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

• Sponsor: Merck Healthcare KGaA, Darmstadt, Germany, an affiliate of Merck KGaA, Darmstadt, Germany (Industry)
• Overall Status: Completed
• CT.gov ID: NCT03979274
• Collaborator: (none)
• Enrollment: 44
• Location: 1
• Arms: 2
• Actual Duration (Months): 1.6
• Patients Per Site Per Month: 26.8

Study Details

Study Description

Brief Summary

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

Condition or Disease	Intervention/Treatment	Phase
Healthy	Drug: Reference Eutirox®; Drug: Test Eutirox®	Phase 1

Study Design

• Study Type: Interventional
• Actual Enrollment: 44 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: None (Open Label)
• Primary Purpose: Other
• Official Title: 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
• Actual Study Start Date: Dec 6, 2019
• Actual Primary Completion Date: Jan 13, 2020
• Actual Study Completion Date: Jan 25, 2020

Arms and Interventions

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.

Outcome Measures

Primary Outcome Measures

1. 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.

2. 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

1. 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.

2. 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.

3. 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).

4. 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.

5. 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.

6. 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.

7. 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.

8. 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.

9. 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 55 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Cecype, Fray Bernardino de Sahagún	Morelia - Michoacan		Mexico	58249

Sponsors and Collaborators

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

Investigators

• Study Director: Medical Responsible, Merck Healthcare KGaA, Darmstadt, Germany, an affiliate of Merck KGaA, Darmstadt, Germany

Study Documents (Full-Text)

• Study Protocol - Oct 18, 2018
• Statistical Analysis Plan - Mar 10, 2020

More Information

Additional Information:

• Trial Awareness and Transparency website

Publications

None provided.

• Responsible Party: Merck Healthcare KGaA, Darmstadt, Germany, an affiliate of Merck KGaA, Darmstadt, Germany
• ClinicalTrials.gov Identifier: NCT03979274
• Other Study ID Numbers: MS200125_0008
• First Posted: Jun 7, 2019
• Last Update Posted: Feb 5, 2021
• Last Verified: Nov 1, 2020

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Merck Healthcare KGaA, Darmstadt, Germany, an affiliate of Merck KGaA, Darmstadt, Germany: Eutirox; Levothyroxine

Study Results

Participant Flow

Arm/Group Title	Reference Eutirox®, Then Test Eutirox®	Test Eutirox®, Then Reference Eutirox®
Arm/Group Description	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.	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.
Period Title: Treatment Period 1
STARTED	22	22
COMPLETED	22	22
NOT COMPLETED	0	0
Period Title: Treatment Period 1
STARTED	22	22
COMPLETED	22	21
NOT COMPLETED	0	1

Baseline Characteristics

Arm/Group Title	All Participants
Arm/Group Description	All participants who received a single oral dose of Reference Eutirox® 600 mcg (200*3 mcg) or a single oral dose of test Eutirox® 600 mcg (200*3 mcg) in either Treatment Period 1 or 2.
Overall Participants	44
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	25.93 (5.93)
Sex: Female, Male (Count of Participants)
Female	8 18.2%
Male	36 81.8%
Race and Ethnicity Not Collected (Count of Participants)

Outcome Measures

1. Primary Outcome

Title	Maximum Serum Concentration in Pre Dose Corrected Data (Cmax[aj]) of Levothyroxine (T4)
Description	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.
Time Frame	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

Outcome Measure Data

Analysis Population Description

Pharmacokinetic (PK) analysis set included all randomized participants who received study medication in both treatment periods. Here, "Number of Participants Analyzed" signifies those participants who were evaluable for this outcome measure.

Arm/Group Title	Refernece Eutirox®	Test Eutirox®
Arm/Group Description	Participants received single oral dose of Reference Eutirox® 600 mcg (3 tablets of 200 mcg) in either Treatment Period 1 or 2 under fasting conditions.	Participants received single oral dose of Test Eutirox® 600 mcg (3 tablets of 200 mcg) in either Treatment Period 1 or 2 under fasting conditions.
Measure Participants	38	38
Mean (Standard Deviation) [nanogram per milliliter (ng/mL)]	67.24 (15.77)	66.44 (15.77)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Refernece Eutirox®, Test Eutirox®
	Comments
	Type of Statistical Test	Equivalence
	Comments	Bio-equivalence Analysis was performed with Equivalence Acceptance Range for 90% Confidence Interval (CI) as 80.00% - 125.00%.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Geometric mean ratio
	Estimated Value	98.53
	Confidence Interval	(2-Sided) 90%; 94.55 to 102.68
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Primary Outcome

Title	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)
Description	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.
Time Frame	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

Outcome Measure Data

Analysis Population Description

PK analysis set included all randomized participants who received study medication in both treatment periods. Here, "Number of Participants Analyzed" signifies those participants who were evaluable for this outcome measure.

