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

Tracking Information

• First Submitted Date: August 18, 2014
• First Posted Date: August 21, 2014
• Results First Submitted Date: July 27, 2018
• Results First Posted Date: November 8, 2018
• Last Update Posted Date: November 8, 2018
• Study Start Date: October 2014
• Actual Primary Completion Date: April 18, 2017 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: October 10, 2018)

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.

• Original Primary Outcome Measures (submitted: August 19, 2014): Adverse Events that Meet Dose-limiting Toxicity (DLT) Criteria Specified in Protocol [ Time Frame: 48-hours following last dose ]

Current Secondary Outcome Measures (submitted: October 10, 2018)

• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.

Original Secondary Outcome Measures (submitted: August 19, 2014)

• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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 ]
• 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.
• 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.
• Number of subjects who confirm positive for anti-drug antibody formation [ Time Frame: Day 30 ]

• Current Other Pre-specified Outcome Measures: Not Provided

Original Other Pre-specified Outcome Measures (submitted: August 19, 2014)

• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.

Descriptive Information

• Brief Title: Safety Evaluation of 3K3A-APC in Ischemic Stroke
• 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
• 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.

• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment
• Condition: Ischemic Stroke

Intervention

• 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
• Drug: Placebo
  Matching placebo, 0.9% sodium chloride in water, given as 100 mL IV infusion
  Other Name: Matching Placebo

Study Arms

• Active Comparator: 120 µg/kg of 3K3A-APC
  3K3A-APC, q12h for up to 5 doses
  Intervention: Biological: 3K3A-APC
• Active Comparator: 240 µg/kg of 3K3A-APC
  3K3A-APC, q12h for up to 5 doses
  Intervention: Biological: 3K3A-APC
• Active Comparator: 360 µg/kg of 3K3A-APC
  3K3A-APC, q12h for up to 5 doses
  Intervention: Biological: 3K3A-APC
• Active Comparator: 540 µg/kg of 3K3A-APC
  3K3A-APC, q12h for up to 5 doses
  Intervention: Biological: 3K3A-APC
• Placebo Comparator: Placebo
  Matching placebo, q12h for up to 5 doses
  Intervention: Drug: Placebo

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.
• 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.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: April 6, 2017): 110
• Original Estimated Enrollment (submitted: August 19, 2014): 100
• Actual Study Completion Date: June 29, 2017
• Actual Primary Completion Date: April 18, 2017 (Final data collection date for primary outcome measure)

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 90 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: 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 )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: Undecided

• Current Responsible Party: ZZ Biotech, LLC
• Original Responsible Party: Same as current
• Current Study Sponsor: ZZ Biotech, LLC
• Original Study Sponsor: Same as current

Collaborators

• National Institute of Neurological Disorders and Stroke (NINDS)
• Cedars-Sinai Medical Center
• Massachusetts General Hospital
• University of Iowa

Investigators

• Principal Investigator: Patrick D. Lyden, MD; Cedars-Sinai Medical Center

• PRS Account: ZZ Biotech, LLC
• Verification Date: October 2018