Networked Drug REpurposing for Mechanism-based neuroPrOtection in Acute Ischaemic STROKE
- Conditions
- Ischemic Stroke, Acute
- Interventions
- Registration Number
- NCT05762146
- Lead Sponsor
- Maastricht University
- Brief Summary
A combination therapy proposed to be evaluated in this trial, consisting of three already registered compounds with a validated disease mechanism and with known safety profiles, targets key proteins in the dysregulated signal network in stroke, and is expected to synergistically result in post-stroke blood-brain barrier stabilization and neuroprotection. The synergistic mode of action will allow for low doses and is expected to reduce possible side effects while maintaining maximal efficacy
- Detailed Description
There is a high need for new drugs \& novel approaches for neuroprotection in stroke treatment.
Pre-clinically, three interrelated in silico predicted drug targets and pharmacological principles all belonging to the same signal network were validated at the preclinical level to be causally relevant in stroke and thus hold promise for the first-in-class mechanism-based, curative neuroprotective therapy of an ischemic stroke:
1. NADPH oxidase type 4 and 5 (NOX4, NOX5), members of a reactive oxygen radical (ROS) forming enzyme family being either upregulated during hypoxia or activated by high post-reperfusion calcium influx causing unphysiological high levels of ROS and thereby blood-brain barrier (BBB) breakdown and neuronal damage, which can be prevented by NOX inhibitors (NOXi).
2. Nitric oxide (NO) synthase type 1 (NOS1), a neuronal signaling enzyme, which in stroke is hyperactivated (excitotoxicity) and produces neurotoxic quantities of NO, which are further toxified by chemically interacting with NADPH oxidase-derived ROS, forming and even more toxic peroxynitrite and which can be prevented by NOS inhibitors (NOSi)
3. Soluble guanylate cyclase (sGC), an enzyme, which forms the BBB stabilizing and neuroprotective second messenger, cyclic GMP (cGMP), but upon stroke is oxidatively damaged to a heme-free apo sGC (by peroxynitrite). Moreover, any remaining sGC is less activated by NO, because NO is scavenged by ROS and deviated into peroxynitrite. Thus, cGMP formation is greatly reduced in stroke, which can be reversed by sGC modulators which increase the activity of both sGC and apo-sGC in an NO-independent manner and thereby reinstall cGMP formation, BB closure and neuroprotection.
Different representatives of the drug classes of NADPH oxidase inhibitors (NOXi), nitric oxide synthase inhibitors (NOSi), and soluble guanylate cyclase modulators were identified and shown to be highly effective when given alone in different small animal experimentation and in vitro human models. However, since all single target approaches in stroke have so far failed in clinical development during the last decades, and NOS, NOX and sGC all belong to the same disease module, an innovative combined, so-called network pharmacology approach is proposed, i.e., a combination of 3 already registered compounds with a validated disease mechanism: the sGC activator riociguat, the NOS1 inhibitor propylthiouracil, and the NOX inhibitor perphenazine.
Riociguat is an sGC stimulator currently approved and marketed for pulmonary hypertension. Post-reperfusion therapy with riociguat, increased cGMP formation and therefore leads to direct neuroprotection and reduced infarct volume in a stroke animal model. Propylthiouracil is already marketed for the treatment of various subtypes of hyperthyroidism and has been identified as a new member of the class of potent and effective NOS1 inhibitors. Pre-clinically, post-reperfusion treatment with propylthiouracil significantly reduced infarct volume in brain ischemia mice models compared to non-treated animals (pre-clinical in-house data, unpublished). Perphenazine is already marketed as an antiemetic and antipsychotic, has the best NOX inhibitory characteristics compared to other compounds of the same drug class, and significantly reduced infarct size in acute ischemic stroke mice models.
In summary, the combination therapy proposed to be evaluated in this trial, consisting of already registered compounds with a validated disease mechanism and with known safety profiles, targets key proteins in the dysregulated signal network in stroke, and is expected to synergistically result in post-stroke blood-brain barrier stabilization and neuroprotection. The synergistic mode of action will allow for low doses and is expected to reduce possible side effects while maintaining maximal efficacy.
Recruitment & Eligibility
- Status
- RECRUITING
- Sex
- All
- Target Recruitment
- 28
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Riociguat +Propylthiouracil +Perphenazine Riociguat Triple combination therapy group: ○ each patient in this group will receive two doses (8 +/- 2 hours between doses) of orally administered combination therapy of riociguat, propylthiouracil, and perphenazine, in addition to standard of care. Riociguat +Propylthiouracil +Perphenazine Propylthiouracil Triple combination therapy group: ○ each patient in this group will receive two doses (8 +/- 2 hours between doses) of orally administered combination therapy of riociguat, propylthiouracil, and perphenazine, in addition to standard of care. Riociguat +Propylthiouracil +Perphenazine Perphenazine Triple combination therapy group: ○ each patient in this group will receive two doses (8 +/- 2 hours between doses) of orally administered combination therapy of riociguat, propylthiouracil, and perphenazine, in addition to standard of care.
- Primary Outcome Measures
Name Time Method SICH as per ECASS III 30 days Frequency of symptomatic intracranial hemorrhages as per ECASS III
- Secondary Outcome Measures
Name Time Method SICH as per Heidelberg Bleeding Classification 30 days Frequency of symptomatic intracranial hemorrhages as per Heidelberg Bleeding Classification
SICH as per SITSMOST 30 days Frequency of symptomatic intracranial hemorrhages as per SITSMOST
SICH as per NINDS 30 days Frequency of symptomatic intracranial hemorrhages as per NINDS
Mortality 30 days Frequency of all cause mortality
SAE 30 days All (S)AEs considered related to the triple combination therapy
Duration of hospital stay 30 days Time from randomization to discharge
Duration of intensive care unit (ICU) stay 30 days Period during which the patient stayed at a ward with capacity for mechanical ventilation
Duration of invasive mechanical ventilation 30 days in hours
Duration of non-invasive mechanical ventilation 30 days in hours
Change of initial 'volume of hypoperfusion' 5 days Change in "ml" of volume of hypoperfusion in initial Computed Tomography Perfusion (CTP) to final 'volume of infarct core' as assessed through follow-up Magnetic Resonance Imaging (MRI).
Change of initial 'volume of infarct core' 5 days Change in "ml" of infarct core of initial Computed Tomography Perfusion (CTP) to final 'volume of infarct core' as assessed through follow-up Magnetic Resonance Imaging (MRI).
mRS 30 days Shift analysis of mRS
NIHSS change 5 days Change from baseline in National Institute of Health Stroke Scale (NIHSS) score
Trial Locations
- Locations (1)
University Hospital Essen, Department of Neurology
🇩🇪Essen, Germany