Thyroid Hormone Supplementation for Hypothyroidism in Hemodialysis Patients

(THYROID-HD Trial)

Overseen By Connie Rhee, MD, MSc

Age: 18+

Sex: Any

Trial Phase: Academic

Sponsor: University of California, Irvine

Must not be taking: Thyroid hormones, Anti-thyroid

Disqualifiers: Kidney transplant, Malignancy, Pregnancy, others

Approved in 6 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: 24 weeks

336 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to determine if levothyroxine, a thyroid hormone supplement, can benefit people on dialysis who have hypothyroidism, a condition where the thyroid gland doesn't produce enough hormones. Researchers seek to assess whether levothyroxine can enhance quality of life, physical performance, and heart health in these patients. They are also examining its effects on metabolism, such as changes in body fat and energy use. Suitable candidates for this trial have been on dialysis for at least four weeks and have thyroid levels outside the normal range, but not excessively high. As an unphased trial, this study provides a unique opportunity to contribute to understanding levothyroxine's benefits for dialysis patients with hypothyroidism.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but you cannot participate if you are actively taking thyroid hormone supplements or anti-thyroid medications.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that levothyroxine, a common treatment for low thyroid hormone levels, is usually well-tolerated by most people. This FDA-approved medication is widely used for thyroid problems. Studies have found that, when taken as directed, it typically doesn't cause major issues.

However, some people might experience mild side effects like a faster heartbeat or higher blood pressure. Following the doctor's instructions and informing them about any other medications being taken is important. This ensures safe use and prevents unwanted reactions. Overall, levothyroxine is considered safe for most people, especially when monitored by a healthcare professional. ^{1 2 3 4 5}

Why are researchers excited about this trial?

Levothyroxine Sodium is unique because it specifically targets thyroid hormone imbalances in hemodialysis patients with hypothyroidism, which is a group that often experiences complex treatment challenges. Unlike standard treatments that might not be tailored for those undergoing dialysis, this approach considers the unique TSH levels found in these patients. Researchers are excited about its potential to provide more precise hormone regulation, possibly leading to better overall management of hypothyroidism in this specific population.

What evidence suggests that levothyroxine might be an effective treatment for hypothyroidism in hemodialysis patients?

Research has shown that levothyroxine, a medication that replaces thyroid hormones, can benefit people with chronic kidney disease (CKD) who have a mild form of underactive thyroid. Studies found that this medication reduced the risk of worsening kidney function by 64%. In this trial, participants will receive either levothyroxine or a placebo at random. Levothyroxine has been linked to better quality of life and heart health for dialysis patients with slightly high thyroid-stimulating hormone (TSH) levels. While some reports mention cost and health benefits of using levothyroxine, there is no clear proof that it improves overall kidney function. This treatment is often prescribed for CKD, but more research is needed to fully understand its safety and effectiveness in these patients. ^{6 7 8 9 10}

Are You a Good Fit for This Trial?

This trial is for people aged 18-75 on hemodialysis with mild to moderate hypothyroidism, not currently treated for thyroid issues. They must have stable heart function and no severe bone disease, weigh less than 450 lbs., and not be pregnant or planning pregnancy.

Inclusion Criteria

I have been on hemodialysis for at least four weeks.

Have ability to provide written informed consent

Your thyroid test results show that your TSH levels are consistently between 3.0 and 10.0mIU/L.

Exclusion Criteria

I am currently taking medication for my thyroid condition.

I am currently on dialysis.

I am currently experiencing worsening heart failure symptoms.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive levothyroxine or placebo for 24 weeks with dose titrations at 8 and 16 weeks based on TSH levels

24 weeks

Regular visits for dose titration and monitoring

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Levothyroxine Sodium
• Placebos

Trial Overview The study tests if Levothyroxine improves life quality and cardiovascular health in dialysis patients compared to a placebo. It also looks at metabolic effects like changes in body fat and energy use.

How Is the Trial Designed?

