Euthyroid, Hypothyroidism, Thyroid Disease, Thyroid Gland, Thyroid Hormones
Conditions
Brief summary
This study will evaluate the safe and effective dose conversion from levothyroxine (synthetic T4) therapy to Armour Thyroid therapy in participants who are on a stable dose of levothyroxine and have thyroid stimulating hormone (TSH) levels within the normal reference range.
Detailed description
This study will include will include a Screening Period, double-blinded Titration Period (at least 18 weeks, up to 36 weeks), and a double-blinded Stabilization Period (12 weeks). Participants will be randomized to receive either their same dose of levothyroxine or an approximately, matching dose of Armour Thyroid, using a dose-conversion chart based on the United States Pharmacopeia (USP) Drug Information 2000, which states that 1 grain of Armour Thyroid is equivalent to 100 mcg of levothyroxine. During the Titration Period, Investigators will have the option to up-or down-titrate a participant's dose as needed based on the participant's TSH level (normal reference range 0.45 - 4.12 mIU/L, inclusive). At Week 18, if a participant's TSH levels are not within the normal reference range, the Investigator may up-or down-titrate the dose by continuing the Titration Period beyond Week 18 for up to a maximum of 3 additional titrations at 6-week intervals. Participants whose TSH levels have not normalized after the maximum 3 additional titrations will not enter the Stabilization Period. At the end of the Titration Period, participants with TSH levels within normal reference range may enter the Stabilization Period. Depending on whether a participant requires additional dose titration after the Week 18 visit, the Stabilization Period may end at Week 30, 36, 42, or 48.
Interventions
DRUGArmour® Thyroid
Administered orally once a day. the daily dose could range from 1/4 - 2 grains.
DRUGLevothyroxine
Administered orally once a day; the daily dose could range from 25- 200 µg.
Sponsors
Allergan
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
* Participants who have a diagnosis of primary hypothyroidism made ≥ 12 months before study entry (Visit 1). * Be on continuous thyroid replacement therapy with synthetic T4 for primary hypothyroidism for at least 12 months immediately prior to the Screening Visit (Visit 1). * Be on a stable Food and Drug Administration (FDA)-approved daily dose of synthetic T4 for a minimum of 3 months prior to the Screening Visit (Visit 1). Must enter the study on the same stable dose. * Have euthyroid status indicated by at least 1 documented TSH value within normal reference range (0.45 - 4.12 mIU/L, inclusive) at a minimum of 6 weeks and maximum of 12 months prior to the Screening Visit (Visit 1). Also have a confirmed TSH value within the normal reference range drawn at the Screening Visit (Visit 1). * Male and female participants willing to minimize the risk of inducing pregnancy for the duration of the clinical study and follow-up period (35 days after last dose of study intervention).
Exclusion criteria
* Any clinical condition or previous surgery that might affect the absorption, distribution, biotransformation, or excretion of Armour Thyroid or synthetic T4. * History of alcohol or other substance abuse within the previous 5 years. * Known or suspected allergy or intolerance to any ingredients of Armour Thyroid, including its excipients, levothyroxine (T4), other thyroid replacement medications, or pork products. * Have received active treatment with an investigational drug within 30 days or 5 half lives, whichever is longer, of Screening Visit (Visit 1). * Current enrollment in an investigational drug or device study or participation in such a study within 60 days of entry into this study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With a Sustained TSH Response | End of the titration period (Week 18, 24, 30, or 36) and end of the stabilization period (Week 30, 36, 42, or 48, depending on the length of the titration period). | Sustained TSH response is defined as TSH values that are within the normal reference range of 0.45 to 4.12 mIU/L, inclusive, at both the end of Titration Period and the end of the Stabilization Period. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With a Titration TSH Response | End of the titration period (Week 18, 24, 30, or 36) | Titration TSH Response is defined as having a TSH value within the normal reference range of 0.45 to 4.12 mIU/L, inclusive, at the end of the Titration Period. |
Countries
United States
Participant flow
Recruitment details
This study enrolled adults with a diagnosis of primary hypothyroidism who were taking a stable daily dose of synthetic T4 hormone (levothyroxine). Participants were enrolled at 27 sites in the United States.
Pre-assignment details
Eligible participants were randomized equally to receive either their same dose of levothyroxine or a matching dose of Armour Thyroid at Baseline. The randomization was stratified by age (\< 65 years, ≥ 65 years).
