Levothyroxine Sodium in Thyroidectomized Patients Taking Proton Pump Inhibitors

• Sponsor: IBSA Institut Biochimique SA (Industry)
• Overall Status: Completed
• CT.gov ID: NCT03094416
• Collaborator: (none)
• Enrollment: 66
• Locations: 9
• Arm: 1
• Actual Duration (Months): 22.5
• Patients Per Site: 7.3
• Patients Per Site Per Month: 0.3

Study Details

Study Description

Brief Summary

This is an open-label therapeutic efficacy study of Tirosint (levothyroxine sodium) capsules in thyroidectomized patients taking proton pump inhibitors and levothyroxine, evaluating changes in serum levels of Thyroid Stimulating Hormone (TSH) upon switch to Tirosint with respect to baseline.

Condition or Disease	Intervention/Treatment	Phase
Hypothyroidism;Postablative	Drug: levothyroxine sodium capsule; Drug: Proton pump inhibitor (PPI); Drug: Levothyroxine Sodium (LT4) Tablets	Phase 4

Study Design

• Study Type: Interventional
• Actual Enrollment: 66 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: An Open-label Therapeutic Efficacy Study of Tirosint (Levothyroxine Sodium) Capsules in Thyroidectomized Patients Taking Proton Pump Inhibitors
• Actual Study Start Date: Jul 30, 2018
• Actual Primary Completion Date: Jun 15, 2020
• Actual Study Completion Date: Jun 15, 2020

Arms and Interventions

Arm

Intervention/Treatment

Experimental: levothyroxine sodium capsules levothyroxine sodium capsules 88 to 250 mcg/day (depending on individual needs) for 3 months

Drug: levothyroxine sodium capsule; after the run-in period, patients will be switched to levothyroxine sodium capsule at the same dose used during run-in; Other Names: Tirosint ; Drug: Proton pump inhibitor (PPI); for the whole study duration all subjects will keep taking their proton pump inhibitor medication, as per prescription and as before inclusion; Other Names: omeprazole, esomeprazole, lansoprazole, dexlansoprazole, pantoprazole, rabeprazole ; Drug: Levothyroxine Sodium (LT4) Tablets; during the run-in period, subjects will continue taking their levothyroxine sodium tablet medication as per prescription and as before inclusion

Outcome Measures

Primary Outcome Measures

1. Thyroid Stimulating Hormone (TSH) [baseline and 12 weeks]

   Change in Serum Levels of TSH (Thyroid Stimulating Hormone) from Baseline

Secondary Outcome Measures

1. Free Thyroxine (FT4) [baseline and 12 weeks]

   Change in Serum Levels of FT4 (free thyroxine) from Baseline

2. Total Thyroxine (TT4) [baseline and 12 weeks]

   Change in Serum Levels of TT4 (total thyroxine) from Baseline

3. Free Triiodothyronine (FT3) [baseline and 12 weeks]

   Change in Serum Levels of FT3 (free triiodothyronine) from Baseline

4. Total Triiodothyronine (TT3) [baseline and 12 weeks]

   Change in Serum Levels of TT3 (total triiodothyronine) from Baseline

Other Outcome Measures

1. Creatine Phosphokinase (CPK) [baseline and 12 weeks]

   Change in Serum Levels of creatine phosphokinase (CPK) from Baseline

2. Sex Hormone Binding Globulin (SHBG) [baseline and 12 weeks]

   Change in Serum Levels of SHBG (sex hormone binding globuline) from Baseline

3. Ferritin [baseline and 12 weeks]

   Change in Serum Levels of ferritin from Baseline

4. Angiotensin Converting Enzyme (ACE) [baseline and 12 weeks]

   Change in Serum Levels of ACE (angiotensin converting enzyme) from Baseline

5. Triglycerides [baseline and 12 weeks]

   Change in triglycerides levels from Baseline

6. Cholesterol, Total [baseline and 12 weeks]

   Change in total cholesterol levels from Baseline

7. Low Density Lipoprotein (LDL)-Cholesterol [baseline and 12 weeks]

   Change in low density lipoprotein (LDL)-cholesterol levels from baseline

8. High Density Lipoprotein (HDL)-Cholesterol [baseline and 12 weeks]

   Change in High Density Lipoprotein (HDL)-cholesterol levels from baseline

9. Very Low Density Lipoprotein (VLDL)-Cholesterol [baseline and 12 weeks]

   Change in Very Low Density Lipoprotein (VLDL)-cholesterol levels from baseline

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 65 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. written informed consent duly read, signed and dated by the subject;

