Lacunar Intervention Trial 1 (LACI-1) "Prevent-SVD"

Recruiting

Phase 2 Results N/A

Trial Description

Phase II pilot randomised, factorial, short term dose escalation, open label, blinded intermediary endpoint trial, in two hospital centres in the UK, of tolerability and safety of cilostazol, isosorbide mononitrate, both or neither in patients with small vessel disease manifest as symptomatic small subcortical stroke.

Detailed Description

A quarter of all ischaemic strokes are lacunar (small vessel) in type, about 35000 per annum in the United Kingdom, and due to an intrinsic, non-atheromatous, non-cardioembolic perforating cerebral arteriolar disease. 'Small vessel disease' also affects the brain diffusely, causing up to 40% of dementias, alone or mixed with Alzheimer's disease, 350,000+ patients estimated currently in the United Kingdom. There is no proven treatment: conventional antiplatelet drugs may be ineffective or even hazardous, antihypertensive treatment and statins have been disappointing. The disease mechanism is poorly understood but endothelial dysfunction, blood-brain barrier failure and vessel stiffness appear to contribute to the pathogenesis. Promising data available for licensed drugs with relevant modes of action, cilostazol (>6000 stroke patients in the Asia Pacific region) and isosorbide mononitrate (ISMN, widely used in cardiac disease) support their testing in small vessel disease. This trial will be a phase 2, randomised, dose-escalation, factorial trial to test short-term administration of cilostazol, Isosorbide Mononitrate, both, or neither, to provide data on patient tolerability of dose (including headache, dizziness), safety (including blood pressure, platelet function), provide mechanistic evidence of efficacy (cerebrovascular reactivity, arterial compliance), and to inform the design of a larger phase 2-3 trial. The trial will recruit 60 patients with small vessel disease, in two expert stroke centres (Edinburgh and Nottingham) where there are suitable patients, expert stroke centres, established trials infrastructures and neuroimaging and platelet testing expertise. The trial will also advance methods to stratify patients by small vessel disease burden in routine practise and data on intermediary mechanistic outcomes to assist in planning future trials testing novel agents for either stroke or dementia.

Conditions

Interventions

  • Cilostazol (PletalĀ®)Drug
    Other Names: Claudiasil
    Intervention Desc: phosphodiesterase 3-inhibitor that enhances vessel wall function with weak antiplatelet effects
    ARM 1: Kind: Experimental
    Label: Group 2
    Description: Cilostazol 100mg bd
    ARM 2: Kind: Experimental
    Label: Group 3
    Description: Isosorbide mononitrate 25mg bd and cilostazol 100mg bd start immediately
    ARM 3: Kind: Experimental
    Label: Group 4
    Description: Isosorbide mononitrate 25mg bd and cilostazol 100mg bd delayed start
  • Isosorbide mononitrate Drug
    Other Names: Isotard
    Intervention Desc: slow release nitric oxide donor that enhances vasodilation and widely used in angina prophyaxis
    ARM 1: Kind: Experimental
    Label: Group 1
    Description: Isosorbide mononitrate 25mg bd
    ARM 2: Kind: Experimental
    Label: Group 3
    Description: Isosorbide mononitrate 25mg bd and cilostazol 100mg bd start immediately
    ARM 3: Kind: Experimental
    Label: Group 4
    Description: Isosorbide mononitrate 25mg bd and cilostazol 100mg bd delayed start

Trial Design

  • Allocation: Randomized
  • Masking: Open Label
  • Purpose: Prevention
  • Endpoint: Safety/Efficacy Study
  • Intervention: Factorial Assignment

Outcomes

Type Measure Time Frame Safety Issue
Primary Tolerability proportion of patients able to tolerate the target dose 8 weeks No
Secondary Safety - bleeding 12 weeks Yes
Secondary Safety - recurrent stroke 12 weeks Yes
Secondary Safety - death 12 weeks Yes
Secondary Safety - blood pressure 8 weeks Yes
Secondary Efficacy - cerebrovascular function 8 weeks No
Secondary Efficacy - systemic arterial stiffness 8 weeks No
Secondary Tolerability Proportion of patients with headache that interferes with daily activities 8 weeks No
Secondary Tolerability Proportion of patients with dizziness that interferes with daily activities 8 weeks No
Secondary Tolerability Proportion of patients with nausea that interferes with daily activities 8 weeks No
Secondary Tolerability Proportion of patients with palpitations 8 weeks No
Secondary Tolerability Proportion of patients with loose stools 8 weeks No
Secondary Tolerability Tablet count 8 weeks No

Sponsors