- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT04532918
Pharmacokinetics of Verinurad and Allopurinol in Combination With Cyclosporine and Rifampicin in Healthy Volunteers
An Open-label, 3-Treatment, 3-Period, Fixed Sequence Study in Healthy Subjects to Assess the Pharmacokinetics of Verinurad and Allopurinol When Administered Alone, and in Combination With Single Doses of Cyclosporine or Rifampicin
Study Overview
Status
Conditions
Intervention / Treatment
Detailed Description
This Phase 1 study will be an open-label, 3-period, 3-treatment, fixed-sequence study in healthy subjects (males and females of non-childbearing potential), performed at a single Clinical Unit.
The study will comprise of the following periods (visits):
- A Screening Period (Visit 1);
- A fixed sequence of 3 Treatment Periods during which subjects will be resident at the Clinical Unit from one day prior to administration of verinurad+allopurinol (Day -1) of Treatment Period 1 until the morning of Day 5 of the Treatment Period 2, and similarly for Treatment Period 3. There will be a washout period between Treatment Periods 2 and 3 dosing. The 3 Treatment Periods, include the washout period (Visits 2 to 3);
- A Follow-up Visit, after the last administration of verinurad+allopurinol (Visit 4).
Study Type
Enrollment (Actual)
Phase
- Phase 1
Contacts and Locations
Study Locations
-
-
-
Berlin, Germany, 14050
- Research Site
-
-
Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Description
Inclusion Criteria:
- Provision of signed and dated, written informed consent form prior to any study specific procedures.
- Healthy male or female subjects aged 18 - 55 years (inclusive) with suitable veins for cannulation or repeated venipuncture.
- Females must be either (1) Of non-childbearing potential, confirmed at Screening by fulfilling one of the following criteria (i) Post-menopausal defined as amenorrhea for at least 12 months or more following cessation of all exogenous hormonal treatments and Follicle-stimulating hormone (FSH) levels in the post-menopausal range (FSH >40 IU/mL).
(ii) Documentation of irreversible surgical sterilisation by hysterectomy, bilateral oophorectomy or bilateral salpingectomy but not tubal ligation.
- Male subjects must adhere to the contraception methods.
- Have a body mass index between 18 and 30 kg/m2 (inclusive) and weigh at least 50 kg and no more than 100 kg (inclusive).
- Must be able to swallow multiple capsules/tablets.
Exclusion Criteria:
- History of any clinically significant disease or disorder which, in the opinion of the Investigator, may either put the volunteer at risk because of participation in the study, or influence the results or the volunteer's ability to participate in the study.
- Subject has a positive test result for severe acute respiratory syndrome coronavirus 2 before dosing in Treatment Period 1.
- Has clinical signs and symptoms consistent with coronavirus disease 2019 (COVID-19) infection, eg fever, dry cough, dyspnea, sore throat, fatigue or confirmed infection by appropriate laboratory test within the last 4 weeks prior to screening or on admission.
- History of severe COVID-19 (extracorporeal membrane oxygenation, mechanically ventilated).
- History or presence of gastrointestinal, hepatic or renal disease, or any other condition known to interfere with absorption, distribution, metabolism, or excretion of drugs.
- Any clinically significant illness, medical/surgical procedure, or trauma within 4 weeks prior to the first administration of verinurad.
- Any clinically significant abnormalities in clinical chemistry, hematology, or urinalysis results, at Screening (Visit 1) and on first admission (Day -1 in Treatment Period 1) as judged by the Investigator, including:
Alanine aminotransferase >1.5 × Upper limit of normal (ULN) Aspartate aminotransferase >1.5 × ULN Bilirubin (total) >1.5 × ULN Gamma glutamyl transpeptidase >1.5 × ULN If any of these tests are out of range, the test can be repeated once at the Screening Visit at the discretion of the Investigator.