2. aged ≥18 and ≤65 years;

3. history of hypothyroidism due to total thyroidectomy;

4. on stable LT4 doses for at least 6 weeks at screening (≥88 mcg daily and ≤250 mcg daily);

5. TSH at screening ≥0.3 and ≤4.0 mIU/L;

6. history of gastroesophageal reflux disease or associated gastrointestinal issues on prescription PPIs (i.e. omeprazole ≥20 mg daily, or esomeprazole ≥ 20 mg daily, or lansoprazole ≥ 15 mg daily, or pantoprazole ≥ 40 mg daily) for at least 8 weeks before screening visit and for whom chronic therapy with PPIs for the next 5 months has been prescribed;

7. for women, adequate and continuative contraceptive measures until the end of the study, if not in menopause;

8. reasonable assumption of understanding the study and willingness to take part to the study and to comply with protocol requirements.

Exclusion Criteria:

1. suspected or ascertained non-compliance with LT4 or PPI therapy;

2. subject requiring changes of levothyroxine dose;

3. use of over-the-counter (OTC) PPIs;

4. history of malabsorption or history of gastric bypass surgery, short-gut syndrome, inflammatory bowel disease and other conditions of the gastrointestinal tract that may affect drug absorption (e.g. celiac disease)3;

5. multiple co-morbidities (e.g. cardiac heart failure, active arrhythmia or history of arrhythmia, particularly atrial fibrillation, uncompensated diabetes mellitus, uncorrected adrenal insufficiency, seriously compromised hepatic, renal and/or respiratory functions);

6. neoplastic pathology, active or in remission for less than 5 years (excluding the basic thyroid pathology);

7. terminal condition;

8. parenteral or assisted enteral feeding;

9. presence of any medical condition or other circumstances which would significantly affect the safety of the subject or decrease the chance of obtaining reliable data, achieving study objectives or completing the study;

10. history of alcoholism, drug abuse or psychiatric diseases that could invalidate the informed consent or limit the subject compliance with protocol requirements;

11. pregnant (positive urine pregnancy test at screening or baseline visits) or breast-feeding subject or subject planning a pregnancy in the next months;

12. known hypersensitivity to the ingredients of the preparation involved in the study3;

13. use of forbidden concomitant medications;

14. regular consumption of soy and soy derivatives, cotton seed meals, walnuts, and dietary fibres;

15. participation in other clinical studies during the 3 months prior to screening;

16. presumption of poor reliability/cooperation;

17. any reason which, in the opinion of the Investigator, would prevent the subject from participating in the study.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	California Head and Neck Specialists	La Jolla	California	United States	92037
2	Coastal Metabolic Research Centre	Ventura	California	United States	93003
3	Washington Hospital Center	Washington	District of Columbia	United States	20010-2975
4	MedStar Union Memorial Hospital	Baltimore	Maryland	United States	21218
5	NYC Health + Hospitals/ Queens	New York	New York	United States	11432
6	Diabetes & Endocrinology Consultants, PC	Morehead City	North Carolina	United States	28557
7	Carolina Ear Nose and Throat Clinic	Orangeburg	South Carolina	United States	29118
8	Virginia Commonwealth University	Richmond	Virginia	United States	23298
9	Stonesifer Endocrine Care & Clinical Research Inc., PS	Federal Way	Washington	United States	98003

Sponsors and Collaborators

• IBSA Institut Biochimique SA

Investigators

• Principal Investigator: Kenneth D Burman, MD, Medstar Health Research Institute

Study Documents (Full-Text)

• Study Protocol - Jun 17, 2019
• Statistical Analysis Plan - Dec 23, 2021

More Information

Publications

None provided.

• Responsible Party: IBSA Institut Biochimique SA
• ClinicalTrials.gov Identifier: NCT03094416
• Other Study ID Numbers: 13US-T404
• First Posted: Mar 29, 2017
• Last Update Posted: Apr 5, 2022
• Last Verified: Apr 1, 2022

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No
• Additional relevant MeSH terms: Hypothyroidism; Esomeprazole; Omeprazole; Rabeprazole; Pantoprazole; Lansoprazole; Dexlansoprazole; Proton Pump Inhibitors

Study Results

Participant Flow

Recruitment Details	Subject were recuited by endocrinologists, either at hospital sites or at private practices
Pre-assignment Detail	Enrolled subjects underwent a run-in period of 28-42 days, that may be extended up to 4 months, until Thyroid Stimulating Hormone (TSH) normalization, if levothyroxine sodium (LT4) dose adjustments were necessary at screening visit.

