Bioequivalence Study of Opiprol® 5 mg Film-Coated Tablets Manufactured by PT Otto Pharmaceutical Industries in Comparison with Concor® 5 mg Film-Coated Tablets Manufactured by PT Merck Tbk, Jakarta, Indonesia Under License from Merck Healthcare KGaA, Darmstadt, Germany
| 1. Background | |
|---|---|
| Registration Number | INA-SHCRF4T |
| Date of registry approval | 18-11-2024 |
| Registration Date | 15-11-2024 |
| Secondary identifiers | Yes |
| Name of issuing authority (for example protocol number, other registries, etc) | 839/STD/PML/2024 |
| Secondary identifier number | 839/STD/PML/2024 |
| Scientific study title | Bioequivalence Study of Opiprol® 5 mg Film-Coated Tablets Manufactured by PT Otto Pharmaceutical Industries in Comparison with Concor® 5 mg Film-Coated Tablets Manufactured by PT Merck Tbk, Jakarta, Indonesia Under License from Merck Healthcare KGaA, Darmstadt, Germany |
| Public (popular study title) | Bioequivalence Study of Opiprol® 5 mg Film-Coated Tablets Manufactured by PT Otto Pharmaceutical Industries in Comparison with Concor® 5 mg Film-Coated Tablets Manufactured by PT Merck Tbk, Jakarta, Indonesia Under License from Merck Healthcare KGaA, Darmstadt, Germany |
| 2. Sponsor and Funding | |
| Primary Sponsor | PT Otto Pharmaceutical Industries |
| Source(s) of monetary or material support | PT Otto Pharmaceutical Industries |
| Other partners | PT. Pharma Metric Labs |
| 3. Contact details | |
| Principal Investigator | |
| Principal investigator | Apt. Drs, I Gusti Putu Bagus Diana Virgo |
| City | Jakarta |
| Country | Indonesia |
| Principal investigator's affiliation | PT Pharma Metric Labs |
| Principal Investigator's email address | gusti.virgo@pharmametriclabs.com |
| Public Queries | |
| Contact person name for public queries | Nabila Mudin S |
| Address for public queries | PT. Pharma Metric Labs Gedung Indra Sentral Cempaka Putih Unit R-U Jalan Letjen Suprapto Kav. 60 Central Jakarta, 10520 Indonesia Tel : +62 21 4265310 Fax : +62 21 4210302 |
| City | Jakarta |
| Country | Indonesia |
| ZIP | 10520 |
| Affiliation for public queries | PT. Pharma Metric Labs |
| Email address for public queries | nabila.pmlabs@gmail.com |
| Phone number for public queries | +62214265310 |
| Scientific Queries | |
| Name of Contact for scientific queries | Anton Hidayat, Pharm |
| Address for scientific queries | PT. Pharma Metric Labs Gedung Indra Sentral Cempaka Putih Unit R-U Jalan Letjen Suprapto Kav. 60 Central Jakarta, 10520 Indonesia Tel : +62 21 4265310 Fax : +62 21 4210302 |
| City | Jakarta |
| Country | Indonesia |
| ZIP | 10520 |
| Affiliation of scientific queries contact | PT. Pharma Metric Labs |
| Email address for scientific queries | anton.hidayat@pharmametriclabs.com |
| 4. IRB & Regulatory | |
| Ethical Approval number | KET-1146/UN2.F1/ETIK/PPM.00.02/2024 |
| Name of Ethics committee | Komite Etik Penelitian Kesehatan Fakultas Kedokteran Universitas Indonesia |
| Date of Ethic approval | 05-08-2024 |
| Contact details of Ethic Committee (phone, email, and office) | Komite Etik Penelitian Kesehatan Fakultas Kedokteran Universitas Indonesia-RSUPN Dr. Cipto Mangunkusumo Gedung H Fakultas Kedokteran UI, Jalan Salemba Raya No.6 Jakarta, 10430 Telp : (021) 3157008 https://komite-etik.fk.ui.ac.id/ |
| Number of Persetujuan Pelaksanaan Uji Klinik (PPUK)/Persetujuan Protokol Uji BE (PPUB) | RG.01.02.321.09.24.02894/UB |
| 5. Status | |
| Countries of recruitment | Indonesia |
| Study sites in Indonesia | PT Pharma Metric Labs |
| Recruitment status | Complete |
| Date of first enrollment | 22-09-2024 |
| Targeted Sample size | 00020 - |
| Number of enrolled participants | 20 |
| Date of study completion (last participant, last visit) | 01-10-2024 |
| 6. Study Design & Purpose | |
| Primary health condition(s) or problem(s) studied (e.g., depression, breast cancer,medication error) | healthy human volunteers |
| Purpose of the study | Bioequivalence study |
| Study type | Interventional |
| Interventional Study category | Bioequivalence study |
| Method of allocation | |
| Description of the allocation concealment mechanism and sequence generation | |
