Bioequivalence study of telmisartan 80 mg tablet produced by PT Amarox Pharma Global in comparison with the comparator drug (Micardis® 80 mg Tablet, Boehringer Ingelheim Pharma GmbH & Co. KG for Boehringer Ingelheim International GmbH, Germany, imported by PT Boehringer Ingelheim Indonesia, Bogor, Indonesia)
| 1. Background | |
|---|---|
| Registration Number | INA-3GA758K |
| Date of registry approval | 27-12-2023 |
| Registration Date | 15-12-2023 |
| Secondary identifiers | Yes |
| Name of issuing authority (for example protocol number, other registries, etc) | PT Amarox Pharma Global |
| Secondary identifier number | BE. 749/EQL/2022 |
| Scientific study title | Bioequivalence study of telmisartan 80 mg tablet produced by PT Amarox Pharma Global in comparison with the comparator drug (Micardis® 80 mg Tablet, Boehringer Ingelheim Pharma GmbH & Co. KG for Boehringer Ingelheim International GmbH, Germany, imported by PT Boehringer Ingelheim Indonesia, Bogor, Indonesia) |
| Public (popular study title) | Bioequivalence study of telmisartan 80 mg tablet produced by PT Amarox Pharma Global in comparison with the comparator drug (Micardis® 80 mg Tablet, Boehringer Ingelheim Pharma GmbH & Co. KG for Boehringer Ingelheim International GmbH, Germany, imported by PT Boehringer Ingelheim Indonesia, Bogor, Indonesia) |
| 2. Sponsor and Funding | |
| Primary Sponsor | PT Amarox Pharma Global |
| Source(s) of monetary or material support | PT Amarox Pharma Global |
| Name of secondary sponsor | - |
| Other partners | PT Equilab International |
| 3. Contact details | |
| Principal Investigator | |
| Principal investigator | dr. Danang Agung Yunaidi |
| City | Jakarta |
| Country | INDONESIA |
| Principal investigator's affiliation | PT Equilab International |
| Principal Investigator's email address | danang@equilab-int.com |
| Public Queries | |
| Contact person name for public queries | Ronal Simanjuntak – PT Equilab International |
| Address for public queries | PT Equilab International, Jl. RS. Fatmawati Persil 33 |
| City | Jakarta |
| Country | INDONESIA |
| ZIP | 12430 |
| Affiliation for public queries | PT Equilab International |
| Email address for public queries | info@equilab-int.com |
| Phone number for public queries | +62 21 7695513, 7515932 |
| Scientific Queries | |
| Name of Contact for scientific queries | Ronal Simanjuntak |
| Address for scientific queries | PT Equilab International, Jl. RS. Fatmawati Persil 33 |
| City | Jakarta |
| Country | INDONESIA |
| ZIP | 12430 |
| Affiliation of scientific queries contact | PT Equilab International |
| Email address for scientific queries | info@equilab-int.com |
| 4. IRB & Regulatory | |
| Ethical Approval number | S-349/UN2.F1/ETIK/PPM.00.02/2023 |
| Name of Ethics committee | Komite Etik Penelitian Kesehatan Fakultas Kedokteran Universitas Indonesia - RSUPN Dr. Cipto Mangunkusumo |
| Date of Ethic approval | 05-06-2023 |
| Contact details of Ethic Committee (phone, email, and office) | Jl. Salemba 6, Jakarta Pusat; Whatsapp: 0856-8701-608; Telp. 021 315 7008; e-Mail: ec_fkui@yahoo.com |
| Number of Persetujuan Pelaksanaan Uji Klinik (PPUK)/Persetujuan Protokol Uji BE (PPUB) | RG.01.02.321.06.23.01827/UB |
| 5. Status | |
| Countries of recruitment | Indonesia |
| Study sites in Indonesia | PT Equilab International |
| Recruitment status | Complete |
| Date of first enrollment | 01-08-2023 |
| Targeted Sample size | 00033 - |
| Number of enrolled participants | 33 |
| Date of study completion (last participant, last visit) | 01-09-2023 |
| 6. Study Design & Purpose | |
| Primary health condition(s) or problem(s) studied (e.g., depression, breast cancer,medication error) | Essential hypertension, cardiovascular disease with type 2 diabetes mellitus, or atherothrombotic cardiovascular disease (history of coronary heart disease, stroke, or peripheral arterial disease) |
| 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) | The participating subjects were required to have an overnight fast and in the next morning (first day of each period) were given orally one tablet of the test drug (telmisartan 80 mg tablet produced by PT Amarox Pharma Global) or one tablet of the comparator drug (Micardis® 80 mg Tablet, Boehringer Ingelheim Pharma GmbH & Co. KG for Boehringer Ingelheim International GmbH, Germany, imported by PT Boehringer Ingelheim Indonesia, Bogor, Indonesia) given with 200 mL of water and swallowed whole without chewing. |
