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Trial registered on ANZCTR


Registration number
ACTRN12614000851662
Ethics application status
Approved
Date submitted
15/07/2014
Date registered
8/08/2014
Date last updated
8/08/2014
Type of registration
Retrospectively registered

Titles & IDs
Public title
Bioequivalence study of three pharmaceutical preparations Atorvastatin tablets.Crossover, randomized, single-dose, three-treatment, three periods and six strings under fasting conditions
Scientific title
A bioequivalence study of three pharmaceutical preparations of Atorvastatin tablets, in healthy male volunteers, to test that the pharmaceutical preparations are interchangeable
Secondary ID [1] 284992 0
'Nil known'
Universal Trial Number (UTN)
U1111-1159-1831
Trial acronym
/A95-10 Bis
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Atorvastatin is an inhibitor of HMG-CoA reductase (statin) indicated as an adjunct therapy to diet to:
Reduce the risk of MI and stroke in patients with type 2 diabetes without CHD, but with multiple risk factors.

Reduce the risk of non-fatal MI, fatal and non-fatal stroke, revascularization procedures, hospitalization for CHF, and angina in patients with CHD.

Reduce elevated total-C, LDL-C, apo B, and TG levels and increase HDL-C in adult patients with primary hyperlipidemia (heterozygous familial and nonfamilial) and mixed dyslipidemia.

Reduce elevated TG in patients with hypertriglyceridemia and primary dysbetalipoproteinemia.

Reduce total-C and LDL-C in patients with homozygous familial hypercholesterolemia (HoFH).

Reduce elevated total-C, LDL-C, and apo B levels in boys and postmenarchal girls, 10 to 17 years of age, with heterozygous familial hypercholesterolemia after failing an adequate trial of diet therapy.
292497 0
Condition category
Condition code
Metabolic and Endocrine 292806 292806 0 0
Normal metabolism and endocrine development and function

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Test 1: Atorvastatin 80 mg coated tablets.

Test 2: Atorvastatin 80 mg tablets.

Treatment is with a single daily dose of 80 mg of Atorvastatin via oral administration. Three treatments (single dose), 3 periods (one day per period) and two-week washout between each period for the removal of the previous dose.
At least 72 hours before the time fixed for the study, the volunteer will receive in writing the appropriate citation where the place, date and time of the baseline is established. As the following notes for the week before the study: No Smoking (passively, as they are not smokers), not drink alcohol, do not consume xanthine beverages (cola, coffee, tea, chocolate, etc.) not consume grapefruit natural juice, not eating grilled food, do not use any other drug from the week before the study. Each volunteer will be welcomed by doctors and nursing staff involved in the study and they ask about the indications received 72 hours prior. They will be placed in facilities Ipharma SA de CV, will receive a light dinner (less than 800 kcal), low residue. You can drink water until 10:00 PM. Will rise at the time indicated by the staff in the clinical area and take a bath. A member of staff will move to room 1 and 2 as appropriate to randomization.
Each subject will be assigned to three experimental units EU, one for each trial period, so that 01 to 60 is for the period 1 (P1) and 61 to 120 at period 2 (P2) and 121 to 180 for the period 3 (P3).

The staff of each experimental unit consists of nurses, doctors, staff quality area, support staff; as well as the principal investigator.

Each subject will be placed a catheter (Inthracat or equivalent) in the vein of the elbow, they made the decision at time 0 and after this will be administered the drug orally under the supervision of physicians.

After drug administration the blood samples were obtained at different times by the staff Ipharma, these will be recorded in the logs corresponding times, will be delivered to preparation laboratory of the Institute for registration, processing and storage.

After about four hours after drug administration, volunteers will be provided fruit and 500 ml sports drink. From about 5 hours may drink water.

After about 8 hours Administration medication, a light lunch will be provided to volunteers.
After about 12 hour’s administration, they will provide a light dinner volunteers.

After taking 24 hours corresponding sample were withdrawn venous catheter and volunteers remain another hour in the Institute. The proof of this first period will terminate after the last blood sample.

The procedure will be similar for periods 2 and 3, with the only difference of treatment allocation, as appropriate to randomization.

At the time of the study and throughout the sampling period will perform a general physical examination protocol including vital signs at the beginning, during and at the end of each period, allowing us to detect the most common adverse effects such as: hypersensitivity, rash, cardiopulmonary complications, etc.

Post-experimental phase
All volunteers will be interviewed one week after the third period. These interviews will be questioned about possible side effects voluntary late onset. The information gathered will be recorded in their records.
Intervention code [1] 289824 0
Treatment: Drugs
Comparator / control treatment
Reference: Atorvastatin 80 mg tablets (Lipitor, Registered Trademark), manufactured by Pfizer Pharmaceuticals LLC, Puerto Rico, Lot No. 00380V, expiration date June 2012.

