Possible Effects of Propylthiouracil, Riociguat and Perphenazine on Circulation of Healthy Volunteers
Condition: Drug Drug Interaction; Safety Issues
Study type: Interventional
Phase: Phase 1

Summary: 
      This trial is part of the Horizon 2020 project, REPO-TRIAL, on in-silico, mechanism-based
      drug repurposing in high unmet-medical-need indications. This project aims to identify
      causal, rather than symptomatic disease mechanisms for highly precise and effective
      interventions. Here a signalling module comprised of reactive oxygen species (ROS) formation
      and cyclic GMP signalling has been identified to be involved in post-stroke
      blood-brain-barrier disruption and neuronal death. It can be targeted by repurposing three
      drugs, which inhibit overshooting nitric oxide (NO) and ROS formation, respectively, and
      stimulate compromised neuroprotective cyclic GMP formation. It is possible that two of the
      drugs (riociguat, perphenazine) may cause a drop and one drug an elevation of blood pressure
      (propylthiouracil) leading to an overall drop in blood pressure. On top of that, the three
      drugs may synergise on blood pressure in a previously not recognised manner. These potential
      safety concerns, expressed in a scientific advice meeting by the Federal Institute for Drugs
      and Medical Devices (BfArM), shall be tested in the present phase I safety trial.

      The trial consists of a screening visit (SCR), a treatment period, and an EOT visit. In the
      treatment period, after a baseline evaluation, single doses of all three substances will be
      administered concurrently. Provocation manoeuvres (tilt table) will be performed with the
      goal of generating maximum safety information on drug-induced blood pressure changes.
      Concurrently, a 24-h electrocardiogram (ECG) will be recorded (Holter ECG) and blood samples
      will be drawn for exploratory biomarker analyses, quantification of riociguat, and optional
      pharmacokinetic analyses of perphenazine and propylthiouracil.
    

Detailed description: 
      This trial is part of the Horizon 2020 project, REPO-TRIAL, on in-silico, mechanism-based
      drug repurposing in high unmet-medical-need indications. This project aims to identify
      causal, rather than symptomatic disease mechanisms for highly precise and effective
      interventions. Here a signalling module comprised of reactive oxygen species (ROS) formation
      and cyclic GMP signalling has been identified to be involved in post-stroke
      blood-brain-barrier disruption and neuronal death. It can be targeted by repurposing three
      drugs, which inhibit overshooting nitric oxide (NO) and ROS formation, respectively, and
      stimulate compromised neuroprotective cyclic GMP formation. It is possible that two of the
      drugs (riociguat, perphenazine) may cause a drop and one drug an elevation of blood pressure
      (propylthiouracil) leading to an overall drop in blood pressure. On top of that, the three
      drugs may synergise on blood pressure in a previously not recognised manner. These potential
      safety concerns, expressed in a scientific advice meeting by the Federal Institute for Drugs
      and Medical Devices (BfArM), shall be tested in the present phase I safety trial.

      Ischemic stroke is the leading cause of acquired disability in adulthood (WHO report). As of
      2020, only one approved pharmacological treatment option, intravenous thrombolysis (rtPA), is
      available. However, intravenous thrombolysis is used only for a fraction of stroke patients
      given its strict inclusion criteria, broad exclusion criteria, and the risk of lethal
      iatrogenic intracranial bleeding. While mechanical recanalization therapy has improved
      patient outcomes, it is also limited by (i) relatively narrow time windows for effective
      treatment, (ii) being available to patients with large vessel occlusions only, and (iii) by
      requiring a dedicated infrastructure to treat these patients.

      Given these limitations there is a need for new approaches to stroke management. The ideal
      intervention would (i) be directly neuroprotective, (ii) reduce the brain infarct volume,
      (iii) improve functional neurological outcomes, (iv) increase survival, (v) be safe, i.e.
      bear no risk to cause secondary bleeding, (vi) be broadly applicable, and (vii) logistically
      compatible with recanalization. NO synthase, NOS1, is overactivated, NADPH oxidases, NOX4 and
      NOX5 get induced and overactivated, NO and NOX-derived reactive non-steroidal
      anti-inflammatory drug oxygens species (ROS) toxify each other; one target being sGC, which
      is oxidatively damaged to no longer contain haeme and no longer respond to NO to form
      neuroprotective cyclic GMP (cGMP). Consequently, inhibiting NOS1 and NOX4/5, and reactivating
      haeme-free apo-sGC synergistically results in post-stroke blood-brain-barrier stabilisation
      and neuroprotection.

      The NOX4/5-NOS1-sGC signalling network is required for vascular endothelial maintenance and
      dysregulated after an ischemic stroke. After an ischemic event, NOX4/5 and NOS enzymes are
      over-activated and lead to an excessive release of ROS in vivo. Such ROS can damage multiple
      cellular structures, including soluble guanylate cyclase (sGC), which no longer responds to
      nitric oxide (NO) to form neuroprotective cyclic GMP (cGMP). Consequently, pre-clinical
      pharmacological inhibition of NOX4/5, NOS1, and restoration of sGC activity lead to reduced
      infarct volumes in vivo, especially when administered in combination.

      The three agents used in the described pre-clinical experiments, perphenazine,
      propylthiouracil, and riociguat, are approved medicines used for non-stroke-related
      indications. Perphenazine, a typical antipsychotic, and propylthiouracil, a thyroid
      peroxidase inhibitor used for the treatment of hyperthyroidism, have previously been
      identified as off-target inhibitors of NOX4 and NOS, respectively. Riociguat, approved for
      treatment of pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary
      hypertension (CTEPH), is a first-in-class sGC stimulator.

      Given the pre-clinical evidence for a signalling-network-based combination therapy consisting
      of perphenazine, propylthiouracil, and riociguat, the investigators hypothesize that combined
      use of these substances as an add-on treatment to the current standard of care will reduce
      infarct volume and improve neurological function in patients with ischemic stroke.
    

Intervention name(s): Propylthiouracil, Riociguat, Perphenazine
Intervention type(s): Drug
Intervention description(s): Administration of propylthiouracil, riociguat, and perphenazine in combination
Investigational medicinal product (IMP):
Propylthiouracil: 100 mg, Riociguat: 1 mg, Perphenazine: 16 mg
Other intervention name(s): Propycil, Adempas
Intervention MeSH terms: Perphenazine; Riociguat; Propylthiouracil
Intervention model: Single Group Assignment
Intervention model description: Evaluation of a potential synergistic blood pressure effect after administration of propylthiouracil, riociguat, and perphenazine
Masking: None (Open Label)
Primary purpose: Other
Keywords: drug-drug interaction; safety issues