Bioequivalence Study of Tamsulosin Hydrochloride 0.4 mg Sustained-Release Film-Coated Tablet (Tamiva® SR) Manufactured by PT Interbat in Comparison with Harnal® OCAS 0.4 mg Film-Coated Prolonged Released Tablet Manufactured by Astellas Pharma Europe B.V, The Netherlands, Imported by PT Combiphar, Indonesia.
| 1. Background | |
|---|---|
| Registration Number | INA-T62XR1K |
| Date of registry approval | 27-03-2024 |
| Registration Date | 22-03-2024 |
| Secondary identifiers | No |
| Name of issuing authority (for example protocol number, other registries, etc) | |
| Secondary identifier number | |
| Scientific study title | Bioequivalence Study of Tamsulosin Hydrochloride 0.4 mg Sustained-Release Film-Coated Tablet (Tamiva® SR) Manufactured by PT Interbat in Comparison with Harnal® OCAS 0.4 mg Film-Coated Prolonged Released Tablet Manufactured by Astellas Pharma Europe B.V, The Netherlands, Imported by PT Combiphar, Indonesia. |
| Public (popular study title) | Bioequivalence Study of Tamsulosin Hydrochloride 0.4 mg Sustained-Release Film-Coated Tablet (Tamiva® SR) Manufactured by PT Interbat in Comparison with Harnal® OCAS 0.4 mg Film-Coated Prolonged Released Tablet Manufactured by Astellas Pharma Europe B.V, The Netherlands, Imported by PT Combiphar, Indonesia. |
| 2. Sponsor and Funding | |
| Primary Sponsor | PT Interbat |
| Source(s) of monetary or material support | PT Interbat |
| Other partners | PT Pharma Metric Labs |
| 3. Contact details | |
| Principal Investigator | |
| Principal investigator | Arini Setiawati, Pharm, PhD |
| City | Jakarta Pusat |
| Country | Indonesia |
| Principal investigator's affiliation | PT Pharma Metric Labs |
| Principal Investigator's email address | arinisetiawati@yahoo.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 |
| 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 | I Gusti Putu Bagus Diana Virgo, 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 |
| City | Jakarta |
| Country | Indonesia |
| ZIP | 10520 |
| Affiliation of scientific queries contact | PT. Pharma Metric Labs |
| Email address for scientific queries | gusti.virgo@pharmametriclabs.com |
| 4. IRB & Regulatory | |
| Ethical Approval number | KET-763/UN2.F1/ETIK/PPM.00.02/2023 |
| Name of Ethics committee | Komite Etik Penelitian Kesehatan Fakultas Kedokteran Universitas Indonesia |
| Date of Ethic approval | 12-06-2023 |
| 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.01.02.321.08.23.01975/UB |
| 5. Status | |
| Countries of recruitment | Indonesia |
| Study sites in Indonesia | PT Pharma Metric Labs |
| Recruitment status | Complete |
| Date of first enrollment | 25-08-2023 |
| Targeted Sample size | 00060 - |
| Number of enrolled participants | 58 |
| Date of study completion (last participant, last visit) | 03-11-2023 |
| 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 | Bioequivalent 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) | Tamiva® SR 0.4 mg film-coated tablet |
| Control intervention (control arm) | Harnal® OCAS 0.4 mg film-coated prolonged release tablet |
| Intervention assignment | Crossover |
| 7. Eligibility Criteria | |
| Gender inclusion criteria | Male |
| Minimum age | 18 |
| Maximum age | 55 |
| Inclusion criteria | Subjects had read the subject information and able to give written informed consent for participation in the study and comply with the study protocol/procedures, Healthy male subjects, Subjects age range 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: 90 – 129 mmHg, Diastolic blood pressure: 60 – 84 mmHg, Pulse/Heart rate: 60 – 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 |
| Exclusion criteria | those with a history of hypersensitivity or contraindication to tamsulosin or allied drugs or other ingredients in the study products or a history of serious allergic reaction to any drug, a significant allergic disease, or allergic reaction, those with a history or presence of medical condition which might significantly influence the pharmacokinetics of the study drug, e.g. chronic gastrointestinal disease, diarrhea, gastric surgery, renal insufficiency, hepatic dysfunction or cardiovascular disease, those with a history or presence of any coagulation disorder or clinically significant hematology abnormalities, those who had history of orthostatic hypotension, those with had presence of cataract or glaucoma, 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 participated in any clinical study within the past 90 days prior to the study, those who had participated in any clinical study within 3 months prior to the study (< 90 days), those who had donated or lost 300 mL (or more) of blood within 3 months prior to the study, those who were smoker
those with a history of direct contact with a COVID-19 positive person in the subject’s neighborhood those with a 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 to SARS CoV-2 antigen test, those who were positive to HIV, HBsAg, and HCV tests (to be kept confidential), those with a 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, AUCt |
| Metric/method of measurement | The plasma concentrations of tamsulosin were determined by means with LC-MS/MS system with the LLoQ was 49.99 pg/mL |
| Timepoint(s) of measurement | Blood samples were drawn prior to study drug administration (0 h/blank), and at 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 16, 24, 36, 48 and 72 hours after drug administration |
| 9. Study Results | |
| Brief summary of study results | This study was performed to investigate whether Tamsulosin Hydrochloride 0.4 mg sustained-release film-coated tablet (Tamiva® SR) manufactured by PT Interbat is bioequivalent to its reference product, Harnal® OCAS 0.4 mg film-coated prolonged released tablet manufactured by Astellas Pharma Europe B.V, The Netherlands, imported by PT Combiphar, Indonesia.
