A Comparative Study of New Formulation and Approved Formulation for Levothyroxine in Healthy Volunteers

Prospective, Single Dose, Randomized, Open Label, Comparative, Cross-study to Establish Bioequivalence Between the New Formulation and the Approved Formulation for Levothyroxine (Eutirox® From Merck, S. A. de C. V.) Given as 3 Tablets of 200 μg p.o. in Healthy Volunteers

The study investigated the bioequivalence between the new and the approved formulation for levothyroxine.

Study Overview

• Status: Completed
• Conditions: Healthy
• Intervention / Treatment: Drug: Reference Eutirox®; Drug: Test Eutirox®

• Study Type: Interventional
• Enrollment (Actual): 44
• Phase: Phase 1

Contacts and Locations

Study Locations

• Mexico
  • Morelia - Michoacan, Mexico, 58249
    • Cecype, Fray Bernardino de Sahagún

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 55 years (ADULT)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Participants who have provided their written consent prior to any study-related activity
• Ethnic origin: Mexicans
• Body mass index from 18 to 27 kilogram per meter square (kg/m^2)
• Normal vital signs (includes heart rate between 50 and 100 beats per minute, respiratory rate between 12 and 20 per minute, systolic blood pressure between 80 and 129 milimeter of mercury (mmHg) , diastolic blood pressure between 50 and 80 mmHg and temperature between 36.0 degree celsius and 37.0 degree celsius. The measurement will be made according to the instructive BE-IT-005 Medición de signos vitales)
• Normal electrocardiogram [ECG]. No abnormalities are allowed, even though they are not relevant (PR, QRS, QT, QTcF should be within normal range; no conduction abnormalities are allowed, etcetera (etc)
• All values in blood and urine tests should be within the normal range or showing no clinically relevant deviation as judged by the Investigator
• Participants with thyroid panel results within normal range (T3 and T4 total and free, as well as thyroid-stimulating hormone (TSH) should be within the normal range)
• Non-smoker at least in the last 3 months
• Other protocol defined inclusion criteria could apply

Exclusion Criteria:

• Participation in the clinical study within 90 days prior to the first dose of the study drug
• History of hypersensitivity to the study drug or its excipients
• History or current asthma or any severe allergy (which requires hospitalization or prolonged therapy), allergy or intolerance to any food that, in the opinion of the investigator, poses a safety risk (allergy to iodine)
• History of cardiovascular, renal, liver, metabolic, gastrointestinal, neurological, endocrine, hematopoietic (any type of anemia) conditions, mental disorder or organic abnormalities that may affect the pharmacokinetic study of the study drug
• Any medical or surgical condition, including findings in the medical history or clinical assessment prior to the study, that in the opinion of the investigator poses a risk or contraindication for the participants participation in the study and may affect the study objectives, conduct or analysis
• History or presence of alcohol abuse (average daily intake not higher than 3 units or weekly intake not higher than 21 units; 1 unit is equivalent to 340 mililiter (mL) of beer, 115 mL of wine or 43 mL of prepared drinks), psychoactive substances or chronic use of drugs
• Participants who have been exposed to agents knows by inducing or inhibiting the liver enzymatic systems or who have taken potentially toxic drugs within the last 30 days to the study start-up
• Participants who take drugs affecting the metabolism of the thyroid hormone, such as: oral contraceptives, hormonal implants, parenteral hormones, steroids, anabolic drugs, androgens, etc., or any drug affecting the levothyroxine's bioavailability such as the proton pump inhibitors or multivitamins, nutritional supplements or herbal products that may affect the study, except for the occasional use of paracetamol
• Participants who have been hospitalized for any reason within the 60 days prior to the study start-up or who have been severely ill within the last 30 days prior to the study start-up
• Participants who have donated or lost 450 mL of blood within the last 60 days prior to the study start-up
• Participants non- smokers, who have smoked tobacco, cigarettes or consumed coffee, snuff or drinks containing xanthines such as caffeine, (tea, cocoa, chocolate, matte, cola, etc.) theobromine, theophylline, among others, affecting the pharmacokinetics of the drug in assessment, drinking alcohol, or charcoal-grilled foods consumed within twenty-four hours prior to administration the dose of medication
• Screening biosafety positive tests for the human immunodeficiency virus (HIV), hepatitis B virus (HBV), hepatitis C virus (HCV) and syphilis Venereal Disease Research Laboratory (VDRL)
• Positive result in the abuse drugs screening tests, such as: amphetamines, benzodiazepines, cocaine, methamphetamines, morphine and tetrahydrocannabinoids
• Presence of alcohol in breath test
• Women pregnancy positive tests (qualitative and quantitative) at the screening and inclusion in each period
• Other protocol defined exclusion criteria could apply

Study Plan

How is the study designed?

