DTPA (Diethylenetriaminepenta-acetate) Chelation for Symptoms After Gadolinium-assisted MRI Exposure

DTPA Chelation for Symptoms After Gadolinium-assisted MRI

The study aims at gathering additional data on the safety and effectiveness of using intravenous administration of the drugs Ca-DTPA/Zn-DTPA to remove the heavy metal gadolinium from the bodies of patients who have retained it and developed symptoms of Gadolinium Deposition Disease following an MRI in which a gadolinium-containing contrast agent was utilized. The outcome data will include measures of symptom relief after as many as six paired Calcium-DTPA/Zinc-DTPA chelation treatments. The study also aims at gathering additional data before and after DTPA treatment regarding levels of certain cytokines in the patients' blood that have been reported to be abnormally elevated in patients with retained gadolinium.

Study Overview

• Status: Withdrawn
• Conditions: Gadolinium Deposition Disease
• Intervention / Treatment: Drug: Calcium DTPA and Zinc DTPA

Detailed Description

This study aims at gathering additional data on the safety and effectiveness of using intravenous administration of the drug DTPA to remove the heavy metal gadolinium from the bodies of patients who have retained it and developed symptoms of Gadolinium Deposition Disease following an MRI in which a gadolinium-containing contrast agent was utilized. The outcome data will include measures of symptom relief, including chronic pain, skin changes, and cognitive complaints, after as many as six paired Calcium-DTPA/Zinc-DTPA chelation treatments. The study also aims at gathering additional data before and after DTPA treatment regarding levels of certain cytokines (chemical messengers) in the patients' blood that have been reported to be abnormally elevated in patients with retained gadolinium.

DTPA is approved as safe and effective by the federal Food and Drug Administration for the removal of certain radioactive heavy metals, has been in use for more than 60 years, is well tolerated, and has been safely used in three studies, that enrolled 25, 21 and 4 patients respectively who were diagnosed with Gadolinium Deposition Disease.Only the first study reported on symptom improvement, and noted that almost all patients experienced benefit after three paired Calcium-DTPA/Zinc-DTPA chelation treatments.

• Study Type: Interventional
• Phase: Early Phase 1

Contacts and Locations

Study Locations

• United States
  • California
    • Stanford, California, United States, 94305
      • Stanford University Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years to 61 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Adults aged 18 - 65 and able to give informed consent.
2. Have had an MRI with contrast at least 3 months and less than 3 years before study enrollment.
3. Have a 24-hour urine analysis 30 days or more post-MRI that documents abnormally high levels of gadolinium excretion.

4. Exhibit within 30 days of the contrast-assisted MRI new onset of 3 or more of the following symptoms:

   1. cognitive disturbance,
   2. extremity pain,
   3. frequent headaches,
   4. chest wall pain,
   5. skin induration,
   6. skin hyper-pigmentation,
   7. skin pain,
   8. arthralgia.
5. Have met these Gadolinium Deposition Disease (GDD) diagnostic criteria for at least 3 months.
6. Received the MRI contrast agent Gadobutrol (Gadovist) and no other MRI contrast agents.

Exclusion Criteria:

1. Diagnosed by the patient's treating MD with an autoimmune or rheumatological disorder such as systemic lupus, rheumatoid arthritis or scleroderma;
2. diagnosed by the patient's treating MD with a condition or conditions that could cause 3 or more of the 8 diagnostic symptoms of GDD;
3. taking a medication or medications that could cause 3 or more of the 8 diagnostic symptoms of GDD;
4. having a condition or conditions and taking a medication or medications that together might account for the presence of 3 or more of the diagnostic symptoms of GDD.
5. Having Wilson's Disease, hemochromatosis, cancer (other than non-melanoma skin cancer), impaired kidney function, or heart disease compromising cardiac function or causing arrhythmia;
6. Participating in another protocol involving a pharmacological or other treatment of GDD.
7. Suffering from a disorder that could raise particular cytokine levels. In addition to autoimmune and rheumatological conditions, these disorders include diabetes mellitus requiring insulin, chronic fatigue syndrome, active infectious disease, covid infection in the past four months, receipt of blood products in the previous 6 months, major depression, and irritable bowel syndrome.
8. Unable for medical reasons or unwilling to discontinue medications known to lower cytokine levels of interest including: lithium, n-acetylcysteine, aspirin, NSAIDs, sertraline and other Selective Serotonin Reuptake Inhibitor antidepressants, and the over-the-counter supplements ashwagandha, astaxanthin, and milk thistle.
9. Prior chelation treatment for GDD.
10. Pregnant, nursing, intending to become pregnant in the next 6 months, unwilling to utilized an approved, effective contraception method during the study's duration.

