 0.9% sodium chloride in water, given as 100 mL IV infusion

DRUGPlacebo

Matching placebo, 0.9% sodium chloride in water, given as 100 mL IV infusion

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)

Eligibility

Sex/Gender

ALL

Age

18 Years to 90 Years

Healthy volunteers

Inclusion criteria

* Acute ischemic stroke * Able to receive IV tPA, mechanical thrombectomy or both * National Institutes of Health Stroke Scale (NIHSS) score of ≥ 5 * Signed informed consent * Mechanical thrombectomy subjects only: onset time to arterial puncture time \< 6 hours

Exclusion criteria

* History of stroke or penetrating head injury within 90 days prior to enrollment * History of previous or current diagnosis of intracranial hemorrhage that represents a potential for re-hemorrhage if subjected to thrombolytic therapy or mechanical thrombectomy * Moyamoya disease, cerebral arterio-venous malformation (AVM), known unsecured aneurysm requiring intervention during the acute study period * Presence of other neurological or non-neurological co-morbidities that may lead, independently of the current stroke, to further deterioration in the subject's neurological status during the trial period * Presence of premorbid neurological deficits and functional limitations assessed by a retrospective Modified Rankin Scale (mRS) score of ≥ 2 * Mechanical thrombectomy subjects only: baseline non-contrast CT scan revealing a large core occlusion as defined by local protocol * Prolonged prothrombin time (PT) or activated partial thromboplastin time (aPTT) * Severe hypertension or hypotension * Glomerular filtration rate (GFR) \<35 mL/min * Blood glucose concentration \< 50 mg/dL * Prior exposure to any exogenous form of APC

Design outcomes

Primary

Measure	Time frame	Description
Number of Participants With Adverse Events That Meet Dose-limiting Toxicity (DLT) Criteria Specified in Protocol	48-hours following last dose	Specific AEs in the study were defined in the protocol to be dose-limiting toxicity events. Any given patient was adjudicated in a binary way to either have had a DLT or not to have had a DLT.

Secondary

Measure	Time frame	Description
PK of 3K3A-APC by Compartmental Analysis (Clearance)	Following a single dose, on Day 1, 2 or 3: End of infusion (EOI) and 20, 40, 60 and 80 minutes following EOI	Measured following a single dose; primary parameters (CL, V) were used to fit the model. Secondary parameters (Cmax, AUC(inf), λz, t1/2) were estimated from the primary parameters.
PK of 3K3A-APC by Compartmental Analysis (Volume of Distribution)	Following a single dose, on Day 1, 2 or 3: End of infusion (EOI) and 20, 40, 60 and 80 minutes following EOI	Measured following a single dose; primary parameters (CL, V) were used to fit the model. Secondary parameters (Cmax, AUC(inf), λz, t1/2) were estimated from the primary parameters.
PK of 3K3A-APC by Compartmental Analysis (Cmax)	Following a single dose, on Day 1, 2 or 3: End of infusion (EOI) and 20, 40, 60 and 80 minutes following EOI	Measured following a single dose; primary parameters (CL, V) were used to fit the model. Secondary parameters (Cmax, AUC(inf), λz, t1/2) were estimated from the primary parameters.
Number of Participants With a Presence of Measurable Bleeds in the Brain (Hemorrhage and Microbleeds) as Determined by 1.5T MRI	Day 30	MRI examination to include-at minimum-T1 and T2 weighted images, as well as diffusion weighted imaging (DWI) and susceptibility weighted imaging (SWI) sequences. Post-tPA microbleeds-defined as hypointensities less than 5mm in diameter seen on SWI-will be counted as tPA-related only if found within the ischemic territory. All other areas of hypointensity on SWI larger than 5mm diameter will be counted as tPA-related regardless of the territory in which they are found. All treated subjects (regardless of dose) will be compared to all placebo subjects using a Pearson chi-square test.
PK of 3K3A-APC by Compartmental Analysis (λz)	Following a single dose, on Day 1, 2 or 3: End of infusion (EOI) and 20, 40, 60 and 80 minutes following EOI	Measured following a single dose; primary parameters (CL, V) were used to fit the model. Secondary parameters (Cmax, AUC(inf), λz, t1/2) were estimated from the primary parameters.
PK of 3K3A-APC by Compartmental Analysis (Half-life)	Following a single dose, on Day 1, 2 or 3: End of infusion (EOI) and 20, 40, 60 and 80 minutes following EOI	Measured following a single dose; primary parameters (CL, V) were used to fit the model. Secondary parameters (Cmax, AUC(inf), λz, t1/2) were estimated from the primary parameters.
PK of 3K3A-APC by Compartmental Analysis (AUC[0-inf])	Following a single dose, on Day 1, 2 or 3: End of infusion (EOI) and 20, 40, 60 and 80 minutes following EOI	Measured following a single dose; primary parameters (CL, V) were used to fit the model. Secondary parameters (Cmax, AUC(inf), λz, t1/2) were estimated from the primary parameters.

