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Trial registered on ANZCTR


Registration number
ACTRN12619000391178
Ethics application status
Approved
Date submitted
23/02/2019
Date registered
12/03/2019
Date last updated
12/03/2019
Date data sharing statement initially provided
12/03/2019
Date results information initially provided
12/03/2019
Type of registration
Retrospectively registered

Titles & IDs
Public title
A bioequivalence study of two pharmaceutical preparations of Amfepramone 75mg in healthy volunteers, to assessment the interchangeability of the pharmaceutical preparations
Scientific title
A bioequivalence study of two pharmaceutical preparations of Amfepramone 75mg in healthy volunteers, to assessment the interchangeability of the pharmaceutical preparations
Secondary ID [1] 297493 0
Nil known
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Obesity. 311682 0
Condition category
Condition code
Diet and Nutrition 310311 310311 0 0
Obesity

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Test and Reference drugs, in a single oral dose (75 mg) in 2 periods under fasting conditions and 2 periods under food conditions From the signing of the informed consent to the medical discharge

Test drug: Amfepramone
Reference drug: Neobes Amfepramone

The study includes two designs (fasting and food) with two periods each of approximately 36 hours of internment and a post-discharge sample taking of 48 hours, in each period of both designs. Between each internment there are a period of 2 weeks of washout.

The study begins with two periods under fasting conditions (2x2x2 design under fasting conditions). After a previous fast of at least 10 hours, the sample of time 0.00 will be obtained. Next, 75 mg of amfepramone will be administered, orally with 250mL of water at room temperature.

Subsequently, the design of two periods in post-prandial conditions will be continued (2x2x2 design with food). After a previous fast of 10 hours, the sample of time 0.00 will be obtained. Likewise, 30 minutes before dosing, each research subject will receive a standard breakfast; the research subjects will have 30 minutes to finish all the breakfast and immediately afterwards the medication will be administered orally, with 250mL of water.

Breakfast is high in calories (approximately 923 kcal: 506.19 kcal fat, 241.51 kcal carbohydrate, 175.3 kcal protein) and high in fat (aprosoimadamente 54.8%).

The staff of the clinical pharmacology center is responsible for the preparation and dispensing of medicines (test or reference) must wear protective glasses, gloves, gown. the medication must always keep its identification label (container label). The study coordinator must verify that the data on the label of the medication container correspond to those of the research subject to whom the medication is delivered. The medical collaborator indicates to the research subjects when they should ingest the medication. The clinical collaborator verifies the swallowing of the medication visualizing the oral cavity of each research subject in charge with the lamp for review and informs the coordinator of the study of the clinical unit of any anomaly. In conclusion throughout the study there is a direct observation by study personnel.
Intervention code [1] 313736 0
Treatment: Drugs
Comparator / control treatment
Neobes Amfepramone 75 mg capsules manufactured by Medix, S.A. of C.V. with sanitary registration number: 60975SSA III
Control group
Active

Outcomes
Primary outcome [1] 319198 0
To evaluate the bioavailability of two different drugs containing the same drug (Amfepramone), comparing the plasma pharmacokinetic parameters Area Under the Curve from time zero to the last determination (ABC0-t), Area under the curve extrapolated to infinity (ABC0-8) and Maximum Plasmatic Concentration (Cmax), of the administration of the same dose in fasting and postprandial, and verify that under each design, both formulations are bioequivalent.
Timepoint [1] 319198 0
The plasma samples were taken:

0.00 (before drug administration)

0.25, 0.50, 0.75, 1.00, 1.25, 1.50, 1.75, 2.00, 2.50, 3.00, 4.00, 6.00, 8.00, 10.00, 12.00, 24.00 and 48.00 h; after drug administration

To determine bioequivalence timepoint:

Five weeks after the last plasma sample collection.
Secondary outcome [1] 367253 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] 367253 0
One week post drug administration in the second period.

Eligibility
Key inclusion criteria
· Healthy male and female research subjects will be included in the study.

· Age between 18 and 55 years old.

· A BMI (Body Mass Index) between 18.0 to 27.0 kg/m2.

· To have signed the authorization for clinical examinations, as well as the informed consent before carrying out any procedure belonging to the study.

· The volunteer agrees to take the necessary measures to avoid conception during the entire study, this commitment is established in the letter of commitment of non-pregnancy and informed consent.

· Negative test results to determine substances of abuse, made during the selection process/beginning of each study period.

· Negative results in pregnancy tests performed during the selection/start process of each study period.

· Negative results in the tests for Ab HIV, AgsHB, Ab HCV and RPR (lictic test).

