| CTRI Number |
CTRI/2026/02/104745 [Registered on: 25/02/2026] Trial Registered Prospectively |
| Last Modified On: |
24/02/2026 |
| Post Graduate Thesis |
Yes |
| Type of Trial |
Interventional |
|
Type of Study
|
Drug
Diagnostic |
| Study Design |
Randomized, Parallel Group, Active Controlled Trial |
|
Public Title of Study
|
Comparison of Levothyroxine alone versus Levothyroxine plus Liothyronine in patients with persistent symptoms despite adequate thyroid hormone replacement |
|
Scientific Title of Study
|
A prospective study exploring determinants of response to combination Levothyroxine–Liothyronine (LT4+LT3) Therapy versus Levothyroxine Monotherapy in Symptomatic Hypothyroid patients with normal TSH Levels. |
| Trial Acronym |
|
|
Secondary IDs if Any
|
| Secondary ID |
Identifier |
| NIL |
NIL |
|
|
Details of Principal Investigator or overall Trial Coordinator (multi-center study)
|
| Name |
Dr Sonali Appaiah |
| Designation |
Associate Professor |
| Affiliation |
|
| Address |
Department of Endocrinology 2nd Floor Unit of Hope Building St Johns Medical College and Hospital
Bangalore
KARNATAKA
560034
India |
| Phone |
9448490363 |
| Fax |
|
| Email |
sonaliappaiah2@gmail.com |
|
Details of Contact Person
Scientific Query
|
| Name |
Dr Sonali Appaiah |
| Designation |
Associate Professor |
| Affiliation |
St. Johns Medical College and Hospital |
| Address |
Department of Endocrinology 2nd Floor Unit of Hope Building St Johns Medical College and Hospital
Bangalore
KARNATAKA
560034
India |
| Phone |
9448490363 |
| Fax |
|
| Email |
sonaliappaiah2@gmail.com |
|
Details of Contact Person
Public Query
|
| Name |
Dr Sonali Appaiah |
| Designation |
Associate Professor |
| Affiliation |
St. Johns Medical College and Hospital |
| Address |
Department of Endocrinology 2nd Floor Unit of Hope Building St Johns Medical College and Hospital
Bangalore
KARNATAKA
560034
India |
| Phone |
9448490363 |
| Fax |
|
| Email |
sonaliappaiah2@gmail.com |
|
|
Source of Monetary or Material Support
|
| Endocrine Society of India |
| St. Johns Medical College and Hospital |
|
|
Primary Sponsor
|
| Name |
St Johns Medical College and Hospital |
| Address |
St. Johns Medical College and Hospital Sarjapur Road Bangalore 560034 |
| Type of Sponsor |
Research institution and hospital |
|
|
Details of Secondary Sponsor
|
|
|
Countries of Recruitment
|
India |
|
Sites of Study
|
| No of Sites = 1 |
| Name of Principal
Investigator |
Name of Site |
Site Address |
Phone/Fax/Email |
| Dr Anindita Menon |
St. Johns Medical College and Hospital |
Department of Endocrinology and Endocrinology Out Patient department, 2nd Floor, Unit of Hope Building
Bangalore
KARNATAKA |
9591804084
anindita_menon@hotmail.com |
|
|
Details of Ethics Committee
|
| No of Ethics Committees= 1 |
| Name of Committee |
Approval Status |
| St.Johns National Academy of Health Sciences |
Approved |
|
|
Regulatory Clearance Status from DCGI
|
|
|
Health Condition / Problems Studied
|
| Health Type |
Condition |
| Patients |
(1) ICD-10 Condition: E038||Other specified hypothyroidism, |
|
|
Intervention / Comparator Agent
|
| Type |
Name |
Details |
| Intervention |
Combination of Levothyroxine and Liothyronine arm |
Route- Oral
Frequency- Levothyroxine once a day and Liothyronine twice a day
Duration of treatment 3 months
Replacing the dose the patient was on with combination doses to maintain LT4 to LT3 in a 15 to 1 ratio
AdjustedLT4 LT3dose
(mcg) (mcg)
150 5 (1-0-1)
112.5 7.5(5mcg 1-0-1/2)
75 5 (1/2-0-1/2)
|
| Comparator Agent |
Levothyroxine alone arm |
Route Oral
Frequency Once a day
Duration of treatment 3 months
Dose of LT4 (mcg)- same dose patient was already on
200
150
100
75 |
|
|
Inclusion Criteria
|
| Age From |
18.00 Year(s) |
| Age To |
65.00 Year(s) |
| Gender |
Both |
| Details |
Normal serum TSH
ThyPRO 39 score more than 32
On stable LT4 dose for more than or equal to 3 months
Adequate replacement more than or equal to 6 months
|
|
| ExclusionCriteria |
| Details |
Diabetes mellitus with a HbA1c more than 7 percent
Serious systemic illness or malignancy
Overt autoimmune disease
Fibromyalgia
Chronic fatigue
Drugs influencing thyroid function, pregnancy, or hormonal contraceptive use.