A single daily dose of 80 mg of Atorvastatin via oral administration, 1 tablet per day and only 1 period.
Control group
Active

Outcomes
Primary outcome [1] 292660 0
Bioequivalence of the tested drugs (T2 80mg and T3 80mg) compared to reference drug (atorvastatin 80mg tablets, Lipitor registered trademark).

Plasma levels of drugs were measured by high-performance liquid chromatography in an Agilent 1100 tandem mass spectrometry (HPLC) equipped with an auto sampler, a binary pump, connected to detector of triple quadrupole (MS/MS) Agilent 6410 (Agilent Technologies).

Tests to determine bioequivalence: classical confidence interval, interval Westlake, range Shuirmann and Double-sided t test of Shuirmann.
Timepoint [1] 292660 0
Four weeks post drug administration in the first period.

Timepoint for each period: Thirty-six hours of internment and the blood samples were taken at 0, 0.25, 0.5, 0.75, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 5.0, 6.0, 8.0, 12.0, 24.0, 36.0 and 48.0 after drug administration.
Secondary outcome [1] 309432 0
Absence of late-onset adverse reactions.

Volunteers will be interviewed by the institute doctors about possible side effects of late onset; and Clinical biochemistry tests such as: hematic biometry, blood chemistry, lipid profile and liver function. The information will be recorded in the clinical records.
Timepoint [1] 309432 0
One week post drug administration in the third period.

Eligibility
Key inclusion criteria
Will be included only those male volunteers who approve the clinical assessment by Ipharma physician’s and pass the clinical biochemistry tests, such as: hematic biometry, blood chemistry, lipid profile and liver function. As well as the absence of any evidence of chronic degenerative disease, and compliant with the following criteria:
-Non-smokers
-18 to 45 years old
- Males
- Body mass index of 20 to 26 Kg/m2
Minimum age
18 Years
Maximum age
45 Years
Gender
Males
Can healthy volunteers participate?
Yes
Key exclusion criteria
Were excluded from the study those who had electrocardiographic, radiologic abnormalities, which were VDRL (+), HIV (+) and / or HBsAg (+); relatives who had angioedema or allergies to medication, chemically related to drugs and generally any allergies or medical history, as these people have a higher risk of drug allergies. Also lead to exclusion of smoking habits and / or addiction, as well as those who were subject to medical treatment; the existence of concurrent or intercurrent disease and those where there was reasonable doubt about the veracity of the answers in the interview. Finally, all those volunteers who were discordant with the Official Mexican Standard NOM-177-SSA1-1998 were excluded.

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Volunteers who have passed clinical trials will be cited for the study. The first 60 volunteers who come to the institute will be accepted will be assigned a key that was previously generated by central randomization computer.

Staff members do not know who will be included as it only recorded the first 60 volunteers.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Once all subjects selected for the study, a randomization request is sent to pharmacokinetic and statistical area in format F-51 A, for treatment allocation (R, T1, T2), key file and key subject, plus bedroom allocation is based on gender; B or D to male, and the duration of treatment in question (1st, 2nd or 3rd). For treatment assignment Subjects will be randomized by an algorithm programmed into R-Project. The randomization algorithm of drugs of randomly generated seed; both drug randomization such as random seed is generated by the algorithm Messener Twister.

Random assignment of subjects to drugs:
For randomization of the order in which they carry out the administration of the treatments during the first period, it will be done by means of that algorithm will be selected randomly to subjects to immediately assign treatment (T1, T2, T3) in a balanced design.
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Crossover
Other design features
Phase
Phase 1
Type of endpoint(s)
Bio-equivalence
Statistical methods / analysis
The sample size calculation was made from the coefficient of variation intra-subject weighted equal to 40.27%. For the calculation was considered a type I or alpha error, maximum of 5% and a type II or beta, more than 20% errors, the latter implies a minimum power of 80% and an acceptance range for the confidence interval to 90 % geometric mean ratio test / reference least squares estimate for ABCs and Cmax parameters, addition to a design by William 3x6x3, 3 formulations, 6 sequences and 3 administration periods.

For the above calculation the statistical package "PowerTOST" from R software was used.

Descriptive statistics of plasma concentrations.
Procedure for data capture and R-Project WinNonlin program. The results of laboratory and clinical area will receive in progressive order. Will be presented and will graph the average plasma concentration and its standard error (raw and log-transformed data).
Descriptive statistics of pharmacokinetic parameters to evaluate:
Area under curve from time zero to the last measurement (AUC0-t)
Area under curve from time zero to infinity (AUC0-8)
Maximum plasma concentration (Cmax)
Time to peak plasma concentration is reached (Tmax)
The pharmacokinetic parametersAUC0-t and AUC0-8 are estimated by the linear and log trapezoidal method with WinNonlin respectively, while Cmax and Tmax are obtained directly from the chromatographic analysis data.
Averages, error or standard deviation and coefficient of variation for the estimated pharmacokinetic parameters are presented.
Histograms of the ratios and logarithmic transformation of the test drug / reference pharmacokinetic parameters AUC0-t, AUC0-8 and Cmax are displayed.
Bioequivalence of drugs RvsP1 and R vs P2 measured by design Willson in 3 periods, 3 treatments and 6 sequences.