Group I: Levothyroxine Experimental Treatment 1 Intervention

Patients will be randomized to levothyroxine or placebo (similar in size, shape, and color to levothyroxine) via permuted blocks stratified by two TSH levels (\>3.0-5.0 and 5.0-10.0mIU/L) to ensure treatment balance across TSH levels. The study medications will be prepared in pill form. In the treatment arm, initial L-T4 doses will be 25mcg vs. 50mcg among patients whose TSH is \>3.0-5.0mIU/L vs. 5.0-10.0mIU/L, respectively. Patients in the placebo arm will receive an equivalent number of placebo pills daily depending upon TSH level. The intervention period is 24 weeks. Patients will undergo up to two subsequent dose titrations after 8- and 16-weeks of treatment, based on interim TSH measurements at these time points. Patients whose TSH levels are higher or lower than the therapeutic TSH target of 0.5-3.0mIU/L will undergo a dose adjustment (+/- 25mcg), while those whose TSH levels are in target range will continue the prior dose.

Group II: Placebo Placebo Group 1 Intervention

Patients will be randomized to levothyroxine or placebo (similar in size, shape, and color to levothyroxine) via permuted blocks stratified by two TSH levels (\>3.0-5.0 and 5.0-10.0mIU/L) to ensure treatment balance across TSH levels. The study medications will be prepared in pill form. In the treatment arm, initial L-T4 doses will be 25mcg vs. 50mcg among patients whose TSH is \>3.0-5.0mIU/L vs. 5.0-10.0mIU/L, respectively. Patients in the placebo arm will receive an equivalent number of placebo pills daily depending upon TSH level. The intervention period is 24 weeks. Patients in the placebo arm will undergo an equivalent titration in placebo pills (as that of the experimental arm) after 8- and 16-weeks of treatment, based on interim TSH measurements at these time points.

Levothyroxine Sodium is already approved in European Union, United States, Canada, Japan, China, Switzerland for the following indications:

Approved in European Union as Levothyroxine Sodium for:

• Hypothyroidism
• Thyroid nodules
• Thyroid cancer

Approved in United States as Levothyroxine Sodium for:

• Hypothyroidism
• Thyroid nodules
• Thyroid cancer
• Goiter

Approved in Canada as Levothyroxine Sodium for:

• Hypothyroidism
• Thyroid nodules
• Thyroid cancer

Approved in Japan as Levothyroxine Sodium for:

• Hypothyroidism
• Thyroid nodules
• Thyroid cancer

Approved in China as Levothyroxine Sodium for:

• Hypothyroidism
• Thyroid nodules
• Thyroid cancer

Approved in Switzerland as Levothyroxine Sodium for:

• Hypothyroidism
• Thyroid nodules
• Thyroid cancer

Who Is Running the Clinical Trial?

University of California, Irvine

Lead Sponsor

Trials

580

Recruited

4,943,000+

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Collaborator

Trials

2,513

Recruited

4,366,000+

Published Research Related to This Trial

Levothyroxine sodium is the preferred treatment for most patients with hypothyroidism, providing stable hormone levels without daily fluctuations, and optimal dosing is guided by maintaining a TSH level of 1-2 mU/L.

In younger patients, starting with a near full dose of levothyroxine is effective, while older patients or those with coronary artery disease should begin with a lower dose to minimize risks of cardiac events and osteoporosis from over-replacement.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Optimizing treatment of hypothyroidism. Clarke, N., Kabadi, UM.[2019]

Levothyroxine sodium treatment effectively prevented progressive renal failure in a 49-year-old female patient with diabetes and hypothyroidism over a period of more than 24 months.

Before treatment, the patient's renal function worsened, as indicated by a negative slope in serum creatinine levels, which improved to a positive slope after starting levothyroxine, suggesting its efficacy in stabilizing renal function.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Prevention of progressive renal failure by levothyroxine sodium in a diabetic patient with renal insufficiency and hypothyroidism. Miura, M., Nomoto, Y., Sakai, H.[2019]

In a study of 20 patients undergoing renal transplantation, it was found that restoring kidney function led to a significant reduction in their need for oral thyroxine, a medication used to treat hypothyroidism.