| Control intervention (control arm) | The participating subjects were required to have an overnight fast and in the next morning (first day of each period) were given orally one tablet of the test drug (telmisartan 80 mg tablet produced by PT Amarox Pharma Global) or one tablet of the comparator drug (Micardis® 80 mg Tablet, Boehringer Ingelheim Pharma GmbH & Co. KG for Boehringer Ingelheim International GmbH, Germany, imported by PT Boehringer Ingelheim Indonesia, Bogor, Indonesia) given with 200 mL of water and swallowed whole without chewing. |
| Intervention assignment | Other |
| 7. Eligibility Criteria | |
| Gender inclusion criteria | Male, Female |
| Minimum age | 18 |
| Maximum age | 55 |
| Inclusion criteria | 1. Able to participate, communicate well with the investigators and would provide written informed consent to participate in the study,
2. Healthy male and female subjects with absence of significant disease or clinically significant abnormal laboratory values on laboratory evaluation, medical history or physical examination during the screening and could be considered healthy based on the evaluation, 3. Aged 18-55 years inclusive, 4. Non-smokers, 5. Body mass index within 18 to 25 kg/m2, 6. Vital signs (after 10 minutes rest) were within the following ranges: • Systolic blood pressure : 110 – 129 mmHg • Diastolic blood pressure : 70 – 84 mmHg • Pulse rate : 60 – 90 bpm, 7. Having a normal value for liver function test (i.e., AST less than 35 IU/L; ALT less than 45 IU/L; AP 53-128 IU/L; total bilirubin less than 1.2 mg/dL; and direct bilirubin less than 0.50 mg/dL) 8. Willing to practice abstention or non-hormonal contraception during the study. |
| Exclusion criteria | 1. History of allergy or hypersensitivity or contraindication to telmisartan or allied drugs,
2. Pregnant or lactating female (urinary pregnancy test was applied to female subjects at screening and before taking the study drug), 3. Any major illness in the past 90 days or clinically significant ongoing chronic medical illness, 4. Presence of any clinically significant abnormal values during screening e.g. significant abnormality of liver function test (AST, ALT, alkaline phosphatase, total bilirubin, direct bilirubin), renal function test (serum creatinine concentration > 1.4 mg/dL and ureum ≥ 1.5 ULN), etc, 5. Positive Hepatitis B surface antigen (HBsAg), anti-HCV, or anti-HIV, 6. Clinically significant hematology abnormalities, 7. Clinically significant electrocardiogram (ECG) abnormalities, 8. Any surgical or medical condition (present or history) which might significantly alter the absorption, distribution, metabolism or excretion of the study drug, e.g. gastrointestinal disease including gastric or duodenal ulcers or history of gastric surgery, 9.Past history of anaphylaxis or angioedema, 10.History of drug or alcohol abuse within 12 months prior to screening for this study, 11.Participation in any clinical trial within the past 90 days calculated from the last visit to this study’s first dosing day, 12.History of any bleeding or coagulative disorders, 13.Presence of difficulty in accessibility of veins in left or right arm, 14.A donation or significant blood loss within 90 days before this study’s first dosing day, 15.Intake of any prescription (especially telmisartan and irbesartan), non-prescription drug (including hormonal contraception), food supplements or herbal medicines within 21 days of this study’s first dosing day, 16. History or presence of hyperkalemia. |
| 8. Study Outcome | |
| Primary Outcome | |
| Name of primary outcome | AUC0-72h dan Cmax |
| Metric/method of measurement | The plasma concentrations of telmisartan were determined by using validated ultra performance liquid chromatography with tandem mass spectroscopy detection (UPLC MS/MS). |
| Timepoint(s) of measurement | Blood samples were drawn before taking the drug (control), and at 10, 20, 30, 45 minutes and 1.00, 1.50, 2.00, 3.00, 4.00, 6.00, 8.00, 10.00, 12.00, 24.00, 48.00 and 72.00 hours after drug administration. |
| 9. Study Results | |
| Brief summary of study results | The aim of the present study was to find out whether the bioavailability of PT Amarox Pharma Global’s formulation of telmisartan 80 mg tablet was equivalent to that of the comparator drug (Micardis® 80 mg Tablet, Boehringer Ingelheim Pharma GmbH & Co. KG for Boehringer Ingelheim International GmbH, Germany, imported by PT Boehringer Ingelheim Indonesia, Bogor, Indonesia).