Arm/Group Title	Tirosint Capsules
Arm/Group Description	During the run-in period, subjects continued taking their levothyroxine sodium tablet medication 88 to 250 mcg/day (depending on individual needs) as per prescription and as before inclusion. After the run-in period, at baseline visit, subjects were switched to Tirosint (levothyroxine sodium) capsules at the same dose used during run-in and for 3 months (treatment period). For the whole study duration (run-in and treatment period), subjects kept taking their proton pump inhibitor medication, as per prescription and as before inclusion.
Period Title: Run-in
STARTED	66
COMPLETED	47
NOT COMPLETED	19
Period Title: Run-in
STARTED	47
COMPLETED	45
NOT COMPLETED	2

Baseline Characteristics

Arm/Group Title	Tirosint Capsules
Arm/Group Description	During the run-in period, subjects continued taking their levothyroxine sodium tablet medication 88 to 250 mcg/day (depending on individual needs) as per prescription and as before inclusion. After the run-in period, at baseline visit, subjects were switched to Tirosint (levothyroxine sodium) capsules at the same dose used during run-in and for 3 months (treatment period). For the whole study duration (run-in and treatment period), subjects kept taking their proton pump inhibitor medication, as per prescription and as before inclusion.
Overall Participants	47
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	55.38 (11.111)
Sex: Female, Male (Count of Participants)
Female	36 76.6%
Male	11 23.4%
Race/Ethnicity, Customized (Count of Participants)
Peru	1 2.1%
Black or African American	6 12.8%
Puerto Rican	1 2.1%
Ecuadorian	1 2.1%
Multiracial	1 2.1%
White	32 68.1%
Asian	3 6.4%
American Indian or Alaska Native	1 2.1%
Hispanic	1 2.1%
Region of Enrollment (Count of Participants)
United States	47 100%
Thyroid Stimulating Hormone (TSH) (mIU/L) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [mIU/L]	1.341 (1.5054)
Body Mass Index (BMI) (kg/m^2) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg/m^2]	32.25 (8.286)

Outcome Measures

1. Primary Outcome

Title	Thyroid Stimulating Hormone (TSH)
Description	Change in Serum Levels of TSH (Thyroid Stimulating Hormone) from Baseline
Time Frame	baseline and 12 weeks

Outcome Measure Data

Analysis Population Description

intention to treat (ITT), 4 subjects not considered in the analysis because of drop-out or LT4 dose change

Arm/Group Title	Tirosint Capsules
Arm/Group Description	During the run-in period, subjects continued taking their levothyroxine sodium tablet medication 88 to 250 mcg/day (depending on individual needs) as per prescription and as before inclusion. After the run-in period, at baseline visit, subjects were switched to Tirosint (levothyroxine sodium) capsules at the same dose used during run-in and for 3 months (treatment period). For the whole study duration (run-in and treatment period), subjects kept taking their proton pump inhibitor medication, as per prescription and as before inclusion.
Measure Participants	43
Mean (Standard Deviation) [mIU/L]	-0.676 (1.3181)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Tirosint Capsules
	Comments
	Type of Statistical Test	Other
	Comments	Normal distribution of data was tested with Shapiro Wilks. Data were log transformed. A mixed model ANCOVA repeated measures model was used to test differences in means at Visit 4 vs baseline on original data. As covariates the following baseline variables were considered: Age, Sex, BMI and the prescribed Tirosint dosage (dose/Kg).
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	level of significance p-value < 0.05
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.783797
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.158271
	Estimation Comments

2. Secondary Outcome

Title	Free Thyroxine (FT4)
Description	Change in Serum Levels of FT4 (free thyroxine) from Baseline
Time Frame	baseline and 12 weeks

Outcome Measure Data

Analysis Population Description

ITT, 4 subjects not considered in the analysis because of drop-out or LT4 dose change

Arm/Group Title	Tirosint Capsules
Arm/Group Description	During the run-in period, subjects continued taking their levothyroxine sodium tablet medication 88 to 250 mcg/day (depending on individual needs) as per prescription and as before inclusion. After the run-in period, at baseline visit, subjects were switched to Tirosint (levothyroxine sodium) capsules at the same dose used during run-in and for 3 months (treatment period). For the whole study duration (run-in and treatment period), subjects kept taking their proton pump inhibitor medication, as per prescription and as before inclusion.
Measure Participants	43
Mean (Standard Deviation) [pmol/L]	0.593 (2.7439)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Tirosint Capsules
	Comments
	Type of Statistical Test	Other
	Comments	Normal distribution of data was tested with Shapiro Wilks. Data were log transformed. A mixed model ANCOVA repeated measures model was used to test differences in means at Visit 4 vs baseline on original data. As covariates the following baseline variables were considered: Age, Sex, BMI and the prescribed Tirosint dosage (dose/Kg).
Statistical Test of Hypothesis	p-Value	0.1607
	Comments	level of significance p-value < 0.05
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.037312
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.026128
	Estimation Comments

