T3 Instillation for Acute Respiratory Distress Syndrome

(ARDS+T3 Trial)

Recruiting at 4 trial locations

Overseen By David Ingbar, MD

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: University of Minnesota

Disqualifiers: Thyroid cancer, Hyperthyroidism, Cardiovascular disease, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: 5 days

68 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. It's best to discuss this with the trial coordinators or your doctor.

What data supports the effectiveness of the drug Liothyronine Sodium (T3) for treating acute respiratory distress syndrome (ARDS)?

Research shows that T3 can enhance lung function by improving alveolar fluid clearance, which is important for recovery in ARDS. In animal studies, a reformulated version of T3 was safely administered to the lungs, paving the way for human trials to assess its impact on lung water levels in ARDS patients. ^{1 2 3 4 5}

Is T3 (Liothyronine Sodium) safe for human use?

T3 (Liothyronine Sodium) has been used safely in various treatments, including thyroid cancer and depression, often in combination with other thyroid hormones. Studies show it can be administered in controlled doses to maintain stable hormone levels without significant side effects. ^{1 6 7 8 9}

How is the drug Liothyronine Sodium (T3) unique in treating Acute Respiratory Distress Syndrome?

Liothyronine Sodium (T3) is unique because it is a thyroid hormone that can be administered in liquid form, potentially allowing for precise dosing adjustments. This is different from standard treatments for Acute Respiratory Distress Syndrome, which typically do not involve thyroid hormones. ^{1 6 7 10 11}

What is the purpose of this trial?

It is hypothesized that instillation of Liothyronine Sodium (T3) into the airspace will be safe, well tolerated, and will increase alveolar fluid clearance and decrease inflammation in patients with ARDS, reflected in improved oxygenation index (OI) and oxygenation saturation index (OSI).

Research Team

David H Ingbar, MD

Principal Investigator

University of Minnesota

Timothy P Rich, MD

Principal Investigator

University of Minnesota

Ronald A Reikoff, MD

Principal Investigator

University of Minnesota

Eligibility Criteria

This trial is for adults over 18 with ARDS needing ventilators in ICU. They must be able to consent or have a representative who can, and not be pregnant or breastfeeding. Excluded are those allergic to the drug, with thyroid cancer, hyperthyroidism, significant heart disease, or unlikely to follow the study through.

Inclusion Criteria

I am not pregnant.

I can give my consent or have someone legally authorized to do so on my behalf.

I am in the ICU and need a machine to help me breathe due to severe lung injury.

Exclusion Criteria

Known allergy to study drug.

Inadequate medical history for determining inclusion/exclusion criteria, as determined by the Principal Investigator and/or Sub- Investigators.

Unlikely to complete the protocol with clinic follow-up after discharge, as determined by the Principal Investigator and/or Sub- Investigators or hospice status.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

1-2 weeks

Treatment

Participants receive Liothyronine Sodium (T3) instilled into the airway twice daily for 5 days or until extubation

5 days

Daily monitoring during treatment

Follow-up

Participants are monitored for safety and effectiveness after treatment, including oxygenation indices and cardiovascular events

120 hours post-dose

Treatment Details

Interventions

• Liothyronine Sodium (T3)

Trial Overview The trial tests if Liothyronine Sodium (T3), instilled directly into the lungs of ARDS patients, is safe and effective at improving lung function by increasing fluid clearance and reducing inflammation as measured by oxygenation levels.

Participant Groups

Group I: Treatment Arm Experimental Treatment 1 Intervention

Liothyronine Sodium (T3+0.9% sodium chloride) modified formulation specifically for airway instillation.

Group II: Control arm Experimental Treatment 1 Intervention

Standard of Care

Liothyronine Sodium (T3) is already approved in United States, European Union for the following indications:

Approved in United States as Cytomel for:

• Hypothyroidism
• Myxedema coma
• Thyroid suppression test
• TSH suppression
• Underactive thyroid

Approved in European Union as Tertroxin for:

• Hypothyroidism
• Myxedema coma

Who Is Running the Clinical Trial?

University of Minnesota

Lead Sponsor

Trials

1,459

Recruited

1,623,000+

Findings from Research

In a study of nine depressed patients receiving levothyroxine (T4) for thyroid disease, seven patients showed a positive response to T3 augmentation therapy after not responding to standard antidepressant treatments.

