Possible Effects of Propylthiouracil, Riociguat and Perphenazine on Circulation of Healthy Volunteers

NCT04776499 | Completed Phase 1

• 2 other identifiers: REPO STROKE I2020-004557-73
• Study Type: interventional
• Target: 8
• Locations: 1 country
• Sites: 1

Brief 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.

Conditions

Drug Drug Interaction; Safety Issues

Keywords

drug-drug interaction; safety issues

Outcome Measures

Primary Outcomes (1)

• Change of blood pressure in supine position

  Change of blood pressure in supine position (individual baseline compared to changes after propylthiouracil, riociguat, and perphenazine). Analysis of the primary endpoint will be done in the complete case set. Systolic and diastolic blood pressure (in supine position for ≥ 5 minutes).

  0.25, 0.5, 0.75, 1.0, 1.5, 2, 3 and 4 hours after drug administration compared to baseline (measured in triplicate 1-2 minutes apart)

Secondary Outcomes (3)

• Time-course of blood pressure

  Blood pressure at 0.25, 0.5, 0.75, 1.0, 1.5, 2, 3, 4, 8, and 24 hours after drug administration compared to baseline

• Pathological provocation test (tilt table)

  Trial day 1 and 2

• Change of heart rate variability

  Trial day 1 and 2

Study Arms (1)

Healthy volunteers receiving propylthiouracil, riociguat, and perphenazine

EXPERIMENTAL

Eight healthy volunteers will be included. Up to 15 healthy volunteers will be screened to reach the goal of 8 exposed volunteers. Sex is not expected to have an impact on the short-term evaluation of the potential drug-drug interactions. Therefore female and male participants will be included in an undefined proportion.

Drug: Propylthiouracil, Riociguat, Perphenazine

Interventions

Propylthiouracil, Riociguat, Perphenazine DRUG

Administration of propylthiouracil, riociguat, and perphenazine in combination Investigational medicinal product (IMP): Propylthiouracil: 100 mg, Riociguat: 1 mg, Perphenazine: 16 mg

Also known as: Propycil, Adempas

Healthy volunteers receiving propylthiouracil, riociguat, and perphenazine

Eligibility Criteria

• Age: 18 Years - 64 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Age 18-64 years (y) inclusive at the time of consent,
• Males and females of child-bearing potential who are willing to use a highly effective method of contraception during the treatment and for 1 week after the administration of the IMP or women not of child-bearing potential (WNCBP) or individuals who are convincingly sexually abstinent.
• Understanding, ability, and willingness to fully comply with trial interventions and restrictions, and
• Ability to provide written, personally signed, and dated informed consent to participate in the trial, in accordance with the International Conference on Harmonisation (ICH) Good Clinical Practice (GCP) Guideline E6, and applicable regulations, prior to any trial-related interventions.
• Healthy volunteers defined as absence of:
• Clinically significant or relevant abnormalities in the medical history, physical examination (e.g. heart murmur), and laboratory evaluation as assessed by the investigator,
• Medical disorder that may make the participant unlikely to fully complete the trial, or any condition that presents undue risk from the IMP or trial interventions,
• Clinically relevant ongoing or clinically relevant history of physical or psychiatric illness as judged by the investigator,
• Blood pressure \< 110 mmHg systolic or \< 65 mmHg diastolic, or known orthostatic dysregulation
• History of syncope
• Resting heart rate \< 50bpm or \> 90 bpm
• QTc prolongation (\> 460 ms)
• Bleeding disorders
• Acute or chronic illness or clinically relevant finding known or expected to modify absorption, distribution, metabolism, or excretion of prophylthiouracil, riociguat, or perphenazine,
• History of hereditary galactose intolerance, lactase deficiency, or glucose-galactose malabsorption

You may not qualify if:

• Any known history of severe allergic or anaphylactic reactions to drugs or food or any other clinically significant allergies (except mild forms of hay fever),
• Any known allergies to compounds or additives of prophylthiouracil, riociguat, or perphenazine,
• A positive human immunodeficiency virus (HIV) or hepatitis C antibody screen,
• A positive result in the drug screening test at SCR,
• Any intake of substances known to induce or inhibit prophylthiouracil, riociguat, or perphenazine metabolizing enzymes or transporters within a period of \< 5 times the respective elimination half-lives (t1/2) or 2 weeks (whatever is longer) with regard to the expected date of first dose of IMP,
• Intake of medication with impact on platelet function (e.g. NSAID) within two weeks prior to the first biomarker blood sample,
• Relevant consumption of grapefruit or products thereof within 7 d prior to the expected date of first dose of IMP and expected noncompliance to refrain from such products until 48 h after exposure,
• Smoking within 24 h prior to visit 1 and/or 48 h post IMP administration, caffeine consumption on treatment day, and expected noncompliance to refrain from these products
• Expected nonadherence to refrain from alcohol 24 h prior to visit 1 until 48 h after exposure, or pathologic alcohol consumption
• Use of an IMP within 30 d prior to the expected date of receiving the first dose of IMP or active enrolment in another drug or vaccine clinical trial.
• Specific contraindications to propylthiouracil
• \- History of agranulocytosis, vasculitis, or liver cell damage
• Specific contraindications to riociguat (not covered above)
• Use of phosphodiesterase 5 (PDE5) inhibitors
• Severe liver damage

