Bioequivalence Study of Two Formulations of Tablets Ramipril/Hydrochlorothiazide 10 mg/25 mg in Healthy Volunteers Under Fasting Conditions

NCT05685277 | Completed Phase 1

• 1 other identifier: RMPL-HCTZ-2021
• Study Type: interventional
• Target: 50
• Locations: 1 country
• Sites: 1

Brief Summary

This is an open-labeled, with blinding bioanalytical stage, randomized, two period, two sequences, single-center, crossover, comparative study, where each participant will be randomly assigned to the reference (Tritace® Plus, 10 mg/25 mg tablets) or the test (Ramipril/Hydrochlorothiazide, 10 mg/25 mg tablets) formulation in each period of study (sequences Test-Reference (TR) or Reference-Test (RT)), in order to evaluate if both formulations are bioequivalent.

Conditions

Bioequivalence

Keywords

Ramipril; Hydrochlorothiazide; Bioequivalence; Tritace® Plus

Outcome Measures

Primary Outcomes (2)

• Cmax of ramipril, ramiprilat and hydrochlorothiazide in plasma after administration of the test and the reference products.

  Maximum observed concentration in plasma.

  Time points 0.00 (prior to each drug administration) and 0.10, 0.20, 0.30, 0.45, 1.00, 1.15, 1.30, 1.45, 2.00, 2.30, 3.00, 3.30, 4.00, 4.30, 5.00, 6.00, 8.00, 10.00, 12.00, 15.00, 24.00, 48.00, 72.00 hours after each drug administration.

• AUC0-72 of ramipril, ramiprilat and hydrochlorothiazide in plasma after administration of the test and the reference products.

  Cumulative area under the concentration time curve calculated from 0 to time of last observed quantifiable concentration (TLQC) at the 72 hour time point using the linear trapezoidal method.

  Time points 0.00 (prior to each drug administration) and 0.10, 0.20, 0.30, 0.45, 1.00, 1.15, 1.30, 1.45, 2.00, 2.30, 3.00, 3.30, 4.00, 4.30, 5.00, 6.00, 8.00, 10.00, 12.00, 15.00, 24.00, 48.00, 72.00 hours after each drug administration.

Secondary Outcomes (8)

• Tmax of ramipril, ramiprilat and hydrochlorothiazide in plasma after administration of the test and the reference products.

  Time points 0.00 (prior to each drug administration) and 0.10, 0.20, 0.30, 0.45, 1.00, 1.15, 1.30, 1.45, 2.00, 2.30, 3.00, 3.30, 4.00, 4.30, 5.00, 6.00, 8.00, 10.00, 12.00, 15.00, 24.00, 48.00, 72.00 hours after each drug administration.

• TLQC of ramipril, ramiprilat and hydrochlorothiazide in plasma after administration of the test and the reference products.

  Time points 0.00 (prior to each drug administration) and 0.10, 0.20, 0.30, 0.45, 1.00, 1.15, 1.30, 1.45, 2.00, 2.30, 3.00, 3.30, 4.00, 4.30, 5.00, 6.00, 8.00, 10.00, 12.00, 15.00, 24.00, 48.00, 72.00 hours after each drug administration.

• AUC0-INF of ramipril, ramiprilat and hydrochlorothiazide in plasma after administration of the test and the reference products.

  Time points 0.00 (prior to each drug administration) and 0.10, 0.20, 0.30, 0.45, 1.00, 1.15, 1.30, 1.45, 2.00, 2.30, 3.00, 3.30, 4.00, 4.30, 5.00, 6.00, 8.00, 10.00, 12.00, 15.00, 24.00, 48.00, 72.00 hours after each drug administration.

• Residual area of ramipril, ramiprilat and hydrochlorothiazide in plasma after administration of the test and the reference products.

  Time points 0.00 (prior to each drug administration) and 0.10, 0.20, 0.30, 0.45, 1.00, 1.15, 1.30, 1.45, 2.00, 2.30, 3.00, 3.30, 4.00, 4.30, 5.00, 6.00, 8.00, 10.00, 12.00, 15.00, 24.00, 48.00, 72.00 hours after each drug administration.

• Time point where the log-linear elimination phase begins (TLIN) of ramipril, ramiprilat and hydrochlorothiazide in plasma after administration of the test and the reference products.

  Time points 0.00 (prior to each drug administration) and 0.10, 0.20, 0.30, 0.45, 1.00, 1.15, 1.30, 1.45, 2.00, 2.30, 3.00, 3.30, 4.00, 4.30, 5.00, 6.00, 8.00, 10.00, 12.00, 15.00, 24.00, 48.00, 72.00 hours after each drug administration.

Study Arms (2)

Sequence TR

OTHER

25 subjects assigned to the sequence TR will receive a single 10 mg/25 mg dose of the test product Ramipril/Hydrochlorothiazide (1 x 10 mg/25 mg tablet), marked as T in the sequence, in Period 1 and a single 10 mg/25 mg dose of the reference product Tritace® Plus (1 x 10 mg/25 mg tablet), marked as R in the sequence, in period 2. These treatments will be administered orally with approximately 200 mL of water, in the morning, following a 10-hour overnight fast. The tablet must be swallowed whole and must not be chewed or broken.

