Safety Evaluation of 3K3A-APC in Ischemic Stroke (RHAPSODY)

• ClinicalTrials.gov Identifier: NCT02222714
• Recruitment Status: Completed
• First Posted: August 21, 2014
• Results First Posted: November 8, 2018
• Last Update Posted: November 8, 2018
• Sponsor: ZZ Biotech, LLC
• Collaborators: National Institute of Neurological Disorders and Stroke (NINDS); Cedars-Sinai Medical Center; Massachusetts General Hospital; University of Iowa
• Information provided by (Responsible Party): ZZ Biotech, LLC

• Study Type: Interventional
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment
• Condition: Ischemic Stroke
• Interventions: Biological: 3K3A-APC; Drug: Placebo
• Enrollment: 110

Participant Flow

Recruitment Details
Pre-assignment Details

Arm/Group Title	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
Arm/Group Description	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	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	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	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	Matching placebo, q12h for up to 5 doses Placebo: Matching placebo, 0.9% sodium chloride in water, given as 100 mL IV infusion
Period Title: Overall Study
Started	15	24	12	15	44
Completed	15	22	8	11	37
Not Completed	0	2	4	4	7
Reason Not Completed
Death	0	2	3	4	6
Withdrawal by Subject	0	0	1	0	1

Baseline Characteristics

Arm/Group Title		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
Arm/Group Description		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	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	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	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	Matching placebo, q12h for up to 5 doses Placebo: Matching placebo, 0.9% sodium chloride in water, given as 100 mL IV infusion	Total of all reporting groups
Overall Number of Baseline Participants		15	24	12	15	44	110
Baseline Analysis Population Description		[Not Specified]
Age, Continuous; Mean (Full Range); Unit of measure: Years
	Number Analyzed	15 participants	24 participants	12 participants	15 participants	44 participants	110 participants
		63.3; (28 to 84)	61.4; (33 to 88)	65.3; (43 to 89)	66.2; (42 to 89)	63.8; (44 to 83)	63.7; (28 to 89)
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	15 participants	24 participants	12 participants	15 participants	44 participants	110 participants
	Female	11 73.3%	12 50.0%	6 50.0%	8 53.3%	20 45.5%	57 51.8%
	Male	4 26.7%	12 50.0%	6 50.0%	7 46.7%	24 54.5%	53 48.2%
Ethnicity (NIH/OMB); Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	15 participants	24 participants	12 participants	15 participants	44 participants	110 participants
	Hispanic or Latino	2 13.3%	1 4.2%	0 0.0%	1 6.7%	7 15.9%	11 10.0%
	Not Hispanic or Latino	11 73.3%	22 91.7%	12 100.0%	13 86.7%	36 81.8%	94 85.5%
	Unknown or Not Reported	2 13.3%	1 4.2%	0 0.0%	1 6.7%	1 2.3%	5 4.5%
History of Hypertension; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	15 participants	24 participants	12 participants	15 participants	44 participants	110 participants
		11 73.3%	21 87.5%	9 75.0%	11 73.3%	33 75.0%	85 77.3%
History of Diabetes; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	15 participants	24 participants	12 participants	15 participants	44 participants	110 participants
		6 40.0%	6 25.0%	2 16.7%	4 26.7%	18 40.9%	36 32.7%

Outcome Measures

1. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

Evaluable participants

Arm/Group Title	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
Arm/Group Description:	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	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	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	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	Matching placebo, q12h for up to 5 doses Placebo: Matching placebo, 0.9% sodium chloride in water, given as 100 mL IV infusion
Overall Number of Participants Analyzed	15	24	12	15	44
Measure Type: Count of Participants; Unit of Measure: Participants
1-hour post dose aPTT out of range	0 0.0%	1 4.2%	0 0.0%	0 0.0%	1 2.3%
SICH associated with neuroworsening	0 0.0%	1 4.2%	0 0.0%	0 0.0%	0 0.0%
ALT/AST, TBL, ALP, AT values out of range	0 0.0%	0 0.0%	0 0.0%	0 0.0%	0 0.0%
Serious bleeding	0 0.0%	0 0.0%	0 0.0%	0 0.0%	0 0.0%
Abnormal lab value related to study treatment	0 0.0%	0 0.0%	1 8.3%	0 0.0%	2 4.5%
Any other AE leading to cessation of dosing	0 0.0%	0 0.0%	0 0.0%	0 0.0%	1 2.3%
Total	0 0.0%	2 8.3%	1 8.3%	0 0.0%	4 9.1%

2. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

Subjects with a Day 30 scan collected.