Any clinically significant abnormal findings in vital signs at Screening Visit and/or on admission (Day -1 in Treatment Period 1) to the Clinical Unit, including, but not limited to, any of the following:
- Systolic blood pressure <90 mmHg or >140 mmHg and/or diastolic blood pressure <50 mmHg or >90 mmHg sustained for more than 10 minutes while resting in a supine position
- Heart rate (resting, supine) <50 or >90 bpm
Any clinically significant abnormalities on 12-lead electrocardiogram at Screening Visit, as judged by the Investigator, including, but not limited to any of the following:
- QTcF > 450 ms or < 340 ms or family history of long QT syndrome,
- Any significant arrhythmia,
- Conduction abnormalities,
- Clinically significant PR(PQ) interval prolongation (> 240 ms); intermittent second or third degree atrioventricular (AV) block, or AV dissociation,
- Complete bundle branch block and/or QRS duration > 120 ms.
- Any positive result at Screening Visit for serum hepatitis B surface antigen or anti-hepatitis B core antibody, hepatitis C antibody, and human immunodeficiency virus antibody.
- Suspicion or known Gilbert's and/or Lesch-Nyhan syndrome
- History of hypersensitivity to drugs with a similar chemical structure or class to verinurad, allopurinol, cyclosporine or rifampicin or excipients.
- Subjects who wear soft contact lenses (due to possible staining from rifampicin), unless the subject is prepared to refrain from wearing soft lenses throughout Treatment Period 3 until after the last PK sample collection.
- Women of childbearing potential.
- Carrier of the Human leukocyte antigen B*58:01 allele.
- Has received another new chemical or biological entity (defined as a compound which has not been approved for marketing in the US or EU) within 30 days or within 5 half-lives (whichever is longer) of the first administration of verinurad in this study.
- Plasma donation within 1 month of screening or any blood donation/loss more than 500 mL during the 3 months prior to screening.
- History of severe allergy/hypersensitivity or ongoing allergy/hypersensitivity, as judged by the Investigator or history of hypersensitivity to drugs with a similar chemical structure or class to Novel uric acid transporter 1 transporter inhibitor & xanthine oxidase inhibitor.
- Current smokers or those who have smoked or used nicotine products within the 3 months prior to screening.
- Positive screen for drugs of abuse, cotinine or alcohol at Screening or on each admission to the Clinical Unit.
- Use of drugs with enzyme-inducing properties such as St John's Wort within 3 weeks prior to the first administration of verinurad.
- Use of any prescribed or non-prescribed medication including antacids, analgesics (other than paracetamol/acetaminophen), herbal remedies, megadose vitamins (intake of 20 to 600 times the recommended daily dose) and minerals during the 2 weeks prior to the first administration of IMP or longer if the medication has a long half-life.
- Known or suspected history of alcohol or drug abuse or excessive intake of alcohol as judged by the Investigator. Excessive intake of alcohol defined as the regular consumption of more than 24 g of alcohol per day for men or 12 g of alcohol per day for women.
- Excessive intake of caffeine-containing drinks or food (eg, coffee, tea, chocolate) as judged by the Investigator. Excessive intake of caffeine defined as the regular consumption of more than 600 mg of caffeine per day or would likely be unable to refrain from the use of caffeine-containing beverages during in-house stay at the investigational site.
- Involvement of any AstraZeneca, Parexel or Clinical Unit employee or their close relatives.
- Judgment by the Investigator that the subject should not participate in the study if they have any ongoing or recent (i.e., during the screening period) minor medical complaints that may interfere with the interpretation of study data or are considered unlikely to comply with study procedures, restrictions, and requirements.
- Subjects who are vegans or have medical dietary restrictions.
- Subjects who cannot communicate reliably with the Investigator and/or are not able to read, speak and understand the German language.
- Vulnerable subjects, eg, kept in detention, protected adults under guardianship, trusteeship, or committed to an institution by governmental or juridical order.
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Other
- Allocation: Non-Randomized
- Interventional Model: Crossover Assignment
- Masking: None (Open Label)
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Experimental: Verinurad + allopurinol
The subjects will receive single oral dose of verinurad 7.5 mg and allopurinol 300 mg under fasted condition.
|
The subjects will receive single oral dose of extended release capsule verinurad 7.5 mg on Day 1 of each treatment period under fasted condition.
