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History of Changes for Study: NCT02222714
Safety Evaluation of 3K3A-APC in Ischemic Stroke (RHAPSODY)
Latest version (submitted October 10, 2018) on ClinicalTrials.gov
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Study Record Versions
Version A B Submitted Date Changes
1 August 19, 2014 None (earliest Version on record)
2 October 19, 2014 Recruitment Status, Study Status and Contacts/Locations
3 October 22, 2014 Contacts/Locations and Study Status
4 October 28, 2014 Contacts/Locations and Study Status
5 October 30, 2014 Contacts/Locations and Study Status
6 November 6, 2014 Contacts/Locations and Study Status
7 November 14, 2014 Contacts/Locations and Study Status
8 November 21, 2014 Contacts/Locations and Study Status
9 December 12, 2014 Study Status, Contacts/Locations and Study Description
10 December 30, 2014 Contacts/Locations and Study Status
11 February 26, 2015 Contacts/Locations and Study Status
12 April 30, 2015 Study Status and Contacts/Locations
13 May 21, 2015 Study Status and Contacts/Locations
14 June 19, 2015 Outcome Measures, Eligibility, Study Description, Study Status and Study Identification
15 November 11, 2015 Study Status and Outcome Measures
16 July 11, 2016 Contacts/Locations and Study Status
17 January 23, 2017 Study Status and Study Description
18 March 13, 2017 Study Status and Contacts/Locations
19 April 6, 2017 Recruitment Status, Study Status, Contacts/Locations, Study Design and Oversight
20 May 23, 2017 Study Status, IPDSharing and Contacts/Locations
21 January 9, 2018 Recruitment Status, Study Status
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Results Submission Events
22 October 10, 2018 Study Status, Outcome Measures, Study Description, Document Section, Results, Eligibility, Arms and Interventions and Study Identification
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Study NCT02222714
Submitted Date:  August 19, 2014 (v1)

Open or close this module Study Identification
Unique Protocol ID: ZZ-3K3A-201 (NN104)
Brief Title: Safety Evaluation of 3K3A-APC in Ischemic Stroke (RHAPSODY)
Official Title: A Multi-center, Phase 2 Study Using a Continual Reassessment Method to Determine the Safety and Tolerability of 3K3A-APC, a Recombinant Variant of Human APC, in Combination With tPA in Moderately Severe Acute Hemispheric Ischemic Stroke
Secondary IDs: 1U01NS088312-01 [U.S. NIH Grant/Contract]
U01NS077352 [U.S. NIH Grant/Contract]
U01NS077179-01 [U.S. NIH Grant/Contract]
Open or close this module Study Status
Record Verification: August 2014
Overall Status: Not yet recruiting
Study Start: September 2014
Primary Completion: January 2017 [Anticipated]
Study Completion: March 2017 [Anticipated]
First Submitted: August 18, 2014
First Submitted that
Met QC Criteria:
August 19, 2014
First Posted: August 21, 2014 [Estimate]
Last Update Submitted that
Met QC Criteria:
August 19, 2014
Last Update Posted: August 21, 2014 [Estimate]
Open or close this module Sponsor/Collaborators
Sponsor: ZZ Biotech, LLC
Responsible Party: Sponsor
Collaborators: National Institute of Neurological Disorders and Stroke (NINDS)
Cedars-Sinai Medical Center
Massachusetts General Hospital
University of Iowa
Open or close this module Oversight
U.S. FDA-regulated Drug:
U.S. FDA-regulated Device:
Data Monitoring: Yes
Open or close this module Study Description
Brief Summary: The purpose of this study is 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).
Detailed Description:

This is a multicenter, prospective, randomized, controlled, double-blinded Phase 2 study intended to evaluate the safety, PK and preliminary efficacy of 3K3A-APC following administration of tPA in subjects with moderately severe acute ischemic stroke.

