Digoxin for the Reinduction of Radioiodine Uptake in Metastatic or Locally Advanced Non-medullary Thyroid Carcinoma (DIGUP-TC)

Non-medullary thyroid carcinoma has a good prognosis in most patients. However, a small subset of patients nevertheless develop metastatic or locally advanced and unresectable disease which in some cases also becomes radioiodine refractory. In these patients treatment options are very limited. Earlier cell line and animal studies have shown that digoxin can reinduce radioiodine uptake in non-medullary thyroid cancer. This study serves as a proof of principle study to assess the possibility of digoxin to reinduce radioiodine uptake in adult humans with metastatic or locally advanced non-medullary radioiodine refractory thyroid carcinoma.

Study Overview

• Status: Completed
• Conditions: Non-Medullary Thyroid Carcinoma
• Intervention / Treatment: Drug: Digoxin tablet

• Study Type: Interventional
• Enrollment (Actual): 8
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Netherlands
  • Nijmegen, Netherlands
    • Radboud University Medical Center

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• Non-medullary thyroid carcinoma
• Having undergone total thyroidectomy and at least 1 treatment with [131]sodium iodine (NaI)
• Presence of local or metastatic disease, radiologically proven. A minimum of 1 target lesion (at least 1cm for soft tissue and 1.5cm for lymph nodes) must be present.
• Radioiodine refractory disease; at least one lesion without therapeutic relevant uptake at previous post-therapeutic scintigraphy and/or negative diagnostic [123]NaI-scan.
• The target lesion must not be eligible for local treatments.
• Hematologic lab values should be at least: absolute neutrophil count >1.4x10^9/liter, hemoglobin>5.5mmol/liter, thrombocytes >99x10^9/liter

Exclusion Criteria:

• Creatinine clearance <50ml/min and/or active kidney disease
• Cardiac arrhythmias
• Electrolyte disorder
• Concomitant drugs that interfere with digoxin metabolism such as P-glycoprotein inductors or inducers, including but not limited to penicillamine, sulfasalazin, tipranavir, amiodarona, diltiazem, itraconazole, ketoconazole, kinidin, lapatinib, propafenon, vemurafenib, verapamil, azithromycin, clarithromycin, erythromycin, roxithromycin, chloroquin, ciclosporin, anti hepatitis C drugs, anti-HIV drugs, hydroxychloroquine.
• Pregnancy, lactating or breast-feeding women.
• Having undergone a procedure with iodine contrast agent within the last 3 months.
• Prior therapy with radioactive iodine <6 months prior to participation.
• External beam radiation therapy <4 weeks prior to participation.
• Having undergone chemotherapy or targeted therapy <4 weeks prior to participation.
• Eastern Cooperative Oncology Group (ECOG) score >2.
• Use of other investigational drugs within 4 weeks preceding the first dose of digoxin treatment.
• Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to digoxin.
• Uncontrolled intercurrent illness that would limit compliance with the study requirements.
• Unwillingness or inability to comply with study and follow-up procedures.
• Other active malignancies other than basal cell carcinoma. Malignancies that have been in complete remission over 2 years are not considered active malignancies.
• Rapidly progressive disease in which urgent start with systemic therapy is required.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Treatment with digoxin; This arm will consist of 10 patients with radioiodine refractory non-medullary thyroid carcinoma. All participants will be treated according to the same protocol.

Drug: Digoxin tablet; Participants will be treated with digoxin tablets for 3 weeks. On the first they, participants will start with a starting dosage of 3x0.25mg with 6 hours between each administration. Thereafter they will continue with a dosage of 1x0.25mg. Participants aged >70 years or with body weight <55kg will initiate a starting dosage of 3x0.125mg with 6 hours between each administration. Thereafter they will continue with a dosage of 1x0.125mg. After one week the blood concentration of digoxin will be measured. According to this blood concentration, the dose of digoxin will be adjusted.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Reinduction of radioiodine uptake in target lesion	At baseline and after 3 weeks of digoxin treatment, a scintigraphy scan will be conducted. Reinduction of radioiodine uptake is defined as enough uptake that a treatment with high-dose radioactive iodine is possible.	3 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Beneficial effects of high-dose radioactive iodine treatment after reinduction	Participants with reinduction of radioiodine uptake in the target lesion will be offered a treatment with high-dose radioactive iodine, according to the guidelines for the treatment of thyroid carcinoma. The beneficial effects of this treatment will be measured after 6 months with a computertomography scan and will be described using the RECIST criteria.	6 months
Safety of digoxin treatment	All serious adverse events (SAE) occuring during the digoxin treatment will be described.	3 weeks

Collaborators and Investigators

• Sponsor: Radboud University Medical Center

Study record dates

Study Major Dates

• Study Start (Actual): December 6, 2022
• Primary Completion (Actual): June 21, 2023
• Study Completion (Actual): January 1, 2024

Study Registration Dates

• First Submitted: August 17, 2022
• First Submitted That Met QC Criteria: August 17, 2022
• First Posted (Actual): August 19, 2022

Study Record Updates

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

More Information

Terms related to this study

• Keywords: Digoxin; Autophagy; Thyroid cancer; Redifferentiation; Radio-iodine refractory
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site; Adenocarcinoma; Neoplasms, Glandular and Epithelial; Endocrine System Diseases; Endocrine Gland Neoplasms; Head and Neck Neoplasms; Adenocarcinoma, Papillary; Carcinoma; Thyroid Diseases; Thyroid Neoplasms; Thyroid Cancer, Papillary; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Arrhythmia Agents; Enzyme Inhibitors; Protective Agents; Cardiotonic Agents; Digoxin
• Other Study ID Numbers: 2022-500477-14-00

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
• product manufactured in and exported from the U.S.: No