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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
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:
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 Description
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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.

Condition or disease Intervention/treatment Phase
Ischemic Stroke Biological: 3K3A-APC Drug: Placebo Phase 2

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.

Study Design
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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 110 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
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 Start Date : October 2014
Actual Primary Completion Date : April 18, 2017
Actual Study Completion Date : June 29, 2017

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Ischemic Stroke
Drug Information available for: Protein C

Arms and Interventions
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Arm Intervention/treatment
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
Other Name: 3K3A-Activated Protein C
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
Other Name: 3K3A-Activated Protein C
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
Other Name: 3K3A-Activated Protein C
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
Other Name: 3K3A-Activated Protein C
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
Other Name: Matching Placebo


Outcome Measures
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Primary Outcome Measures :
  1. Number of Participants With Adverse Events That Meet Dose-limiting Toxicity (DLT) Criteria Specified in Protocol [ Time Frame: 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 Outcome Measures :
  1. Number of Participants With a Presence of Measurable Bleeds in the Brain (Hemorrhage and Microbleeds) 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.

  2. PK of 3K3A-APC by Compartmental Analysis (Clearance) [ 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. PK of 3K3A-APC by Compartmental Analysis (Volume of Distribution) [ 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. PK of 3K3A-APC by Compartmental Analysis (Cmax) [ 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. PK of 3K3A-APC by Compartmental Analysis (AUC[0-inf]) [ 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. PK of 3K3A-APC by Compartmental Analysis (λz) [ 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. PK of 3K3A-APC by Compartmental Analysis (Half-life) [ 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.


Eligibility Criteria
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Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years to 90 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02222714


Locations
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United States, California
Stroke Center
Los Angeles, California, United States, 90048
United States, Illinois
Stroke Center
Chicago, Illinois, United States, 60611
United States, Kansas
Stroke Center
Kansas City, Kansas, United States, 66160
United States, Massachusetts
Stroke Center
Boston, Massachusetts, United States, 02114
United States, Missouri
Stroke Center
Saint Louis, Missouri, United States, 63110
United States, New York
Stroke Center
Buffalo, New York, United States, 14209
Stroke Center
New York, New York, United States, 10032
Stroke Center
Rochester, New York, United States, 14642
United States, Ohio
Stroke Center
Cincinnati, Ohio, United States, 45208
Stroke Center
Columbus, Ohio, United States, 43210
United States, Pennsylvania
Stroke Center
Pittsburgh, Pennsylvania, United States, 15213
United States, Tennessee
Stroke Center
Nashville, Tennessee, United States, 37232
United States, Texas
Stroke Center
Dallas, Texas, United States, 75390
United States, Utah
Stroke Center
Salt Lake City, Utah, United States, 84132
United States, Virginia
Stroke Center
Charlottesville, Virginia, United States, 22904
Sponsors and Collaborators
ZZ Biotech, LLC
National Institute of Neurological Disorders and Stroke (NINDS)
Cedars-Sinai Medical Center
Massachusetts General Hospital
University of Iowa
Investigators
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Principal Investigator: Patrick D. Lyden, MD Cedars-Sinai Medical Center
  Study Documents (Full-Text)

Documents provided by ZZ Biotech, LLC:
Statistical Analysis Plan  [PDF] December 7, 2017
Study Protocol  [PDF] October 7, 2016

More Information
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Publications:

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.

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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 Posted: August 21, 2014    Key Record Dates
Results First Posted: November 8, 2018
Last Update Posted: November 8, 2018
Last Verified: October 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by ZZ Biotech, LLC:
ischemic stroke
stroke
APC
3K3A
 3K3A-APC
activated protein C
RHAPSODY
Additional relevant MeSH terms:
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Stroke
Ischemic Stroke
Cerebral Infarction
Ischemia
Cerebrovascular Disorders
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Vascular Diseases
Cardiovascular Diseases
 Pathologic Processes
Brain Infarction
Brain Ischemia
Infarction
Necrosis
Protein C
Anticoagulants
Fibrinolytic Agents
Fibrin Modulating Agents
Molecular Mechanisms of Pharmacological Action