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Ischemic StrokePhase 2RHAPSODYNCT02222714

Safety Evaluation of 3K3A-APC in Ischemic Stroke

A Phase 2 study testing 3K3A-APC in people with Ischemic Stroke, run by ZZ Biotech, LLC at 15 sites in United States.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial 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… Read more about this study

Who is it for?
Ages 18 to 90 years
Conditions the study is for
Ischemic Stroke
What is being tested?
3K3A-APC
Type of treatment
Injection or infusion
Could I receive a placebo?
Yes, some participants may receive a placebo
How many people
110 participants
Where
15 sitesUnited States
Study dates
Oct 2014to 29 Jun 2017
Phase
Phase 2
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 to 90 years
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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

Who cannot join

  • 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
Show all 11Show fewer
  • 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

Trial locations and contacts

15 sites in 1 country.

15 sites in 1 country

United States15 sites
  • Stroke Center

    Boston, Massachusetts, 02114

  • Stroke Center

    Buffalo, New York, 14209

  • Stroke Center

    Charlottesville, Virginia, 22904

  • Stroke Center

    Chicago, Illinois, 60611

  • Stroke Center

    Cincinnati, Ohio, 45208

  • Stroke Center

    Columbus, Ohio, 43210

  • Stroke Center

    Dallas, Texas, 75390

  • Stroke Center

    Kansas City, Kansas, 66160

  • Stroke Center

    Los Angeles, California, 90048

  • Stroke Center

    Nashville, Tennessee, 37232

  • Stroke Center

    New York, New York, 10032

  • Stroke Center

    Pittsburgh, Pennsylvania, 15213

  • Stroke Center

    Rochester, New York, 14642

  • Stroke Center

    Salt Lake City, Utah, 84132

  • Stroke Center

    St Louis, Missouri, 63110

Other trials in United States

About this study

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

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.

Read the 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.

Conditions
Ischemic Stroke
Being tested
3K3A-APC, Placebo
Keywords
ischemic stroke, stroke, APC, 3K3A, 3K3A-APC, activated protein C, RHAPSODY
Medical subject headings
Ischemic Stroke, Stroke

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • 3K3A-APCBiological

    Also called 3K3A-Activated Protein C

    3K3A-APC, diluted in 0.9% sodium chloride in water, given as 100 mL IV infusion

  • PlaceboDrug

    Also called Matching Placebo

    Matching placebo, 0.9% sodium chloride in water, given as 100 mL IV infusion

Study groups in NCT02222714
Study groupRoleWhat they receive
120 µg/kg of 3K3A-APCActive comparator3K3A-APC, q12h for up to 5 doses
Receives: Biological: 3K3A-APC
240 µg/kg of 3K3A-APCActive comparator3K3A-APC, q12h for up to 5 doses
Receives: Biological: 3K3A-APC
360 µg/kg of 3K3A-APCActive comparator3K3A-APC, q12h for up to 5 doses
Receives: Biological: 3K3A-APC
540 µg/kg of 3K3A-APCActive comparator3K3A-APC, q12h for up to 5 doses
Receives: Biological: 3K3A-APC
PlaceboPlacebo comparatorMatching placebo, q12h for up to 5 doses
Receives: Drug: Placebo

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. 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.

    Measured: 48-hours following last dose

Secondary outcomes (7)
  1. 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.

    Measured: Day 30

  2. 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.

    Measured: Following a single dose, on Day 1, 2 or 3: End of infusion (EOI) and 20, 40, 60 and 80 minutes following EOI

  3. 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.

    Measured: Following a single dose, on Day 1, 2 or 3: End of infusion (EOI) and 20, 40, 60 and 80 minutes following EOI

  4. 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.

    Measured: Following a single dose, on Day 1, 2 or 3: End of infusion (EOI) and 20, 40, 60 and 80 minutes following EOI

  5. 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.

    Measured: Following a single dose, on Day 1, 2 or 3: End of infusion (EOI) and 20, 40, 60 and 80 minutes following EOI

  6. 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.

    Measured: Following a single dose, on Day 1, 2 or 3: End of infusion (EOI) and 20, 40, 60 and 80 minutes following EOI

  7. 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.

    Measured: Following a single dose, on Day 1, 2 or 3: End of infusion (EOI) and 20, 40, 60 and 80 minutes following EOI

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted21 Aug 2014 (estimated)
  2. Study startOct 2014
  3. Primary completion18 Apr 2017
  4. Study completion29 Jun 2017

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Masking
Quadruple blind
Who is masked
Participant, Care provider, Investigator, Outcomes assessor
Enrolment
110 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT02222714
Sponsor's protocol ID
ZZ-3K3A-201 (NN104)
Other IDs
1U01NS088312-01, U01NS077352, U01NS077179-01
Acronym
RHAPSODY
Status last verified
Oct 2018
First submitted
18 Aug 2014
Last updated
8 Nov 2018
Data monitoring committee
Yes
FDA-regulated drug
Yes
FDA-regulated device
No
Individual data sharing
Undecided

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. doi: 10.2174/1381612819666131230131454.

    PubMed 24372304
  • 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.

    PubMed 30450637
  • 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.

    PubMed 27803392

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing 3K3A-APC in people with Ischemic Stroke, run by ZZ Biotech, LLC at 15 sites in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 5 inclusion and 11 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 8 Nov 2018. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 15 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 8 Nov 2018). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Number of Participants With Adverse Events That Meet Dose-limiting Toxicity (DLT) Criteria Specified in Protocol (time frame: 48-hours following last dose). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT02222714, which also lists 3 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 8 Nov 2018.

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