Arm/Group Title	Refernece Eutirox®	Test Eutirox®
Arm/Group Description	Participants received single oral dose of Reference Eutirox® 600 mcg (3 tablets of 200 mcg) in either Treatment Period 1 or 2 under fasting conditions.	Participants received single oral dose of Test Eutirox® 600 mcg (3 tablets of 200 mcg) in either Treatment Period 1 or 2 under fasting conditions.
Measure Participants	38	38
Mean (Standard Deviation) [nanogram*hour per milliliter (ng*hr/mL)]	1738.65 (438.93)	1693.89 (389.50)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Refernece Eutirox®, Test Eutirox®
	Comments
	Type of Statistical Test	Equivalence
	Comments	Bio-equivalence Analysis was performed with Equivalence Acceptance Range for 90% Confidence Interval (CI) as 80.00% - 125.00%.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Geometric mean ratio
	Estimated Value	97.59
	Confidence Interval	(2-Sided) 90%; 91.34 to 104.26
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Time to Reach Maximum Serum Concentration (Tmax) of Levothyroxine (T4)
Description	Tmax was obtained directly from serum concentration-time curve.
Time Frame	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

Outcome Measure Data

Analysis Population Description

PK analysis set included all randomized participants who received study medication in both treatment periods.

Arm/Group Title	Refernece Eutirox®	Test Eutirox®
Arm/Group Description	Participants received single oral dose of Reference Eutirox® 600 mcg (3 tablets of 200 mcg) in either Treatment Period 1 or 2 under fasting conditions.	Participants received single oral dose of Test Eutirox® 600 mcg (3 tablets of 200 mcg) in either Treatment Period 1 or 2 under fasting conditions.
Measure Participants	43	43
Mean (Standard Deviation) [hour]	3.52 (1.19)	3.50 (1.14)

4. Secondary Outcome

Title	Elimination Half-Life (t1/2) of Levothyroxine (T4)
Description	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.
Time Frame	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

Outcome Measure Data

Analysis Population Description

PK analysis set included all randomized participants who received study medication in both treatment periods.

Arm/Group Title	Refernece Eutirox®	Test Eutirox®
Arm/Group Description	Participants received single oral dose of Reference Eutirox® 600 mcg (3 tablets of 200 mcg) in either Treatment Period 1 or 2 under fasting conditions.	Participants received single oral dose of Test Eutirox® 600 mcg (3 tablets of 200 mcg) in either Treatment Period 1 or 2 under fasting conditions.
Measure Participants	43	43
Mean (Standard Deviation) [hour]	186.40 (96.26)	189.10 (102.07)

5. Secondary Outcome

Title	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)
Description	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).
Time Frame	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

Outcome Measure Data

Analysis Population Description

PK analysis set included all randomized participants who received study medication in both treatment periods.

Arm/Group Title	Refernece Eutirox®	Test Eutirox®
Arm/Group Description	Participants received single oral dose of Reference Eutirox® 600 mcg (3 tablets of 200 mcg) in either Treatment Period 1 or 2 under fasting conditions.	Participants received single oral dose of Test Eutirox® 600 mcg (3 tablets of 200 mcg) in either Treatment Period 1 or 2 under fasting conditions.
Measure Participants	43	43
Mean (Standard Deviation) [ng*hour/mL]	5229.98 (562.73)	5218.87 (587.42)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Refernece Eutirox®, Test Eutirox®
	Comments
	Type of Statistical Test	Equivalence
	Comments	Bio-equivalence Analysis was performed with Equivalence Acceptance Range for 90% Confidence Interval (CI) as 80.00% - 125.00%.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Geometric mean ratio
	Estimated Value	99.73
	Confidence Interval	(2-Sided) 90%; 98.45 to 101.03
	Parameter Dispersion	Type: Value:
	Estimation Comments

6. Secondary Outcome

Title	Maximum Serum Concentration (Cmax) of Levothyroxine (T4)
Description	Cmax was obtained directly from the concentration versus time curve.
Time Frame	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

Outcome Measure Data

Analysis Population Description

PK analysis set included all randomized participants who received study medication in both treatment periods.

Arm/Group Title	Refernece Eutirox®	Test Eutirox®
Arm/Group Description	Participants received single oral dose of Reference Eutirox® 600 mcg (3 tablets of 200 mcg) in either Treatment Period 1 or 2 under fasting conditions.	Participants received single oral dose of Test Eutirox® 600 mcg (3 tablets of 200 mcg) in either Treatment Period 1 or 2 under fasting conditions.
Measure Participants	43	43
Mean (Standard Deviation) [ng/mL]	139.80 (16.16)	139.17 (19.24)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Refernece Eutirox®, Test Eutirox®
	Comments
	Type of Statistical Test	Equivalence
	Comments	Bio-equivalence Analysis was performed with Equivalence Acceptance Range for 90% Confidence Interval (CI) as 80.00% - 125.00%.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Geometric mean ratio
	Estimated Value	99.26
	Confidence Interval	(2-Sided) 90%; 97.70 to 100.85
	Parameter Dispersion	Type: Value:
	Estimation Comments

7. Secondary Outcome

Title	Number of Participants With Clinically Significant Abnormalities in Physical Examination
Description	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.
Time Frame	Baseline up to Day 37

Outcome Measure Data

Analysis Population Description

Safety analysis set included all randomized participants who received at least one dose of study medication.

