Effect of Vitamin C Supplementation in Patients With Primary Hypothyroidism

Effect of Vitamin C Supplementation in Patients With Primary Hypothyroidism Requiring High Levothyroxine Dosage; a Randomized Control Trial

Thyroid disease affects almost a quarter of a billion individuals worldwide and more than 50% of them being not aware of this condition. The commonest thyroid disease is iodine deficiency related thyroid dysfunction with nearly 2 billion people around the globe at risk with insufficient iodine intake. Autoimmune thyroid disorders are commonest cause of thyroid dysfunction in iodine sufficient parts of the world. Sub-optimally or untreated hypothyroidism can lead to cognitive decline, dyslipidemia, hypertension, infertility as well as cardiovascular and neuromuscular problems. The prevalence of hypothyroidism can vary in general population with up-to 5.3% people with overt hypothyroidism based on studies from the West, with estimated 10% of the population having subclinical hypothyroidism globally. In the gulf region however, there are no national studies that provide insight into exact prevalence of hypothyroidism, however some cross-sectional screening studies indicate frequency of hypothyroidism to be as high as 5-10%.

Levothyroxine is a synthetic hormone with structure similar to naturally occurring thyroxine, and it is used as replacement monotherapy of hypothyroidism. It is mainly absorbed via small intestine. The optimal daily levothyroxine dosage requirement is 1.6 microgram/kg body weight/day, which can normalize TSH in most patients, however many studies indicate that nearly half the patient on replacement therapy may not attain a normal TSH and require further doses, possibly due to interference or malabsorption. Multiple dose change and repeated diagnostic procedures in these patients can not only increased health costs but increased of ensuing complications secondary to sub-optimally controlled hypothyroidism. Instead of increasing levothyroxine doses and getting variable response, recent study have shown improvement in thyroid function by adding on vitamin C alongside levothyroxine dose, albeit only in a specific subset of patient having gastritis. The effect of Vitamin C on improving levothyroxine also been shown to be effective over a short period in a non-randomized, non-controlled setting. Our study aims to investigate whether addition of vitamin C to levothyroxine can improve the biochemical and clinical thyroid status in a randomized controlled setting.

Study Overview

• Status: Recruiting
• Conditions: Hypothyroidism; Vitamin C Deficiency; Primary Hypothyroidism
• Intervention / Treatment: Drug: Oral Rehydration Salt Formulations; Drug: Vitamin C

Detailed Description

Nearly 20-50% patients with hypothyroidism do not achieve normal TSH on levothyroxine replacement and two common reasons are interference in absorption and compliance. This study aims to evaluate the effects of oral vitamin C given alongside oral levothyroxine in compliant patient with clinical/biochemical hypothyroidism despite being on optimal daily dose of levothyroxine, in terms of biochemical improvement of thyroid function status. This may help patients requiring more than recommended daily dose (> 1.6 ug/kg per day of oral levothyroxine) to achieve euthyroid status without increasing total levothyroxine dose by just adding vitamin C (which authors feel may help with improving absorption of Levothyroxine).

OBJECTIVE:

To measure the biochemical and clinical responses in thyroid status with additional oral vitamin C in patients with features of hypothyroidism who are already on recommended daily dose of >1.6 ug/kg/day of oral levothyroxine.

METHODOLOGY:

STUDY DESIGN:

This is a prospective randomized controlled study in which all adult patients known to have primary hypothyroidism, attending Tawam Hospital Endocrine clinic for the last 6 months, and fulfilling the criteria below, will be selected. We will aim to include minimum 32 patients. The study power calculations for population of Al Ain estimated 650,000 with an estimated global prevalence of hypothyroidism being around 6% and expected 20-50% (taken as 33%) with suboptimal thyroid function, indicates need for minimum 31 patient with confidence interval of 95% and margin of error as 5%. The patients will be randomized to either control or intervention group (16 in each group).

• Study Type: Interventional
• Enrollment (Estimated): 40
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Adnan Agha, FRCP; Phone Number: 7677 +971562790723; Email: adnanagha@uaeu.ac.ae

Study Locations

• United Arab Emirates
  • Abu Dhabi
    • Al Ain, Abu Dhabi, United Arab Emirates, 15551
      • Recruiting
      • Internal Medicine, College of Medicine and Health Sciences
      • Contact: Adnan Agha; Phone Number: 7677 +971-3-7673333; Email: adnanagha@uaeu.ac.ae

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 99 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Age > 18; both male or female
• Diagnosed to have Primary hypothyroidism > 6 months.
• Under follow up in Endocrine clinic in Tawam hospital during the 6 months
• No evidence of secondary hypothyroidism (no pituitary problems/surgery or thyroid surgery/ablation)
• TSH > 4 despite being on > 1.6 ug/kg/day of Levothyroxine for more than 8 weeks

Exclusion Criteria:

• Presence of coeliac disease
• Presence of selenium or iodine deficiency
• Gastric/intestinal resection surgery or confirmed malabsorption syndromes
• Known mental health issues affecting compliance
• Patient unable to consent.
• Overt biochemical hypothyroidism with TSH > 20 or T4 < 6

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Control / Crossover; The patients in control group will have a oral rehydration effervescent tablet to take with their usual dose of Levothyroxine for 12 weeks, with thyroid function tests assessed at 6 and 12 weeks. Crossover: After first 12 weeks, the control group will then be provided vitamin C (intervention) effervescent tablets to use 1 gram daily with their usual dose of Levothyroxine for 12 weeks, with thyroid function tests assessed at 6 and 12 weeks to see if there is any difference on biochemical testing or clinical scores.	Drug: Oral Rehydration Salt Formulations; The patients in control group will have a oral rehydration effervescent tablet to take with their usual dose of Levothyroxine for 12 weeks, with thyroid function tests assessed at 6 and 12 weeks. The control group will then be provided vitamin C (intervention) effervescent tablets to use 1 gram daily with their usual dose of Levothyroxine for 12 weeks, with thyroid function tests assessed at 6 and 12 weeks to see if there is any difference on biochemical testing or clinical scores.; Other Names: Vitamin C
Experimental: Intervention; The patient in test group will be provided vitamin C effervescent tablets to use 1 gram daily with their usual dose of Levothyroxine for 12 weeks, with thyroid function tests assessed at 6 and 12 weeks. The patients who wish to continue at the end of 12 weeks will be provided another 12 weeks supply of vitamin C effervescent tablets to use 1 gram daily with their usual dose of Levothyroxine for with thyroid function tests and clinical score assessed at the end of week 24.	Drug: Vitamin C; The patient in test group will be provided vitamin C effervescent tablets to use 1 gram daily with their usual dose of Levothyroxine for 12 weeks, with thyroid function tests assessed at 6 and 12 weeks. The patients who wish to continue at the end of 12 weeks will be provided another 12 weeks supply of vitamin C effervescent tablets to use 1 gram daily with their usual dose of Levothyroxine for with thyroid function tests and clinical score assessed at the end of week 24.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Thyroid function (TSH)	The primary outcome will be assessing the change in TSH levels in mIU/ml before and after supplementation the same levothyroxine dose with and without intervention (1 gram of effervescent vitamin C).	24 weeks
Change in Thyroid function (T4)	The primary outcome will be assessing the change in T4 levels in pmol/L before and after supplementation the same levothyroxine dose with and without intervention (1 gram of effervescent vitamin C).	24 weeks
Change in Thyroid function (T3)	The primary outcome will be assessing the change in T3 levels in pmol/L before and after supplementation the same levothyroxine dose with and without intervention (1 gram of effervescent vitamin C).	24 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in clinical status	The clinical response will be assessed by evaluating for any change in Billewicz index scoring scale questionnaires before and after intervention. Billewicz index score ≥ +25 for overt hypothyroidism; score of -30 to +25 (above -30 and below +25) for subclinical hypothyroidism; and score ≤ -30 for excluding hypothyroidism)	24 weeks

Collaborators and Investigators

• Sponsor: Dr Adnan Agha
• Investigators: Principal Investigator: Adnan Agha, United Arab Emirates University

Publications and helpful links

General Publications

• de Benoist B, McLean E, Andersson M, Rogers L. Iodine deficiency in 2007: global progress since 2003. Food Nutr Bull. 2008 Sep;29(3):195-202. doi: 10.1177/156482650802900305.
• Jubiz W, Ramirez M. Effect of vitamin C on the absorption of levothyroxine in patients with hypothyroidism and gastritis. J Clin Endocrinol Metab. 2014 Jun;99(6):E1031-4. doi: 10.1210/jc.2013-4360. Epub 2014 Mar 6.
• Virili C, Antonelli A, Santaguida MG, Benvenga S, Centanni M. Gastrointestinal Malabsorption of Thyroxine. Endocr Rev. 2019 Feb 1;40(1):118-136. doi: 10.1210/er.2018-00168.

Study record dates

Study Major Dates

• Study Start (Actual): November 1, 2023
• Primary Completion (Estimated): March 1, 2024
• Study Completion (Estimated): June 1, 2024

Study Registration Dates

• First Submitted: February 2, 2023
• First Submitted That Met QC Criteria: February 14, 2023
• First Posted (Actual): February 17, 2023

Study Record Updates

• Last Update Posted (Actual): January 11, 2024
• Last Update Submitted That Met QC Criteria: January 10, 2024
• Last Verified: January 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Endocrine System Diseases; Hematologic Diseases; Nutrition Disorders; Hemorrhagic Disorders; Thyroid Diseases; Hemostatic Disorders; Avitaminosis; Deficiency Diseases; Malnutrition; Hypothyroidism; Scurvy; Ascorbic Acid Deficiency; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Protective Agents; Micronutrients; Antioxidants; Vitamins; Ascorbic Acid
• Other Study ID Numbers: UAEU_CMHS_IM_DOH_2023/56

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No