Drug: Ramipril/Hydrochlorothiazide tablet 10 mg/25 mg; Drug: Tritace® Plus tablet 10 mg/25 mg

Sequence RT

OTHER

25 subjects assigned to the sequence RT will receive a single 10 mg/25 mg dose of the test product Tritace® Plus (1 x 10 mg/25 mg tablet), marked as R in the sequence, in Period 1 and a single 10 mg/25 mg dose of the reference product Ramipril/Hydrochlorothiazide (1 x 10 mg/25 mg tablet), marked as T in the sequence, in period 2. These treatments will be administered orally with approximately 200 mL of water, in the morning, following a 10-hour overnight fast. The tablet must be swallowed whole and must not be chewed or broken.

Drug: Ramipril/Hydrochlorothiazide tablet 10 mg/25 mg; Drug: Tritace® Plus tablet 10 mg/25 mg

Interventions

Ramipril/Hydrochlorothiazide tablet 10 mg/25 mg DRUG

Ramipril/Hydrochlorothiazide is manufactured by Pharmtechnology LLC, Republic of Belarus. Each tablet contains 10 mg of ramipril and 25 mg of hydrochlorothiazide.

Also known as: The test product

Sequence RT; Sequence TR

Tritace® Plus tablet 10 mg/25 mg DRUG

Tritace® Plus is manufactured by Sanofi S.p.A., Italy (holder of the registration certificate: Sanofi-Aventis Deutschland GmbH, Germany). Each tablet contains 10 mg of ramipril and 25 mg of hydrochlorothiazide.

Also known as: The reference product

Sequence RT; Sequence TR

Eligibility Criteria

• Age: 18 Years - 45 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Healthy men or women aged between 18 to 45 years, inclusive;
• Body mass index 18.5-30.0 kg/m², inclusive;
• Verified diagnosis "healthy" according to the standard clinical, laboratory and instrumental examination methods;
• The level of systolic blood pressure (SBP) ≥100 mm Hg and ≤ 130 mm Hg and diastolic blood pressure (DBP) ≥ 70 mm Hg and ≤ 90 mm Hg; heart rate more than 60 beats/min and less than 90 beats/min at the time of screening, respiratory rate more than 12 and less than 20 per minute at the time of screening, body temperature above 35.9 ° C and below 36.9 °C at the time of screening;
• Subjects are able to understand the requirements of the study;
• Subjects are able to accept all the restrictions imposed during the course of the study;
• Availability of written informed consent of the volunteer to participate in the study in accordance with applicable law, obtained before the start of any research procedures;
• For female subject with preserved reproductive potential: negative pregnancy test and consent to use adequate methods of contraception from the first day of screening up to 30 days after taking the drug in the second period, or the absence of reproductive potential; in the case of using hormonal contraceptives, they must be canceled at least 2 months before the first day of screening;
• For male: consent to use adequate methods of contraception with partners with preserved reproductive potential from the first day of screening up to 30 days after taking the drug in the second period.

You may not qualify if:

• Drug intolerance to any drug;
• Burdened allergic history;
• Lactose intolerance, lactase deficiency, glucose-galactose malabsorption;
• Acute infectious diseases or allergic reactions requiring treatment (including drug allergies) less than 4 weeks before the first day of screening;
• Surgical interventions on the gastrointestinal tract, with the exception of appendectomy;
• Volunteers with suspected hypersensitivity to study drugs or any of their components;
• Chronic diseases of the cardiovascular, bronchopulmonary, neuroendocrine system, as well as diseases of the gastrointestinal tract, liver, kidneys, blood or other conditions that make it impossible for a volunteer to participate in the study according to the opinion of the researcher;
• The value of standard laboratory and instrumental parameters that go beyond the reference values;
• Positive test for syphilis, hepatitis B, hepatitis C, HIV or nasal and oropharyngeal swab for SARS-CoV-2;
• Positive test for alcohol in exhaled air;
• Positive urine analysis for the content of narcotic and potent substances;
• For women - positive pregnancy test;
• Any diet, such as vegetarian, within 2 weeks prior to the first day of screening;
• Intake of more than 10 units alcohol per week (1 unit of alcohol is equivalent to 500 ml of beer, 200 ml of wine or 50 ml of spirits ethyl 40%) or history of alcoholism, drug addiction, drug abuse;
• Inability to go without food for at least 12 hours and the inability to take the drug on an empty stomach;

Sponsors & Collaborators

• Pharmtechnology LLC: lead
• Ligand Research, LLC: collaborator

Study Sites (1)

Separate medical division "Comed" (Ligand Research LLC)

Moscow, Russia

Location

MeSH Terms

Interventions

Ramipril; Hydrochlorothiazide; Tablets

Intervention Hierarchy (Ancestors)

Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Chlorothiazide; Benzothiadiazines; Sulfonamides; Sulfones; Sulfur Compounds; Organic Chemicals; Thiazides; Dosage Forms; Pharmaceutical Preparations

Study Officials

• Sergey Filatov

  Ligand Research, LLC

  STUDY DIRECTOR

• Irina Rodyukova

  Ligand Research, LLC

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: OUTCOMES ASSESSOR
• Purpose: OTHER
• Intervention Model: CROSSOVER
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 5, 2023
• First Posted: January 17, 2023
• Study Start: December 28, 2022
• Primary Completion: February 22, 2023
• Study Completion: July 31, 2023
• Last Updated: January 8, 2024

Record last verified: 2023-08

Data Sharing

• IPD Sharing: Will not share

Locations

RU (1)