The subjects will receive single oral dose of tablet allopurinol 300 mg on Day 1 of each treatment period under fasted condition.
|
Experimental: Verinurad + allopurinol + cyclosporine
The subjects will receive single oral dose of verinurad 7.5 mg, allopurinol 300 mg and cyclosporine 600 mg under fasted condition.
|
The subjects will receive single oral dose of extended release capsule verinurad 7.5 mg on Day 1 of each treatment period under fasted condition.
The subjects will receive single oral dose of tablet allopurinol 300 mg on Day 1 of each treatment period under fasted condition.
The subjects will receive single oral dose of soft capsule cyclosporine 600 mg on Day 1 of treatment period 2 under fasted condition.
Other Names:
|
Experimental: Verinurad + allopurinol + rifampicin
The subjects will receive single oral dose of verinurad 7.5 mg, allopurinol 300 mg and rifampicin 600 mg under fasted condition.
|
The subjects will receive single oral dose of extended release capsule verinurad 7.5 mg on Day 1 of each treatment period under fasted condition.
The subjects will receive single oral dose of tablet allopurinol 300 mg on Day 1 of each treatment period under fasted condition.
The subjects will receive single oral dose of film coated tablets rifampicin 600 mg on Day 1 of treatment period 3 under fasted condition.
Other Names:
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Geometric Mean Ratio of Maximum Observed Plasma Peak Concentration (Cmax) for Verinurad
Time Frame: Days 1 to 5 (pre-dose and post-dose)
|
Evaluation of a single dose of cyclosporine or rifampicin on the PK of verinurad.
Verinurad Cmax ratio of geometric mean of test treatment (verinurad+allopurinol with [cyclosporine or rifampicin], relative to reference treatment (verinurad+allopurinol alone) in each treatment period.
|
Days 1 to 5 (pre-dose and post-dose)
|
Geometric Mean Ratio of Area Under Plasma Concentration-time Curve From Time Zero to Infinity (AUCinf) for Verinurad
Time Frame: Days 1 to 5 (pre-dose and post-dose)
|
Evaluation of a single dose of cyclosporine or rifampicin on the PK of verinurad.
Verinurad AUCinf ratio of geometric means of test treatment, relative to reference treatment in each treatment period.
|
Days 1 to 5 (pre-dose and post-dose)
|
Geometric Mean Ratio of Area Under the Plasma Concentration-time Curve From Zero to Time of Last Quantifiable Concentration (AUClast) for Verinurad
Time Frame: Days 1 to 5 (pre-dose and post-dose)
|
Evaluation of a single dose of cyclosporine or rifampicin on the PK of verinurad.
Verinurad AUClast ratio of geometric means of test treatment, relative to reference treatment in each treatment period.
|
Days 1 to 5 (pre-dose and post-dose)
|
Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Geometric Mean Ratio of Cmax for Verinurad Metabolites: M1 and M8
Time Frame: Days 1 to 5 (pre-dose and post-dose)
|
Evaluation of a single dose of cyclosporine or rifampicin on the PK of verinurad metabolites M1 and M8.
Cmax ratio of geometric means of test treatment, relative to reference treatment in each treatment period.
|
Days 1 to 5 (pre-dose and post-dose)
|
Geometric Mean Ratio of AUCinf for Verinurad Metabolites: M1 and M8
Time Frame: Days 1 to 5 (pre-dose and post-dose)
|
Evaluation of a single dose of cyclosporine or rifampicin on the PK of verinurad metabolites M1 and M8.
AUCinf ratio of geometric means of test treatment, relative to reference treatment in each treatment period.
|
Days 1 to 5 (pre-dose and post-dose)
|
Geometric Mean Ratio of AUClast for Verinurad Metabolites: M1 and M8
Time Frame: Days 1 to 5 (pre-dose and post-dose)
|
Evaluation of a single dose of cyclosporine or rifampicin on the PK of verinurad metabolites M1 and M8.