Arm/Group Title	Refernece Eutirox®	Test Eutirox®
Arm/Group Description	Participants received single oral dose of Reference Eutirox® 600 mcg (3 tablets of 200 mcg) in either Treatment Period 1 or 2 under fasting conditions.	Participants received single oral dose of Test Eutirox® 600 mcg (3 tablets of 200 mcg) in either Treatment Period 1 or 2 under fasting conditions.
Measure Participants	44	44
Count of Participants [Participants]	0 0%	0 NaN

8. Secondary Outcome

Title	Number of Participants With Clinically Significant Abnormalities in Vital Signs
Description	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.
Time Frame	Baseline up to Day 37

Outcome Measure Data

Analysis Population Description

Safety analysis set included all randomized participants who received at least one dose of study medication.

Arm/Group Title	Refernece Eutirox®	Test Eutirox®
Arm/Group Description	Participants received single oral dose of Reference Eutirox® 600 mcg (3 tablets of 200 mcg) in either Treatment Period 1 or 2 under fasting conditions.	Participants received single oral dose of Test Eutirox® 600 mcg (3 tablets of 200 mcg) in either Treatment Period 1 or 2 under fasting conditions.
Measure Participants	44	44
Count of Participants [Participants]	0 0%	0 NaN

9. Secondary Outcome

Title	Number of Participants With Clinically Significant Abnormalities in Laboratory Parameters
Description	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.
Time Frame	Baseline up to Day 37

Outcome Measure Data

Analysis Population Description

Safety analysis set included all randomized participants who received at least one dose of study medication.

Arm/Group Title	Refernece Eutirox®	Test Eutirox®
Arm/Group Description	Participants received single oral dose of Reference Eutirox® 600 mcg (3 tablets of 200 mcg) in either Treatment Period 1 or 2 under fasting conditions.	Participants received single oral dose of Test Eutirox® 600 mcg (3 tablets of 200 mcg) in either Treatment Period 1 or 2 under fasting conditions.
Measure Participants	44	44
Count of Participants [Participants]	0 0%	2 NaN

10. Secondary Outcome

Title	Number of Participants With Clinically Significant Abnormalities in Electrocardiogram (ECG)
Description	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 Frame	Baseline up to Day 37

Outcome Measure Data

Analysis Population Description

Safety analysis set included all randomized participants who received at least one dose of study medication.

Arm/Group Title	Refernece Eutirox®	Test Eutirox®
Arm/Group Description	Participants received single oral dose of Reference Eutirox® 600 mcg (3 tablets of 200 mcg) in either Treatment Period 1 or 2 under fasting conditions.	Participants received single oral dose of Test Eutirox® 600 mcg (3 tablets of 200 mcg) in either Treatment Period 1 or 2 under fasting conditions.
Measure Participants	44	44
Count of Participants [Participants]	0 0%	0 NaN

11. Secondary Outcome

Title	Number of Participants With Adverse Events (AEs)
Description	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.
Time Frame	Baseline up to Day 51

Outcome Measure Data

Analysis Population Description

Safety analysis set included all randomized participants who received at least one dose of study medication.

Arm/Group Title	Refernece Eutirox®	Test Eutirox®
Arm/Group Description	Participants received single oral dose of Reference Eutirox® 600 mcg (3 tablets of 200 mcg) in either Treatment Period 1 or 2 under fasting conditions.	Participants received single oral dose of Test Eutirox® 600 mcg (3 tablets of 200 mcg) in either Treatment Period 1 or 2 under fasting conditions.
Measure Participants	44	44
Count of Participants [Participants]	0 0%	4 NaN

Adverse Events

Time Frame	Baseline up to Day 51
Arm/Group Title	Reference Eutirox®		Test Eutirox®
Arm/Group Description	Participants received single oral dose of Reference Eutirox® 600 mcg (3 tablets of 200 mcg) in either Treatment Period 1 or 2 under fasting conditions.		Participants received single oral dose of Test Eutirox® 600 mcg (3 tablets of 200 mcg) in either Treatment Period 1 or 2 under fasting conditions.
All Cause Mortality
	Reference Eutirox®		Test Eutirox®
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/44 (0%)		0/44 (0%)
Serious Adverse Events
	Reference Eutirox®		Test Eutirox®
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/44 (0%)		0/44 (0%)
Other (Not Including Serious) Adverse Events
	Reference Eutirox®		Test Eutirox®
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/44 (0%)		4/44 (9.1%)
Investigations
Elevated Alanine Aminotransferase	0/44 (0%)		2/44 (4.5%)
Elevated Aspartate Aminotransferase	0/44 (0%)		2/44 (4.5%)
Nervous system disorders
Dizziness	0/44 (0%)		1/44 (2.3%)
Respiratory, thoracic and mediastinal disorders
Nasal congestion	0/44 (0%)		1/44 (2.3%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.