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

Phase 1

Completed

Conditions: Healthy

Interventions: Drug: Reference Eutirox®
Drug: Test Eutirox®

Registration Number: NCT03979274

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

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

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 44

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 & Design

Study Type: INTERVENTIONAL

Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
Reference Eutirox®, then Test Eutirox®	Reference 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.
Reference Eutirox®, then Test Eutirox®	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.
Test Eutirox®, then Reference Eutirox®	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.
Test Eutirox®, then Reference Eutirox®	Test 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.

Primary Outcome Measures

Name	Time	Method
Maximum Serum Concentration in Pre Dose Corrected Data (Cmax[aj]) of Levothyroxine (T4)	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	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.
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)	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	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.

Secondary Outcome Measures

Name	Time	Method
Elimination Half-Life (t1/2) of Levothyroxine (T4)	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	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.
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)	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 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).
Number of Participants With Clinically Significant Abnormalities in Physical Examination	Baseline up to Day 37	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.
Number of Participants With Clinically Significant Abnormalities in Laboratory Parameters	Baseline up to Day 37	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.
Maximum Serum Concentration (Cmax) of Levothyroxine (T4)	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	Cmax was obtained directly from the concentration versus time curve.
Number of Participants With Clinically Significant Abnormalities in Vital Signs	Baseline up to Day 37	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.
Number of Participants With Clinically Significant Abnormalities in Electrocardiogram (ECG)	Baseline up to Day 37	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.
Time to Reach Maximum Serum Concentration (Tmax) of Levothyroxine (T4)	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	Tmax was obtained directly from serum concentration-time curve.
Number of Participants With Adverse Events (AEs)	Baseline up to Day 51	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.