AUClast ratio of geometric means of test treatment, relative to reference treatment in each treatment period is reported.
|
Days 1 to 5 (pre-dose and post-dose)
|
Geometric Mean Ratio of Cmax for Allopurinol and Oxypurinol
Time Frame: Days 1 to 5 (pre-dose and post-dose)
|
Evaluation of a single dose of cyclosporine or rifampicin on the PK of allopurinol and oxypurinol.
Cmax ratio of geometric means of test geometric means of test treatment, relative to reference treatment in each treatment period is reported.
|
Days 1 to 5 (pre-dose and post-dose)
|
Geometric Mean Ratio of AUCinf for Allopurinol and Oxypurinol
Time Frame: Days 1 to 5 (pre-dose and post-dose)
|
Evaluation of a single dose of cyclosporine or rifampicin on the PK of allopurinol and oxypurinol.
AUCinf ratio of geometric means of test geometric means of test treatment, relative to reference treatment in each treatment period is reported.
|
Days 1 to 5 (pre-dose and post-dose)
|
Geometric Mean Ratio of AUClast for Allopurinol and Oxypurinol
Time Frame: Days 1 to 5 (pre-dose and post-dose)
|
Evaluation of a single dose of cyclosporine or rifampicin on the PK of allopurinol and oxypurinol.
AUClast ratio of geometric means of test geometric means of test treatment, relative to reference treatment in each treatment period is reported.
|
Days 1 to 5 (pre-dose and post-dose)
|
Area Under Plasma Concentration-time Curve From Zero to 24 Hours Post-dose AUC(0-24) of Verinurad, M1, M8, Allopurinol and Oxypurinol
Time Frame: Days 1 to 5 (pre-dose and post-dose)
|
AUC(0-24) of verinurad, M1, M8, allopurinol and oxypurinol when verinurad+allopurinol administered alone or in combination with cyclosporine or rifampicin in each treatment period.
|
Days 1 to 5 (pre-dose and post-dose)
|
Time to Reach Peak or Maximum Plasma Concentration (Tmax) for Verinurad, M1, M8, Allopurinol and Oxypurinol
Time Frame: Days 1 to 5 (pre-dose and post-dose)
|
tmax of verinurad, M1, M8, allopurinol and oxypurinol when verinurad+allopurinol administered alone or in combination with cyclosporine or rifampicin in each treatment period.
|
Days 1 to 5 (pre-dose and post-dose)
|
Half-life Associated With Terminal Slope (λz) of a Semi-logarithmic Concentration Time Curve (t½λz) of Verinurad, M1, M8, Allopurinol and Oxypurinol
Time Frame: Days 1 to 5 (pre-dose and post-dose)
|
t½λz of verinurad, M1, M8, allopurinol and oxypurinol when verinurad+allopurinol administered alone or in combination with cyclosporine or rifampicin in each treatment period.
|
Days 1 to 5 (pre-dose and post-dose)
|
Terminal Elimination Rate Constant (λz) of Verinurad, M1, M8, Allopurinol and Oxypurinol
Time Frame: Days 1 to 5 (pre-dose and post-dose)
|
λz of verinurad, M1, M8, allopurinol and oxypurinol when verinurad+allopurinol administered alone or in combination with cyclosporine or rifampicin in each treatment period.
|
Days 1 to 5 (pre-dose and post-dose)
|
Apparent Total Body Clearance of Drug From Plasma After Extravascular Administration (CL/F) for Verinurad and Allopurinol
Time Frame: Days 1 to 5 (pre-dose and post-dose)
|
CL/F for verinurad and allopurinol when verinurad+allopurinol administered alone or in combination with cyclosporine or rifampicin in each treatment period.
|
Days 1 to 5 (pre-dose and post-dose)
|
Mean Residence Time of the Unchanged Drug in the Systemic Circulation (MRTinf) for Verinurad and Allopurinol
Time Frame: Days 1 to 5 (pre-dose and post-dose)
|
MRTinf for verinurad and allopurinol when verinurad+allopurinol administered alone or in combination with cyclosporine or rifampicin in each treatment period.
