Preventing Cognitive Decline and Dementia From Cerebral Small Vessel Disease: The LACI-1 Trial. Protocol and Statistical Analysis Plan of a Phase IIa Dose Escalation Trial Testing Tolerability, Safety and Effect on Intermediary Endpoints of Isosorbide Mononitrate and Cilostazol, Separately and in Combination

Int J Stroke. 2018 Jul;13(5):530-538. doi: 10.1177/1747493017731947. Epub 2017 Sep 14.

Abstract

Rationale The pathophysiology of most lacunar stroke, a form of small vessel disease, is thought to differ from large artery atherothrombo- or cardio-embolic stroke. Licensed drugs, isosorbide mononitrate and cilostazol, have promising mechanisms of action to support their testing to prevent stroke recurrence, cognitive impairment, or radiological progression after lacunar stroke. Aim LACI-1 will assess the tolerability, safety, and efficacy, by dose, of isosorbide mononitrate and cilostazol, alone and in combination, in patients with ischemic lacunar stroke. Sample size A sample of 60 provides 80+% power (significance 0.05) to detect a difference of 35% (90% versus 55%) between those reaching target dose on one versus both drugs. Methods and design LACI-1 is a phase IIa partial factorial, dose-escalation, prospective, randomized, open label, blinded endpoint trial. Participants are randomized to isosorbide mononitrate and/or cilostazol for 11 weeks with dose escalation to target as tolerated in two centers (Edinburgh, Nottingham). At three visits, tolerability, safety, blood pressure, pulse wave velocity, and platelet function are assessed, plus magnetic resonance imaging to assess cerebrovascular reactivity in a subgroup. Study outcomes Primary: proportion of patients completing study achieving target maximum dose. Secondary symptoms whilst taking medications; safety (hemorrhage, recurrent vascular events, falls); blood pressure, platelet function, arterial stiffness, and cerebrovascular reactivity. Discussion This study will inform the design of a larger phase III trial of isosorbide mononitrate and cilostazol in lacunar stroke, whilst providing data on the drugs' effects on vascular and platelet function. Trial registration ISRCTN (ISRCTN12580546) and EudraCT (2015-001953-33).

Keywords: Lacunar stroke; blood–brain barrier; cerebrovascular reactivity; cilostazol; endothelium; isosorbide mononitrate; small vessel disease; white matter hyperintensities.

Publication types

  • Clinical Trial, Phase II
  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Age Factors
  • Cerebral Small Vessel Diseases / complications
  • Cerebral Small Vessel Diseases / diagnostic imaging
  • Cerebral Small Vessel Diseases / drug therapy
  • Cilostazol / therapeutic use*
  • Cognition Disorders / etiology*
  • Cognition Disorders / prevention & control*
  • Dementia / etiology
  • Dementia / prevention & control*
  • Double-Blind Method
  • Female
  • Follow-Up Studies
  • Humans
  • Isosorbide Dinitrate / analogs & derivatives*
  • Isosorbide Dinitrate / therapeutic use
  • Magnetic Resonance Imaging
  • Male
  • Neuropsychological Tests
  • Severity of Illness Index
  • Treatment Outcome
  • United Kingdom
  • Vasodilator Agents / therapeutic use*

Substances

  • Vasodilator Agents
  • Isosorbide Dinitrate
  • isosorbide-5-mononitrate
  • Cilostazol

Associated data

  • EudraCT/2015-001953-33
  • ISRCTN/ISRCTN12580546