This study was designed as a randomized, single blind, two-period, two-treatment, two-sequence, single dose, two-way crossover study with at least one week washout period in 40 (forty) healthy subjects under fasted condition in stage 1 (one) of study and 20 (twenty) healthy subjects under fasted condition in stage 2 (two) of study. 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 (Tamiva® SR) or one tablet of the reference drug (Harnal® OCAS). Blood samples were drawn prior to study drug administration (0 h/blank), and at 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 16, 24, 36, 48 and 72 hours after drug administration. Following a washout period of at least one week, this procedure was repeated using the alternate drug. The plasma concentrations of tamsulosin were determined by means with LC-MS/MS system with the LLoQ was 49.99 pg/mL. In the first stage of this study, which involved 40 enrolled subjects, only 38 subjects completed the study and were statistically evaluated. Subject Number (SN) 017 was withdrawn at +72 hours after drug administration in period one of study due to adverse event, that was a headache, and it was resolved without taking any concomitant medication. While for SN 030 was withdrawn at quarantine night before period two of study drug administration due to personal reason. Adverse events recorded in this study was dizziness and headache. The details can be seen in Table IV. Summary of Adverse Events of Subjects in Tamsulosin Hydrochloride 0.4 mg Bioequivalence Study page 43 – 46. Study protocol deviation related to clinical phase was blood sampling deviations due to study phlebotomist had difficulty to access the subject’s vena and subject late checked in. The details can be previewed in Table V. Summary of Study Protocol Deviations in Tamsulosin Hydrochloride 0.4 mg Bioequivalence Study page 47 – 50. While the Protocol deviation related to analytical phase was chromatographic condition of method LC-MS/MS of tamsulosin and actual concentration of LLOQ tamsulosin was 49.99 pg/mL. It is listed in Table VI. Summary of Analytical Activity in Tamsulosin Hydrochloride 0.4 mg Bioequivalence Study page 51. The first stage study results were as follows : 90.00% confidence intervals of geometric means ratio of the two bioavailability parameters of tamsulosin were 87.20% - 120.25% for Cmax and 84.43% – 114.68% for AUCt. These results showed that Tamsulosin Hydrochloride 0.4 mg Sustained-Release Film-Coated Tablet (Tamiva® SR) was bioequivalent towards its reference product, Harnal® OCAS 0.4 mg Film-Coated Prolonged Released Tablet. However, the power of study was not adequate to fulfil 80% power study. The GM ratio of AUCt was 98.40% and the intra-subject CV of AUCt obtained was 39.53%. Hence, the power of study obtained was 60.98%. The study power did not meet the requirements of Indonesian NADFC (BPOM). Based on the Shuirman's table, it was required a total of 56 subjects to achieve the 80% power study. In this case, we conducted stage two with additional of 20 subjects, of which 18 (eighteen) subjects were the minimal requirement to achieve 80% power study and another 2 (two) subjects were required to anticipate subject drop out during study period. After the second stage of study was conducted, all subjects were completed the study and statistically evaluated. The pharmacokinetic analysis of the two stages study was performed by using 94.12% confidence interval. The two products are bioequivalent when the 94.12% confidence intervals of the tamsulosin geometric mean ratio between test and reference products fall within the range of 80.00 – 125.00% for Cmax and AUCt. The results from these two stages of bioequivalence study, Tamiva® SR film-coated tablet (test product) in comparison with Harnal® OCAS 0.4 mg film-coated prolonged released tablet (reference drug) were as follows: 94.12% confidence intervals of geometric means ratio of the two bioavailability parameters of tamsulosin were 92.41% - 122.48% for Cmax and 88.55% - 115.40% for AUCt, with 90.57% as the power of study. These results showed that Tamiva® SR film-coated tablet was bioequivalent toward its reference product, Harnal® OCAS 0.4 mg film-coated prolonged released tablet. |
| Date of results summaries | 01-12-2023 |
| 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 5 subjects per session. Study team in charge used medical personal protective equipment that consisted of surgical pants, head cap, face shield, N95 mask, goggles, hand gloves, and shoes’ cover. Beside the study team, the subjects were also instructed to wear face mask, washed their hands properly prior to registration/consenting procedures, wore the provided hand gloves, and implement physical distancing with a minimal of 1 meter distance among each other during the screening process. 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 and anti SARS CoV-2 antigen test 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 includes 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 HIV, HBsAg, HCV tests. Subject should be received the complete primary SARS CoV-2 vaccine and the first booster. SARS CoV-2 antigen test was carried out for subjects who had not received the vaccine. SARS CoV-2 antigen test was performed on the screening day and on 1 day prior to the study day on period 1 and 2, by swabbing the subject nasopharynx and examine the sample using provided test kit. If any subject showed positive result on the examination, the subject was withdrawn from the study and properly compensated. The subject was asked to perform isolation/quarantine for minimum 10 days and should remain in isolation/quarantine until 3 days after no more COVID-19 symptoms appeared, or another relevant procedure in accordance with the Indonesian health authority. The COVID-19 diagnosed subject was asked to perform isolation/quarantine for minimum 10 days and should remain in isolation/quarantine until 3 days after no more COVID-19 symptoms appeared, or another relevant procedure in accordance with the Indonesian health authority. They also instructed to report their condition to the appointed healthcare facility. As for this event if it’s occurred, Investigator reported the event as the Serious Adverse Event to the Sponsor and Ethics Committee. 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 and headache that occurred to SN 014 and SN 017. AE were resolved without taking concomitant medication |
| Outcome measures | 1. Cmax
-GMR : 106.39% -94.12% CI :92.41- 122.48% -CV : 39.31% 2. AUCt -GMR : 101.09% -94.12% CI :88.55 - 115.40% -CV : 36.95% |
| 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 available |