|
Days 1 to 5 (pre-dose and post-dose)
|
Volume of Distribution (Apparent) at Steady State Following Extravascular Administration (Vss/F) of Verinurad and Allopurinol
Time Frame: Days 1 to 5 (pre-dose and post-dose)
|
Vss/F of verinurad and allopurinol when verinurad+allopurinol administered alone or in combination with cyclosporine or rifampicin in each treatment period.
|
Days 1 to 5 (pre-dose and post-dose)
|
Volume of Distribution (Apparent) at Steady State Following Extravascular Administration (Based on the Terminal Phase) (Vz/F) of Verinurad and Allopurinol
Time Frame: Days 1 to 5 (pre-dose and post-dose)
|
Vz/F of verinurad and allopurinol when verinurad+allopurinol administered alone or in combination with cyclosporine or rifampicin in each treatment period.
|
Days 1 to 5 (pre-dose and post-dose)
|
Metabolite:Parent (MP) Cmax Ratios for M1 and M8: Verinurad
Time Frame: Days 1 to 5 (pre-dose and post-dose)
|
Metabolite:parent (MP) Cmax ratios for M1 and M8: verinurad when verinurad+allopurinol administered alone or in combination with cyclosporine or rifampicin in each treatment period.
|
Days 1 to 5 (pre-dose and post-dose)
|
Metabolite:Parent (MP) AUCinf Ratios for M1 and M8: Verinurad
Time Frame: Days 1 to 5 (pre-dose and post-dose)
|
Metabolite:parent (MP) AUCinf ratios for M1 and M8: verinurad when verinurad+allopurinol administered alone or in combination with cyclosporine or rifampicin in each treatment period.
|
Days 1 to 5 (pre-dose and post-dose)
|
Metabolite:Parent (MP) AUClast Ratios for M1 and M8: Verinurad
Time Frame: Days 1 to 5 (pre-dose and post-dose)
|
Metabolite:parent (MP) AUClast ratios for M1 and M8: verinurad when verinurad+allopurinol administered alone or in combination with cyclosporine or rifampicin in each treatment period.
|
Days 1 to 5 (pre-dose and post-dose)
|
Number of Participants With Adverse Events (AEs) and Serious AEs (SAEs)
Time Frame: From screening (Day -28 to -2) until Follow-up or Early Termination (7-14 days after last verinurad dose)
|
Assessment the safety and tolerability of verinurad and allopurinol in combination with cyclosporine or rifampicin
|
From screening (Day -28 to -2) until Follow-up or Early Termination (7-14 days after last verinurad dose)
|
Collaborators and Investigators
Sponsor
Collaborators
Publications and helpful links
Helpful Links
Study record dates
Study Major Dates
Study Start (Actual)
Primary Completion (Actual)
Study Completion (Actual)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Actual)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Keywords
Additional Relevant MeSH Terms
- Urologic Diseases
- Renal Insufficiency
- Kidney Diseases
- Renal Insufficiency, Chronic
- Physiological Effects of Drugs
- Molecular Mechanisms of Pharmacological Action
- Anti-Infective Agents
- Nucleic Acid Synthesis Inhibitors
- Enzyme Inhibitors
- Antirheumatic Agents
- Antimetabolites
- Immunosuppressive Agents
- Immunologic Factors
- Protective Agents
- Dermatologic Agents
- Anti-Bacterial Agents
- Leprostatic Agents
- Cytochrome P-450 Enzyme Inducers
- Antifungal Agents
- Cytochrome P-450 CYP3A Inducers
- Antioxidants
- Antitubercular Agents
- Free Radical Scavengers
- Gout Suppressants
- Antibiotics, Antitubercular
- Cytochrome P-450 CYP2B6 Inducers
- Cytochrome P-450 CYP2C8 Inducers
- Cytochrome P-450 CYP2C19 Inducers
- Cytochrome P-450 CYP2C9 Inducers
- Calcineurin Inhibitors
- Rifampin
- Allopurinol
- Cyclosporine
- Cyclosporins
- Verinurad
Other Study ID Numbers
- D5495C00013
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
IPD Plan Description
Qualified researchers can request access to anonymized individual patient-level data from AstraZeneca group of companies sponsored clinical trials via the request portal. All requests will be evaluated as per the AZ disclosure commitment: https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.