Design Details

• Primary Purpose: OTHER
• Allocation: RANDOMIZED
• Interventional Model: CROSSOVER
• Masking: NONE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Reference Eutirox®, then Test Eutirox®; Participants received single oral dose of Reference Eutirox® 600 microgram (mcg) (3 tablets of 200 mcg) in Treatment Period 1 followed by single oral dosing of Test Eutirox® 600 mcg (3 tablets of 200 mcg) in Treatment Period 2. A wash-out period of 35 days was maintained between the Treatment Periods 1 and 2.	Drug: Reference Eutirox®; Participants received single oral dose of Reference Eutirox® 600 microgram (3 tablets of 200 microgram) either in treatment period 1 or 2.; Drug: Test Eutirox®; Participants received single oral dose of Test Eutirox® 600 microgram (3 tablets of 200 microgram) either in treatment 1 or 2.
EXPERIMENTAL: Test Eutirox®, then Reference Eutirox®; Participants received single oral dose of Test Eutirox® 600 mcg (3 tablets of 200 mcg) in Treatment Period 1 followed by single oral dosing of Reference Eutirox® 600 mcg (3 tablets of 200 mcg) in Treatment Period 2. A wash-out period of 35 days was maintained between the Treatment Periods 1 and 2.	Drug: Reference Eutirox®; Participants received single oral dose of Reference Eutirox® 600 microgram (3 tablets of 200 microgram) either in treatment period 1 or 2.; Drug: Test Eutirox®; Participants received single oral dose of Test Eutirox® 600 microgram (3 tablets of 200 microgram) either in treatment 1 or 2.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Maximum Serum Concentration in Pre Dose Corrected Data (Cmax[aj]) of Levothyroxine (T4)	Cmax was obtained from the concentration time curve. Cmax[aj] was the maximum serum concentration in pre dose corrected data where pre dose corrected data was obtained by subtracting pre dose level of Levothyroxine (T4) from level of Levothyroxine (T4) after administration.	Pre-dose, 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 3.25, 3.5, 3.75, 4.0, 4.25, 4.5, 4.75, 5.0, 5.5, 6.0, 6.5, 8.0, 10.0, 12.0, 24.0, 36.0 and 48.0 hours post-dose
Area Under Serum Concentration-Time Curve From Time Zero to The Last Sampling Time in Pre Dose Corrected Data (AUC0-t [aj]) of Levothyroxine (T4)	AUC0-t was defined as area under the curve of the serum concentration as a function of time, from time 0 until the last sampling time by means of the trapezoidal rule. AUC0-t [aj] was the area under the serum concentration-time curve from time zero to the last sampling time in pre dose corrected data where pre dose corrected data was obtained by subtracting pre dose level of Levothyroxine (T4) from level of Levothyroxine (T4) after administration.	Pre-dose, 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 3.25, 3.5, 3.75, 4.0, 4.25, 4.5, 4.75, 5.0, 5.5, 6.0, 6.5, 8.0, 10.0, 12.0, 24.0, 36.0 and 48.0 hours post-dose

