Safety Evaluation of 3K3A-APC in Ischemic Stroke "RHAPSODY"

Active, not recruiting

Phase 2 Results N/A

Trial Description

The purpose of this study is 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 is 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 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).
Eligible subjects will receive 3K3A-APC or placebo every 12 hours for up to 5 doses (approximately 3 days), or until discharge from the hospital, whichever occurs first. Subjects will be monitored for safety evaluations through Day 7 (or discharge, if earlier) and are expected to be seen on Day 7, 14, 30 and 90 for safety and outcome evaluations.

Conditions

Interventions

  • Placebo Drug
    Intervention Desc: Matching placebo, 0.9% sodium chloride in water, given as 100 mL IV infusion
    ARM 1: Kind: Experimental
    Label: Placebo
    Description: Matching placebo, q12h for up to 5 doses
  • 3K3A-APC Biological
    Intervention Desc: 3K3A-APC, diluted in 0.9% sodium chloride in water, given as 100 mL IV infusion
    ARM 1: Kind: Experimental
    Label: 120 µg/kg of 3K3A-APC
    Description: 3K3A-APC, q12h for up to 5 doses
    ARM 2: Kind: Experimental
    Label: 240 µg/kg of 3K3A-APC
    Description: 3K3A-APC, q12h for up to 5 doses
    ARM 3: Kind: Experimental
    Label: 360 µg/kg of 3K3A-APC
    Description: 3K3A-APC, q12h for up to 5 doses
    ARM 4: Kind: Experimental
    Label: 540 µg/kg of 3K3A-APC
    Description: 3K3A-APC, q12h for up to 5 doses

Trial Design

  • Allocation: Randomized
  • Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
  • Purpose: Treatment
  • Endpoint: Safety Study
  • Intervention: Parallel Assignment

Outcomes

Type Measure Time Frame Safety Issue
Primary Adverse Events that Meet Dose-limiting Toxicity (DLT) Criteria Specified in Protocol 48-hours following last dose Yes
Secondary Maximum Observed Plasma Concentration (Cmax) of 3K3A-APC by Compartmental Analysis Following a single dose, on Day 1, 2 or 3: End of infusion (EOI) and 20, 40, 60 and 80 minutes following EOI No
Secondary Area Under the Plasma Concentration-time Curve (AUC) From Time 0 to Infinity [AUC(0-inf)] for 3K3A-APC by Compartmental Analysis Following a single dose, on Day 1, 2 or 3: End of infusion (EOI) and 20, 40, 60 and 80 minutes following EOI No
Secondary Elimination Rate Constant (λz) for 3K3A-APC by Compartmental Analysis Following a single dose, on Day 1, 2 or 3: End of infusion (EOI) and 20, 40, 60 and 80 minutes following EOI No
Secondary Half-life (t1/2) of 3K3A-APC by Compartmental Analysis Following a single dose, on Day 1, 2 or 3: End of infusion (EOI) and 20, 40, 60 and 80 minutes following EOI No
Secondary Total Clearance (CL) of 3K3A-APC by Compartmental Analysis Following a single dose, on Day 1, 2 or 3: End of infusion (EOI) and 20, 40, 60 and 80 minutes following EOI No
Secondary Volume of Distribution (V) of 3K3A-APC by Compartmental Analysis Following a single dose, on Day 1, 2 or 3: End of infusion (EOI) and 20, 40, 60 and 80 minutes following EOI No
Secondary Relationship between the change from baseline in activated partial thromboplastin time (aPTT) and the concurrently measured 3K3A-APC plasma concentration Following a single dose, on Day 1, 2 or 3: 60 minutes following EOI No
Secondary Number of measurable bleeds in the brain (symptomatic & asymptomatic) as determined by 1.5T MRI Day 7 (or discharge) Yes
Secondary Number of subjects who confirm positive for anti-drug antibody formation Day 30 Yes
Secondary Presence of measurable bleeds in the brain (hemorrhage and microbleeds) as determined by 1.5T MRI Day 30 Yes

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