Randomized, open-label, single dose, two-period, cross-over bioequivalence study comparing test formulation Rosuvastatin/Amlodipine/Ramipril capsule, hard 10mg/5mg/5mg versus reference products Crestor 10 mg film coated tablets, Norvasc 5 mg tablets, Tritace 5 mg tablets in healthy male and female subjects under fasting conditions.

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Adamed Pharma S.A.

Participant type

Healthy volunteers

Age range

18-64 years

Gender

Male and Female

Therapeutic area

Diseases [C] - Cardiovascular Diseases [C14]

Trial duration

19 Jun 2023 → 22 Aug 2023

Decision date (initial)

2023-05-16

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

Adamed Pharma S.A.

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Bioequivalence

To evaluate the pharmacokinetic properties and to compare the bioavailability of Test Product (T) versus Reference Products taken concurrently (R1 + R2 + R3) in healthy volunteers under fasting conditions.

Secondary objectives 1

1. To evaluate the safety and tolerability of Test Product (T) and Reference Products (R1, R2 and R3) in healthy volunteers.

Conditions and MedDRA coding

Not applicable (submitted trial is a bioequivalence study in healthy subject).

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 8

1. Healthy males and non-pregnant and non-breast-feeding females*, ≥18 and ≤ 60 years of age (on the day of Informed Consent Form signing). Caucasian race. *Pregnancy will be tested during screening and check-in procedure for each Period.
2. Non-smoker or past smoker (who has stopped smoking at least 3 months before the first dosing).
3. Body Mass Index (BMI) ≥ 18.5 and ≤ 30.0 kg/m2, (on the day of screening).
4. Subject is available for the whole study and has provided his/her written informed consent.
5. Subjects in good health, as determined by screening medical history, physical examination, vital signs assessments (heart rate, systolic and diastolic blood pressure, and body temperature) and 12-lead ECG. Minor deviations outside the reference ranges will be acceptable, if deemed not clinically significant by the Investigator.
6. All laboratory screening results within the normal range or deemed clinically insignificant by Investigator.
7. Acceptance of use of contraceptive measures during the whole study by both female and male subjects*. *Methods of highly effective contraception for female subjects of childbearing potential: -combined (estrogen and progestogen containing) hormonal contraception, either oral, intravaginal or transdermal or progestogen-only hormonal contraception associated with inhibition of ovulation, either oral, injectable or implantable, or intrauterine hormone-releasing system or bilateral tubal occlusion or vasectomised (sterilised) partner (provided that it is a sole sexual partner of the subject and medical assessment of the surgical success has been provided to the partner) or intrauterine device (non-hormonal) since at least 30 days prior to the first dosing and use one of the barrier methods or abstinence from any sexual intercourse or hormonal intrauterine device or oral hormonal contraceptives or substitution if taken without significant changes in dose for 90 days before the first dosing and without change during the study. Highly effective contraception should be combined with use of barrier method with spermicide (condom, diaphragm). Recommended methods of contraception for male subjects - to not donate sperm from the first study drug administration to at least 30 after the last drug administration. If a female partner of male participant in the study is of childbearing potential, the couple needs to use the above described highly effective contraception methods. If a female partner of male participant in the study is pregnant, the recommended contraception method is that the male must use barrier method (condom). Premenarcheal women, women with documented hysterectomy, bilateral salpingectomy, bilateral oophorectomy and postmenopausal women are not considered of childbearing potential. Postmenopausal state is defined as no menses for 12 months without an alternative medical cause. These contraception precautions are required during the study course and for at least 30 days after the last dose of IMP.
8. The subject speaks and understands Czech fluently.