Arm/Group Title	3K3A-APC Total	Placebo
Arm/Group Description:	All 3K3A-APC treated groups combined	Placebo group
Overall Number of Participants Analyzed	43	37
Measure Type: Count of Participants; Unit of Measure: Participants
Hemorrhage (>0.06mL)	24 55.8%	25 67.6%
Microbleed (>0)	7 16.3%	8 21.6%

3. Secondary Outcome

Title	PK of 3K3A-APC by Compartmental Analysis (Clearance)
Description	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.
Time Frame	Following a single dose, on Day 1, 2 or 3: End of infusion (EOI) and 20, 40, 60 and 80 minutes following EOI

Outcome Measure Data

Analysis Population Description

The PK population included all subjects who had sufficient data for PK analysis, and who had not been excluded from analysis for protocol deviations that could impact the calculation or interpretation of the PK parameters.

Arm/Group Title	120 µg/kg of 3K3A-APC	240 µg/kg of 3K3A-APC	360 µg/kg of 3K3A-APC	540 µg/kg of 3K3A-APC
Arm/Group Description:	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	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	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	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
Overall Number of Participants Analyzed	5	3	5	8
Geometric Mean (Geometric Coefficient of Variation); Unit of Measure: mL/hr
	20994; (57.1%)	17814; (16.7%)	18504; (49.9%)	24403; (70.5%)

4. Secondary Outcome

Title	PK of 3K3A-APC by Compartmental Analysis (Volume of Distribution)
Description	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.
Time Frame	Following a single dose, on Day 1, 2 or 3: End of infusion (EOI) and 20, 40, 60 and 80 minutes following EOI

Outcome Measure Data

Analysis Population Description

The PK population included all subjects who had sufficient data for PK analysis, and who had not been excluded from analysis for protocol deviations that could impact the calculation or interpretation of the PK parameters.

Arm/Group Title	120 µg/kg of 3K3A-APC	240 µg/kg of 3K3A-APC	360 µg/kg of 3K3A-APC	540 µg/kg of 3K3A-APC
Arm/Group Description:	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	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	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	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
Overall Number of Participants Analyzed	5	3	5	8
Geometric Mean (Geometric Coefficient of Variation); Unit of Measure: mL
	8242; (46.9%)	6051; (25.6%)	7164; (79.0%)	11437; (125%)

5. Secondary Outcome

Title	PK of 3K3A-APC by Compartmental Analysis (Cmax)
Description	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.
Time Frame	Following a single dose, on Day 1, 2 or 3: End of infusion (EOI) and 20, 40, 60 and 80 minutes following EOI

Outcome Measure Data

Analysis Population Description

The PK population included all subjects who had sufficient data for PK analysis, and who had not been excluded from analysis for protocol deviations that could impact the calculation or interpretation of the PK parameters.

Arm/Group Title	120 µg/kg of 3K3A-APC	240 µg/kg of 3K3A-APC	360 µg/kg of 3K3A-APC	540 µg/kg of 3K3A-APC
Arm/Group Description:	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	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	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	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
Overall Number of Participants Analyzed	5	3	5	8
Geometric Mean (Geometric Coefficient of Variation); Unit of Measure: ng/mL
	0.957; (59.1%)	2.37; (11.0%)	2.80; (77.6%)	3.32; (138%)

6. Secondary Outcome

Title	PK of 3K3A-APC by Compartmental Analysis (AUC[0-inf])
Description	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.
Time Frame	Following a single dose, on Day 1, 2 or 3: End of infusion (EOI) and 20, 40, 60 and 80 minutes following EOI

Outcome Measure Data

Analysis Population Description

The PK population included all subjects who had sufficient data for PK analysis, and who had not been excluded from analysis for protocol deviations that could impact the calculation or interpretation of the PK parameters.