| Masking | |
| Study intervention (study arm) | Opiprol® 5 mg film-coated tablets |
| Control intervention (control arm) | Concor® 5 mg film-coated tablets |
| Intervention assignment | Crossover |
| 7. Eligibility Criteria | |
| Gender inclusion criteria | Male, Female |
| Minimum age | 18 |
| Maximum age | 55 |
| Inclusion criteria | Subjects had read the subject information and were able to give written informed consent for participation in the study and comply with the study protocol/procedures, Subjects healthy male and female, Subjects’ age ranges from 18 – 55 years, Subjects’ body mass index between 18 – 25 kg/m2, Subjects had a normal electrocardiogram, Subjects had resting vital signs (after 10 – 15 minutes of resting) were within the following range, Systolic blood pressure: 110 – 129 mmHg, Diastolic blood pressure: 70 – 84 mmHg,Pulse/Heart rate: 70 – 100 beats per minute, Subjects had no significant disease or clinically significant abnormal laboratory values on laboratory evaluation, medical history or physical examination during screening,Subjects had received the complete primary SARS CoV-2 vaccine |
| Exclusion criteria | those who were pregnant and/or nursing women (for women), those with history of contraindication or hypersensitivity to bisoprolol, or other allied drugs, or other ingredients in the study products, or a history of serious allergic reaction to any drug, significant allergic disease, or allergic reaction
those with a history or presence of medical condition which might significantly influence the pharmacokinetic of the study drug, e.g. chronic gastrointestinal disease, diarrhea, gastric /intestinal surgery, renal insufficiency, hepatic dysfunction or any cardiovascular disease,those with history or presence of any coagulation disorder or clinically significant hematology abnormalities, those who had history or presence of bronchial asthma or chronic obstructive pulmonary disease (COPD), those who had history or presence of psoriasis those who had history or presence of diabetes mellitus, those who disagree to use non-hormonal contraceptives methods (condom) before any intercourse with their spouse within study period, those who using any medication (prescription or non-prescription drug, food supplement, herbal medicine), particularly the medication known to affect the pharmacokinetics of the study drug, within one week prior to the drug administration day, those who participate in any clinical study within the past 90 days prior to the study, those who donate or lost 300 mL (or more) of blood within 3 months prior to the study, those who were smoker, those who had history of direct contact with a COVID-19 positive person in the subject’s neighborhood within the last 14 days prior to screening those who had history or present of sore throat, fever (with temperature more than 37°C), cough, cold, anosmia/loss of smell, or dyspnea within the last 14 days, those who were positive result for HIV, HbsAg, and HCV tests (to be kept confidential), those who had history of drug or alcohol abuse within 12 months prior to screening for this study, those who were unlikely to comply with the protocol, e.g. uncooperative attitude, inability to return for follow up visits, poor venous access |
| 8. Study Outcome | |
| Primary Outcome | |
| Name of primary outcome | Cmax and AUCt |
| Metric/method of measurement | The plasma concentrations of bisoprolol were determined by means of a validated LC-MS/MS method with the LLoQ was 0.50 ng/mL. |
| Timepoint(s) of measurement | Blood samples were drawn before dosing (0 h/blank) and at 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 7, 9, 12, 18, 24 and 30 hours after drug administration |
| 9. Study Results | |
| Brief summary of study results | This study was performed to investigate whether Opiprol® 5 mg film-coated tablets manufactured by PT Otto Pharmaceutical Industries was bioequivalent towards its reference product, Concor® 5 mg film-coated tablets manufactured by PT Merck Tbk, Jakarta, Indonesia under license from Merck Healthcare KGaA, Darmstadt, Germany.
