Healthy
Conditions
Keywords
Eutirox®, Puran T4®, Levothyroxine
Brief summary
The study was to verify if the test formulation of Levothyroxine sodium presents an equivalent rate and extension of absorption to the comparator formulation when administered with the same dosage and under fasting conditions and after baseline correction concentrations.
Interventions
DRUGPuran T4®
Participants who received a single oral dose of Puran T4® 600 mcg tablets (3 tablets of 200 mcg Levothyroxine sodium) in either Treatment Period 1 or 2 under fasting conditions.
DRUGEutirox®
Participants who received a single oral dose of Eutirox® 600 mcg tablets (3 tablets of 200 mcg Levothyroxine sodium) in either Treatment Period 1 or 2 under fasting conditions.
Sponsors
Merck Healthcare KGaA, Darmstadt, Germany, an affiliate of Merck KGaA, Darmstadt, Germany
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
OTHER
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 50 Years
Healthy volunteers
Yes
Inclusion criteria
* To have freely agreed and signed the consent form, after all essential elements of the protocol have been clarified, before any procedure * Body Mass Index (BMI) of the research participants must be comprised within the range of 18.50 to 27.00 * No abnormal findings on medical history that, in the opinion of the investigator, constitutes a risk or a contraindication for the participation of the participant in the study or that could interfere with the study objectives, conduct or evaluation * Normal vital signs: heart rate between 50 and 100 beats per minute; Systolic pressure between 80 and 129 millimeters of mercury (mmHg); diastolic pressure between 50 and 89 mmHg; temperature between 36.0 and 37.0 degrees Celsius * Electrocardiogram (ECG) normal (abnormalities, even if clinically not relevant, are not permitted \[example {e.g.}: PR, QRS, QT, QTcF\] should be within normal range, no conduction abnormalities etcetera \[etc.\]) * All values for biochemistry and hematology tests of blood and urine within the normal range or showing no clinically relevant deviation as judged by the Investigator * Other protocol defined inclusion criteria could apply
Exclusion criteria
* Supplementary tests results out of the values considered as normal, unless considered clinically irrelevant * Research participants who are submitted to surgery before the beginning of the study will be carefully evaluated by the doctor regarding the enrollment in the study complying to an exclusion period ranging from 4 to 8 weeks * Positive test for hepatitis B, hepatitis C, or human immunodeficiency virus (HIV) in pre-study tests * Participants with a history of hypersensitivity/allergy to study drug or excipients, history or presence of asthma or any serious allergy (requiring hospitalization or prolonged systemic treatment), any food allergy or intolerance which in the opinion of the Investigator represents a safety risk (e.g., iodine allergy, etc.) * Has participated in any experimental trial or has taken any experimental drug within 6 months previous to this study (RDC \[resolution of the collegiate board\] Resolution 34, dated June 3, 2008) * Participants that prior to the dosing takes any other medication and had not passed at least seven half-lives of elimination of the drug, in this case, be considered by the Principal Investigator the non-inclusion of the participant in the study. Participants taking medications known to affect thyroid hormone metabolism, e.g., oral contraceptives, hormonal implants, parenteral hormones, anabolic steroids, androgens, etc., or the bioavailability of levothyroxine like proton pump Inhibitors * Has a history of alcohol abuse or has ingested alcohol 24 hours previous to the hospitalization period * Other protocol defined
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Baseline Corrected Maximum Observed Plasma Concentration (Cmax[Adj]) of Levothyroxine Sodium | Pre-dose, 24, 36, 48 and 72 hours post-dose | Cmax was obtained from plasma concentration time curve. Maximum plasmatic concentration observed adjusted by basal level correction was reported. |
| Baseline Corrected Area Under The Plasma Concentration-time Curve From Time Zero to 72 Hours (AUC0-72 [Adj]) of Levothyroxine Sodium | Pre-dose, 24, 36, 48 and 72 hours post-dose | The AUC 0-72 was defined as the area under the plasma concentration versus time curve from time zero (pre-dose) to 72 hours post-dose. Area under the plasma curve from time 0 hours to time 72 hours adjusted by basal levels correction was reported. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to Reach Maximum Plasma Concentration (Tmax) of Levothyroxine Sodium | Pre-dose, 24, 36, 48 and 72 hours post-dose | Tmax was obtained from plasma concentration time curve. |
| Area Under the Plasma Concentration-time Curve From Time Zero to 72 Hours (AUC 0-72) of Levothyroxine Sodium | Pre-dose, 24, 36, 48 and 72 hours post-dose | The AUC 0-72 was defined as the area under the plasma concentration versus time curve from time zero (pre-dose) to 72 hours post-dose. |
| Maximum Observed Plasma Concentration (Cmax) of Levothyroxine Sodium | Pre-dose, 24, 36, 48 and 72 hours post-dose | Cmax was obtained from plasma concentration time curve. |
Countries
Brazil
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| First Puran T4®, Then Eutirox® Participants received single oral dose of Puran T4® 600 micrograms (mcg) (3 tablets of 200 mcg Levothyroxine sodium) in Treatment Period 1 followed by single oral dose of Eutirox® 600 mcg (3 tablets of 200 mcg Levothyroxine sodium) in Treatment Period 2 under fasting conditions. A wash-out period of 70 days was maintained between the Treatment Periods 1 and 2. | 36 |