The geometric mean ratios (90% confidence intervals) of the test drug/comparator drug for telmisartan were 90.74% (86.43 – 95.27%) for AUC0-t and 86.07% (74.59 – 99.32%) for Cmax. Hence, the 90% confidence intervals of the test/comparator ratios for AUC0-72h and Cmax of telmisartan were within the acceptance range for bioequivalence. The tmax values of test drug and comparator drug for telmisartan were compared using Wilcoxon matched-pairs test on the original data and the result was found not significantly different. The half-life values of the test and the comparator drugs were compared using Student’s paired t-test and the result was not significantly different, demonstrating a comparable rate of drug elimination from the body. There was one mild adverse event during Period 2 which was reported as headache encountered in one subject (S21). There was no concomitant medication used during this study. That event was solved and considered unlikely related to the study drug. During follow up study, there was one clinically significant of laboratory abnormality which was reported as increased erythrocyte encountered in one subject (S23). That subject was unable to be contacted to conduct re-follow up study and it remains unresolved. However, the case was considered unlikely related to the study drug. Based on the results of the single dose study above, it was concluded that the telmisartan 80 mg tablet produced by PT Amarox Pharma Global was bioequivalent to the comparator drugs (Micardis® 80 mg Tablet, Boehringer Ingelheim Pharma GmbH & Co. KG for Boehringer Ingelheim International GmbH, Germany, imported by PT Boehringer Ingelheim Indonesia, Bogor, Indonesia) when administered under fasting condition in healthy subjects. |
| Date of results summaries | 13-11-2023 |
| Participant flow | Screening : 48 subjects
Not eligible : 10 subjects Eligible : 38 subjects Randomized : 33 subjects Period 1 Dosing : 33 subjects Dropout : 2 subjects due to personal matter at +48h Completed : 31 subjects Period 2 Dosing : 31 subjects Dropout : 1 subject due to personal matter at +48h Completed : 30 subjects Period 3 Not attend : 1 subject didn’t attend due to personal matter Dosing : 29 subjects Completed : 29 subjects TRR: 9 subjects RTR: 10 subjects RRT: 10 subjects |
| Baseline characteristic | |
| Adverse events | There was one mild adverse event during Period 2 which was reported as headache encountered in one subject (S21). There was no concomitant medication used during this study. That event was solved and considered unlikely related to the study drug.
During follow up study, there was one clinically significant of laboratory abnormality which was reported as increased erythrocyte encountered in one subject (S23). That subject was unable to be contacted to conduct re-follow up study and it remains unresolved. However, the case was considered unlikely related to the study drug |
| Outcome measures | Geomean ratio T/R (90%CI)
AUC0-72h = 90.74% (86.43 – 95.27%) Cmax = 86.07% (74.59 – 99.32%) %CVwr AUC0-72h = 12.48% Cmax = 41.20% |
| 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)) | Undecided |
| Plan for IPD sharing (what IPD will be shared, when, by what mechanism, with whom, and for what types of analyses) | |
| Other important informations | Disposition subjects Screening : 48 subjects Not eligible : 10 subjects Eligible : 38 subjects Enrolled (Randomized) : 33 subjects Completed : 29 subjects The number of subjects in this study (29 subjects) was adequate following this study has more than 80% power to confirm a statistical conclusion. |