Digoxin for the Reinduction or Radioiodine Uptake in Metastatic or Locally Advanced Non-medullary Thyroid Carcinoma.
- Trial ID
- 2022-500477-14-00
- Protocol
- 113327
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to evaluate the **beneficial effects** of digoxin in patients with non-medullary thyroid carcinoma (NMTC) who present with locally advanced or metastatic disease and exhibit insufficient accumulation of radioiodine (RaI). The focus is on the reinduction of RaI uptake, which is clinically relevant as it may enhance the effectiveness of RaI therapy, a critical treatment modality for NMTC.
Secondary objectives include:
- Investigating the beneficial effects of RaI therapy on tumor progression following the reinduction of RaI uptake with digoxin, and assessing the safety profile of digoxin treatment.
- Exploring alterations in responding and non-responding tumor lesions after re-differentiation treatment at the transcriptional and translational levels, as well as assessing autophagy activity in primary tumors and target lesions, contingent on the availability of material.
Participants
The clinical trial involves participants diagnosed with **non-medullary thyroid carcinoma (NMTC)**, specifically those with locally advanced or metastatic disease. The study population includes both male and female subjects aged 18 years and older. Participants have undergone total thyroidectomy and at least one treatment with radioactive iodine (RaI). The trial focuses on individuals with RaI refractory disease, characterized by at least one lesion without therapeutic relevant RaI uptake. The trial does not include a vulnerable population. The sponsor has not provided information regarding the total number of participants. Participants were selected based on specific inclusion criteria, such as the presence of radiologically proven local or metastatic disease and the requirement for target lesions not eligible for local treatments. Lifestyle considerations such as diet, physical activity, or habits are not specified in the available data.
Plans and Procedures
The clinical trial is designed to evaluate the **beneficial effects of digoxin** in patients with non-medullary thyroid carcinoma (NMTC) who have locally advanced or metastatic disease with insufficient accumulation of radioiodine (RaI) on reinduction of RaI uptake. This is a Phase 4, randomized, double-blind, controlled trial. The trial is expected to last approximately two years, with an estimated recruitment start date of September 1, 2022, and an estimated end date of September 1, 2024.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as a diagnosis of NMTC, age of 18 years or older, and previous treatment with RaI. The presence of local or metastatic disease must be radiologically proven, with at least one target lesion meeting specific size criteria. Follow-up visits will occur at regular intervals to monitor the reinduction of RaI uptake, assess the biochemical response, and evaluate toxicity and quality of life. The primary endpoint is the number and percentage of subjects with reinduction of RaI uptake in RaI refractory target lesions, assessed using RaI scintigraphy. Secondary endpoints include the proportion of subjects with a favorable response to RaI treatment after six months, biochemical response measured by thyroglobulin levels, and toxicity assessment using CTAE criteria v4.0.
The expected length of participant involvement is up to three months for the administration of **digoxin** and two months for the administration of **sodium iodide (123 I)**, with the possibility of early termination if adverse effects occur or if the participant withdraws consent. Participants will receive digoxin orally and sodium iodide (123 I) via intravenous injection. Conditions that may lead to early termination from the study include the development of significant adverse events, non-compliance with study procedures, or withdrawal of consent by the participant. The trial aims to provide valuable insights into the therapeutic potential of digoxin in enhancing RaI uptake in NMTC patients.
Treatment
The clinical trial involves the administration of **Lanoxin 125**, a pharmaceutical product containing the active substance **digoxin**. This medication is provided in the form of a **tablet** with a dosage strength of 0.125 mg. The route of administration is **oral use**, and the maximum daily dose is 0.25 mg, with a total maximum dose of 3.5 mg over a treatment period of up to 3 weeks. The product is manufactured by Aspen Pharma Trading Limited and is classified under the ATC code C01AA05, indicating its role as a cardiac glycoside. Participant compliance with the dosing schedule will be monitored throughout the trial to ensure adherence to the prescribed regimen.
Additionally, the trial includes the use of **Sodium Iodide (I123) Injection**, which serves as an auxiliary treatment. This product is a **solution for injection** with a concentration of 37 MBq/ml. The active substance, **sodium iodide (123 I)**, is administered via **intravenous injection**. The maximum daily dose is 148 MBq, with a total maximum dose of 296 MBq over a treatment period of up to 2 days. This product is manufactured by Curium Netherlands B.V. and is classified under the ATC code V09FX02. The administration of this auxiliary treatment will be carefully monitored to ensure proper dosing and participant safety.
Efficacy
Efficacy in this clinical trial will be assessed through both primary and secondary endpoints. The primary endpoint focuses on the reinduction of radioactive iodine (RaI) uptake in RaI refractory target lesions in patients with non-medullary thyroid carcinoma (NMTC). This will be evaluated by measuring the number and percentage of subjects showing reinduction of RaI uptake using RaI scintigraphy.