Arm/Group Title	120 µg/kg of 3K3A-APC	240 µg/kg of 3K3A-APC	360 µg/kg of 3K3A-APC	540 µg/kg of 3K3A-APC
Arm/Group Description:	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	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	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	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
Overall Number of Participants Analyzed	5	3	5	8
Geometric Mean (Geometric Coefficient of Variation); Unit of Measure: hr▪ng/mL
	0.513; (64.7%)	1.16; (6.79%)	1.49; (56.1%)	2.06; (92.7%)

7. Secondary Outcome

Title	PK of 3K3A-APC by Compartmental Analysis (λz)
Description	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.
Time Frame	Following a single dose, on Day 1, 2 or 3: End of infusion (EOI) and 20, 40, 60 and 80 minutes following EOI

Outcome Measure Data

Analysis Population Description

The PK population included all subjects who had sufficient data for PK analysis, and who had not been excluded from analysis for protocol deviations that could impact the calculation or interpretation of the PK parameters.

Arm/Group Title	120 µg/kg of 3K3A-APC	240 µg/kg of 3K3A-APC	360 µg/kg of 3K3A-APC	540 µg/kg of 3K3A-APC
Arm/Group Description:	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	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	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	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
Overall Number of Participants Analyzed	5	3	5	8
Geometric Mean (Geometric Coefficient of Variation); Unit of Measure: 1/hr
	2.55; (13.4%)	2.94; (10.5%)	2.58; (34.9%)	2.13; (45.2%)

8. Secondary Outcome

Title	PK of 3K3A-APC by Compartmental Analysis (Half-life)
Description	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.
Time Frame	Following a single dose, on Day 1, 2 or 3: End of infusion (EOI) and 20, 40, 60 and 80 minutes following EOI

Outcome Measure Data

Analysis Population Description

The PK population included all subjects who had sufficient data for PK analysis, and who had not been excluded from analysis for protocol deviations that could impact the calculation or interpretation of the PK parameters.

Arm/Group Title	120 µg/kg of 3K3A-APC	240 µg/kg of 3K3A-APC	360 µg/kg of 3K3A-APC	540 µg/kg of 3K3A-APC
Arm/Group Description:	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	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	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	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
Overall Number of Participants Analyzed	5	3	5	8
Geometric Mean (Geometric Coefficient of Variation); Unit of Measure: hr
	0.272; (13.4%)	0.235; (10.5%)	0.268; (34.9%)	0.325; (45.2%)