Approximately 100 subjects will be randomized, which includes the planned 88 subjects in groups of four to either 3K3A-APC or placebo (in a 3:1 ratio) and the additional placebo subjects who will be enrolled during safety review pauses. This study will utilize a modified version of the continual reassessment method (CRM) in order to establish a maximum tolerated dose (MTD).

Eligible subjects will receive 3K3A-APC or placebo every 12 hours for up to 5 doses (approximately 3 days), or until discharge from the hospital, whichever occurs first. Subjects will be monitored for safety evaluations through Day 7 (or discharge, if earlier) and are expected to be seen on Day 7, 30 and 90 for safety and outcome evaluations.

Open or close this module Conditions
Conditions: Ischemic Stroke
Keywords: ischemic stroke
stroke
APC
3K3A
3K3A-APC
activated protein C
RHAPSODY
Open or close this module Study Design
Study Type: Interventional
Primary Purpose: Treatment
Study Phase: Phase 2
Interventional Study Model: Parallel Assignment
Number of Arms: 5
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Allocation: Randomized
Enrollment: 100 [Anticipated]
Open or close this module Arms and Interventions
Arms Assigned Interventions
Active Comparator: 120 µg/kg of 3K3A-APC
3K3A-APC, q12h for up to 5 doses
Biological: 3K3A-APC
3K3A-APC, diluted in 0.9% sodium chloride in water, given as 100 mL IV infusion
Active Comparator: 240 µg/kg of 3K3A-APC
3K3A-APC, q12h for up to 5 doses
Biological: 3K3A-APC
3K3A-APC, diluted in 0.9% sodium chloride in water, given as 100 mL IV infusion
Active Comparator: 360 µg/kg of 3K3A-APC
3K3A-APC, q12h for up to 5 doses
Biological: 3K3A-APC
3K3A-APC, diluted in 0.9% sodium chloride in water, given as 100 mL IV infusion
Active Comparator: 540 µg/kg of 3K3A-APC
3K3A-APC, q12h for up to 5 doses
Biological: 3K3A-APC
3K3A-APC, diluted in 0.9% sodium chloride in water, given as 100 mL IV infusion
Placebo Comparator: Placebo
Matching placebo, q12h for up to 5 doses
Drug: Placebo
Matching placebo, 0.9% sodium chloride in water, given as 100 mL IV infusion
Open or close this module Outcome Measures
Primary Outcome Measures:
1. Adverse Events that Meet Dose-limiting Toxicity (DLT) Criteria Specified in Protocol
[ Time Frame: 48-hours following last dose ]

Secondary Outcome Measures:
1. Maximum Observed Plasma Concentration (Cmax) of 3K3A-APC by Compartmental Analysis
[ 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 ]

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.
2. Area Under the Plasma Concentration-time Curve (AUC) From Time 0 to Infinity [AUC(0-inf)] for 3K3A-APC by Compartmental Analysis
[ 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 ]

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.
3. Elimination Rate Constant (λz) for 3K3A-APC by Compartmental Analysis
[ 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 ]

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.
4. Half-life (t1/2) of 3K3A-APC by Compartmental Analysis
[ 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 ]

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.
5. Total Clearance (CL) of 3K3A-APC by Compartmental Analysis
[ 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 ]

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.
6. Volume of Distribution (V) of 3K3A-APC by Compartmental Analysis
[ 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 ]

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.
7. Relationship between the change from baseline in activated partial thromboplastin time (aPTT) and the concurrently measured 3K3A-APC plasma concentration
[ Time Frame: Following a single dose, on Day 1, 2 or 3: 60 minutes following EOI ]

8. Number of measurable bleeds in the brain (symptomatic & asymptomatic) as determined by 1.5T MRI
[ Time Frame: Day 7 (or discharge) ]

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.
9. Number of measurable bleeds in the brain (symptomatic & asymptomatic) as determined by 1.5T MRI
[ Time Frame: 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.
10. Number of subjects who confirm positive for anti-drug antibody formation
[ Time Frame: Day 30 ]

Other Outcome Measures:
1. National Institutes of Health Stroke Scale (NIHSS) score
[ Time Frame: Day 7 ]