Secondary endpoints include several measures: the proportion of subjects with a favorable response to RaI treatment after six months, assessed according to RECIST criteria; biochemical response to RaI treatment after six months, measured by thyroglobulin (TG) levels; toxicity assessment using the Common Terminology Criteria for Adverse Events (CTAE) version 4.0; and quality of life evaluated through the EORTC QLQ-C30 questionnaire. Additionally, correlations between molecular patterns in pre-treatment biopsies and other study endpoints will be explored, if available.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Being diagnosed with NMTC.
- Being aged ≥18 years.
- Having undergone total thyroidectomy and at least 1 treatment with RaI.
- The presence of local or metastatic disease, radiologically proven. A minimum of 1 target lesion (minimum of 1.0 cm for soft tissue and 1.5 cm for lymph nodes) must be present.
- RaI refractory disease: at least one lesion (target lesion, needs to fulfil the above-mentioned criteria) without therapeutic relevant RaI uptake at previous post-therapeutic RaI scintigraphy and/or negative diagnostic RaI scan.
- Target lesion must not be eligible for local treatments (radiotherapy, radiofrequency ablation, etc.). In case of multiple lesions, local treatment is allowed, but these lesions are not considered target lesions.
Exclusion Criteria
- Contraindications for digoxin: Creatinine clearance < 50 ml/min and/or active kidney disease; Cardiac arrhythmias (history of arrhythmias and arrhythmias at ECG); Electrolyte disorders
- Pregnancy, lactating or breast-feeding women. Negative pregnancy test is mandatory within 7 days prior to starting the study premenopausal women. Women of non-childbearing potential may be included without pregnancy test if they are either surgically sterile or have been postmenopausal for ≥ 1 year. Fertile men and women must use an effective method of contraception during treatment and for at least 6 months after completion of treatment as directed by their physician. Effective methods of contraception are defined as those, which result in a low failure rate (i.e., less than 1% per year) when used consistently and correctly (for example implants, injectables, combined oral contraception or intra-uterine devices). At the discretion of the investigator, acceptable methods of contraception may include total abstinence in cases where the lifestyle of the patient ensures compliance. (Periodic abstinence [e.g., calendar, ovulation, symptothermal, postovulation methods] and withdrawal are not acceptable methods of contraception).
- Having undergone a CT-scan with contrast agent within the last three months (this would reduce the iodide uptake).
- Prior therapy with 131I <6 months prior to initiation of therapy on this protocol. A diagnostic study using <400 MBq of 131I is not considered 131I-therapy.
- External beam radiation therapy < 4 weeks prior to initiation of therapy on this protocol. (Previous treatment with radiation for any indication is allowed if the investigator judges that the previous radiation does not significantly compromise patient safety on this protocol).
- Chemotherapy or targeted therapy (e.g., tyrosine kinase inhibitor) is not allowed < 4 weeks prior to the initiation of therapy on this protocol.
- Eastern Cooperative Oncology Group (ECOG) score >2.
- Use of other investigational drugs within 4 weeks preceding the first dose of drug treatment during this study.
- A known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to the investigational drug.
- Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection or psychiatric illness/social situations that would limit compliance with study requirements.
- Unwillingness or inability to comply with study and follow-up procedures.
- Condition of patient which is critical to participate in this study in the discretion of the PI.
- Rapidly progressive disease in which urgent start with systemic therapy is required.
- Concomitant drugs that interfere with digoxin metabolism such as P-glycoprotein inductors or inhibitors, including but not limited to penicillamin, sufasalazin, tipranavir, amiodaron, diltiazem, itraconazol, ketoconazol, kinidin, lapatinib, propafenon, vemurafenib, verapamil, azitromycin, claritromycin, erythromycin, roxitromycin, chloroquin, ciclosporin, anti HCV drugs, anti-HIV drugs, hydroxychloroquine.
- Patients who do not have normal organ and bone marrow function as defined below: Absolute neutrophil count (ANC) >1.5x109/L; Hemoglobin ≥ 9 g/dL; Platelets ≥ 100 x 109/L.
- Other active malignancies other than basal cell carcinoma. Malignancies that have been in complete remission for >2 years are not considered active malignancies.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 The Netherlands | Not Recruiting | 01 Sept 2022 | — |
| Netherlands | — | — | 10 |
Sites & Investigators
Research sites
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
Lanoxin 125, tabletten 0,125 mg | Test | TABLETTEN | ORAL USE | 0.25 | 3 | PRD981194 |
Sodium Iodide (I123) Injection, oplossing voor injectie 37 MBq/ml | Other | OPLOSSING VOOR INJECTIE | INTRAVENOUS INJECTION | 148 | 2 | PRD5822487 |