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time to Reach Maximum Serum Concentration (Tmax) of Levothyroxine (T4)	Tmax was obtained directly from serum concentration-time curve.	Pre-dose, 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 3.25, 3.5, 3.75, 4.0, 4.25, 4.5, 4.75, 5.0, 5.5, 6.0, 6.5, 8.0, 10.0, 12.0, 24.0, 36.0 and 48.0 hours post-dose
Elimination Half-Life (t1/2) of Levothyroxine (T4)	t1/2 was the time measured for the concentration to decrease by one half. Terminal half-life calculated by natural log 2 divided by elimination constant.	Pre-dose, 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 3.25, 3.5, 3.75, 4.0, 4.25, 4.5, 4.75, 5.0, 5.5, 6.0, 6.5, 8.0, 10.0, 12.0, 24.0, 36.0 and 48.0 hours post-dose
Area Under The Curve of the Serum Concentration as a Function of Time, From Time Zero to The Last Sampling Time (AUC0-t) of Levothyroxine (T4)	Area under the serum concentration versus time curve from time zero to the last sampling time t at which the concentration was at or above the lower limit of quantification (LLOQ).	Pre-dose, 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 3.25, 3.5, 3.75, 4.0, 4.25, 4.5, 4.75, 5.0, 5.5, 6.0, 6.5, 8.0, 10.0, 12.0, 24.0, 36.0 and 48.0 hours post-dose
Maximum Serum Concentration (Cmax) of Levothyroxine (T4)	Cmax was obtained directly from the concentration versus time curve.	Pre-dose, 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 3.25, 3.5, 3.75, 4.0, 4.25, 4.5, 4.75, 5.0, 5.5, 6.0, 6.5, 8.0, 10.0, 12.0, 24.0, 36.0 and 48.0 hours post-dose
Number of Participants With Clinically Significant Abnormalities in Physical Examination	Physical examination included assessments of the general appearance, skin and mucosa, superficial lymph nodes, head and neck, chest, abdomen, musculoskeletal, and neurological systems. Number of participants with clinically significant abnormalities in physical examination findings were reported. Investigator decided clinical significance.	Baseline up to Day 37
Number of Participants With Clinically Significant Abnormalities in Vital Signs	Vital sign assessment included blood pressure, pulse rate, body temperature and respiration. Number of participants with clinically significant abnormalities in vital signs were reported. Investigator decided clinical significance.	Baseline up to Day 37
Number of Participants With Clinically Significant Abnormalities in Laboratory Parameters	The laboratory measurements included hematology, blood chemistry and urinalysis. Number of participants with clinically significant abnormalities in laboratory parameters were reported. Investigator decided clinical significance.	Baseline up to Day 37
Number of Participants With Clinically Significant Abnormalities in Electrocardiogram (ECG)	The ECG recordings were obtained after 5 minutes of rest in a semi-supine position. ECG recordings included rhythm, ventricular rate, PR interval, QRS duration, QT and QTc intervals. Number of participants with clinically significant abnormalities in ECG were reported. Investigator decided clinical significance.	Baseline up to Day 37
Number of Participants With Adverse Events (AEs)	An Adverse event (AE) was defined as any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease associated with the use of study drug, whether or not considered related to the study drug or worsening of pre-existing medical condition, whether or not related to study drug. Number of participants with adverse events were reported.	Baseline up to Day 51

Collaborators and Investigators

• Sponsor: Merck Healthcare KGaA, Darmstadt, Germany, an affiliate of Merck KGaA, Darmstadt, Germany

Publications and helpful links

Helpful Links

• Trial Awareness and Transparency website

Study record dates

Study Major Dates

• Study Start (ACTUAL): December 6, 2019
• Primary Completion (ACTUAL): January 13, 2020
• Study Completion (ACTUAL): January 25, 2020

Study Registration Dates

• First Submitted: June 6, 2019
• First Submitted That Met QC Criteria: June 6, 2019
• First Posted (ACTUAL): June 7, 2019

Study Record Updates

• Last Update Posted (ACTUAL): February 5, 2021
• Last Update Submitted That Met QC Criteria: January 11, 2021
• Last Verified: November 1, 2020

More Information

Terms related to this study

• Keywords: Levothyroxine; Eutirox
• Other Study ID Numbers: MS200125_0008

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: Per company policy, following approval of a new product or a new indication for an approved product in both the EU and the US, Merck Healthcare KGaA, Darmstadt, Germany, an affiliate of Merck KGaA, Darmstadt, Germany, will share study protocols, anonymized patient level and study level data and redacted clinical study reports from clinical trials in patients with qualified scientific and medical researchers, upon request, as necessary for conducting legitimate research. Further information on how to request data can be found on our website https://www.merckgroup.com/en/research/our-approach-to-research-and development/healthcare/clinical-trials/commitment-responsible-data-sharing.html

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No