Countries

United States

Participant flow

Participants by arm

Arm	Count
120 µg/kg of 3K3A-APC 3K3A-APC, q12h for up to 5 doses 3K3A-APC: 3K3A-APC, diluted in 0.9% sodium chloride in water, given as 100 mL IV infusion	15
240 µg/kg of 3K3A-APC 3K3A-APC, q12h for up to 5 doses 3K3A-APC: 3K3A-APC, diluted in 0.9% sodium chloride in water, given as 100 mL IV infusion	24
360 µg/kg of 3K3A-APC 3K3A-APC, q12h for up to 5 doses 3K3A-APC: 3K3A-APC, diluted in 0.9% sodium chloride in water, given as 100 mL IV infusion	12
540 µg/kg of 3K3A-APC 3K3A-APC, q12h for up to 5 doses 3K3A-APC: 3K3A-APC, diluted in 0.9% sodium chloride in water, given as 100 mL IV infusion	15
Placebo Matching placebo, q12h for up to 5 doses Placebo: Matching placebo, 0.9% sodium chloride in water, given as 100 mL IV infusion	44
Total	110

Withdrawals & dropouts

Period	Reason	FG000	FG001	FG002	FG003	FG004
Overall Study	Death	0	2	3	4	6
Overall Study	Withdrawal by Subject	0	0	1	0	1

Baseline characteristics

Characteristic	120 µg/kg of 3K3A-APC	240 µg/kg of 3K3A-APC	360 µg/kg of 3K3A-APC	540 µg/kg of 3K3A-APC	Placebo	Total
Age, Continuous	63.3 years	61.4 years	65.3 years	66.2 years	63.8 years	63.7 years
Ethnicity (NIH/OMB) Hispanic or Latino	2 Participants	1 Participants	0 Participants	1 Participants	7 Participants	11 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	11 Participants	22 Participants	12 Participants	13 Participants	36 Participants	94 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	2 Participants	1 Participants	0 Participants	1 Participants	1 Participants	5 Participants
History of Diabetes	6 Participants	6 Participants	2 Participants	4 Participants	18 Participants	36 Participants
History of Hypertension	11 Participants	21 Participants	9 Participants	11 Participants	33 Participants	85 Participants
Sex: Female, Male Female	11 Participants	12 Participants	6 Participants	8 Participants	20 Participants	57 Participants
Sex: Female, Male Male	4 Participants	12 Participants	6 Participants	7 Participants	24 Participants	53 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk	EG002 affected / at risk	EG003 affected / at risk	EG004 affected / at risk	EG005 affected / at risk
deaths Total, all-cause mortality	0 / 15	2 / 24	3 / 12	4 / 15	9 / 66	6 / 44
other Total, other adverse events	10 / 15	18 / 24	8 / 12	9 / 15	45 / 66	36 / 44
serious Total, serious adverse events	8 / 15	9 / 24	4 / 12	9 / 15	30 / 66	18 / 44

Outcome results

Primary

Number of Participants With Adverse Events That Meet Dose-limiting Toxicity (DLT) Criteria Specified in Protocol

Specific AEs in the study were defined in the protocol to be dose-limiting toxicity events. Any given patient was adjudicated in a binary way to either have had a DLT or not to have had a DLT.