Adverse Events

Time Frame	AEs were collected through Study Day 7 and were followed until resolution or a new baseline was established, up to Study Day 90. SAEs were collected through Study Day 30, and were followed until resolution (or resolution with sequelae), up to Study Day 90.
Adverse Event Reporting Description	Standard definitions of adverse events and serious adverse events were used.
Arm/Group Title	120 µg/kg of 3K3A-APC	240 µg/kg of 3K3A-APC	360 µg/kg of 3K3A-APC	540 µg/kg of 3K3A-APC	3K3A-APC Total	Placebo
Arm/Group Description	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	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	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	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	All 3K3A-APC treated groups combined	Matching placebo, q12h for up to 5 doses Placebo: Matching placebo, 0.9% sodium chloride in water, given as 100 mL IV infusion
All-Cause Mortality
	120 µg/kg of 3K3A-APC	240 µg/kg of 3K3A-APC	360 µg/kg of 3K3A-APC	540 µg/kg of 3K3A-APC	3K3A-APC Total	Placebo
	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	0/15 (0.00%)	2/24 (8.33%)	3/12 (25.00%)	4/15 (26.67%)	9/66 (13.64%)	6/44 (13.64%)
Serious Adverse Events
	120 µg/kg of 3K3A-APC	240 µg/kg of 3K3A-APC	360 µg/kg of 3K3A-APC	540 µg/kg of 3K3A-APC	3K3A-APC Total	Placebo
	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	8/15 (53.33%)	9/24 (37.50%)	4/12 (33.33%)	9/15 (60.00%)	30/66 (45.45%)	18/44 (40.91%)
Blood and lymphatic system disorders
Anaemia † 1	1/15 (6.67%)	1/24 (4.17%)	0/12 (0.00%)	0/15 (0.00%)	2/66 (3.03%)	1/44 (2.27%)
Leukocytosis † 1	0/15 (0.00%)	0/24 (0.00%)	0/12 (0.00%)	0/15 (0.00%)	0/66 (0.00%)	1/44 (2.27%)
Cardiac disorders
Atrial fibrillation † 1	4/15 (26.67%)	0/24 (0.00%)	0/12 (0.00%)	1/15 (6.67%)	5/66 (7.58%)	4/44 (9.09%)
Bradycardia † 1	0/15 (0.00%)	0/24 (0.00%)	0/12 (0.00%)	0/15 (0.00%)	0/66 (0.00%)	1/44 (2.27%)
Cardiac arrest † 1	0/15 (0.00%)	0/24 (0.00%)	0/12 (0.00%)	1/15 (6.67%)	1/66 (1.52%)	1/44 (2.27%)
Cardiac failure congestive † 1	1/15 (6.67%)	0/24 (0.00%)	0/12 (0.00%)	0/15 (0.00%)	1/66 (1.52%)	0/44 (0.00%)
Intracardiac thrombus † 1	0/15 (0.00%)	1/24 (4.17%)	0/12 (0.00%)	0/15 (0.00%)	1/66 (1.52%)	0/44 (0.00%)
Myocardial infarction † 1	0/15 (0.00%)	1/24 (4.17%)	0/12 (0.00%)	0/15 (0.00%)	1/66 (1.52%)	0/44 (0.00%)
Pericarditis † 1	0/15 (0.00%)	0/24 (0.00%)	1/12 (8.33%)	0/15 (0.00%)	1/66 (1.52%)	0/44 (0.00%)
Gastrointestinal disorders
Duodenal ulcer haemorrhage † 1	0/15 (0.00%)	1/24 (4.17%)	0/12 (0.00%)	0/15 (0.00%)	1/66 (1.52%)	0/44 (0.00%)
Retroperitoneal haematoma † 1	0/15 (0.00%)	1/24 (4.17%)	0/12 (0.00%)	0/15 (0.00%)	1/66 (1.52%)	0/44 (0.00%)
General disorders
Chest pain † 1	0/15 (0.00%)	0/24 (0.00%)	1/12 (8.33%)	0/15 (0.00%)	1/66 (1.52%)	0/44 (0.00%)
Infections and infestations
