BIOEQUIVALENCE STUDY OF SPIRONOLACTONE 100 MG FILM-COATED TABLET PRODUCED BY PT DEXA MEDICA IN COMPARISON WITH THE COMPARATOR DRUG (ALDACTONE® 100 MG FILM-COATED TABLET, MANUFACTURED BY PFIZER AUSTRALIA PTY LTD, AUSTRALIA)

1. Background
Registration Number	INA-PY9YS39
Date of registry approval	15-11-2023
Registration Date	02-06-2023
Secondary identifiers	Yes
Name of issuing authority (for example protocol number, other registries, etc)	PT Dexa Medica
Secondary identifier number	BE. 597/EQL/2019
Scientific study title	BIOEQUIVALENCE STUDY OF SPIRONOLACTONE 100 MG FILM-COATED TABLET PRODUCED BY PT DEXA MEDICA IN COMPARISON WITH THE COMPARATOR DRUG (ALDACTONE® 100 MG FILM-COATED TABLET, MANUFACTURED BY PFIZER AUSTRALIA PTY LTD, AUSTRALIA)
Public (popular study title)	BIOEQUIVALENCE STUDY OF SPIRONOLACTONE 100 MG FILM-COATED TABLET PRODUCED BY PT DEXA MEDICA IN COMPARISON WITH THE COMPARATOR DRUG (ALDACTONE® 100 MG FILM-COATED TABLET, MANUFACTURED BY PFIZER AUSTRALIA PTY LTD, AUSTRALIA)

2. Sponsor and Funding
Primary Sponsor	PT Dexa Medica
Source(s) of monetary or material support	PT Dexa Medica
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	0852-2211-6630
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	KET 1403/UN2.F1/ETIK/PPM.00.02/2022
Name of Ethics committee	Komite Etik Penelitian Kesehatan Fakultas Kedokteran Universitas Indonesia - RSUPN Dr. Cipto Mangunkusumo
Date of Ethic approval	19-12-2022
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.01.02.321.01.23.01502/UB

5. Status
Countries of recruitment	Indonesia
Study sites in Indonesia	PT Equilab International
Recruitment status	Complete
Date of first enrollment	24-01-2023
Targeted Sample size	00033 -
Number of enrolled participants	33
Date of study completion (last participant, last visit)	30-01-2023

6. Study Design & Purpose
Primary health condition(s) or problem(s) studied (e.g., depression, breast cancer,medication error)	essential hypertension, Congestive heart failure, cirrhosis, nephrotic syndrome, idiopathic edema, malignant hypertension, hypokalemia, female hirsuitism
Purpose of the study	Bioequivelence 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)	Spironolactone 100 mg produced by Dexa Medica, Batch no A-18138-01-F-PSC-11
Control intervention (control arm)	Spironolactone 100 mg produced by Pfizer Australia Pty Ltd, Australia (Aldactone 100 mg Film-coated Tablet)
Intervention assignment	Crossover

7. Eligibility Criteria
Gender inclusion criteria	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) Preferably non-smokers or smoke less than 10 cigarettes per day; (5) Body mass index within 18 to 25 kg/m2; (6) Normal blood potassium level (3.5 – 5.1 mmol/L). (7) Vital signs (after 10 minutes rest) were within the following ranges (Systolic blood pressure: 100 – 129 mmHg; Diastolic blood pressure: 60 – 84 mmHg; Pulse rate: 60 – 90 bpm); (8) Willing to practice abstention or contraception during the study.
Exclusion criteria	(1) History of allergy or hypersensitivity or contraindication to spironolactone 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 ≥ 1.5 ULN), 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) Positive result for COVID-19 rapid antigen test; (7) Clinically significant hematology abnormalities; (8) Clinically significant electrocardiogram (ECG) abnormalities; (9) 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; (10) Past history of anaphylaxis or angioedema; (11) History of drug or alcohol abuse within 12 months prior to screening for this study; (12) Participation in any clinical trial within the past 90 days calculated from the last visit to this study’s first dosing day; (13) History of any bleeding or coagulative disorders; (14) Presence of difficulty in accessibility of veins in left or right arm; (15) A donation or significant blood loss within 90 days before this study’s first dosing day; (16) Intake of any prescription (especially spironolactone and apixaban), non-prescription drug (including hormonal contraception), food supplements or herbal medicines within 21 days of this study’s first dosing day.

8. Study Outcome
Primary Outcome
Name of primary outcome	AUC0-t and Cmax
Metric/method of measurement	The plasma concentrations of spironolactone were determined by using validated ultra performance liquid chromatography with tandem mass spectrometry detection (UPLC-MS/MS method).
Timepoint(s) of measurement	Blood samples were drawn before taking the drug (control), and at 0.25, 0.50, 0.75, 1.00, 1.25, 1.50, 1.75, 2.00, 2.50, 3.00, 3.50, 4.00, 5.00, 6.00, 7.00, 8.00, and 10.00 hours after drug administration.

9. Study Results
Brief summary of study results	The aim of the present study was to compare the bioavailability of spironolactone 100 mg film-coated tablet (produced by PT Dexa Medica, Indonesia) as the test drug with Aldactone® 100 mg Film-Coated Tablet (manufactured by Pfizer Australia Pty Ltd, Australia) as the comparator drug. This was an open-label, randomized, single-dose, three-period, three-sequence partial replicated design study under fasting conditions which included 33 healthy adult male and female subjects. All subjects were completed and analyzed for plasma concentration of spironolactone. The geometric mean ratios (90% confidence intervals) of the test drug/comparator drug were 105.74% (100.69 – 111.05%) for AUC0-t and 111.05% (103.09 – 119.63%) for Cmax. The 90% confidence intervals of the test/comparator ratios for AUC0-t and Cmax of spironolactone were within the acceptance range for bioequivalence. The tmax values of the two drugs (test and comparator drugs) were calculated using Wilcoxon matched-pairs test on the original data and the result were significantly different, demonstrating that the absorption of the test drug was expected to be faster than the comparator drug since the range of both comparator drugs tmax are wider. Although tmax of test drug was faster than of comparator drug, the maximum plasma concentration (Cmax) of test drug itself was concluded equivalent to Cmax of comparator drug. Therefore, their efficacy was expected to be similar. The half-life values (t1/2) of the test and the comparator drug were calculated utilizing Student’s paired t-test and the result were not significantly different, demonstrating a comparable rate of drug elimination from the body. There was neither adverse event nor concomitant medication occurred during this bioequivalence study.
Date of results summaries	28-06-2023
Participant flow	Not Specified
Baseline characteristic
Adverse events	Not Specified
Outcome measures	Please complete the information

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	Disposition Subjects Screening: 50 subjects Not eligible: 14 subjects Eligible: 36 subjects Enrolled (randomized): 33 subjects Completed: 33 subjects The number of subjects in this study (33 subjects) was adequate following this study has more than 80% power to confirm a statistical conclusion. It was concluded that the spironolactone 100 mg tablet produced by PT Dexa Medica was bioequivalent to the comparator drug (Aldactone® 100 mg Film-Coated Tablet, manufactured by Pfizer Australia Pty Ltd, Australia) in healthy subjects, based on the findings that the 90% confidence intervals for AUC0-t and Cmax were within the range of 80.00 125.00%. Both the test drug and comparator drug were tolerated by all subjects.