The study suggests that factors like iodide excess and drug interactions during dialysis may have contributed to both the hypothyroidism and the increased thyroxine requirements, highlighting the importance of monitoring thyroid function after transplantation to prevent potential health issues.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Changes in thyroxine requirements in patients with hypothyroidism undergoing renal transplantation. Thomas, MC., Mathew, TH., Russ, GR.[2013]

L-Thyroxin Henning 100 demonstrated significantly higher bioavailability compared to Eferox 100, leading to higher free thyroxine (fT4) levels and a greater reduction in serum TSH levels after 14 days of treatment in a study involving 60 euthyroid volunteers.

The study suggests that when switching between different LT4 preparations, regular monitoring of serum TSH and fT4 levels is essential to prevent metabolic imbalances, as individual factors like gender and body weight can influence bioavailability.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Randomized, double-blind crossover study of bioavailability of levothyroxine]. Krehan, A., Dittmar, M., Hoppen, A., et al.[2019]

A 49-year-old woman with hypothyroidism experienced liver dysfunction after increasing her levothyroxine dose, which was resolved after stopping the medication, indicating a case of levothyroxine-induced liver injury.

Switching to a different levothyroxine formulation (Letrox®) without lactose and gradually increasing the dose helped maintain normal liver enzyme levels, suggesting that careful dosing and formulation choice are important in preventing drug-induced liver injury.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Liver dysfunction induced by Levothyroxine Sodium Tablets (Euthyrox®) in a hypothyroid patient with Hashimoto's thyroiditis: case report and literature review. Yu, H., Zhang, W., Shen, C., et al.[2020]

A 71-year-old female patient with end-stage renal disease and uncontrolled hypothyroidism was successfully treated with intravenous (IV) levothyroxine during hemodialysis sessions after refusing oral and intramuscular forms of the medication.

The patient's thyroid function normalized within 19 weeks of starting IV levothyroxine, leading to a resolution of her psychosis, highlighting the efficacy of this unconventional treatment approach when standard methods are not feasible.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

INTRAVENOUS LEVOTHYROXINE DURING HEMODIALYSIS IN A PATIENT WITH HYPOTHYROIDISM AND NON-ADHERENCE TO ORAL MEDICATIONS. Avichal, D., Kravets, I.[2022]

In a study of 107 hemodialysis patients across four centers, there was no evidence of thyroid dysfunction despite the presence of low-T3 syndrome, indicating that hypothyroidism may not be prevalent in this population.

Significant differences in thyroid hormone levels were observed between centers, with the center showing the highest hormone levels also having the best metabolic control, suggesting that factors like patient management and dialysis techniques may influence thyroid hormone concentrations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Center-specific variations of thyroid hormone serum levels in hemodialysis patients. Weissel, M., Stummvoll, HK., Kovarik, J., et al.[2018]

Levothyroxine sodium (LT4) is the primary treatment for hypothyroidism, aiming to achieve normal thyroid-stimulating hormone (TSH) levels, with dosages typically starting at 50-100 micrograms for adults without heart disease risk, and lower for older patients or those at risk.

Regular monitoring of TSH levels is crucial after establishing the appropriate LT4 dose, with evaluations starting at six months and continuing annually, to ensure effective management of the condition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Treatment of hypothyroidism]. Massol, J.[2013]

Levothyroxine (LT4) therapy significantly reduced urinary albumin excretion rate (UAER) and improved cholesterol levels in 136 patients with early type 2 diabetic nephropathy and subclinical hypothyroidism after 48 weeks of treatment.

The study suggests that LT4 may offer kidney protection in these patients, but further research with larger sample sizes and longer follow-up is needed to confirm these findings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Can levothyroxine treatment reduce urinary albumin excretion rate in patients with early type 2 diabetic nephropathy and subclinical hypothyroidism? A randomized double-blind and placebo-controlled study. Liu, P., Liu, R., Chen, X., et al.[2018]

In a study of 3965 adult patients using levothyroxine (LT4), those taking oral liquid formulations showed greater variability in thyroid stimulating hormone (TSH) levels compared to tablet users, indicating potential differences in absorption or metabolism.