Pneumonia † 1	0/15 (0.00%)	0/24 (0.00%)	0/12 (0.00%)	0/15 (0.00%)	0/66 (0.00%)	1/44 (2.27%)
Septic shock † 1	0/15 (0.00%)	1/24 (4.17%)	0/12 (0.00%)	0/15 (0.00%)	1/66 (1.52%)	0/44 (0.00%)
Staphylococcal infection † 1	1/15 (6.67%)	0/24 (0.00%)	0/12 (0.00%)	0/15 (0.00%)	1/66 (1.52%)	0/44 (0.00%)
Urosepsis † 1	0/15 (0.00%)	0/24 (0.00%)	0/12 (0.00%)	0/15 (0.00%)	0/66 (0.00%)	1/44 (2.27%)
Investigations
Blood fibrinogen decreased † 1	0/15 (0.00%)	1/24 (4.17%)	0/12 (0.00%)	2/15 (13.33%)	3/66 (4.55%)	1/44 (2.27%)
Blood glucose increased † 1	0/15 (0.00%)	0/24 (0.00%)	0/12 (0.00%)	0/15 (0.00%)	0/66 (0.00%)	1/44 (2.27%)
Blood potassium decreased † 1	0/15 (0.00%)	1/24 (4.17%)	0/12 (0.00%)	0/15 (0.00%)	1/66 (1.52%)	0/44 (0.00%)
Blood sodium increased † 1	0/15 (0.00%)	1/24 (4.17%)	0/12 (0.00%)	0/15 (0.00%)	1/66 (1.52%)	0/44 (0.00%)
Ejection fraction decreased † 1	0/15 (0.00%)	0/24 (0.00%)	0/12 (0.00%)	1/15 (6.67%)	1/66 (1.52%)	0/44 (0.00%)
Hepatic enzyme increased † 1	0/15 (0.00%)	0/24 (0.00%)	1/12 (8.33%)	0/15 (0.00%)	1/66 (1.52%)	0/44 (0.00%)
Lymphocyte count decreased † 1	0/15 (0.00%)	1/24 (4.17%)	0/12 (0.00%)	0/15 (0.00%)	1/66 (1.52%)	1/44 (2.27%)
Troponin increased † 1	0/15 (0.00%)	0/24 (0.00%)	0/12 (0.00%)	1/15 (6.67%)	1/66 (1.52%)	0/44 (0.00%)
Nervous system disorders
Brain oedema † 1	0/15 (0.00%)	1/24 (4.17%)	0/12 (0.00%)	4/15 (26.67%)	5/66 (7.58%)	3/44 (6.82%)
Carotid artery stenosis † 1	0/15 (0.00%)	1/24 (4.17%)	0/12 (0.00%)	0/15 (0.00%)	1/66 (1.52%)	0/44 (0.00%)
Cerebral haemorrhage † 1	0/15 (0.00%)	3/24 (12.50%)	0/12 (0.00%)	0/15 (0.00%)	3/66 (4.55%)	2/44 (4.55%)
Cerebrovascular accident † 1	1/15 (6.67%)	3/24 (12.50%)	0/12 (0.00%)	1/15 (6.67%)	5/66 (7.58%)	3/44 (6.82%)
Convulsion † 1	2/15 (13.33%)	0/24 (0.00%)	0/12 (0.00%)	0/15 (0.00%)	2/66 (3.03%)	1/44 (2.27%)
Haemorrhage intracranial † 1	0/15 (0.00%)	0/24 (0.00%)	0/12 (0.00%)	1/15 (6.67%)	1/66 (1.52%)	1/44 (2.27%)
Psychiatric disorders
Agitation † 1	0/15 (0.00%)	0/24 (0.00%)	0/12 (0.00%)	0/15 (0.00%)	0/66 (0.00%)	1/44 (2.27%)
Respiratory, thoracic and mediastinal disorders
Acute respiratory failure † 1	0/15 (0.00%)	1/24 (4.17%)	0/12 (0.00%)	0/15 (0.00%)	1/66 (1.52%)	1/44 (2.27%)
Bronchospasm † 1	1/15 (6.67%)	0/24 (0.00%)	0/12 (0.00%)	0/15 (0.00%)	1/66 (1.52%)	0/44 (0.00%)
Pneumonia aspiration † 1	1/15 (6.67%)	0/24 (0.00%)	0/12 (0.00%)	1/15 (6.67%)	2/66 (3.03%)	1/44 (2.27%)
Pneumothorax † 1	0/15 (0.00%)	0/24 (0.00%)	0/12 (0.00%)	0/15 (0.00%)	0/66 (0.00%)	1/44 (2.27%)
Pulmonary embolism † 1	0/15 (0.00%)	0/24 (0.00%)	0/12 (0.00%)	0/15 (0.00%)	0/66 (0.00%)	1/44 (2.27%)
Pulmonary oedema † 1	1/15 (6.67%)	0/24 (0.00%)	0/12 (0.00%)	0/15 (0.00%)	1/66 (1.52%)	1/44 (2.27%)
Respiratory distress † 1	0/15 (0.00%)	0/24 (0.00%)	1/12 (8.33%)	0/15 (0.00%)	1/66 (1.52%)	0/44 (0.00%)