Participants by arm
| Arm | Count |
|---|---|
| Armour® Thyroid Participants were randomized to receive Armour Thyroid at a dose corresponding to their pre-randomized dose of synthetic T4. During the first 18 to 36 weeks (titration period) the dose of Armour Thyroid could be titrated based on levels of TSH, in order to achieve TSH levels within the normal reference range (0.45 - 4.12 mIU/L, inclusive). Once TSH levels were within the normal reference range, participants continued to receive a stable dose of Armour Thyroid for an additional 12 weeks (stabilization period). | 141 |
| Levothyroxine Participants were randomized to receive levothyroxine at their pre-randomized dose. During the first 18 to 36 weeks (titration period) the dose of levothyroxine could be titrated based on levels of TSH in order to achieve TSH levels within the normal reference range (0.45-4.12 mIU/L, inclusive). Once TSH levels were within the normal reference range, participants continued to receive a stable dose of levothyroxine for an additional 12 weeks (stabilization period). | 143 |
| Total | 284 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Stabilization Period | Adverse Event | 4 | 2 |
| Stabilization Period | Lack of Efficacy | 4 | 2 |
| Stabilization Period | Lost to Follow-up | 0 | 1 |
| Stabilization Period | Other | 2 | 2 |
| Stabilization Period | Protocol Deviation | 0 | 2 |
| Stabilization Period | Withdrawal by Subject | 1 | 1 |
| Titration Period | Adverse Event | 9 | 5 |
| Titration Period | Death | 1 | 1 |
| Titration Period | Lack of Efficacy | 2 | 0 |
| Titration Period | Lost to Follow-up | 0 | 1 |
| Titration Period | Non-compliance with Study Drug | 2 | 0 |
| Titration Period | Other | 4 | 9 |
| Titration Period | Physician Decision | 2 | 0 |
| Titration Period | Withdrawal by Subject | 6 | 3 |
Baseline characteristics
| Characteristic | Armour® Thyroid | Levothyroxine | Total |
|---|---|---|---|
| Age, Continuous | 54.0 years STANDARD_DEVIATION 12.94 | 53.4 years STANDARD_DEVIATION 13.97 | 53.7 years STANDARD_DEVIATION 13.45 |
| Age, Customized < 65 years | 108 Participants | 109 Participants | 217 Participants |
| Age, Customized >= 65 years | 33 Participants | 34 Participants | 67 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 17 Participants | 21 Participants | 38 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 124 Participants | 122 Participants | 246 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) Asian | 2 Participants | 5 Participants | 7 Participants |
| Race (NIH/OMB) Black or African American | 14 Participants | 10 Participants | 24 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 2 Participants | 2 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 124 Participants | 124 Participants | 248 Participants |
| Sex: Female, Male Female | 122 Participants | 112 Participants | 234 Participants |
| Sex: Female, Male Male | 19 Participants | 31 Participants | 50 Participants |
| Thyroid Stimulating Hormone (TSH) Level | 1.81 mIU/L STANDARD_DEVIATION 1.175 | 2.08 mIU/L STANDARD_DEVIATION 1.507 | 1.95 mIU/L STANDARD_DEVIATION 1.357 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 1 / 141 | 1 / 143 |
| other Total, other adverse events | 15 / 141 | 9 / 143 |
| serious Total, serious adverse events | 4 / 141 | 7 / 143 |
Outcome results
Primary
Percentage of Participants With a Sustained TSH Response
Sustained TSH response is defined as TSH values that are within the normal reference range of 0.45 to 4.12 mIU/L, inclusive, at both the end of Titration Period and the end of the Stabilization Period.
Time frame: End of the titration period (Week 18, 24, 30, or 36) and end of the stabilization period (Week 30, 36, 42, or 48, depending on the length of the titration period).
Population: All randomized participants who took at least 1 dose of study intervention (intent-to-treat population). The non-responder imputation incorporating multiple imputation to handle missing data due to coronavirus disease 2019 (COVID-19) (NRI-C) was performed for participants who had missing TSH values either at the end of the Titration Period or at the end of the Stabilization Period.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Armour® Thyroid | Percentage of Participants With a Sustained TSH Response | 60.76 percentage of participants |
| Levothyroxine | Percentage of Participants With a Sustained TSH Response | 75.92 percentage of participants |
Comparison: The null hypothesis was that Armour Thyroid would be inferior to levothyroxine for the primary efficacy endpoint, sustained TSH response. The non-inferiority hypothesis test was performed at a 1-sided 2.5% level of significance (equivalent to a two-sided 5% level of significance).95% CI: [-26.1, -4.23]
Secondary
Percentage of Participants With a Titration TSH Response
Titration TSH Response is defined as having a TSH value within the normal reference range of 0.45 to 4.12 mIU/L, inclusive, at the end of the Titration Period.
Time frame: End of the titration period (Week 18, 24, 30, or 36)
Population: All randomized participants who took at least 1 dose of study intervention (intent-to-treat population). The non-responder imputation incorporating multiple imputation to handle missing data due to COVID-19 (NRI-C) was performed for participants who had missing TSH values at the end of Titration Period.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Armour® Thyroid | Percentage of Participants With a Titration TSH Response | 80.62 percentage of participants |
| Levothyroxine | Percentage of Participants With a Titration TSH Response | 91.13 percentage of participants |
Comparison: The null hypothesis was that Armour Thyroid would be inferior to levothyroxine for titration TSH response. The non-inferiority hypothesis test was performed at a 1-sided 2.5% level of significance.95% CI: [-18.65, -2.38]