3. Secondary Outcome

Title	Total Thyroxine (TT4)
Description	Change in Serum Levels of TT4 (total thyroxine) from Baseline
Time Frame	baseline and 12 weeks

Outcome Measure Data

Analysis Population Description

ITT, 4 subjects not considered in the analysis because of drop-out or LT4 dose change

Arm/Group Title	Tirosint Capsules
Arm/Group Description	During the run-in period, subjects continued taking their levothyroxine sodium tablet medication 88 to 250 mcg/day (depending on individual needs) as per prescription and as before inclusion. After the run-in period, at baseline visit, subjects were switched to Tirosint (levothyroxine sodium) capsules at the same dose used during run-in and for 3 months (treatment period). For the whole study duration (run-in and treatment period), subjects kept taking their proton pump inhibitor medication, as per prescription and as before inclusion.
Measure Participants	43
Mean (Standard Deviation) [nmol/L]	2.558 (27.2426)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Tirosint Capsules
	Comments
	Type of Statistical Test	Other
	Comments	Normal distribution of data was tested with Shapiro Wilks. Data were log transformed. A mixed model ANCOVA repeated measures model was used to test differences in means at Visit 4 vs baseline on original data. As covariates the following baseline variables were considered: Age, Sex, BMI and the prescribed Tirosint dosage (dose/Kg).
Statistical Test of Hypothesis	p-Value	0.4204
	Comments	level of significance p-value < 0.05
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	3.397559
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 4.174962
	Estimation Comments

4. Secondary Outcome

Title	Free Triiodothyronine (FT3)
Description	Change in Serum Levels of FT3 (free triiodothyronine) from Baseline
Time Frame	baseline and 12 weeks

Outcome Measure Data

Analysis Population Description

ITT, 4 subjects not considered in the analysis because of drop-out or LT4 dose change

Arm/Group Title	Tirosint Capsules
Arm/Group Description	During the run-in period, subjects continued taking their levothyroxine sodium tablet medication 88 to 250 mcg/day (depending on individual needs) as per prescription and as before inclusion. After the run-in period, at baseline visit, subjects were switched to Tirosint (levothyroxine sodium) capsules at the same dose used during run-in and for 3 months (treatment period). For the whole study duration (run-in and treatment period), subjects kept taking their proton pump inhibitor medication, as per prescription and as before inclusion.
Measure Participants	43
Mean (Standard Deviation) [pmol/L]	0.263 (0.5716)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Tirosint Capsules
	Comments
	Type of Statistical Test	Other
	Comments	Normal distribution of data was tested with Shapiro Wilks. Data were log transformed. A mixed model ANCOVA repeated measures model was used to test differences in means at Visit 4 vs baseline on original data. As covariates the following baseline variables were considered: Age, Sex, BMI and the prescribed Tirosint dosage (dose/Kg).
Statistical Test of Hypothesis	p-Value	0.0062
	Comments	level of significance p-value < 0.05
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.055199
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.019171
	Estimation Comments

5. Secondary Outcome

Title	Total Triiodothyronine (TT3)
Description	Change in Serum Levels of TT3 (total triiodothyronine) from Baseline
Time Frame	baseline and 12 weeks

Outcome Measure Data

Analysis Population Description

ITT, 4 subjects not considered in the analysis because of drop-out or LT4 dose change

Arm/Group Title	Tirosint Capsules
Arm/Group Description	During the run-in period, subjects continued taking their levothyroxine sodium tablet medication 88 to 250 mcg/day (depending on individual needs) as per prescription and as before inclusion. After the run-in period, at baseline visit, subjects were switched to Tirosint (levothyroxine sodium) capsules at the same dose used during run-in and for 3 months (treatment period). For the whole study duration (run-in and treatment period), subjects kept taking their proton pump inhibitor medication, as per prescription and as before inclusion.
Measure Participants	43
Mean (Standard Deviation) [nmol/L]	0.098 (0.3158)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Tirosint Capsules
	Comments
	Type of Statistical Test	Other
	Comments	A mixed model ANCOVA repeated measures model was used to test differences in means at Visit 4 vs baseline on original data. As covariates the following baseline variables were considered: Age, Sex, BMI and the prescribed Tirosint dosage (dose/Kg). Normal distribution of data was tested with Shapiro Wilks. No data transformation was done.
Statistical Test of Hypothesis	p-Value	0.0438
	Comments	level of significance p-value < 0.05
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.100127
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.048171
	Estimation Comments

