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

Gordon W. Blair, Jason P. Appleton, Zhe Kang Law, Fergus Doubal, Katie Flaherty, Richard Dooley, Kirsten Shuler, Carla Richardson, Iona Hamilton, Yulu Shi, Michael Stringer, Julia Boyd, Michael J. Thrippleton, Nikola Sprigg, Philip M. Bath, Joanna M. Wardlaw

Research output: Contribution to journalArticle

9 Citations (Scopus)

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).

Original languageEnglish
Pages (from-to)530-538
Number of pages9
JournalInternational Journal of Stroke
Volume13
Issue number5
DOIs
Publication statusPublished - 1 Jul 2018

Fingerprint

isosorbide-5-mononitrate
Cerebral Small Vessel Diseases
Lacunar Stroke
Dementia
Safety
Blood Platelets
Blood Vessels
Stroke
Pharmaceutical Preparations
Blood Pressure
Pulse Wave Analysis
Vascular Stiffness
Sample Size
Arteries
Magnetic Resonance Imaging
Outcome Assessment (Health Care)
Hemorrhage
Recurrence
Cognitive Dysfunction
cilostazol

Keywords

  • blood–brain barrier
  • cerebrovascular reactivity
  • cilostazol
  • endothelium
  • isosorbide mononitrate
  • Lacunar stroke
  • small vessel disease
  • white matter hyperintensities

ASJC Scopus subject areas

  • Neurology

Cite this

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. / Blair, Gordon W.; Appleton, Jason P.; Law, Zhe Kang; Doubal, Fergus; Flaherty, Katie; Dooley, Richard; Shuler, Kirsten; Richardson, Carla; Hamilton, Iona; Shi, Yulu; Stringer, Michael; Boyd, Julia; Thrippleton, Michael J.; Sprigg, Nikola; Bath, Philip M.; Wardlaw, Joanna M.

In: International Journal of Stroke, Vol. 13, No. 5, 01.07.2018, p. 530-538.

Research output: Contribution to journalArticle

Blair, Gordon W. ; Appleton, Jason P. ; Law, Zhe Kang ; Doubal, Fergus ; Flaherty, Katie ; Dooley, Richard ; Shuler, Kirsten ; Richardson, Carla ; Hamilton, Iona ; Shi, Yulu ; Stringer, Michael ; Boyd, Julia ; Thrippleton, Michael J. ; Sprigg, Nikola ; Bath, Philip M. ; Wardlaw, Joanna M. / 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. In: International Journal of Stroke. 2018 ; Vol. 13, No. 5. pp. 530-538.
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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).",
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