The findings suggest that T3 may have a unique role in enhancing the effects of antidepressants in patients with thyroid disease, indicating a potential mechanism for thyroid hormone involvement in depression treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

T3 augmentation of antidepressant treatment in T4-replaced thyroid patients. Cooke, RG., Joffe, RT., Levitt, AJ.[2013]

In a study of six male subjects with primary hypothyroidism, serum levels of T4 and T3 decreased while rT3 increased during hospitalization for acute illness, but returned to normal levels shortly after discharge.

The transient changes in thyroid hormone levels and TSH suggest that healthcare providers should avoid making frequent adjustments to Levothyroxine (LT4) doses during acute illnesses, as these fluctuations are similar to those seen in healthy individuals.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Thyroid hormone indices during illness in six hypothyroid subjects rendered euthyroid with levothyroxine therapy. Wadwekar, D., Kabadi, UM.[2015]

A reformulated version of the thyroid hormone T3, when administered intratracheally in a safe dose, showed no significant adverse effects in a preclinical study with healthy rats, paving the way for future clinical trials.

This study supports the initiation of a phase I/II clinical trial to evaluate the safety and tolerability of T3 in patients with acute respiratory distress syndrome (ARDS), including those affected by COVID-19, highlighting its potential as a treatment for pulmonary edema.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Preclinical Safety Study of Thyroid Hormone Instilled into the Lungs of Healthy Rats-an Investigational Therapy for ARDS. Flory, CM., Norris, BJ., Larson, NA., et al.[2021]

A 78-year-old woman developed severe hypothyroidism after total thyroidectomy for hyperthyroidism, which worsened despite increasing doses of levothyroxine, leading to respiratory failure.

The addition of liothyronine (T3) to her treatment resulted in complete recovery, indicating that her body had impaired conversion of T4 (thyroxine) to T3 (triiodothyronine), which was crucial for her recovery.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Hypothyroidism and muscular respiratory failure successfully treated with liothyronine. Finsterer, J., Prainer, C., Stöllberger, C., et al.[2013]

Combined treatment with levothyroxine and liothyronine for hypothyroidism has shown potential benefits in mood, quality of life, and psychometric performance in some studies, suggesting it may be preferred by patients over levothyroxine alone.

Despite these potential benefits, the addition of liothyronine could lead to adverse events, and until more clear advantages are established, levothyroxine alone remains the recommended treatment for hypothyroidism.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment of hypothyroidism with levothyroxine or a combination of levothyroxine plus L-triiodothyronine. Escobar-Morreale, HF., Botella-Carretero, JI., Morreale de Escobar, G.[2015]

In a study of 21 high-risk patients with differentiated thyroid cancer (DTC) who did not achieve target TSH levels on levothyroxine alone, the addition of liquid liothyronine (L-T3) helped all patients reach the desired TSH suppression after dose adjustments.

The use of liquid L-T3 was safe, with no adverse events reported, and allowed for individualized dosing based on body weight, making it a promising option for optimizing TSH levels in patients with DTC.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Liquid liothyronine to obtain target TSH in differentiated thyroid cancer patients. Trimboli, P., Centanni, M., Virili, C.[2022]

The pharmacokinetics (PK) of L-triiodothyronine (LT3) in patients without endogenous thyroid hormone production was characterized, showing a rapid distribution phase and a slow elimination phase, which is crucial for designing effective combination therapies with levothyroxine (LT4).

A proposed dosing strategy of low-dose LT3 (0.07 mcg/kg twice daily) in combination with LT4 can maintain serum T3 levels within the reference range, minimizing the risk of supraphysiologic levels and ensuring safer treatment for thyroid cancer patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacokinetics of L-Triiodothyronine in Patients Undergoing Thyroid Hormone Therapy Withdrawal. Van Tassell, B., Wohlford, GF., Linderman, JD., et al.[2020]

In a study of patients with hypothyroidism switching from levothyroxine to liothyronine, once-daily liothyronine administration resulted in significant fluctuations in serum T3 levels, with peak concentrations reaching 292.8 ng/dL after dosing.