|
|
|
Method of Generating Random Sequence
|
Computer generated randomization |
|
Method of Concealment
|
Sequentially numbered, sealed, opaque envelopes |
|
Blinding/Masking
|
Outcome Assessor Blinded |
|
Primary Outcome
|
| Outcome |
TimePoints |
| To compare the effect of combination levothyroxine–liothyronine (LT4+LT3) therapy versus levothyroxine (LT4) monotherapy on thyroid-related quality of life (assessed by the ThyPRO-39 questionnaire) in symptomatic hypothyroid patients with normal TSH levels. |
Baseline
3 months |
|
|
Secondary Outcome
|
| Outcome |
TimePoints |
| To evaluate the effects of LT4+LT3 combination therapy compared to LT4 monotherapy on thyroid-related biochemical parameters—including serum lipid profile, sex hormone–binding globulin (SHBG), and the fT3/fT4 ratio—and on thyroid hormone sensitivity as measured by the Thyroid Feedback Quantile-based Index (TFQI). |
3 months |
| To determine correlations between improvements in quality-of-life scores and changes in biochemical markers of thyroid hormone action (fT3/fT4 ratio, SHBG, lipid profile, and Thyroid hormone sensitivity index [Thyroid Feedback Quantile-based Index- TFQI]) following combination therapy, and to identify potential serum biomarkers that may serve as surrogate indicators of tissue-level thyroid hormone activity for guiding individualized thyroid hormone replacement strategies |
3 months |
To evaluate whether baseline TFQI can predict clinical and biochemical response to LT4+LT3 therapy, thereby identifying patient subgroups most likely to benefit from combination treatment.
|
3 months |
|
|
Target Sample Size
|
Total Sample Size="50"
Sample Size from India="50"
Final Enrollment numbers achieved (Total)= "Applicable only for Completed/Terminated trials"
Final Enrollment numbers achieved (India)="Applicable only for Completed/Terminated trials" |
|
Phase of Trial
|
Phase 4 |
|
Date of First Enrollment (India)
|
16/04/2026 |
| Date of Study Completion (India) |
Applicable only for Completed/Terminated trials |
| Date of First Enrollment (Global) |
Date Missing |
| Date of Study Completion (Global) |
Applicable only for Completed/Terminated trials |
|
Estimated Duration of Trial
|
Years="2"
Months="0"
Days="0" |
|
Recruitment Status of Trial (Global)
|
Not Yet Recruiting |
| Recruitment Status of Trial (India) |
Not Yet Recruiting |
|
Publication Details
|
N/A |
|
Individual Participant Data (IPD) Sharing Statement
|
Will individual participant data (IPD) be shared publicly (including data dictionaries)?
Response - NO
|
|
Brief Summary
|
This study proposes a prospective, open label, randomized controlled trial to evaluate determinants of response to combination levothyroxine liothyronine (LT4 and LT3) therapy compared with levothyroxine (LT4) monotherapy in symptomatic hypothyroid patients with normal TSH levels. Although LT4 monotherapy achieves biochemical euthyroidism in most patients, approximately 5 to 10 percent continue to experience persistent symptoms such as fatigue, cognitive dysfunction, mood disturbances, and weight gain. This suggests possible tissue level hypothyroidism due to impaired peripheral conversion of T4 to T3, altered intracellular transport, or genetic variations affecting thyroid hormone metabolism and action. Combination therapy may better replicate physiological thyroid hormone signalling in selected individuals, but predictors of response remain unclear. Adults aged 18 to 65 years with normal serum TSH, a ThyPRO 39 score greater than 32, and stable LT4 therapy will be enrolled. Participants will be randomized to continue LT4 monotherapy or switch to LT4 and LT3 in a fixed physiological ratio of 15 to 1. Quality of life will be assessed using the validated ThyPRO 39 questionnaire. Biochemical parameters including serum TSH, free T4, free T3, lipid profile, sex hormone binding globulin (SHBG), and the free T3 to free T4 ratio will be measured. Thyroid hormone sensitivity will be assessed using the Thyroid Feedback Quantile based Index (TFQI). The primary outcome is the change in ThyPRO 39 composite score at 12 weeks. Secondary outcomes include changes in biochemical markers and correlations between quality of life improvement and surrogate markers of tissue thyroid hormone action. The study aims to identify biochemical predictors that may help select patients most likely to benefit from combination therapy and support a personalized approach to hypothyroidism management. |