· Values of clinical biochemical tests: Hematic Biometrics, Urinalysis, Biochemical Profile: (Glucose, Ureic Nitrogen, Urea, Creatinine, Uric Acid, Cholesterol, Triglycerides, Total Proteins, Albumin, Globulin, Bilirubin (total, indirect and direct), Phosphatase Alkaline, Lactic Dehydrogenase, AST, ALT, Calcium, Phosphorus, Sodium, Potassium, Chlorine and Iron), are in a range between the minimum value and the maximum value of the normal values accepted for said tests.

· In cases of exception, a candidate may be accepted in which any of the aforementioned tests exceeds the maximum and minimum values accepted as normal, as long as it is an isolated value and there are no other statements presuming that the limit value was related with a future illness, or the remnant of another. These must be approved by the clinical area and declared as "clinically insignificant".

· Electrocardiogram free of anomalies; It will be valid for three months from the date of execution.
Minimum age
18 Years
Maximum age
55 Years
Gender
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
·Electrocardiographic abnormalities

· Positive results in the examination of substance abuse, during the pre-selection/beginning of each period.

· Positive results in pregnancy tests performed during the selection/start process of each study period.

· Positive results in tests for Ab HIV, AgsHB, Ab HCV, RPR.

· Personal or family history of allergy to the drugs in question, chemically related drugs, or food allergies provided in the protocol diet.

· Subjects in which the medication in question is contraindicated.

· Subjects intolerant to venipuncture.

· Tobacco abuse (more than 5 cigarettes a day)

· Drug addiction.

· People subjected to a medical treatment.

· Women in breastfeeding period.

· People presenting swallowing or phagophobia problems.

· People with a history of glaucoma, hypertension, anorexia, thyroid problems.

· People presenting any obstructive disease of the urinary tract or gastrointestinal tract.

· Existence of concurrent or intercurrent disease.

· Existence of doubt based on the veracity of the answers in the interrogation.

· Have participated in studies of bioequivalence or bioavailability according to the Program of Research Subjects of COFEPRIS, or have donated blood 3 months before this study.

· Presence of a medical condition that requires regular medication (prescription or free sale) with systemic absorption.

· Have smoked (more than 5 cigarettes a day); consumed alcoholic beverages; drinks with xanthines (cola drinks, coffee, tea, chocolate, energy drinks, etc.); grapefruit, natural juice of grapefruit and / or its derivatives; food prepared on charcoal, food supplements, herbal remedies or have used any other medicine (example: inhibitors of MAO monoamine oxidase or beta-blockers, tricyclic antidepressants, anti-flu drugs containing ephedrine, anorexigenic etc.) within 48 hours before the study .

· History of drug addiction or alcohol abuse.

· Labor subordination between the researcher and the research subject.

· Present pressure> 140 mm Hg (systolic) or> 90 mm Hg (diastolic).

· Present values in clinical laboratory tests outside of clinically significant range.

· Did not sign the Informed Consent and the commitment of non-pregnancy, corresponding to the study.

Finally, all research subjects who do not comply with the indications regarding diet, habits, who have mental incapacity to follow instructions and make decisions, who do not meet all the inclusion criteria described above and finally, who disagree with Official Mexican Standard NOM-177-SSA1-2013.

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)
Allocation is not concealed.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
In the area of recruitment of research subjects, the progressive number will be assigned for each selected subject, in addition to the data and other information that this area has to collect according to the study to be performed. It will be documented.
Once the Clinical Unit has selected the research subjects that will participate in the study, a request for randomization will be sent to the statistical area for the assignment of medicines, R or P, File Code and Subject Code. The random assignment will be done in two, blocks under a balanced design, in such a way that half of the subjects will be assigned the R-P administration sequence and to the other half of subjects the P-R sequence, this will be done for each medication administration condition. At the beginning of each design, the randomization sequence should be balanced. The random assignment will be carried out in the software R, through its internal algorithm Mersenne Twister. This randomization algorithm has been previously validated according to the DIEHARD test set for the evaluation of random number generators. The lists of the random assignment of sequences will be documented.
The documented randomization schemes will be used for each 2x2x2 design under fasting and food conditions.
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s

The people assessing the outcomes
Intervention assignment
Crossover
Other design features
Phase
Phase 3
Type of endpoint(s)
Bio-equivalence
Statistical methods / analysis
For sample size calculation, the intrasubject CV obtained in a previous pilot study (Anfepramona/A359-16P) was considered. It was assumed that CV was 25.77 % for both the Cmax and AUC. Considering a confidence level of 95%, a significance level of 5%, and a minimum power of 80%, a sample size of 30 would suffice.