Respiratory failure † 1	0/15 (0.00%)	1/24 (4.17%)	1/12 (8.33%)	0/15 (0.00%)	2/66 (3.03%)	0/44 (0.00%)
Surgical and medical procedures
Aneurysm repair † 1	0/15 (0.00%)	0/24 (0.00%)	0/12 (0.00%)	0/15 (0.00%)	0/66 (0.00%)	1/44 (2.27%)
Vascular disorders
Deep vein thrombosis † 1	0/15 (0.00%)	0/24 (0.00%)	0/12 (0.00%)	1/15 (6.67%)	1/66 (1.52%)	1/44 (2.27%)
Hypotension † 1	0/15 (0.00%)	1/24 (4.17%)	0/12 (0.00%)	0/15 (0.00%)	1/66 (1.52%)	3/44 (6.82%)
1 Term from vocabulary, MedDRA; † Indicates events were collected by systematic assessment
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	120 µg/kg of 3K3A-APC	240 µg/kg of 3K3A-APC	360 µg/kg of 3K3A-APC	540 µg/kg of 3K3A-APC	3K3A-APC Total	Placebo
	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	10/15 (66.67%)	18/24 (75.00%)	8/12 (66.67%)	9/15 (60.00%)	45/66 (68.18%)	36/44 (81.82%)
Blood and lymphatic system disorders
Anaemia † 1	5/15 (33.33%)	4/24 (16.67%)	2/12 (16.67%)	2/15 (13.33%)	13/66 (19.70%)	6/44 (13.64%)
Leukocytosis † 1	0/15 (0.00%)	3/24 (12.50%)	1/12 (8.33%)	2/15 (13.33%)	6/66 (9.09%)	6/44 (13.64%)
Cardiac disorders
Bradycardia † 1	1/15 (6.67%)	0/24 (0.00%)	0/12 (0.00%)	0/15 (0.00%)	1/66 (1.52%)	5/44 (11.36%)
Gastrointestinal disorders
Constipation † 1	0/15 (0.00%)	5/24 (20.83%)	1/12 (8.33%)	0/15 (0.00%)	6/66 (9.09%)	4/44 (9.09%)
General disorders
Pyrexia † 1	1/15 (6.67%)	2/24 (8.33%)	1/12 (8.33%)	0/15 (0.00%)	4/66 (6.06%)	4/44 (9.09%)
Infections and infestations
Urinary tract infection † 1	1/15 (6.67%)	5/24 (20.83%)	3/12 (25.00%)	1/15 (6.67%)	10/66 (15.15%)	8/44 (18.18%)
Injury, poisoning and procedural complications
Contusion † 1	0/15 (0.00%)	3/24 (12.50%)	0/12 (0.00%)	0/15 (0.00%)	3/66 (4.55%)	3/44 (6.82%)
Investigations
Activated partial thromboplastin time prolonged † 1	0/15 (0.00%)	4/24 (16.67%)	0/12 (0.00%)	0/15 (0.00%)	4/66 (6.06%)	2/44 (4.55%)
Blood calcium decreased † 1	1/15 (6.67%)	2/24 (8.33%)	1/12 (8.33%)	1/15 (6.67%)	5/66 (7.58%)	1/44 (2.27%)
Blood fibrinogen decreased † 1	0/15 (0.00%)	3/24 (12.50%)	0/12 (0.00%)	0/15 (0.00%)	3/66 (4.55%)	4/44 (9.09%)
Lymphocyte count decreased † 1	2/15 (13.33%)	0/24 (0.00%)	0/12 (0.00%)	1/15 (6.67%)	3/66 (4.55%)	3/44 (6.82%)
Prothrombin time prolonged † 1	1/15 (6.67%)	3/24 (12.50%)	0/12 (0.00%)	1/15 (6.67%)	5/66 (7.58%)	6/44 (13.64%)
Nervous system disorders
Haemorrhage intracranial † 1	2/15 (13.33%)	4/24 (16.67%)	4/12 (33.33%)	4/15 (26.67%)	14/66 (21.21%)	16/44 (36.36%)
Headache † 1	1/15 (6.67%)	6/24 (25.00%)	2/12 (16.67%)	3/15 (20.00%)	12/66 (18.18%)	10/44 (22.73%)
Renal and urinary disorders
Haematuria † 1	1/15 (6.67%)	0/24 (0.00%)	1/12 (8.33%)	1/15 (6.67%)	3/66 (4.55%)	4/44 (9.09%)
Vascular disorders
Hypotension † 1	0/15 (0.00%)	2/24 (8.33%)	1/12 (8.33%)	0/15 (0.00%)	3/66 (4.55%)	3/44 (6.82%)
1 Term from vocabulary, MedDRA; † Indicates events were collected by systematic assessment