6. Other Pre-specified Outcome

Title	Creatine Phosphokinase (CPK)
Description	Change in Serum Levels of creatine phosphokinase (CPK) from Baseline
Time Frame	baseline and 12 weeks

Outcome Measure Data

Analysis Population Description

ITT, 6 subjects not considered in the analysis because of drop-out, LT4 dose change or laboratory test not performed

Arm/Group Title	Tirosint Capsules
Arm/Group Description	During the run-in period, subjects continued taking their levothyroxine sodium tablet medication 88 to 250 mcg/day (depending on individual needs) as per prescription and as before inclusion. After the run-in period, at baseline visit, subjects were switched to Tirosint (levothyroxine sodium) capsules at the same dose used during run-in and for 3 months (treatment period). For the whole study duration (run-in and treatment period), subjects kept taking their proton pump inhibitor medication, as per prescription and as before inclusion.
Measure Participants	41
Mean (Standard Deviation) [U/L]	-35.073 (125.1454)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Tirosint Capsules
	Comments
	Type of Statistical Test	Other
	Comments	Normal distribution of data was tested with Shapiro Wilks. Data were log transformed. A mixed model ANCOVA repeated measures model was used to test differences in means at Visit 4 vs baseline on original data. As covariates the following baseline variables were considered: Age, Sex, BMI and the prescribed Tirosint dosage (dose/Kg).
Statistical Test of Hypothesis	p-Value	0.0254
	Comments	level of significance p-value < 0.05
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.216479
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.093366
	Estimation Comments

7. Other Pre-specified Outcome

Title	Sex Hormone Binding Globulin (SHBG)
Description	Change in Serum Levels of SHBG (sex hormone binding globuline) from Baseline
Time Frame	baseline and 12 weeks

Outcome Measure Data

Analysis Population Description

ITT, 4 subjects not considered in the analysis because of drop-out or LT4 dose change

Arm/Group Title	Tirosint Capsules
Arm/Group Description	During the run-in period, subjects continued taking their levothyroxine sodium tablet medication 88 to 250 mcg/day (depending on individual needs) as per prescription and as before inclusion. After the run-in period, at baseline visit, subjects were switched to Tirosint (levothyroxine sodium) capsules at the same dose used during run-in and for 3 months (treatment period). For the whole study duration (run-in and treatment period), subjects kept taking their proton pump inhibitor medication, as per prescription and as before inclusion.
Measure Participants	43
Mean (Standard Deviation) [nmol/L]	0.884 (19.1861)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Tirosint Capsules
	Comments
	Type of Statistical Test	Other
	Comments	Normal distribution of data was tested with Shapiro Wilks. Data were log transformed. A mixed model ANCOVA repeated measures model was used to test differences in means at Visit 4 vs baseline on original data. As covariates the following baseline variables were considered: Age, Sex, BMI and the prescribed Tirosint dosage (dose/Kg).
Statistical Test of Hypothesis	p-Value	0.7619
	Comments	level of significance p-value < 0.05
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.011187
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.036679
	Estimation Comments

8. Other Pre-specified Outcome

Title	Ferritin
Description	Change in Serum Levels of ferritin from Baseline
Time Frame	baseline and 12 weeks

Outcome Measure Data

Analysis Population Description

ITT, 4 subjects not considered in the analysis because of drop-out or LT4 dose change

Arm/Group Title	Tirosint Capsules
Arm/Group Description	During the run-in period, subjects continued taking their levothyroxine sodium tablet medication 88 to 250 mcg/day (depending on individual needs) as per prescription and as before inclusion. After the run-in period, at baseline visit, subjects were switched to Tirosint (levothyroxine sodium) capsules at the same dose used during run-in and for 3 months (treatment period). For the whole study duration (run-in and treatment period), subjects kept taking their proton pump inhibitor medication, as per prescription and as before inclusion.
Measure Participants	43
Mean (Standard Deviation) [mcg/L]	-6.442 (30.2390)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Tirosint Capsules
	Comments
	Type of Statistical Test	Other
	Comments	Normal distribution of data was tested with Shapiro Wilks. Data were log transformed. A mixed model ANCOVA repeated measures model was used to test differences in means at Visit 4 vs baseline on original data. As covariates the following baseline variables were considered: Age, Sex, BMI and the prescribed Tirosint dosage (dose/Kg).
Statistical Test of Hypothesis	p-Value	0.0655
	Comments	level of significance p-value < 0.05
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.121537
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.064264
	Estimation Comments