Exclusion criteria 35

1. Acute or chronic diseases and/or clinical finding which may interfere with the aims of the study or with the drug’s safety, tolerability, bioavailability and/or pharmacokinetics of the IMP.
2. Existing gastrointestinal diseases, renal or hepatic diseases and/or pathological findings, which might interfere with the drug’s safety, tolerability, absorption and/or pharmacokinetics.
3. History or presence of serious clinical illness that can impact the fate of drugs (their absorption and/or distribution and/or metabolism and/or elimination).
4. History or severe allergy or allergic reactions to the study drugs or related drugs (e.g. ACE, dihydropyridine derivates) or any of the excipients.
5. Clinically significant illness within 28 days before the first dosing, including major surgery.
6. Serious mental disease and/or inability to cooperate with clinical team.
7. Orthostatic hypotension in history or during the screening procedure.
8. Drug, alcohol (≥ 40 g pure ethanol per day for men or ≥ 20 g pure ethanol per day for women), solvents or caffeine abuse.
9. Use of organ-toxic drugs within 90 days before the first dosing (e.g. any drug with a well-defined potential for toxicity to a major organ or system such as chloramphenicol, which may cause bone marrow suppression).
10. Use of systemic drugs known to alter hepatic metabolism within 90 days prior to the first dosing.
11. Any systemic prescription treatment within 28 days before the first dosing, except hormonal contraceptives or substitution taken without significant changes in dose for 90 days prior to the first dosing.
12. Any systemic over-the-counter (OTC) drug treatment and/or vitamins and/or herbal treatment (e.g. Saint John´s Wort) and/or food supplements within 14 days before the first dosing.
13. Donation or loss of at least 500 mL of blood within 90 days or donation of plasma or platelets within 14 days before the first dosing.
14. Getting a tattoo, body piercing or any cosmetic treatment involving skin penetration within 90 days before the screening unless evaluated by Investigator as non-significant for inclusion in the study.
15. Positive results of drugs of abuse in urine at screening and at check-in.
16. Positive result of alcohol breath test at screening and at check-in.
17. Positive result of urine cotinine test at screening.
18. Body temperature is out of the range of 35.7-36.9 °C at screening and at check-in.
19. Sitting blood pressure after a minimum of 5 minutes of rest is out of the range of 105-140 mmHg for systolic BP and/or 70-90 mmHg for diastolic BP and/or heart rate out of the range of 50-100 bpm during the screening procedure.
20. Any significant clinical abnormality, including a positive result of HBsAg and/or HCV and/or HIV test during screening procedure.
21. Anaemia, haemoglobin below 120 g/L for women and 130 g/L for men at screening.
22. Positive result of blood pregnancy test at screening or positive urine pregnancy test at check-in or breast-feeding or lack of results of pregnancy test.
23. Less than 45 days between exit procedure in previous study and the first dosing in this study.
24. Liver disease with elevation of serum transaminases present or in history, level of ALT, AST or GGT ≥ 3 x ULN at the screening.
25. Level of serum sodium or potassium out of normal range unless evaluated by Investigator as non-significant for inclusion in the study.
26. Creatine kinase (CK) out of normal range unless evaluated by Investigator as non-significant for inclusion in the study.
27. Impaired kidney function, clearance of creatinine (MDRD) < 1 mL/s.
28. Current or history of skeletal muscles disorders (muscular toxicity, myopathy and rhabdomyolysis) or current skeletal muscles injuries, including a family history of hereditary muscular disorders.
29. History of angioedema.
30. Current or history of heart failure, hypertension, aortal or mitral valve stenosis or hypertrophic cardiomyopathy.
31. History or presence of lactose intolerance, galactose intolerance or glucose-galactose malabsorption syndrome.
32. Current or history of hypothyreosis.
33. Subject was vaccinated against COVID-19 less than 14 days before the screening and/or subject plans to be vaccinated against COVID-19 during the study.
34. Subject was hospitalized for COVID-19 related reasons.
35. Positive PCR test for SARS-CoV-2 or positive antigen test, if required for safety reasons before hospitalization in the study.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. AUC(0-72h) or AUC(0-t), and Cmax. 90% confidence intervals for the Test to Reference ratio of LSM for rosuvastatin, amlodipine and ramipril and a based on ln-transformed data of AUC(0-t) or AUC(0-72h) and Cmax will be calculated and compared with acceptance limits AUC(0-t) or AUC(0-72h) 80.00 ‒ 125.00%, Cmax 80.00 ‒ 125.00%

Secondary endpoints 1

1. tmax, AUC(0-∞), AUCres, t1/2 and λz (if applicable)

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Comparator 3

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Adamed Pharma S.A.

Sponsor organisation

Adamed Pharma S.A.

Address

Ul Mariana Adamkiewicza 6a

City

Czosnow

Postcode

05-152

Country

Poland

Scientific contact point

Organisation

Adamed Pharma S.A.

Contact name

Pharmacokinetic Study Team

Public contact point

Organisation

Adamed Pharma S.A.

Contact name

Pharmacokinetic Study Team

Locations

1 EU/EEA country · 1 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Summary of results Art. 37(4) CTR

Layperson summary Annex V

Documents 3 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

3 submissions — initial application plus substantial / non-substantial modifications