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

Descriptive statistics of the volunteers included in the study.
Descriptive statistics of the volunteers included in the study.
The pharmacokinetic parameters of each design: ABC0-t, ABC0-8, Cmax, Ke, T1/2 and Tmax were estimated using a non-compartmental method; the farmacokinetic parameters ABC0-t and ABC0-8 were estimated through the linear-logarithmic trapezoidal method; whereas Cmax and Tmax were obtained directly from the decoded data; with this information of the pharmacokinetic parameters, the descriptive statistics were calculated; later, the ANOVA of logarithmically transformed pharmacokinetic parameters ABC0-t, ABC0-8 and Cmax was performed in order to study a possible effect of the factors that could affect the response variables. They are presented: the Classic Interval and the Power of the Test. The unilateral double t test of Schuirmann is included. The descriptive and inferential statistics of the two designs, both plasma concentrations and pharmacokinetic parameters were carried out through software R.

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] 21301 0
Mexico
State/province [1] 21301 0
Nuevo Leon

Funding & Sponsors
Funding source category [1] 302057 0
Commercial sector/Industry
Name [1] 302057 0
Investigación Farmacéutica, S.A. de C.V.
Address [1] 302057 0
Mexico City:
Av. Insurgentes Sur 2453
Floor 9, Office 902
Tizapan, Del. Alvaro Obregon
PC 01090 Mexico.
Country [1] 302057 0
Mexico
Primary sponsor type
Commercial sector/Industry
Name
Investigación Farmacéutica, S.A. de C.V.
Address
Mexico City:
Av. Insurgentes Sur 2453
Floor 9, Office 902
Tizapan, Del. Alvaro Obregon
PC 01090 Mexico.
Country
Mexico
Secondary sponsor category [1] 301868 0
None
Name [1] 301868 0
Address [1] 301868 0
Country [1] 301868 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 302739 0
Research Ethics Committee and Research Committee Ipharma S.A. of C.V.
Ethics committee address [1] 302739 0
Monterrey City:
Celaya 322,
Mitras Centro,
PC 64460 Monterrey, N.L.
Mexico
Ethics committee country [1] 302739 0
Mexico
Date submitted for ethics approval [1] 302739 0
30/07/2016
Approval date [1] 302739 0
30/08/2016
Ethics approval number [1] 302739 0
/A394-16

Summary
Brief summary
In the present study the bioequivalence of two different drugs, the same type of pharmaceutical form at the same dose, containing the same drug (amfepramone), 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 (ABC0-8); maximum plasma concentration (Cmax), have similarity to each other in 36 healthy male and females volunteers; and thus determine if they are bioequivalent.
Trial website
http://siipris03.cofepris.gob.mx/Resoluciones/Consultas/ConWebRegEnsayosClinicosDetalle.asp?idsolicitud=3330
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 91226 0
Dr Everardo Pineyro Garza
Address 91226 0
Ipharma S.A. de C.V.
Monterrey City:
Celaya 322,
Mitras Centro,
PC 64460 Monterrey, N.L.
Mexico
Country 91226 0
Mexico
Phone 91226 0
+528183487843
Fax 91226 0
+528183487843
Email 91226 0
epineyro@i-pharma.com.mx
Contact person for public queries
Name 91227 0
Dr Everardo Pineyro Garza
Address 91227 0
Ipharma S.A. de C.V.
Monterrey City:
Celaya 322,
Mitras Centro,
PC 64460 Monterrey, N.L.
Mexico
Country 91227 0
Mexico
Phone 91227 0
+528183487843
Fax 91227 0
+528183487843
Email 91227 0
epineyro@i-pharma.com.mx
Contact person for scientific queries
Name 91228 0
Dr Magdalena Gómez Silva
Address 91228 0
Ipharma S.A. de C.V.
Monterrey City:
Celaya 322,
Mitras Centro,
PC 64460 Monterrey, N.L.
Mexico
Country 91228 0
Mexico
Phone 91228 0
+528183487843
Fax 91228 0
+528183487843
Email 91228 0
magda.gomez@i-pharma.com.mx

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
Due to the Mexican federal law of protection of personal data in possession of individuals.

All data generated and analysed during this study are confidential, but if necessary some additional information are available from the principal investigator on reasonable request and as long as the anonymity of the study subjects is guaranteed.
What supporting documents are/will be available?
Other
'Other' documents specified
Document of the authorization and conclusion of the study by the Federal Commission for Protection Against Health Risks (COFEPRIS) in Mexico.
How or where can supporting documents be obtained?
Type [1] 1436 0
Other
Citation [1] 1436 0
Link [1] 1436 0
Email [1] 1436 0
Other [1] 1436 0
Document of the authorization of the study by the Federal Commission for Protection Against Health Risks (COFEPRIS) in Mexico.
Type [2] 1437 0
Other
Citation [2] 1437 0
Link [2] 1437 0
Email [2] 1437 0
Other [2] 1437 0
Document of the conclusion of the study by the Federal Commission for Protection Against Health Risks (COFEPRIS) in Mexico.
Summary results
Have study results been published in a peer-reviewed journal?
No
Other publications
Have study results been made publicly available in another format?
No
Results – plain English summary
The Amfepramone/A394-16 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 in the same substance amfepramone, are bioequivalent.