The 7-day NIHSS mean scores will be compared using a Kruskal-Wallis test. The comparisons will evaluate all treated subjects (regardless of dose) versus all placebo subjects.
2. Modified Rankin Scale (mRS) score
[ Time Frame: Day 90 ]

The 90-day mRS will be compared using a Pearson chi-square test. The comparisons will evaluate all treated subjects (regardless of dose) versus all placebo subjects.
3. Barthel Index (BI) score
[ Time Frame: Day 90 ]

The 90-day BI will be compared using a Kruskal-Wallis test. The comparisons will evaluate all treated subjects (regardless of dose) versus all placebo subjects.
4. Infarct volume
[ Time Frame: Day 90 ]

The mean infarct volume at 90 days (MRI, or CT if unable to obtain MRI) will be compared using a linear regression model. Median and categorical infarct volumes (based upon quartiles) will be compared. The comparisons will evaluate all treated subjects (regardless of dose) versus all placebo subjects.
5. National Institutes of Health Stroke Scale (NIHSS) score
[ Time Frame: Day 7 ]

The change from Baseline NIHSS to 7-day NIHSS will be compared using a linear regression model, with baseline NIHSS score as a covariate. The comparisons will evaluate all treated subjects (regardless of dose) versus all placebo subjects.
6. The Relationship between the 7-day NIHSS score and the 90-day mRS
[ Time Frame: Days 7 and 90 ]

The relationship between the 7-day NIHSS score and the 90-day mRS will be examined using a linear regression model. The degree of fit and the R-square will be determined, and the model will be used to assess the potential for using the 7-day outcome in subsequent studies.The comparisons will evaluate all treated subjects (regardless of dose) versus all placebo subjects.
7. National Institutes of Health Stroke Scale (NIHSS) score
[ Time Frame: Day 7 ]

The 7-day NIHSS mean scores will be compared using a Kruskal-Wallis test. The comparisons will evaluate all subjects receiving the dose selected as the MTD versus all placebo subjects.
8. Modified Rankin Scale (mRS) score
[ Time Frame: Day 90 ]

The 90-day mRS will be compared using a Pearson chi-square test. The comparisons will evaluate all subjects receiving the dose selected as the MTD versus all placebo subjects.
9. Barthel Index (BI) score
[ Time Frame: Day 90 ]

The 90-day BI will be compared using a Kruskal-Wallis test. The comparisons will evaluate all subjects receiving the dose selected as the MTD versus all placebo subjects.
10. Infarct volume
[ Time Frame: Day 90 ]

The mean infarct volume at 90 days (MRI, or CT if unable to obtain MRI) will be compared using a linear regression model. Median and categorical infarct volumes (based upon quartiles) will be compared.The comparisons will evaluate all subjects receiving the dose selected as the MTD versus all placebo subjects.
11. National Institutes of Health Stroke Scale (NIHSS) score
[ Time Frame: Day 7 ]

The change from Baseline NIHSS to 7-day NIHSS will be compared using a linear regression model, with baseline NIHSS score as a covariate. The comparisons will evaluate all subjects receiving the dose selected as the MTD versus all placebo subjects.
12. The Relationship between the 7-day NIHSS score and the 90-day mRS
[ Time Frame: Days 7 and 90 ]

The relationship between the 7-day NIHSS score and the 90-day mRS will be examined using a linear regression model. The degree of fit and the R-square will be determined, and the model will be used to assess the potential for using the 7-day outcome in subsequent studies.The comparisons will evaluate all subjects receiving the dose selected as the MTD versus all placebo subjects.
Open or close this module Eligibility
Minimum Age: 18 Years
Maximum Age: 80 Years
Sex: All
Gender Based:
Accepts Healthy Volunteers: No
Criteria:

Inclusion Criteria:

  • Acute hemispheric ischemic stroke
  • Able to receive IV tPA
  • National Institutes of Health Stroke Scale (NIHSS) score of 7 to 20
  • Signed informed consent

