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

Primary Purpose

Ischemic Stroke

Status
Completed
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
3K3A-APC
Placebo
Sponsored by
ZZ Biotech, LLC
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Ischemic Stroke focused on measuring ischemic stroke, stroke, APC, 3K3A, 3K3A-APC, activated protein C, RHAPSODY

Eligibility Criteria

18 Years - 90 Years (Adult, Older Adult)All SexesDoes not accept 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

Sites / Locations

  • Stroke Center
  • Stroke Center
  • Stroke Center
  • Stroke Center
  • Stroke Center
  • Stroke Center
  • Stroke Center
  • Stroke Center
  • Stroke Center
  • Stroke Center
  • Stroke Center
  • Stroke Center
  • Stroke Center
  • Stroke Center
  • Stroke Center

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm 5

Arm Type

Active Comparator

Active Comparator

Active Comparator

Active Comparator

Placebo Comparator

Arm Label

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 Description

3K3A-APC, q12h for up to 5 doses

3K3A-APC, q12h for up to 5 doses

3K3A-APC, q12h for up to 5 doses

3K3A-APC, q12h for up to 5 doses

Matching placebo, q12h for up to 5 doses

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

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.
PK of 3K3A-APC by Compartmental Analysis (Clearance)
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)
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)
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])
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 (λz)
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)
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.

Full Information

First Posted
August 18, 2014
Last Updated
October 10, 2018
Sponsor
ZZ Biotech, LLC
Collaborators
National Institute of Neurological Disorders and Stroke (NINDS), Cedars-Sinai Medical Center, Massachusetts General Hospital, University of Iowa
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1. Study Identification

Unique Protocol Identification Number
NCT02222714
Brief Title
Safety Evaluation of 3K3A-APC in Ischemic Stroke
Acronym
RHAPSODY
Official Title
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
Study Type
Interventional

2. Study Status

Record Verification Date
October 2018
Overall Recruitment Status
Completed
Study Start Date
October 2014 (undefined)
Primary Completion Date
April 18, 2017 (Actual)
Study Completion Date
June 29, 2017 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
ZZ Biotech, LLC
Collaborators
National Institute of Neurological Disorders and Stroke (NINDS), Cedars-Sinai Medical Center, Massachusetts General Hospital, University of Iowa

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Ischemic Stroke
Keywords
ischemic stroke, stroke, APC, 3K3A, 3K3A-APC, activated protein C, RHAPSODY

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
110 (Actual)

8. Arms, Groups, and Interventions

Arm Title
120 µg/kg of 3K3A-APC
Arm Type
Active Comparator
Arm Description
3K3A-APC, q12h for up to 5 doses
Arm Title
240 µg/kg of 3K3A-APC
Arm Type
Active Comparator
Arm Description
3K3A-APC, q12h for up to 5 doses
Arm Title
360 µg/kg of 3K3A-APC
Arm Type
Active Comparator
Arm Description
3K3A-APC, q12h for up to 5 doses
Arm Title
540 µg/kg of 3K3A-APC
Arm Type
Active Comparator
Arm Description
3K3A-APC, q12h for up to 5 doses
Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
Matching placebo, q12h for up to 5 doses
Intervention Type
Biological
Intervention Name(s)
3K3A-APC
Other Intervention Name(s)
3K3A-Activated Protein C
Intervention Description
3K3A-APC, diluted in 0.9% sodium chloride in water, given as 100 mL IV infusion
Intervention Type
Drug
Intervention Name(s)
Placebo
Other Intervention Name(s)
Matching Placebo
Intervention Description
Matching placebo, 0.9% sodium chloride in water, given as 100 mL IV infusion
Primary Outcome Measure Information:
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
Secondary Outcome Measure Information:
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
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
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
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
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
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
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

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
90 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Patrick D. Lyden, MD
Organizational Affiliation
Cedars-Sinai Medical Center
Official's Role
Principal Investigator
Facility Information:
Facility Name
Stroke Center
City
Los Angeles
State/Province
California
ZIP/Postal Code
90048
Country
United States
Facility Name
Stroke Center
City
Chicago
State/Province
Illinois
ZIP/Postal Code
60611
Country
United States
Facility Name
Stroke Center
City
Kansas City
State/Province
Kansas
ZIP/Postal Code
66160
Country
United States
Facility Name
Stroke Center
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02114
Country
United States
Facility Name
Stroke Center
City
Saint Louis
State/Province
Missouri
ZIP/Postal Code
63110
Country
United States
Facility Name
Stroke Center
City
Buffalo
State/Province
New York
ZIP/Postal Code
14209
Country
United States
Facility Name
Stroke Center
City
New York
State/Province
New York
ZIP/Postal Code
10032
Country
United States
Facility Name
Stroke Center
City
Rochester
State/Province
New York
ZIP/Postal Code
14642
Country
United States
Facility Name
Stroke Center
City
Cincinnati
State/Province
Ohio
ZIP/Postal Code
45208
Country
United States
Facility Name
Stroke Center
City
Columbus
State/Province
Ohio
ZIP/Postal Code
43210
Country
United States
Facility Name
Stroke Center
City
Pittsburgh
State/Province
Pennsylvania
ZIP/Postal Code
15213
Country
United States
Facility Name
Stroke Center
City
Nashville
State/Province
Tennessee
ZIP/Postal Code
37232
Country
United States
Facility Name
Stroke Center
City
Dallas
State/Province
Texas
ZIP/Postal Code
75390
Country
United States
Facility Name
Stroke Center
City
Salt Lake City
State/Province
Utah
ZIP/Postal Code
84132
Country
United States
Facility Name
Stroke Center
City
Charlottesville
State/Province
Virginia
ZIP/Postal Code
22904
Country
United States

12. IPD Sharing Statement

Plan to Share IPD
Undecided
Citations:
PubMed Identifier
24372304
Citation
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. doi: 10.2174/1381612819666131230131454.
Results Reference
background
PubMed Identifier
30450637
Citation
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.
Results Reference
derived
PubMed Identifier
27803392
Citation
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. doi: 10.1161/STROKEAHA.116.013881. Epub 2016 Nov 1.
Results Reference
derived

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Safety Evaluation of 3K3A-APC in Ischemic Stroke

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