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment outside Australia
Country [1] 6218 0
Mexico
State/province [1] 6218 0
Nuevo Leon

Funding & Sponsors
Funding source category [1] 289606 0
Commercial sector/Industry
Name [1] 289606 0
Ipharma S. A. de C.V.
Address [1] 289606 0
Francisco Fernandez Trevino No. 130 Col. Leones C.P. 64600, Monterrey, Nuevo Leon, Mexico
Country [1] 289606 0
Mexico
Primary sponsor type
Commercial sector/Industry
Name
Ipharma S. A. de C.V.
Address
Francisco Fernandez Trevino No. 130 Col. Leones C.P. 64600, Monterrey, Nuevo Leon, Mexico
Country
Mexico
Secondary sponsor category [1] 288289 0
None
Name [1] 288289 0
Address [1] 288289 0
Country [1] 288289 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 291342 0
Comite de Etica Ipharma, S. A. de C. V.
Ethics committee address [1] 291342 0
Francisco Fernandez Trevino No. 201 Col. Leones C.P. 64600, Monterrey, Nuevo Leon, Mexico
Ethics committee country [1] 291342 0
Mexico
Date submitted for ethics approval [1] 291342 0
Approval date [1] 291342 0
13/01/2011
Ethics approval number [1] 291342 0
98

Summary
Brief summary
In the present study the bioequivalence of three different drugs, the same type of pharmaceutical form at the same dose, containing the same drug (atorvastatin), but may have different excipients was evaluated. Compared if their plasma pharmacokinetic parameters, expressed as area under curve from time zero to the last measurement (AUC0-t); area under curve from time zero to infinity (AUC0-8); maximum plasma concentration (Cmax); and time to peak plasma concentration is reached (Tmax), have similarity to each other.
In 60 healthy male non-smoking volunteers, bioequivalence of drugs R (reference), Test 1 (T1) and test 2 (T2) was evaluated through a design WILLSON 3 periods, 3 treatments and 6 sequences.
The analysis of plasma levels of atorvastatin was performed by extracting the proteins and subsequent quantification by HPLC/MS-MS in a concentration range of: 0.5 to 100 ng/mL.
The Atorvastatina/A95-10Bis study was conducted in a timely and manner required.
Adverse effects: No adverse reactions occurred during, and after the end of the clinical protocol.
Clinical protocol deviations: There were no clinical protocol deviations.
Selection of subjects: All volunteers included in the study successfully met the criteria for selection and inclusion.
It is established that drugs test T1 and T2 in the same substance atorvastatin, are bioequivalent.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 49978 0
Dr Everardo Pineyro Garza
Address 49978 0
Principal investigator: Everardo Pineyro Garza

Ipharma S. A. de C. V.

Francisco Fernandez Trevino No. 130 Col. Leones C.P. 64600, Monterrey, Nuevo Leon, Mexico
Country 49978 0
Mexico
Phone 49978 0
+528183487843
Fax 49978 0
+528183487843
Email 49978 0
epineyro@i-pharma.com.mx
Contact person for public queries
Name 49979 0
Dr Everardo Pineyro Garza
Address 49979 0
Principal investigator: Everardo Pineyro Garza

Contact person: Everardo Pineyro Garza, Micaela Rodriguez

Ipharma S. A. de C. V.

Francisco Fernandez Trevino No. 130 Col. Leones C.P. 64600, Monterrey, Nuevo Leon, Mexico
Country 49979 0
Mexico
Phone 49979 0
+528183487843
Fax 49979 0
+528183487843
Email 49979 0
epineyro@i-pharma.com.mx
Contact person for scientific queries
Name 49980 0
Dr Magdalena Gomez Silva
Address 49980 0
Principal investigator: Everardo Pineyro Garza

Contact person: Magdalena Gomez Silva, Adrian Fernandez

Ipharma S. A. de C. V.

Francisco Fernandez Trevino No. 130 Col. Leones C.P. 64600, Monterrey, Nuevo Leon, Mexico
Country 49980 0
Mexico
Phone 49980 0
+528183487843
Fax 49980 0
+528183487843
Email 49980 0
magda.gomez@i-pharma.com.mx

No information has been provided regarding IPD availability
Summary results
Have study results been published in a peer-reviewed journal?
Other publications
Have study results been made publicly available in another format?
Results – basic reporting
Results – plain English summary