Yes, indicates that AZ are accepting requests for IPD, but this does not mean all requests will be shared.
IPD Sharing Time Frame
IPD Sharing Access Criteria
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
Clinical Trials on Chronic Kidney Disease
-
3-C Institute for Social DevelopmentUniversity of North Carolina, Chapel HillCompletedChronic Kidney Diseases | Chronic Kidney Disease Stage 5 | Chronic Kidney Disease stage4 | Pediatric Kidney Disease | Chronic Kidney Disease stage3 | Chronic Kidney Disease Stage V | Chronic Kidney Disease, Stage IV (Severe) | Chronic Kidney Disease Stage 2 | Chronic Kidney Disease, Stage IUnited States
-
Universiti Putra MalaysiaRecruitingChronic Kidney Diseases | Chronic Kidney Disease Stage 5 | Chronic Kidney Disease stage4 | Chronic Kidney Disease stage3 | Chronic Kidney Disease Requiring Chronic DialysisMalaysia
-
National Taiwan University HospitalCompletedChronic Kidney Disease stage4 | Chronic Kidney Disease stage3 | Chronic Kidney Disease Stage 2 | Chronic Kidney Disease Stage 1Taiwan
-
Centre Hospitalier le MansLe Mans UniversiteWithdrawnFatigue | Chronic Kidney Disease Stage 5 | Chronic Kidney Disease stage3 | Chronic Kidney Failure | Chronic Kidney Disease, Stage 4 (Severe)
-
Centre Hospitalier le MansLe Mans UniversiteRecruitingFatigue | Chronic Kidney Disease Stage 5 | Chronic Kidney Disease stage4 | Chronic Kidney Disease Stage 3BFrance
-
American Academy of Family PhysiciansUniversity of Colorado, Denver; National Institute of Diabetes and Digestive... and other collaboratorsCompletedChronic Kidney Disease | Chronic Renal Insufficiency | Chronic Kidney Insufficiency | Chronic Renal Diseases | Kidney Insufficiency, ChronicUnited States
-
Lund UniversityBaxter Healthcare Corporation; Universidad de CórdobaCompletedEnd Stage Kidney Disease | Chronic Kidney Disease Requiring Chronic DialysisArgentina
-
Centre Hospitalier Saint Joseph Saint Luc de LyonNot yet recruitingKidney Failure, Chronic | Diet Habit | Chronic Kidney Disease stage3 | Chronic Kidney Disease Stage 3B | Chronic Kidney Disease, Stage 3 (Moderate) | Chronic Kidney Disease Stage 3A (Disorder)France
-
A.C. AbrahamsCompletedEnd Stage Renal Disease | Chronic Kidney Disease | End Stage Kidney Disease | Chronic Kidney FailureNetherlands
-
Far Eastern Memorial HospitalActive, not recruitingMetabolic Syndrome | Chronic Disease | Chronic Kidney Disease Stage 5 | Chronic Kidney Disease Stage 3 | Chronic Kidney Disease Stage 4 | Chronic Kidney Disease Stage 2 | Chronic Kidney Disease Stage 1Taiwan
Clinical Trials on Verinurad
-
AstraZenecaCompletedChronic Kidney DiseaseGermany
-
AstraZenecaCompletedType 2 Diabetes | Albuminuria | HyperuricemiaUnited States
-
AstraZenecaParexelCompletedHealthy Volunteers (Intended Indication: Chronic Kidney Disease)Germany
-
AstraZenecaParexelCompletedChronic Kidney DiseaseGermany
-
Ardea Biosciences, Inc.Completed
-
AstraZenecaCompletedHeart Failure With Preserved Ejection Fraction (HFpEF)United States, Germany, Canada, Korea, Republic of, Austria, Slovakia, Australia, Bulgaria, Russian Federation, Argentina, Poland, Mexico
-
Ardea Biosciences, Inc.Completed
-
AstraZenecaCompletedChronic Kidney DiseaseUnited States, Italy, Spain, France, Czechia, Israel, Slovakia, South Africa, Hungary, Poland, Mexico, Romania