iA)             Title:  Dose of levothyroxine and the number to visits required to achieve euthyroidism in a newly diagnosed primary hypothyroidism after Levothyroxine initiation based on customized calculated dose.           

B)             Research Question/ Aim of the study: The levothyroxine per kg body weight dose varies from 0.3–2.82 μg/kg.  To find the efficacy of customized dose of levothyroxine in newly diagnosed hypothyroidism and number of visits needed at attain euthyroidism in newly diagnosed primary hypothyroidism versus fixed dose levothyroxine.

C)             Hypothesis: We assessed if calculated customized dose of levothyroxine was effective in achieving euthyroidism in newly diagnosed primary hypothyroidism as equally effective as fixed dose or superior in reducing the number of visits to euthyroidism.  

D)            Study Objectives:

1.      Dose of levothyroxine at Euthyroidism in adults presenting with primary hypothyroidism

2.      The number of visits taken by patients to achieve euthyroidism started on the calculated customized dose of levothyroxine versus fixed dose of levothyroxine.

3.      Effect of Hemoglobin level on the dose of levothyroxine required at euthyroidism  

4.      Prevalence of other chronic disease such as diabetes, hypertension, CKD, metabolic syndrome will also be analyzed.

5.      Episodes of iatrogenic thyrotoxicosis in both arms

6.      All the subjects will be followed even after 6 months till euthyroidism and then for 2 years for assessing the stability of levothyroxine dose after achieving euthyroidism in both arm

E)             Background knowledge on the subject (within 500 words):

The only treatment available in hypothyroidism is replacement of levothyroxine. The dose of levothyroxine depends on the demand which in turn dependent on endogenous thyroid hormone production. The level of

thyroid hormones in the blood circulation is determined by the endogenous secretion of thyroid hormones, their metabolism, and exogenous replacement therapy. The commonest cause of primary hypothyroidism in iodine sufficient are is Hashimoto’s thyroiditis. The disease has an indolent course and severity of disease varies form subclinical hypothyroidism to minimal residual function. Studies have evaluated the requirement of replacement doses in primary hypothyroidism based on body weight. The dose of Levothyroxine for replacement varies with the etiology of hypothyroidism. Although the average replacement dose of LT4 is approximately 1.6 μg/kg body weight in autoimmune hypothyroidism, the range of required dose is wide and varies from 25–50 to ≥200–225μg/kg body weight. The recommended dose of 1.6 μg/kg is based on the assumption of minimal residual thyroid function. Few guidelines have been developed to assist calculation of levothyroxine dose in subclinical hypothyroidism and primary hypothyroidism with minimal residual function exists. 

F)             Rationale of Study: Primary hypothyroidism is a common disorder especially in women. Primary hypothyroidism has very simple management with goal to achieve and maintain euthyroidism. However, a number of visits may be required by subjects to achieve euthyroid state as the dose is to be titrated based on the laboratory reports till euthyroidism is achieved. The investigations required in monitoring of disease include TSH and free T4 or total T4. These investigations are not easily available at small towns and in addition are costly. The factors as mentioned puts a significant financial burden on patient, government and health care system due to the cost of investigation required and the number of visits required by patient to attain the euthyroidism and finding the levothyroxine dose needed as replacement to maintain euthyroidism.  Current recommendations suggest a dose of 1.6 mcg/kg daily in all cases of overt hypothyroidism and range specific dose for subclinical hypothyroidism. Based on a previous study a formula-based dose of levothyroxine may reduce the time needed to achieve euthyroidism. The study aims to find the difference in risk of iatrogenic thyrotoxicosis on full replacement of levothyroxine versus customized dose based on serum TSH.  

G)            Novelty of the study: Very few studies have been done to assess the efficacy of calculated dose in achieving euthyroidism. The study will access the efficacy of the calculated dose in primary hypothyroidism in adults.

H)            Brief methodology:

Type of Study: A prospective randomized non-inferiority and equivalence study

Primary endpoint: Dose of levothyroxine at Euthyroidism

Sample size: Based on a previous pilot study for customized dose, we found around 60% of participants achieved euthyroidism on the customized dose of levothyroxine. A previous study showed efficacy of achieving euthyroidism in 52 % of participants with fixed dose combination. Considering a non-inferiority randomized study design. Hence, we hypothesized around 60±5% of participants will achieve euthyroidism on the calculated dose and 52% on fixed dose respectively. Superiority margin of 10% was taken. We considered alpha of 5 % and Confidence interval of 95%. The calculated sample size of 152 with 76 in each group. Considering an expected dropout rate of 30% a final sample size of 200 was calculated with 1:1 distribution between two groups.

Inclusion Criteria:

1.      Age above 18 years and <60 years,

2.      newly diagnosed with primary hypothyroidism (all overt hypothyroidism cases, and Thyroid peroxidase antibody positive subclinical hypothyroidism) and

3.      treatment-naïve (not started on thyroid hormone treatment).

Exclusion Criteria:

1.      pregnancy,

2.      central hypothyroidism,

3.      within two years of post-radiotherapy or radioiodine ablation,

4.      post total thyroidectomy cases,

5.      major co-morbidities,

6.      co-prescription of treatment known to affect thyroid hormone metabolism.

I)              Statistical Analysis (including sample size calculation): The median duration of follow up needed will be calculated by Kaplan Meier curve. The proportion of the participants achieving euthyroidism will be expressed as percentage. The final dose at euthyroidism will be expressed as mean ±SD.

J)              Expected outcome of the study: We expect around 60 percent of the participants will achieve euthyroidism at first visit based on calculated dose.

K)             Duration by which the project is likely to be completed: We expect project to be completed in 2years and 6 months.

L)             Time bound milestones: We will be recruiting participants with newly diagnosed primary hypothyroidism throughout the period of study and each participant will be followed till euthyroidism or maximum 6 months of follow up on treatment.