NN104 / ZZ-3K3A-201: 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 activated protein C (APC), in combination with tissue plasminogen activator (tPA)

  • Prabhakaran, Shyam (PD/PI)

Project: Research project

Project Details

Description

SYNOPSIS

Investigational Product
3K3A-APC, a Recombinant Variant of Human Activated Protein C (APC) in which 3 lysine residues (191-193) of the 37-loop are replaced by 3 alanine residues.


Study Title
ZZ-3K3A-201: 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 Activated Protein C (APC), in combination with tissue plasminogen activator (tPA) in moderately severe acute hemispheric ischemic stroke.





Primary:

Objectives

• To evaluate the safety of multiple ascending intravenous (IV) doses of 3K3A-APC following tPA administration in subjects who have experienced moderately severe acute hemispheric ischemic stroke.
Secondary:
• To investigate the pharmacokinetic (PK) properties of 3K3A-APC following administration of tPA in adults with acute ischemic stroke.
• To evaluate the effect of 3K3A-APC on all (symptomatic and asymptomatic) bleeding in the brain as determined by MRI at Day 7 (or discharge, whichever is sooner) and Day 30.
Exploratory:
• To collect the 7-day National Institute of Health Scale (NIHSS) scores as a predictor for 90-day modified Rankin Scale (mRS).
• To collect the 90-day mRS
• To collect the 90-day Barthel Index (BI)
• To collect infarct volume at 90 days (CT or T1 MRI)





Design:

Design and Outcomes

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)1.

For the purposes of this study, we assume an established background symptomatic intracerebral hemorrhage (sICH) rate of 3-5%2,3. Correspondingly, the MTD will be

defined as the highest dose with a DLT rate of 10% or less. Subjects will be enrolled to 3K3A-APC dose cohorts in groups of four (three to specified treatment dose and one to placebo). Subjects will generally be enrolled at the dose estimated from the assumed dose-response model and prior data to be closest to the MTD. However, the initial cohort will start at the lowest dose level (120 µg/kg) and the dose level may only be escalated by one dose across the next subsequent cohort (there are no restrictions on dose level de-escalation). Intra-subject dose modification is not permitted during the study. After the final group of subjects is enrolled, the final MTD will be defined as the dose with estimated toxicity probability closest to the target toxicity level of 10%.

The design will proceed as follows:

• Enroll the first 4 subjects.
o Treat one of the four subjects (chosen randomly) with placebo.
o Treat the other three subjects with the lowest dose: 120 µg/kg.
o Observe the number of subjects (out of the three treated subjects) that
have a DLT per study definition.
o Based upon the observed information from the three treated subjects, refit the assumed dose-response curve.
• Using the re-estimated dose-response curve, determine which dose level of the four under consideration has an estimated probability of toxicity closest to 10%.
o Treat the next cohort of subjec
StatusFinished
Effective start/end date9/15/146/30/17

Funding

  • Massachusetts General Hospital (NN104//U01NS088312)
  • National Institute of Neurological Disorders and Stroke (NN104//U01NS088312)

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