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: Chelation with open-label Ca-DTPA and Zn-DTPA; Six chelation treatments utilizing Ca-DTPA on day 1 and Zn-DTPA on day 2. Paired, 2-chelation day treatments will take place at intervals of one week or more.

Drug: Calcium DTPA and Zinc DTPA; Intravenous administration of 2.5 mL (500 mg) of Ca-DTPA over one minute, followed by 900 mL of normal saline infusion over about 90 minutes, followed by 2.5 mL (500 mg) of Ca-DTPA over one minute, followed by infusion of the remaining 100 mL of normal saline over about 10 minutes. Procedure repeated with Zn-DTPA the following day. Two-day procedure repeated at an interval of one week or more for a total of six 2-day treatment sessions.; Other Names: Diethylenetriaminepenta-acetate

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
0-10 Scale of Pain Severity (Higher is more severe pain)	Rating scale of pain severity	2 days before first DTPA treatment
0-10 Scale of Pain Severity	Rating scale of pain severity	5-6 days after first 2-day DTPA treatment
0-10 Scale of Pain Severity	Rating scale of pain severity	5-6 days after second 2-day DTPA treatment
0-10 Scale of Pain Severity	Rating scale of pain severity	5-6 days after third 2-day DTPA treatment
0-10 Scale of Pain Severity	Rating scale of pain severity	5-6 days after fourth 2-day DTPA treatment
0-10 Scale of Pain Severity	Rating scale of pain severity	5-6 days after fifth 2-day DTPA treatment
0-10 Scale of Pain Severity	Rating scale of pain severity	5-6 days after sixth 2-day DTPA treatment
0-10 Scale of Pain Severity	Rating scale of pain severity	One month after sixth 2-day DTPA treatment

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Gadolinium Deposition Disease Symptom rating scale (higher number = symptom is more troubling0	Scale rating common symptoms seen in Gadolinium Deposition Disease	2 days before first DTPA treatment treatment
Gadolinium Deposition Disease Symptom rating scale	Scale rating common symptoms seen in Gadolinium Deposition Disease	5 to 6 days after first DTPA treatment treatment
Gadolinium Deposition Disease Symptom rating scale	Scale rating common symptoms seen in Gadolinium Deposition Disease	5 to 6 days after third DTPA treatment treatment
Gadolinium Deposition Disease Symptom rating scale	Scale rating common symptoms seen in Gadolinium Deposition Disease	5 to 6 days after fourth DTPA treatment treatment
Gadolinium Deposition Disease Symptom rating scale	Scale rating common symptoms seen in Gadolinium Deposition Disease	5 to 6 days after fifth DTPA treatment treatment
Gadolinium Deposition Disease Symptom rating scale	Scale rating common symptoms seen in Gadolinium Deposition Disease	5 to 6 days after sixth DTPA treatment treatment
Gadolinium Deposition Disease Symptom rating scale	Scale rating common symptoms seen in Gadolinium Deposition Disease	one month after sixth DTPA treatment treatment
Cognitive Function - Short Form 8a (Promis Item Bank v2.0) (Higher score = more cognitive complaint)	Measure of cognitive function	2 days before first 2-day DTPA chelation
Cognitive Function - Short Form 8a (Promis Item Bank v2.0)	Measure of cognitive function	5 to 6 after first 2-day DTPA chelation
Cognitive Function - Short Form 8a (Promis Item Bank v2.0)	Measure of cognitive function	5 to 6 after second 2-day DTPA chelation
Cognitive Function - Short Form 8a (Promis Item Bank v2.0)	Measure of cognitive function	5 to 6 after third 2-day DTPA chelation
Cognitive Function - Short Form 8a (Promis Item Bank v2.0)	Measure of cognitive function	5 to 6 after fourth 2-day DTPA chelation
Cognitive Function - Short Form 8a (Promis Item Bank v2.0)	Measure of cognitive function	5 to 6 after fifth 2-day DTPA chelation
Cognitive Function - Short Form 8a (Promis Item Bank v2.0)	Measure of cognitive function	5 to 6 after sixth 2-day DTPA chelation
Cognitive Function - Short Form 8a (Promis Item Bank v2.0)	Measure of cognitive function	one month after sixth 2-day DTPA chelation