| First Eutirox®, Then Puran T4® Participants received single oral dose of Eutirox® 600 mcg (3 tablets of 200 mcg Levothyroxine sodium) in Treatment Period 1 followed by single oral dose of Puran T4® 600 mcg (3 tablets of 200 mcg Levothyroxine sodium) in Treatment Period 2 under fasting conditions. A wash-out period of 70 days was maintained between the Treatment Periods 1 and 2. | 36 |
| Total | 72 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Treatment Period 1 | Adverse Event | 1 | 1 |
| Treatment Period 1 | Protocol Violation | 4 | 5 |
| Treatment Period 1 | Withdrawal by Subject | 3 | 0 |
| Treatment Period 2 | Adverse Event | 0 | 1 |
| Treatment Period 2 | Protocol Violation | 2 | 0 |
Baseline characteristics
| Characteristic | First Puran T4®, Then Eutirox® | First Eutirox®, Then Puran T4® | Total |
|---|---|---|---|
| Age, Continuous | 35.0 Years STANDARD_DEVIATION 8.7 | 35.9 Years STANDARD_DEVIATION 9.3 | 35.5 Years STANDARD_DEVIATION 8.9 |
| Race and Ethnicity Not Collected | — | — | 0 Participants |
| Sex: Female, Male Female | 18 Participants | 18 Participants | 36 Participants |
| Sex: Female, Male Male | 18 Participants | 18 Participants | 36 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 72 | 0 / 72 |
| other Total, other adverse events | 2 / 72 | 5 / 72 |
| serious Total, serious adverse events | 0 / 72 | 0 / 72 |
Outcome results
Primary
Baseline Corrected Area Under The Plasma Concentration-time Curve From Time Zero to 72 Hours (AUC0-72 [Adj]) of Levothyroxine Sodium
The AUC 0-72 was defined as the area under the plasma concentration versus time curve from time zero (pre-dose) to 72 hours post-dose. Area under the plasma curve from time 0 hours to time 72 hours adjusted by basal levels correction was reported.
Time frame: Pre-dose, 24, 36, 48 and 72 hours post-dose
Population: PK analysis set included all participants who completed both periods and had valid PK parameters in both.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Puran T4® | Baseline Corrected Area Under The Plasma Concentration-time Curve From Time Zero to 72 Hours (AUC0-72 [Adj]) of Levothyroxine Sodium | 2682.371 Hour* ng/mL | Standard Deviation 795.263 |
| Eutirox® | Baseline Corrected Area Under The Plasma Concentration-time Curve From Time Zero to 72 Hours (AUC0-72 [Adj]) of Levothyroxine Sodium | 2516.055 Hour* ng/mL | Standard Deviation 716.575 |
90% CI: [88.2, 99.5]
Primary
Baseline Corrected Maximum Observed Plasma Concentration (Cmax[Adj]) of Levothyroxine Sodium
Cmax was obtained from plasma concentration time curve. Maximum plasmatic concentration observed adjusted by basal level correction was reported.
Time frame: Pre-dose, 24, 36, 48 and 72 hours post-dose
Population: Pharmacokinetic (PK) analysis set included all participants who completed both periods and had valid PK parameters in both.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Puran T4® | Baseline Corrected Maximum Observed Plasma Concentration (Cmax[Adj]) of Levothyroxine Sodium | 67.258 Nanogram per milliliter (ng/mL) | Standard Deviation 19.654 |
| Eutirox® | Baseline Corrected Maximum Observed Plasma Concentration (Cmax[Adj]) of Levothyroxine Sodium | 60.552 Nanogram per milliliter (ng/mL) | Standard Deviation 13.61 |
90% CI: [86.3, 95.6]
Secondary
Area Under the Plasma Concentration-time Curve From Time Zero to 72 Hours (AUC 0-72) of Levothyroxine Sodium
The AUC 0-72 was defined as the area under the plasma concentration versus time curve from time zero (pre-dose) to 72 hours post-dose.
Time frame: Pre-dose, 24, 36, 48 and 72 hours post-dose
Population: PK analysis set included all participants who completed both periods and had valid PK parameters in both.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Puran T4® | Area Under the Plasma Concentration-time Curve From Time Zero to 72 Hours (AUC 0-72) of Levothyroxine Sodium | 7204.615 Hour* ng/mL | Standard Deviation 1337.674 |
| Eutirox® | Area Under the Plasma Concentration-time Curve From Time Zero to 72 Hours (AUC 0-72) of Levothyroxine Sodium | 7004.507 Hour* ng/mL | Standard Deviation 1154.596 |
90% CI: [94.7, 100]
Secondary
Maximum Observed Plasma Concentration (Cmax) of Levothyroxine Sodium
Cmax was obtained from plasma concentration time curve.
Time frame: Pre-dose, 24, 36, 48 and 72 hours post-dose
Population: PK analysis set included all participants who completed both periods and had valid PK parameters in both.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Puran T4® | Maximum Observed Plasma Concentration (Cmax) of Levothyroxine Sodium | 130.069 ng/mL | Standard Deviation 25.464 |
| Eutirox® | Maximum Observed Plasma Concentration (Cmax) of Levothyroxine Sodium | 122.895 ng/mL | Standard Deviation 18.957 |
90% CI: [92, 97.8]
Secondary
Time to Reach Maximum Plasma Concentration (Tmax) of Levothyroxine Sodium
Tmax was obtained from plasma concentration time curve.
Time frame: Pre-dose, 24, 36, 48 and 72 hours post-dose
Population: PK analysis set included all participants who completed both periods and had valid PK parameters in both.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Puran T4® | Time to Reach Maximum Plasma Concentration (Tmax) of Levothyroxine Sodium | 3.50 Hours |
| Eutirox® | Time to Reach Maximum Plasma Concentration (Tmax) of Levothyroxine Sodium | 4.00 Hours |