During drug-drug interactions (DDIs), patients using oral liquid LT4 had less increase in prescribed daily dosages (PDDs) compared to those using tablets, suggesting that liquid formulations may be more stable in complex therapeutic regimens.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Drug interactions in users of tablet vs. oral liquid levothyroxine formulations: a real-world evidence study in primary care. Guglielmi, V., Bellia, A., Bianchini, E., et al.[2019]

In a study of 200 patients with stage 3-4 chronic kidney disease (CKD), treatment with levothyroxine improved nutritional indicators such as weight, grip strength, hemoglobin, and serum albumin compared to a control group.

Levothyroxine treatment also led to an increase in estimated glomerular filtration rate (eGFR) in the treatment group, indicating a delay in kidney disease progression, particularly more effective in patients with stage 3 CKD than in those with stage 4.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FAVORABLE EFFECT OF LEVOTHYROXINE ON NUTRITIONAL STATUS OF PATIENTS WITH STAGE 3-4 CHRONIC KIDNEY DISEASE. Tang, W., Chen, Q., Chen, L., et al.[2023]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11897748/

Thyroid hormone replacement therapy in dialysis/renal ... This article reviews the mechanism of hypothyroidism in dialysis/renal insufficiency patients and describes the importance and precautions of thyroid hormone ...

2. withpower.com withpower.com/trial/phase-thyroid-diseases-6-2019-879ae

Thyroid Hormone Supplementation for Hypothyroidism in ... This trial tests if levothyroxine, a thyroid hormone replacement, can improve quality of life and heart health in dialysis patients with slightly high TSH ...

3. sciencedirect.com sciencedirect.com/science/article/pii/S2214623724000309

Cross-section of thyroidology and nephrology This study showed that thyroid hormone replacement in subclinical hypothyroidism among patients with CKD resulted in risk reduction for halving eGFR of 64 % and ...

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC7889570/

Effect of Levothyroxine on Kidney Function in Chronic ... Levothyroxine use was associated with economic and clinical benefit in some patients with CKD + SCH, despite an absence of overall benefit on eGFR.

5. researchgate.net researchgate.net/publication/394060913_Levothyroxine_treatment_for_subclinical_hypothyroidism_and_risk_of_adverse_renal_outcomes_a_population-based_cohort_study

Levothyroxine treatment for subclinical hypothyroidism and ... The primary outcome was a composite end point of end-stage renal disease (requiring dialysis) and lowering of the estimated glomerular ...

6. ncbi.nlm.nih.gov ncbi.nlm.nih.gov/books/NBK539808/

Levothyroxine - StatPearls - NCBI Bookshelf - NIH Oral levothyroxine is primarily indicated for treating primary, secondary, and tertiary hypothyroidism. Primary hypothyroidism is when the problem occurs in the ...

7. accessdata.fda.gov accessdata.fda.gov/drugsatfda_docs/label/2008/021402s017lbl.pdf

021402s017, SYNTHROID LEVOTHYROXINE SODIUM Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.

8. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC7338005/

Thyroid Disease in End-Stage Renal Disease - PMC Emerging data show that hypothyroidism is associated with higher risk of cardiovascular disease, worse patient-centered outcomes, and survival in the advanced ...

9. medsafe.govt.nz medsafe.govt.nz/profs/datasheet/s/Synthroidtab.pdf

Data Sheet - Synthroid Levothyroxine sodium should be administered with caution to patients in whom there is a suspicion of thyroid gland autonomy, in view of the fact ...

10. accessdata.fda.gov accessdata.fda.gov/drugsatfda_docs/nda/2000/21210_unithroid_medr.pdf

10/19/99 & 6/21/2000 Drug: Unithroid (Levothyroxine sodium ... This review summarizes in detail published literature relating to the safety and efficacy of levothyroxine sodium as replacement or ...