9. Other Pre-specified Outcome

Title	Angiotensin Converting Enzyme (ACE)
Description	Change in Serum Levels of ACE (angiotensin converting enzyme) from Baseline
Time Frame	baseline and 12 weeks

Outcome Measure Data

Analysis Population Description

ITT, 9 subjects not considered in the analysis because of drop-out, LT4 dose change or laboratory test not performed

Arm/Group Title	Tirosint Capsules
Arm/Group Description	During the run-in period, subjects continued taking their levothyroxine sodium tablet medication 88 to 250 mcg/day (depending on individual needs) as per prescription and as before inclusion. After the run-in period, at baseline visit, subjects were switched to Tirosint (levothyroxine sodium) capsules at the same dose used during run-in and for 3 months (treatment period). For the whole study duration (run-in and treatment period), subjects kept taking their proton pump inhibitor medication, as per prescription and as before inclusion.
Measure Participants	38
Mean (Standard Deviation) [U/L]	-0.395 (11.6237)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Tirosint Capsules
	Comments
	Type of Statistical Test	Other
	Comments	Normal distribution of data was tested with Shapiro Wilks. Data were log transformed. A mixed model ANCOVA repeated measures model was used to test differences in means at Visit 4 vs baseline on original data. As covariates the following baseline variables were considered: Age, Sex, BMI and the prescribed Tirosint dosage (dose/Kg).
Statistical Test of Hypothesis	p-Value	0.5542
	Comments	level of significance p-value < 0.05
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.031636
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.053033
	Estimation Comments

10. Other Pre-specified Outcome

Title	Triglycerides
Description	Change in triglycerides levels from Baseline
Time Frame	baseline and 12 weeks

Outcome Measure Data

Analysis Population Description

ITT, 7 subjects not considered in the analysis because of drop-out, LT4 dose change or laboratory test not performed

Arm/Group Title	Tirosint Capsules
Arm/Group Description	During the run-in period, subjects continued taking their levothyroxine sodium tablet medication 88 to 250 mcg/day (depending on individual needs) as per prescription and as before inclusion. After the run-in period, at baseline visit, subjects were switched to Tirosint (levothyroxine sodium) capsules at the same dose used during run-in and for 3 months (treatment period). For the whole study duration (run-in and treatment period), subjects kept taking their proton pump inhibitor medication, as per prescription and as before inclusion.
Measure Participants	40
Mean (Standard Deviation) [mmol/L]	0.075 (0.5419)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Tirosint Capsules
	Comments
	Type of Statistical Test	Other
	Comments	Normal distribution of data was tested with Shapiro Wilks. Data were log transformed. A mixed model ANCOVA repeated measures model was used to test differences in means at Visit 4 vs baseline on original data. As covariates the following baseline variables were considered: Age, Sex, BMI and the prescribed Tirosint dosage (dose/Kg).
Statistical Test of Hypothesis	p-Value	0.6820
	Comments	level of significance p-value < 0.05
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.019322
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.046827
	Estimation Comments

11. Other Pre-specified Outcome

Title	Cholesterol, Total
Description	Change in total cholesterol levels from Baseline
Time Frame	baseline and 12 weeks

Outcome Measure Data

Analysis Population Description

ITT, 7 subjects not considered in the analysis because of drop-out, LT4 dose change or laboratory test not performed

Arm/Group Title	Tirosint Capsules
Arm/Group Description	During the run-in period, subjects continued taking their levothyroxine sodium tablet medication 88 to 250 mcg/day (depending on individual needs) as per prescription and as before inclusion. After the run-in period, at baseline visit, subjects were switched to Tirosint (levothyroxine sodium) capsules at the same dose used during run-in and for 3 months (treatment period). For the whole study duration (run-in and treatment period), subjects kept taking their proton pump inhibitor medication, as per prescription and as before inclusion.
Measure Participants	40
Mean (Standard Deviation) [mmol/L]	-0.198 (0.6685)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Tirosint Capsules
	Comments
	Type of Statistical Test	Other
	Comments	Normal distribution of data was tested with Shapiro Wilks. Data were log transformed. A mixed model ANCOVA repeated measures model was used to test differences in means at Visit 4 vs baseline on original data. As covariates the following baseline variables were considered: Age, Sex, BMI and the prescribed Tirosint dosage (dose/Kg).
Statistical Test of Hypothesis	p-Value	0.0468
	Comments	level of significance p-value < 0.05
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.049243
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.024025
	Estimation Comments