Limitations and Caveats

The study was designed and powered for evaluating DLTs and identifying a maximum tolerated dose, not for efficacy endpoints.

More Information

Certain Agreements

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

There is NOT 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.

Results Point of Contact

• Name/Title: Patrick Lyden, MD, FAAN, FAHA
• Organization: Cedars-Sinai Medical Center
• Phone: (310) 423-5166
• EMail: Patrick.Lyden@cshs.org

Publications:

Lyden P, Levy H, Weymer S, Pryor K, Kramer W, Griffin JH, Davis TP, Zlokovic B. Phase 1 safety, tolerability and pharmacokinetics of 3K3A-APC in healthy adult volunteers. Curr Pharm Des. 2013;19(42):7479-85.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Lyden P, Pryor KE, Coffey CS, Cudkowicz M, Conwit R, Jadhav A, Sawyer RN Jr, Claassen J, Adeoye O, Song S, Hannon P, Rost NS, Hinduja A, Torbey M, Lee JM, Benesch C, Rippee M, Rymer M, Froehler MT, Clarke Haley E, Johnson M, Yankey J, Magee K, Qidwai J, Levy H, Mark Haacke E, Fawaz M, Davis TP, Toga AW, Griffin JH, Zlokovic BV; NeuroNEXT Clinical Trials Network NN104 Investigators. Final Results of the RHAPSODY Trial: A Multi-Center, Phase 2 Trial Using a Continual Reassessment Method to Determine the Safety and Tolerability of 3K3A-APC, A Recombinant Variant of Human Activated Protein C, in Combination with Tissue Plasminogen Activator, Mechanical Thrombectomy or both in Moderate to Severe Acute Ischemic Stroke. Ann Neurol. 2019 Jan;85(1):125-136. doi: 10.1002/ana.25383. Epub 2019 Jan 7.

Lyden P, Weymer S, Coffey C, Cudkowicz M, Berg S, O'Brien S, Fisher M, Haley EC, Khatri P, Saver J, Levine S, Levy H, Rymer M, Wechsler L, Jadhav A, McNeil E, Waddy S, Pryor K. Selecting Patients for Intra-Arterial Therapy in the Context of a Clinical Trial for Neuroprotection. Stroke. 2016 Dec;47(12):2979-2985. Epub 2016 Nov 1.

• Responsible Party: ZZ Biotech, LLC
• ClinicalTrials.gov Identifier: NCT02222714
• Other Study ID Numbers: ZZ-3K3A-201 (NN104); 1U01NS088312-01 ( U.S. NIH Grant/Contract ); U01NS077352 ( U.S. NIH Grant/Contract ); U01NS077179-01 ( U.S. NIH Grant/Contract )
• First Submitted: August 18, 2014
• First Posted: August 21, 2014
• Results First Submitted: July 27, 2018
• Results First Posted: November 8, 2018
• Last Update Posted: November 8, 2018