Clinical trial NCT05359835: DTPA (Diethylenetriaminepenta-acetate) Chelation for Symptoms After Gadolinium-assisted MRI Exposure
Official title: DTPA Chelation for Symptoms After Gadolinium-assisted MRI
Study type: INTERVENTIONAL
Overall status: WITHDRAWN
Phase: EARLY_PHASE1
Conditions: Gadolinium Deposition Disease
Lead sponsor: Stanford University
Sponsor class: OTHER
First posted: 2022-05-04
Enrollment: 0
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention model description: Six adult patients aged 18 to 65 who meet diagnostic criteria for Gadolinium Deposition Disease and study inclusion criteria, and are free of exclusion criteria will be enrolled.
Primary purpose: TREATMENT

Brief summary: 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.

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.

Eligibility criteria: 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.

Primary outcomes:
measure: 0-10 Scale of Pain Severity (Higher is more severe pain)
timeFrame: 2 days before first DTPA treatment
measure: 0-10 Scale of Pain Severity
timeFrame: 5-6 days after first 2-day DTPA treatment
measure: 0-10 Scale of Pain Severity
timeFrame: 5-6 days after second 2-day DTPA treatment
measure: 0-10 Scale of Pain Severity
timeFrame: 5-6 days after third 2-day DTPA treatment
measure: 0-10 Scale of Pain Severity
timeFrame: 5-6 days after fourth 2-day DTPA treatment
measure: 0-10 Scale of Pain Severity
timeFrame: 5-6 days after fifth 2-day DTPA treatment
measure: 0-10 Scale of Pain Severity
timeFrame: 5-6 days after sixth 2-day DTPA treatment
measure: 0-10 Scale of Pain Severity
timeFrame: One month after sixth 2-day DTPA treatment
Secondary outcomes:
measure: Gadolinium Deposition Disease Symptom rating scale (higher number = symptom is more troubling0
timeFrame: 2 days before first DTPA treatment treatment
measure: Gadolinium Deposition Disease Symptom rating scale
timeFrame: 5 to 6 days after first DTPA treatment treatment
measure: Gadolinium Deposition Disease Symptom rating scale
timeFrame: 5 to 6 days after third DTPA treatment treatment
measure: Gadolinium Deposition Disease Symptom rating scale
timeFrame: 5 to 6 days after fourth DTPA treatment treatment
measure: Gadolinium Deposition Disease Symptom rating scale
timeFrame: 5 to 6 days after fifth DTPA treatment treatment
measure: Gadolinium Deposition Disease Symptom rating scale
timeFrame: 5 to 6 days after sixth DTPA treatment treatment
measure: Gadolinium Deposition Disease Symptom rating scale
timeFrame: one month after sixth DTPA treatment treatment
measure: Cognitive Function - Short Form 8a (Promis Item Bank v2.0) (Higher score = more cognitive complaint)
timeFrame: 2 days before first 2-day DTPA chelation
measure: Cognitive Function - Short Form 8a (Promis Item Bank v2.0)
timeFrame: 5 to 6 after first 2-day DTPA chelation
measure: Cognitive Function - Short Form 8a (Promis Item Bank v2.0)
timeFrame: 5 to 6 after second 2-day DTPA chelation
measure: Cognitive Function - Short Form 8a (Promis Item Bank v2.0)
timeFrame: 5 to 6 after third 2-day DTPA chelation
measure: Cognitive Function - Short Form 8a (Promis Item Bank v2.0)
timeFrame: 5 to 6 after fourth 2-day DTPA chelation
measure: Cognitive Function - Short Form 8a (Promis Item Bank v2.0)
timeFrame: 5 to 6 after fifth 2-day DTPA chelation
measure: Cognitive Function - Short Form 8a (Promis Item Bank v2.0)
timeFrame: 5 to 6 after sixth 2-day DTPA chelation
measure: Cognitive Function - Short Form 8a (Promis Item Bank v2.0)
timeFrame: one month after sixth 2-day DTPA chelation
Other outcomes:
Locations:
city: Stanford
country: United States
facility: Stanford University Medical Center
state: California
Study officials:
affiliation: Stanford University
name: Lorrin M Koran, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.