Time frame: 48-hours following last dose

Population: Evaluable participants

Arm	Measure	Group	Value (COUNT_OF_PARTICIPANTS)
120 µg/kg of 3K3A-APC	Number of Participants With Adverse Events That Meet Dose-limiting Toxicity (DLT) Criteria Specified in Protocol	1-hour post dose aPTT out of range	0 Participants
120 µg/kg of 3K3A-APC	Number of Participants With Adverse Events That Meet Dose-limiting Toxicity (DLT) Criteria Specified in Protocol	Serious bleeding	0 Participants
120 µg/kg of 3K3A-APC	Number of Participants With Adverse Events That Meet Dose-limiting Toxicity (DLT) Criteria Specified in Protocol	ALT/AST, TBL, ALP, AT values out of range	0 Participants
120 µg/kg of 3K3A-APC	Number of Participants With Adverse Events That Meet Dose-limiting Toxicity (DLT) Criteria Specified in Protocol	Any other AE leading to cessation of dosing	0 Participants
120 µg/kg of 3K3A-APC	Number of Participants With Adverse Events That Meet Dose-limiting Toxicity (DLT) Criteria Specified in Protocol	Abnormal lab value related to study treatment	0 Participants
120 µg/kg of 3K3A-APC	Number of Participants With Adverse Events That Meet Dose-limiting Toxicity (DLT) Criteria Specified in Protocol	Total	0 Participants
120 µg/kg of 3K3A-APC	Number of Participants With Adverse Events That Meet Dose-limiting Toxicity (DLT) Criteria Specified in Protocol	SICH associated with neuroworsening	0 Participants
240 µg/kg of 3K3A-APC	Number of Participants With Adverse Events That Meet Dose-limiting Toxicity (DLT) Criteria Specified in Protocol	Serious bleeding	0 Participants
240 µg/kg of 3K3A-APC	Number of Participants With Adverse Events That Meet Dose-limiting Toxicity (DLT) Criteria Specified in Protocol	1-hour post dose aPTT out of range	1 Participants
240 µg/kg of 3K3A-APC	Number of Participants With Adverse Events That Meet Dose-limiting Toxicity (DLT) Criteria Specified in Protocol	SICH associated with neuroworsening	1 Participants
240 µg/kg of 3K3A-APC	Number of Participants With Adverse Events That Meet Dose-limiting Toxicity (DLT) Criteria Specified in Protocol	ALT/AST, TBL, ALP, AT values out of range	0 Participants
240 µg/kg of 3K3A-APC	Number of Participants With Adverse Events That Meet Dose-limiting Toxicity (DLT) Criteria Specified in Protocol	Abnormal lab value related to study treatment	0 Participants
240 µg/kg of 3K3A-APC	Number of Participants With Adverse Events That Meet Dose-limiting Toxicity (DLT) Criteria Specified in Protocol	Any other AE leading to cessation of dosing	0 Participants
240 µg/kg of 3K3A-APC	Number of Participants With Adverse Events That Meet Dose-limiting Toxicity (DLT) Criteria Specified in Protocol	Total	2 Participants
360 µg/kg of 3K3A-APC	Number of Participants With Adverse Events That Meet Dose-limiting Toxicity (DLT) Criteria Specified in Protocol	SICH associated with neuroworsening	0 Participants
360 µg/kg of 3K3A-APC	Number of Participants With Adverse Events That Meet Dose-limiting Toxicity (DLT) Criteria Specified in Protocol	Total	1 Participants
360 µg/kg of 3K3A-APC	Number of Participants With Adverse Events That Meet Dose-limiting Toxicity (DLT) Criteria Specified in Protocol	Abnormal lab value related to study treatment	1 Participants
360 µg/kg of 3K3A-APC	Number of Participants With Adverse Events That Meet Dose-limiting Toxicity (DLT) Criteria Specified in Protocol	Any other AE leading to cessation of dosing	0 Participants
360 µg/kg of 3K3A-APC	Number of Participants With Adverse Events That Meet Dose-limiting Toxicity (DLT) Criteria Specified in Protocol	Serious bleeding	0 Participants
360 µg/kg of 3K3A-APC	Number of Participants With Adverse Events That Meet Dose-limiting Toxicity (DLT) Criteria Specified in Protocol	ALT/AST, TBL, ALP, AT values out of range	0 Participants
360 µg/kg of 3K3A-APC	Number of Participants With Adverse Events That Meet Dose-limiting Toxicity (DLT) Criteria Specified in Protocol	1-hour post dose aPTT out of range	0 Participants
540 µg/kg of 3K3A-APC	Number of Participants With Adverse Events That Meet Dose-limiting Toxicity (DLT) Criteria Specified in Protocol	Abnormal lab value related to study treatment	0 Participants
540 µg/kg of 3K3A-APC	Number of Participants With Adverse Events That Meet Dose-limiting Toxicity (DLT) Criteria Specified in Protocol	Serious bleeding	0 Participants
540 µg/kg of 3K3A-APC	Number of Participants With Adverse Events That Meet Dose-limiting Toxicity (DLT) Criteria Specified in Protocol	1-hour post dose aPTT out of range	0 Participants
540 µg/kg of 3K3A-APC	Number of Participants With Adverse Events That Meet Dose-limiting Toxicity (DLT) Criteria Specified in Protocol	ALT/AST, TBL, ALP, AT values out of range	0 Participants
540 µg/kg of 3K3A-APC	Number of Participants With Adverse Events That Meet Dose-limiting Toxicity (DLT) Criteria Specified in Protocol	Total	0 Participants
540 µg/kg of 3K3A-APC	Number of Participants With Adverse Events That Meet Dose-limiting Toxicity (DLT) Criteria Specified in Protocol	Any other AE leading to cessation of dosing	0 Participants
540 µg/kg of 3K3A-APC	Number of Participants With Adverse Events That Meet Dose-limiting Toxicity (DLT) Criteria Specified in Protocol	SICH associated with neuroworsening	0 Participants
Placebo	Number of Participants With Adverse Events That Meet Dose-limiting Toxicity (DLT) Criteria Specified in Protocol	1-hour post dose aPTT out of range	1 Participants
Placebo	Number of Participants With Adverse Events That Meet Dose-limiting Toxicity (DLT) Criteria Specified in Protocol	Total	4 Participants
Placebo	Number of Participants With Adverse Events That Meet Dose-limiting Toxicity (DLT) Criteria Specified in Protocol	Any other AE leading to cessation of dosing	1 Participants
Placebo	Number of Participants With Adverse Events That Meet Dose-limiting Toxicity (DLT) Criteria Specified in Protocol	SICH associated with neuroworsening	0 Participants
Placebo	Number of Participants With Adverse Events That Meet Dose-limiting Toxicity (DLT) Criteria Specified in Protocol	Abnormal lab value related to study treatment	2 Participants
Placebo	Number of Participants With Adverse Events That Meet Dose-limiting Toxicity (DLT) Criteria Specified in Protocol	Serious bleeding	0 Participants
Placebo	Number of Participants With Adverse Events That Meet Dose-limiting Toxicity (DLT) Criteria Specified in Protocol	ALT/AST, TBL, ALP, AT values out of range	0 Participants