Despite the increase in T3 levels, serum TSH did not return to baseline levels seen with levothyroxine therapy, indicating that liothyronine monotherapy may not fully replicate the hormonal balance achieved with levothyroxine.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Daily Administration of Short-Acting Liothyronine Is Associated with Significant Triiodothyronine Excursions and Fails to Alter Thyroid-Responsive Parameters. Jonklaas, J., Burman, KD.[2022]

A single dose of 50-mcg liothyronine in 12 healthy participants resulted in a peak in triiodothyronine levels at 2.5 hours, followed by a transient increase in heart rate that was significant by 5 hours after administration.

The administration of liothyronine led to a sustained suppression of TSH levels for 2-3 days, indicating that while the increase in triiodothyronine was short-lived, its effects on TSH were prolonged.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Single-dose T3 administration: kinetics and effects on biochemical and physiological parameters. Jonklaas, J., Burman, KD., Wang, H., et al.[2021]

Three cases of myxedema coma were successfully treated with I-triiodothyronine (T3) administered either nasogastrically or intravenously, highlighting the efficacy of T3 in rapidly correcting severe hypothyroidism symptoms in critically ill patients.

In cases where oral T3 was not absorbed due to intestinal issues, intravenous T3 was effective in restoring metabolic function, while oral thyroxine (T4) alone was insufficient to raise serum T3 levels in these patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Management of myxedema coma: report on three successfully treated cases with nasogastric or intravenous administration of triiodothyronine. Pereira, VG., Haron, ES., Lima-Neto, N., et al.[2018]

Poly-zinc-liothyronine (PZL) capsules provide a more stable release of T3 hormone compared to traditional liothyronine (LT3), resulting in a lower peak and a longer duration of elevated T3 levels in the blood, which is beneficial for managing hypothyroidism.

In a study with hypothyroid male Wistar rats, PZL treatment led to a more gradual decrease in serum TSH levels and restored T3-dependent biological effects, indicating its potential for improved long-term management of thyroid hormone levels.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Metal Coordinated Poly-Zinc-Liothyronine Provides Stable Circulating Triiodothyronine Levels in Hypothyroid Rats. Da Conceição, RR., Fernandes, GW., Fonseca, TL., et al.[2020]

References

1. United States pubmed.ncbi.nlm.nih.gov

T3 augmentation of antidepressant treatment in T4-replaced thyroid patients. [2013]

2. Germany pubmed.ncbi.nlm.nih.gov

Thyroid hormone indices during illness in six hypothyroid subjects rendered euthyroid with levothyroxine therapy. [2015]

3. United States pubmed.ncbi.nlm.nih.gov

A Preclinical Safety Study of Thyroid Hormone Instilled into the Lungs of Healthy Rats-an Investigational Therapy for ARDS. [2021]

4. United States pubmed.ncbi.nlm.nih.gov

Hypothyroidism and muscular respiratory failure successfully treated with liothyronine. [2013]

5. Netherlands pubmed.ncbi.nlm.nih.gov

Treatment of hypothyroidism with levothyroxine or a combination of levothyroxine plus L-triiodothyronine. [2015]

6. Japan pubmed.ncbi.nlm.nih.gov

Liquid liothyronine to obtain target TSH in differentiated thyroid cancer patients. [2022]

7. United States pubmed.ncbi.nlm.nih.gov

Pharmacokinetics of L-Triiodothyronine in Patients Undergoing Thyroid Hormone Therapy Withdrawal. [2020]

8. United States pubmed.ncbi.nlm.nih.gov

Daily Administration of Short-Acting Liothyronine Is Associated with Significant Triiodothyronine Excursions and Fails to Alter Thyroid-Responsive Parameters. [2022]

9. United States pubmed.ncbi.nlm.nih.gov

Single-dose T3 administration: kinetics and effects on biochemical and physiological parameters. [2021]

10. Italy pubmed.ncbi.nlm.nih.gov

Management of myxedema coma: report on three successfully treated cases with nasogastric or intravenous administration of triiodothyronine. [2018]

11. United States pubmed.ncbi.nlm.nih.gov

Metal Coordinated Poly-Zinc-Liothyronine Provides Stable Circulating Triiodothyronine Levels in Hypothyroid Rats. [2020]