12. Other Pre-specified Outcome

Title	Low Density Lipoprotein (LDL)-Cholesterol
Description	Change in low density lipoprotein (LDL)-cholesterol levels from baseline
Time Frame	baseline and 12 weeks

Outcome Measure Data

Analysis Population Description

ITT, 8 subjects not considered in the analysis because of drop-out, LT4 dose change or laboratory test not performed

Arm/Group Title	Tirosint Capsules
Arm/Group Description	During the run-in period, subjects continued taking their levothyroxine sodium tablet medication 88 to 250 mcg/day (depending on individual needs) as per prescription and as before inclusion. After the run-in period, at baseline visit, subjects were switched to Tirosint (levothyroxine sodium) capsules at the same dose used during run-in and for 3 months (treatment period). For the whole study duration (run-in and treatment period), subjects kept taking their proton pump inhibitor medication, as per prescription and as before inclusion.
Measure Participants	39
Mean (Standard Deviation) [mmol/L]	-0.210 (0.5609)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Tirosint Capsules
	Comments
	Type of Statistical Test	Other
	Comments	A mixed model ANCOVA repeated measures model was used to test differences in means at Visit 4 vs baseline on original data. As covariates the following baseline variables were considered: Age, Sex, BMI and the prescribed Tirosint dosage (dose/Kg). Normal distribution of data was tested with Shapiro Wilks. No data transformation was done.
Statistical Test of Hypothesis	p-Value	0.0203
	Comments	level of significance p-value < 0.05
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.213171
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.088103
	Estimation Comments

13. Other Pre-specified Outcome

Title	High Density Lipoprotein (HDL)-Cholesterol
Description	Change in High Density Lipoprotein (HDL)-cholesterol levels from baseline
Time Frame	baseline and 12 weeks

Outcome Measure Data

Analysis Population Description

ITT, 7 subjects not considered in the analysis because of drop-out, LT4 dose change or laboratory test not performed

Arm/Group Title	Tirosint Capsules
Arm/Group Description	During the run-in period, subjects continued taking their levothyroxine sodium tablet medication 88 to 250 mcg/day (depending on individual needs) as per prescription and as before inclusion. After the run-in period, at baseline visit, subjects were switched to Tirosint (levothyroxine sodium) capsules at the same dose used during run-in and for 3 months (treatment period). For the whole study duration (run-in and treatment period), subjects kept taking their proton pump inhibitor medication, as per prescription and as before inclusion.
Measure Participants	40
Mean (Standard Deviation) [mmol/L]	-0.029 (0.2460)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Tirosint Capsules
	Comments
	Type of Statistical Test	Other
	Comments	A mixed model ANCOVA repeated measures model was used to test differences in means at Visit 4 vs baseline on original data. As covariates the following baseline variables were considered: Age, Sex, BMI and the prescribed Tirosint dosage (dose/Kg). Normal distribution of data was tested with Shapiro Wilks. No data transformation was done.
Statistical Test of Hypothesis	p-Value	0.4291
	Comments	level of significance p-value < 0.05
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.030904
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.038699
	Estimation Comments

14. Other Pre-specified Outcome

Title	Very Low Density Lipoprotein (VLDL)-Cholesterol
Description	Change in Very Low Density Lipoprotein (VLDL)-cholesterol levels from baseline
Time Frame	baseline and 12 weeks

Outcome Measure Data

Analysis Population Description

ITT, 8 subjects not considered in the analysis because of drop-out, LT4 dose change or laboratory test not performed

Arm/Group Title	Tirosint Capsules
Arm/Group Description	During the run-in period, subjects continued taking their levothyroxine sodium tablet medication 88 to 250 mcg/day (depending on individual needs) as per prescription and as before inclusion. After the run-in period, at baseline visit, subjects were switched to Tirosint (levothyroxine sodium) capsules at the same dose used during run-in and for 3 months (treatment period). For the whole study duration (run-in and treatment period), subjects kept taking their proton pump inhibitor medication, as per prescription and as before inclusion.
Measure Participants	39
Mean (Standard Deviation) [mmol/L]	0.049 (0.2338)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Tirosint Capsules
	Comments
	Type of Statistical Test	Other
	Comments	Normal distribution of data was tested with Shapiro Wilks. Data were log transformed. A mixed model ANCOVA repeated measures model was used to test differences in means at Visit 4 vs baseline on original data. As covariates the following baseline variables were considered: Age, Sex, BMI and the prescribed Tirosint dosage (dose/Kg).
Statistical Test of Hypothesis	p-Value	0.5967
	Comments	level of significance p-value < 0.05
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.025502
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.047802
	Estimation Comments