Collaborators and Investigators

• Sponsor: Stanford University
• Investigators: Principal Investigator: Lorrin M Koran, MD, Stanford University

Publications and helpful links

General Publications

• Semelka RC, Ramalho M, Jay M, Hickey L, Hickey J. Intravenous Calcium-/Zinc-Diethylene Triamine Penta-Acetic Acid in Patients With Presumed Gadolinium Deposition Disease: A Preliminary Report on 25 Patients. Invest Radiol. 2018 Jun;53(6):373-379. doi: 10.1097/RLI.0000000000000453.
• Maecker HT, Wang W, Rosenberg-Hasson Y, Semelka RC, Hickey J, Koran LM. An initial investigation of serum cytokine levels in patients with gadolinium retention. Radiol Bras. 2020 Sep-Oct;53(5):306-313. doi: 10.1590/0100-3984.2019.0075.
• Maecker HT, Siebert JC, Rosenberg-Hasson Y, Koran LM, Ramalho M, Semelka RC. Dynamic Serial Cytokine Measurements During Intravenous Ca-DTPA Chelation in Gadolinium Deposition Disease and Gadolinium Storage Condition: A Pilot Study. Invest Radiol. 2022 Jan 1;57(1):71-76. doi: 10.1097/RLI.0000000000000803.
• Goetzl EJ, Maecker HT, Rosenberg-Hasson Y, Koran LM. Altered Functional Mitochondrial Protein Levels in Plasma Neuron-Derived Extracellular Vesicles of Patients With Gadolinium Deposition. Front Toxicol. 2022 Jan 12;3:797496. doi: 10.3389/ftox.2021.797496. eCollection 2021.
• Denmark D, Ruhoy I, Wittmann B, Ashki H, Koran LM. Altered Plasma Mitochondrial Metabolites in Persistently Symptomatic Individuals after a GBCA-Assisted MRI. Toxics. 2022 Jan 26;10(2):56. doi: 10.3390/toxics10020056.

Study record dates

Study Major Dates

• Study Start (Estimated): April 11, 2023
• Primary Completion (Actual): September 12, 2024
• Study Completion (Actual): September 13, 2024

Study Registration Dates

• First Submitted: April 26, 2022
• First Submitted That Met QC Criteria: April 28, 2022
• First Posted (Actual): May 4, 2022

Study Record Updates

• Last Update Posted (Actual): May 16, 2025
• Last Update Submitted That Met QC Criteria: May 13, 2025
• Last Verified: May 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Calcium-Regulating Hormones and Agents; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Protective Agents; Antidotes; Anticoagulants; Chelating Agents; Sequestering Agents; Iron Chelating Agents; Calcium Chelating Agents; Calcium; Edetic Acid; Pentetic Acid
• Other Study ID Numbers: 65231

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: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No