Sponsors & Collaborators

• Maastricht University: lead
• European Commission: collaborator

Study Sites (1)

UniversitätsKlinikum Heidelberg - Medizinische Klinik

Heidelberg, 69120, Germany

Location

Related Publications (5)

• Casas AI, Geuss E, Kleikers PWM, Mencl S, Herrmann AM, Buendia I, Egea J, Meuth SG, Lopez MG, Kleinschnitz C, Schmidt HHHW. NOX4-dependent neuronal autotoxicity and BBB breakdown explain the superior sensitivity of the brain to ischemic damage. Proc Natl Acad Sci U S A. 2017 Nov 14;114(46):12315-12320. doi: 10.1073/pnas.1705034114. Epub 2017 Oct 31.

  PMID: 29087944 BACKGROUND

• Casas AI, Hassan AA, Larsen SJ, Gomez-Rangel V, Elbatreek M, Kleikers PWM, Guney E, Egea J, Lopez MG, Baumbach J, Schmidt HHHW. From single drug targets to synergistic network pharmacology in ischemic stroke. Proc Natl Acad Sci U S A. 2019 Apr 2;116(14):7129-7136. doi: 10.1073/pnas.1820799116. Epub 2019 Mar 20.

  PMID: 30894481 BACKGROUND

• Casas AI, Kleikers PW, Geuss E, Langhauser F, Adler T, Busch DH, Gailus-Durner V, de Angelis MH, Egea J, Lopez MG, Kleinschnitz C, Schmidt HH. Calcium-dependent blood-brain barrier breakdown by NOX5 limits postreperfusion benefit in stroke. J Clin Invest. 2019 Mar 18;129(4):1772-1778. doi: 10.1172/JCI124283. eCollection 2019 Mar 18.

  PMID: 30882367 BACKGROUND

• Kleinschnitz C, Grund H, Wingler K, Armitage ME, Jones E, Mittal M, Barit D, Schwarz T, Geis C, Kraft P, Barthel K, Schuhmann MK, Herrmann AM, Meuth SG, Stoll G, Meurer S, Schrewe A, Becker L, Gailus-Durner V, Fuchs H, Klopstock T, de Angelis MH, Jandeleit-Dahm K, Shah AM, Weissmann N, Schmidt HH. Post-stroke inhibition of induced NADPH oxidase type 4 prevents oxidative stress and neurodegeneration. PLoS Biol. 2010 Sep 21;8(9):e1000479. doi: 10.1371/journal.pbio.1000479.

  PMID: 20877715 BACKGROUND

• Langhauser F, Casas AI, Dao VT, Guney E, Menche J, Geuss E, Kleikers PWM, Lopez MG, Barabasi AL, Kleinschnitz C, Schmidt HHHW. A diseasome cluster-based drug repurposing of soluble guanylate cyclase activators from smooth muscle relaxation to direct neuroprotection. NPJ Syst Biol Appl. 2018 Feb 5;4:8. doi: 10.1038/s41540-017-0039-7. eCollection 2018.

  PMID: 29423274 BACKGROUND

MeSH Terms

Interventions

Propylthiouracil; riociguat; Perphenazine

Intervention Hierarchy (Ancestors)

Thiouracil; Uracil; Pyrimidinones; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Phenothiazines; Sulfur Compounds; Organic Chemicals; Heterocyclic Compounds, 3-Ring; Heterocyclic Compounds, Fused-Ring

Study Officials

• Walter E. Haefeli, Prof. Dr.

  University Hospital Heidelberg

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: OTHER
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Evaluation of a potential synergistic blood pressure effect after administration of propylthiouracil, riociguat, and perphenazine

Study Record Dates

• First Submitted: February 23, 2021
• First Posted: March 1, 2021
• Study Start: March 18, 2021
• Primary Completion: February 28, 2022
• Study Completion: February 28, 2022
• Last Updated: April 4, 2022

Record last verified: 2022-03

Locations

DE (1)