Investigation

3.1. Investigators and Study Administrative Structure

The clinical part of the study was performed in IPRC (Amman, Jordan) under the supervision of Naji Najib, the Principal Investigator; and Usam Harb, M.D., Clinical Investigator. The calculations of the pharmacokinetics and statistical evaluation of data were performed at IPRC. Data entry was performed by Lara AL-Zaghari (B.Sc. Pharm.) and the results were authorized by Prof. Naji Najib. Bioanalysis was performed at IPRC using the in-house developed and validated method under the supervision of Mohammad Bader (B.Sc. Chem.), HPLC Manager. The final report of the study was authored by Lara AL-Zaghari (B.Sc. Pharm.). The quality assurance unit (QAU) was entirely involved in auditing and checking, throughout the study conduction and completion.The curriculum vita of each investigator and coinvesti-gator is enclosed in the section "Curriculum Vitae of the Investigators and Coinvestigators" (Appendix A.5), "Curriculum Vitae." In addition to IPRC's clinical staff, nurses were present in both periods I and II, and were assigned their responsibilities under the supervision of IPRC's Clinical Investigator.

3.2. Study Objectives

In this study, the bioavailability of a single dose of one tablet (1000 mg) of Gulf Pharmaceutical Industries (Julphar) (Dialon) and Merck (Glucophage), 1000 mg metformin hydrochloride per tablet, were compared under fasting conditions. Bioequivalence was investigated by determining the 90% confidence limits for the log-transformed ratio (test product/reference product) for the bioequivalence parameters (Cmax, AUCo t, and AUCo «), while other pharmacokinetic parameters of Ke, t(i/2)e/ ¿max, and (AUCo->■t/AUCo->■ »)% were reported. The influence of sequence, product, and period effect was tested by ANOVA.

3.3. Investigational Plan

This study was a single-center, open-label, randomized, single-dose study with two-way crossover design to compare the bioavailability of metformin between two products, in 24 healthy (one to four) alternates adult, male volunteers.

The study was conducted according to ICH GCP guidelines adopted by EMEA. For all the steps carried out in this study, IPRC has written standard operating procedures (SOPs), of which IPRC personnel have control of the training on and the use of the SOPs. The IRB of IPRC, Amman, Jordan, reviewed the study protocol and approval was given on 26/10/2004 (see section "Approval of the IRB" in Appendix A.2). The clinical part of the study was initiated at IPRC, by the first screening examination on 17/11/2004. After the screening examination, subjects were sequenced according to a preassigned randomization plan. The first administration of the study drug, as well as, the first blood collection for drug analysis took place on 23/11/2004. A washout period of one week between the two study drug administrations was allowed. The last study drug administration took place on 30/11/2004, while the last blood collection for drug analysis took place on 01/12/2004. Blood sampling per each study period was carried out as per sampling schedule (Fig. 1).

The clinical study site facilities were designed and equipped appropriately to accommodate all running activities of the study. A detailed description of the study site facilities is mentioned under "Description of Study Facilities."

FIGURE 1 Study design and plan.

3.4. Rationale of Study Design

Bioequivalence evaluation is usually carried out by comparing the in vivo rate and extent of drug absorption of a test and reference formulation in healthy subjects. In a standard in vivo bioequivalence study design, study participants received test and reference products on separate occasions, in single dose, with random assignment to the two possible sequences of product administration. Samples of plasma were analyzed for drug concentrations, and pharmacokinetic parameters were obtained from the resulting concentration-time curves. These pharmacokinetic parameters were then analyzed statistically to determine whether the test and reference products yielded comparable values. Standard statistical methodology based on the two one-sided tests procedure to determine whether average values for pharmacokinetic parameters measured after administration of the test and reference products are comparable. This procedure involves the calculation of a 90% confidence interval for the ratio (or difference) between the test and reference product pharmacokinetic variable averages. The limits of the observed confidence intervals were within a predetermined range for the ratio (or difference) of the product averages. The determination of the confidence interval range and the statistical level of significance based on parametric (normal theory) standard noncompartmental procedures was employed for the analysis of pharmacokinetic data derived from in vivo bioequivalence studies. An ANOVA was performed on the pharmacokinetic parameters to assess the effect of variables [subject (sequence), subject, period, and formulation] on the study outcome. On the basis of these considerations, a single-dose, two-treatment, two-period, two-sequence crossover bioequivalence study on healthy normal subjects was adopted. The study was conducted in preplanned scheme, as depicted in Table 3 below.

3.5. Selection of Study Population

For participation in the study, subjects had to meet the selection criteria outlined in the study protocol. Volunteers were informed, by IPRC representative, about the aim of the study and any potential risk associated with the study. Volunteers signed a written informed consent statement after which they were run in the study, and they were free to withdraw at any time during the course of the study.

3.5.1. Study Subjects Demography

The following demographic data for each subject were obtained:

■ Volunteer name, age, height, weight, date of birth, race, medical history, and vital signs.

■ Complete physical examination and neurological assessment.

■ Urine analysis and blood (hematology, biochemistry, and serology).

TABLE 3 Study Schematic

Study period3

TABLE 3 Study Schematic

Procedure

Screeningb

Period I

Period II

Follow-up0

Subject identification

Informed consent

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