Adverse Events

Time Frame	Adverse events were collected for the whole study duration (from the signature of the informed consent until the end of the study and/or the follow-up planned period), an average of 18 weeks
Arm/Group Title	Treatment Period: Tirosint Capsules		Run-in Period: LT4 Tablets
Arm/Group Description	After the run-in period, at baseline visit, subjects were switched to Tirosint (levothyroxine sodium) capsules at the same dose used during run-in and for 3 months (treatment period). For the whole study duration (run-in and treatment period), subjects kept taking their proton pump inhibitor medication, as per prescription and as before inclusion.		During the run-in period, subjects continued taking their levothyroxine sodium tablet medication 88 to 250 mcg/day (depending on individual needs) as per prescription and as before inclusion. For the whole study duration (run-in and treatment period), subjects kept taking their proton pump inhibitor medication, as per prescription and as before inclusion.
All Cause Mortality
	Treatment Period: Tirosint Capsules		Run-in Period: LT4 Tablets
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/47 (0%)		0/47 (0%)
Serious Adverse Events
	Treatment Period: Tirosint Capsules		Run-in Period: LT4 Tablets
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/47 (2.1%)		2/47 (4.3%)
Cardiac disorders
Bradycardia	0/47 (0%)	0	1/47 (2.1%)	1
Infections and infestations
Bronchitis	0/47 (0%)	0	1/47 (2.1%)	1
Urinary tract infection	0/47 (0%)	0	1/47 (2.1%)	1
Metabolism and nutrition disorders
Dehydration	0/47 (0%)	0	1/47 (2.1%)	1
Respiratory, thoracic and mediastinal disorders
Asthma	1/47 (2.1%)	1	0/47 (0%)	0
Other (Not Including Serious) Adverse Events
	Treatment Period: Tirosint Capsules		Run-in Period: LT4 Tablets
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	13/47 (27.7%)		10/47 (21.3%)
Gastrointestinal disorders
Diarrhoea	2/47 (4.3%)	2	1/47 (2.1%)	1
Nausea	1/47 (2.1%)	1	1/47 (2.1%)	1
Vomiting	1/47 (2.1%)	1	1/47 (2.1%)	1
Constipation	1/47 (2.1%)	1	0/47 (0%)	0
Abdominal pain upper	0/47 (0%)	0	1/47 (2.1%)	1
General disorders
Fatigue	0/47 (0%)	0	2/47 (4.3%)	2
Infections and infestations
Upper respiratory tract infection	2/47 (4.3%)	2	1/47 (2.1%)	1
Bronchitis	1/47 (2.1%)	1	2/47 (4.3%)	2
Urinary tract infection	1/47 (2.1%)	1	0/47 (0%)	0
Pharyngitis	0/47 (0%)	0	1/47 (2.1%)	1
Gastroenteritis	1/47 (2.1%)	2	0/47 (0%)	0
Subcutaneous abscess	1/47 (2.1%)	1	0/47 (0%)	0
Injury, poisoning and procedural complications
Joint injury	0/47 (0%)	0	1/47 (2.1%)	1
Muscle strain	0/47 (0%)	0	1/47 (2.1%)	1
Metabolism and nutrition disorders
Hyperlipidaemia	1/47 (2.1%)	1	0/47 (0%)	0
Musculoskeletal and connective tissue disorders
Arthralgia	1/47 (2.1%)	1	0/47 (0%)	0
Back pain	1/47 (2.1%)	1	0/47 (0%)	0
Musculoskeletal pain	1/47 (2.1%)	1	0/47 (0%)	0
Nervous system disorders
Headache	0/47 (0%)	0	2/47 (4.3%)	2
Dizziness	1/47 (2.1%)	1	0/47 (0%)	0
Respiratory, thoracic and mediastinal disorders
Cough	1/47 (2.1%)	1	0/47 (0%)	0

Limitations/Caveats

Due to Covid-19 pandemic outbreak leading to discontinuation of subjects, primary endpoint was assessed on 43 subjects instead of 48 subjects (as planned in the sample size calculation). The a-posteriori study power is 91%.

More Information

Certain Agreements

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

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.