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

• Status: Recruiting
• Trial end date: 2021-04-30
• Target enrollment: 0
• Participant gender: All

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.

• Phase: Phase 1
• Accepts Healthy Volunteers?: Accepts Healthy Volunteers

Details

• Lead Sponsor: Maastricht University
• Collaborator: European Commission
• Treatments: Perphenazine; Propylthiouracil; Riociguat

Criteria

Inclusion Criteria:

1. Age 18-64 years (y) inclusive at the time of consent,

2. 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.

3. Understanding, ability, and willingness to fully comply with trial interventions and restrictions, and

4. 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.

5. Healthy volunteers defined as absence of:

1. Clinically significant or relevant abnormalities in the medical history, physical examination (e.g. heart murmur), and laboratory evaluation as assessed by the investigator,

2. 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,

3. Clinically relevant ongoing or clinically relevant history of physical or psychiatric illness as judged by the investigator,

4. Blood pressure < 110 mmHg systolic or < 65 mmHg diastolic, or known orthostatic dysregulation

5. History of syncope

6. Resting heart rate < 50bpm or > 90 bpm

7. QTc prolongation (> 460 ms)

8. Bleeding disorders

9. Acute or chronic illness or clinically relevant finding known or expected to modify absorption, distribution, metabolism, or excretion of prophylthiouracil, riociguat, or perphenazine,

10. History of hereditary galactose intolerance, lactase deficiency, or glucose-galactose malabsorption

11. Clinically relevant findings in any of the following investigations at SCR. (Minor deviations of laboratory values from the normal range can be acceptable, if judged by the investigator to be of no clinical relevance for this trial.), i. Haemoglobin (Hb) < 12 g/dl (males) or < 11 g/dl (females), ii. Creatinine (Crea) clearance (Cl) < 60 ml/min (Cockcroft-Gault), iii. Bilirubin > upper limit of normal (ULN) x 1.2; In case of suspected Gilbert's disease: non-fasting total bilirubin ≤ ULN x 1.2 and fasting total bilirubin ≤ ULN x 1.5 are acceptable, iv. Alanine aminotransferase (ALT) > ULN x 1.1, v. Aspartate aminotransferase (AST) > ULN x 1.2, vi. Creatine kinase (CK) not within normal limits (volunteers with CK elevations between ULN and ULN x 3 may be included if troponin T is negative), and vii. Thyroid-stimulating hormone (TSH) not within normal limits.

12. Regular medication except for hormonal contraception, iodide, and levothyroxine

Exclusion Criteria:

1. 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),

2. Any known allergies to compounds or additives of prophylthiouracil, riociguat, or perphenazine,

3. A positive human immunodeficiency virus (HIV) or hepatitis C antibody screen,

4. A positive result in the drug screening test at SCR,

5. 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,

6. Intake of medication with impact on platelet function (e.g. NSAID) within two weeks prior to the first biomarker blood sample,

7. 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,

8. 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

9. Expected nonadherence to refrain from alcohol 24 h prior to visit 1 until 48 h after exposure, or pathologic alcohol consumption

10. 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.

11. Specific contraindications to propylthiouracil

• History of agranulocytosis, vasculitis, or liver cell damage

12. Specific contraindications to riociguat (not covered above)

• Use of phosphodiesterase 5 (PDE5) inhibitors

• Severe liver damage

• Pregnancy

• Use of nitrates or NO donors

13. Specific contraindication to perphenazine:

• Hypersensitivity to perphenazine, other drugs of this substance class, or any of its excipients

• Acute intoxication with central depressant drugs (e.g. opiates, hypnotics, antidepressants, antiepileptics, neuroleptics, tranquilizers), or alcohol

• Severe damage of blood cells or of bone marrow

• Severe liver disease

• Severe depression

• Comatose state