Secondary

Number of Participants With a Presence of Measurable Bleeds in the Brain (Hemorrhage and Microbleeds) as Determined by 1.5T MRI

MRI examination to include-at minimum-T1 and T2 weighted images, as well as diffusion weighted imaging (DWI) and susceptibility weighted imaging (SWI) sequences. Post-tPA microbleeds-defined as hypointensities less than 5mm in diameter seen on SWI-will be counted as tPA-related only if found within the ischemic territory. All other areas of hypointensity on SWI larger than 5mm diameter will be counted as tPA-related regardless of the territory in which they are found. All treated subjects (regardless of dose) will be compared to all placebo subjects using a Pearson chi-square test.

Time frame: Day 30

Population: Subjects with a Day 30 scan collected.

Arm	Measure	Group	Value (COUNT_OF_PARTICIPANTS)
120 µg/kg of 3K3A-APC	Number of Participants With a Presence of Measurable Bleeds in the Brain (Hemorrhage and Microbleeds) as Determined by 1.5T MRI	Hemorrhage (>0.06mL)	24 Participants
120 µg/kg of 3K3A-APC	Number of Participants With a Presence of Measurable Bleeds in the Brain (Hemorrhage and Microbleeds) as Determined by 1.5T MRI	Microbleed (>0)	7 Participants
240 µg/kg of 3K3A-APC	Number of Participants With a Presence of Measurable Bleeds in the Brain (Hemorrhage and Microbleeds) as Determined by 1.5T MRI	Hemorrhage (>0.06mL)	25 Participants
240 µg/kg of 3K3A-APC	Number of Participants With a Presence of Measurable Bleeds in the Brain (Hemorrhage and Microbleeds) as Determined by 1.5T MRI	Microbleed (>0)	8 Participants

Secondary

PK of 3K3A-APC by Compartmental Analysis (AUC[0-inf])

Measured following a single dose; primary parameters (CL, V) were used to fit the model. Secondary parameters (Cmax, AUC(inf), λz, t1/2) were estimated from the primary parameters.