This study was designed as a randomized, single-blind, two-period, two-treatment, two-sequence, single dose, two-way cross-over study with at least 7 days washout period (7 days actual washout period) in 20 healthy subjects under fasted condition. The subjects were informed about the study procedure and signed the informed consent form. This study protocol was approved by the Ethics Committee of the Medical Faculty, University of Indonesia and the Indonesian National Agency of Drug and Food Control. The study was conducted following an oral administration of one tablet of the test drug (Opiprol® 5 mg film-coated tablets) or one tablet of the reference drug (Concor® 5 mg film-coated tablets). Blood samples were drawn before dosing (0 h/blank) and at 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 7, 9, 12, 18, 24 and 30 hours after drug administration. Following seven days washout period, this procedure was repeated using the alternate drug. The plasma concentrations of bisoprolol were determined by means of a validated LC-MS/MS method with the LLoQ was 0.50 ng/mL. From a total of 20 healthy enrolled subjects, all subjects completed the study and statistically evaluated. Adverse events recorded in this study was dizziness, the details provided in the table section, Table IV. Summary of Adverse Events of Subjects in Bisoprolol Fumarate 5 mg Film-Coated Tablets Bioequivalence Study page 21 and 22. Study protocol deviation related to clinical phase was blood sampling time deviation and SARS CoV-2 antigen test prior to screening, period one and period two drug administration day for subject who has not received complete primary and first booster of SARS CoV-2 vaccine i.e., SN 003, SN 007, SN 013, SN 017 and SN 018. It is presented in Table V. Summary of Study Protocol Deviations in Bisoprolol Fumarate 5 mg Film-Coated Tablets Bioequivalence Study page 23. There was no protocol deviation related to analytical phase; it is presented in Table VI. Summary of Analytical Activity in Bisoprolol Fumarate 5 mg Film-Coated Tablets Bioequivalence Study page 24. The applied pharmacokinetic parameters in this study were area under the concentration-time curve of bisoprolol from time zero to 30 hours (AUCt), area under the concentration-time curve from time zero to infinite (AUCinf), maximum concentration (Cmax), time required to reach the maximum concentration (tmax) and the elimination half-life (t½). Results from this bioequivalence study of Opiprol® 5 mg Film-Coated Tablets (test product) in comparison with Concor® 5 mg film-coated tablets (reference drug) were as following: 90.00% confidence intervals of geometric means ratio of the two bioavailability parameters of bisoprolol were 100.85% - 109.73% for Cmax and 100.77% - 107.53% for AUCt. These results showed that, Opiprol® 5 mg Film-Coated Tablets was bioequivalent towards its reference product, Concor® 5 mg film-coated tablets. |
| Date of results summaries | 16-10-2024 |
| Participant flow | Subject screening and selection took place prior to the sampling period and only after the subject agreed to participate in the study by signing off the Informed Consent Form.
Subject screening was conducted with limited of number of people/subject candidates, with maximum 10 subjects per session. Study team in charge wore medical personal protective equipment and the subjects asked to wash their hands before entering the screening room. Informed consent was obtained from each subject before the screening process and the participation must be voluntary. All subjects were informed of possible side effects or adverse events and advised that they were free to withdraw from the study at any stage. The subject information sheet and consent form was provided in the subjects' first language (Bahasa Indonesia). The investigator informed all subjects about the details of the study, i.e. the objective and the procedure, as well as the study rules or restrictions to be followed during the study and the possible adverse effects of the drug. Medical history, physical examination, laboratory tests (routine hematology, blood biochemistry and urinalysis), electrocardiograph, pregnancy test and HIV, HBsAg, HCV tests were carried out to screen and obtain eligible subjects who met the inclusion and exclusion criteria. The Study Coordinator or Study Physician documented the subjects' demographic data which included full name, gender, date of birth, age, address, race, height, weight, and smoking and alcohol consumption habit. The medical history was taken included systemic review of allergies, family history, and surgical history. The physical examination includes overall appearance, eyes, ears, nose, throat, head and neck, heart, lung, abdomen (including liver and spleen), lymph nodes, skin, musculoskeletal, and nervous system examination. The vital signs were also be measured, which included blood pressure, pulse rate, respiration rate and body temperature. The clinical laboratory examination covered routine hematology (hemoglobin, leucocyte, white blood cell differential counts, erythrocyte, platelet, hematocrit, and erythrocyte sedimentation rate), blood chemistry (alanine aminotransferase/ALT/SGPT, aspartate aminotransferase/AST/SGOT), alkaline phosphatase, bilirubin, blood glucose level, ureum, and creatinine), and urinalysis (density, pH, leucocyte, nitrite, albumin/protein, glucose, ketone (acetone), urobilinogen, bilirubin, and blood count). A total of 15 mL of blood was drawn from each subject for the laboratory test, including for HIV, HBsAg, HCV tests. Subject were received the complete primary SARS CoV-2 vaccine. Pregnancy test was carried out for female subjects in screening process and on the day of sampling just before drug administration. Women of childbearing potential were advised to take the necessary precaution to prevent pregnancy and to report to the Investigator or Study Physician if they suspected pregnancy. All included subjects met the inclusion and exclusion criteria. The screening data of all subjects were evaluated and subjects with any current or past medical conditions which might significantly affected the study results and assessment were excluded from the study. Investigator or Study Physician decision was needed to decide subject's eligibility if there was an abnormal result, whether it was clinically significant or not. The results of screening were recorded in the Case Report Form. |
| Baseline characteristic | |
| Adverse events | Adverse events recorded in this study was dizziness |
| Outcome measures | Cmax :
1. GMR : 105.20% 2. 90% CI of the GMR : 100.85 - 109.73% 3. CV : 7.69% AUCt : 1. GMR : 104.09% 2. 90% CI of the GMR : 100.77 - 107.53% 3. CV : 5.92% |
| 10. Publication | |
| URL hyperlink(s) related to results and publications | |
| IPD sharing statement (Statement regarding the intended sharing of deidentified individual clinical trial participant-level data (IPD)) | No |
| Plan for IPD sharing (what IPD will be shared, when, by what mechanism, with whom, and for what types of analyses) | |
| Other important informations | Not Specified |