Exclusion Criteria:

  • History of stroke or penetrating head injury within 90 days prior to enrollment
  • History of previous or current diagnosis of intracranial hemorrhage, moyamoya disease, cerebral arterio-venous malformation (AVM), known unsecured aneurysm, or intracranial neoplasm
  • 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
  • Use of oral anticoagulants or heparin within 48 hours
  • Prolonged prothrombin time (PT) or aPTT
  • Gastrointestinal, respiratory or urinary tract hemorrhage within 30 days prior to enrollment
  • Severe hypertension or hypotension
  • Glomerular filtration rate (GFR) <35 mL/min
  • Platelet count < 75,000/mm3
  • Blood glucose concentration < 50 mg/dL
  • Prior exposure to any exogenous form of APC
Open or close this module Contacts/Locations
Central Contact Person: NeuroNEXT Clinical Coordinating Center
Email: ESIMPSON1@mgh.harvard.edu
Study Officials: Patrick D. Lyden, MD
Principal Investigator
Cedars-Sinai Medical Center
Locations: United States, California
Stroke Center
Los Angeles, California, United States, 90048
Contact:Contact: NeuroNEXT Clinical Coordinating Center ESIMPSON1@mgh.harvard.edu
United States, Illinois
Stroke Center
Chicago, Illinois, United States, 60611
Contact:Contact: NeuroNEXT Clinical Coordinating Center ESIMPSON1@mgh.harvard.edu
United States, Kansas
Stroke Center
Kansas City, Kansas, United States, 66160
Contact:Contact: NeuroNEXT Clinical Coordinating Center ESIMPSON1@mgh.harvard.edu
United States, Massachusetts
Stroke Center
Boston, Massachusetts, United States, 02114
Contact:Contact: NeuroNEXT Clinical Coordinating Center ESIMPSON1@mgh.harvard.edu
United States, Missouri
Stroke Center
St. Louis, Missouri, United States, 63110
Contact:Contact: NeuroNEXT Clinical Coordinating Center ESIMPSON1@mgh.harvard.edu
United States, New York
Stroke Center
Buffalo, New York, United States, 14209
Contact:Contact: NeuroNEXT Clinical Coordinating Center ESIMPSON1@mgh.harvard.edu
Stroke Center
New York, New York, United States, 10032
Contact:Contact: NeuroNEXT Clinical Coordinating Center ESIMPSON1@mgh.harvard.edu
United States, Ohio
Stroke Center
Cincinnati, Ohio, United States, 45208
Contact:Contact: NeuroNEXT Clinical Coordinating Center ESIMPSON1@mgh.harvard.edu
Stroke Center
Columbus, Ohio, United States, 43210
Contact:Contact: NeuroNEXT Clinical Coordinating Center ESIMPSON1@mgh.harvard.edu
United States, Oregon
Stroke Center
Portland, Oregon, United States, 97239
Contact:Contact: NeuroNEXT Clinical Coordinating Center ESIMPSON1@mgh.harvard.edu
United States, Pennsylvania
Stroke Center
Pittsburg, Pennsylvania, United States, 15213
Contact:Contact: NeuroNEXT Clinical Coordinating Center ESIMPSON1@mgh.harvard.edu
United States, Tennessee
Stroke Center
Nashville, Tennessee, United States, 37232
Contact:Contact: NeuroNEXT Clinical Coordinating Center ESIMPSON1@mgh.harvard.edu
United States, Texas
Stroke Center
Dallas, Texas, United States, 75390
Contact:Contact: NeuroNEXT Clinical Coordinating Center ESIMPSON1@mgh.harvard.edu
United States, Utah
Stroke Center
Salt Lake City, Utah, United States, 84132
Contact:Contact: NeuroNEXT Clinical Coordinating Center ESIMPSON1@mgh.harvard.edu
Open or close this module IPDSharing
Plan to Share IPD:
Open or close this module References
Citations: 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. PubMed 24372304
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