Sodium Thiosulfate Treatment of Vascular Calcification in ESRD
Study Details
Study Description
Brief Summary
Cardiovascular disease is the major cause of death in the hemodialysis population and calcification of the major arteries (coronary, aorta, and carotid) are a play a central role in this process. The major causes of the calcification are many, including high levels of phosphorus, low levels of inhibitors of calcification, positive calcium balance, and oxidative stress. Once vascular calcification is present, it is usually progressive. There is no known treatment to reverse established vascular calcification.
Sodium thiosulfate has been used extensively and safely to treat calcific uremic arteriopathy (a disease, in part due to calcification of small arteries) in dialysis patients. It increases the solubility of calcium by up to 100,000 fold and is also a potent anti-oxidant. It therefore has to potential to also decrease the amount of calcium in large arteries in dialysis patients and, hence improve survival.
We will study hemodialysis (HD) patients at high risk for cardiovascular disease and death by obtaining a multidetector computerized tomography (MDCT) Scan of the coronary arteries, carotid arteries and aorta and an assessment of coronary artery stenoses by a simultaneous intravenous infusion of contrast. At the same setting, we will perform tests of pulse wave velocity (PWV) and carotid ultrasound carotid intima-media thickness(CIMT)studies. In those patients at high risk for cardiovascular death, defined as a coronary artery calcification score (CACS)of greater than 50, sodium thiosulfate at a dose of 12.5-25 gm/1.73 M2 will be infused over 15-30 minutes after each dialysis treatment for 5 months. The above studies will then be repeated.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
N/A |
Detailed Description
Hypothesis 1: The treatment of HD patients with high CAC scores with sodium thiosulfate for 5 months will decrease the amount of calcium in their coronary arteries.
Patients who are at high risk for having coronary calcification (history of MI, ischemic heart disease, peripheral or carotid artery disease) will be selected to undergo testing. We will recruit 60 HD patients receiving treatment in our units to undergo MDCT scanning along with non-invasive testing of PWV and CIMT. Assuming that 60% will have a CAC score of ≥50, 36 patients will be treated with sodium thiosulfate. We will administer 25% sodium thiosulfate solution (American Reagent Laboratories, Shirley, NY) at a dose of 12.5-25g/1.73m2 per over 15-30 minutes after each hemodialysis session for a total of 60 treatments (5 months). Assuming a 35% attrition rate, 23 patients will complete the entire protocol and undergo a repeat study of the initial battery of tests.
Rationale for treatment with sodium thiosulfate: Sodium thiosulfate, used as an antidote for cyanide poisoning for more than a century, is also an anti-oxidant, and binds with calcium to form a highly soluble calcium thiosulfate salt. The solubility of calcium thiosulfate salt is 250-100,000 fold higher than calcium oxalate or calcium phosphate salt. It has been used to treat recurrent calcium kidney stones and tumoral calcinosis (ectopic calcification usually around joints). It has also been used successfully in treating calcific uremic arteriopathy, a disease of small artery and soft tissue calcification, in several studies of dialysis patients and in our own experience of 5 patients. By 2 months there is radiological evidence of reduction in soft tissue calcification. Unpublished data also have demonstrated regression of established aortic calcification in uremic rats.
Sodium thiosulfate is a FDA approved medication for the treatment of cyanide poisoning. It is classified by the FDA as "generally recognized as safe". There are no known contraindications. The only side effects reported during intravenous (IV) administration in ESRD patients are nausea, vomiting and hyperosmia during the administration, which can be alleviated by pre-administration of anti-emetic medications. Sodium thiosulfate is slowly given through the dialysis venous line toward the end of HD treatments. The selected dose for this pilot study is the same as that used for the treatment of calcific uremic arteriopathy.
We will freeze 10 ml of serum obtained prior to and then monthly during treatment for subsequent analyses. Included in the analysis will be Fetuin-A levels but other relevant markers will be considered. Blood will also be frozen for future genomic studies.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Active Treatment This is the only arm and involves active treatment with sodium thiosulfate in those subjects with high coronary artery calcium scores. |
Drug: sodium thiosulfate
sodium thiosulfate 12.5-25 gm/M2 after each thrice weekly hemodialysis treatments for 5 months.
|
Outcome Measures
Primary Outcome Measures
- Change in Annualized Coronary Calcium Volume Score After Treatment With Sodium Thiosulfate. [5 months]
We will compare the annualized coronary calcium volume score obtained at the baseline CT of the coronary arteries with another CT obtained of the same coronary arteries following 5 months of sodium thiosulfate treatment.
Eligibility Criteria
Criteria
Inclusion Criteria:
-
Hemodialysis patient with thrice weekly treatments
-
Coronary artery calcium score greater than 50
-
Age greater than 18
-
Compliant with hemodialysis treatments
-
Informed consent
Exclusion Criteria:
-
Allergy to sodium thiosulfate
-
Pregnancy
-
Incarceration
-
Enrollment in another study
-
Life expectancy less than 5 months
-
Expectation of recovery of renal function
-
Urine output of greater than 200 ml/day or contrast allergy will not receive intravenous contrast
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Washington University | Saint Louis | Missouri | United States | 63110 |
Sponsors and Collaborators
- Washington University School of Medicine
- Barnes-Jewish Hospital
- Genzyme, a Sanofi Company
Investigators
- Principal Investigator: James A Delmez, MD, Washington University School of Medicine
Study Documents (Full-Text)
None provided.More Information
Additional Information:
- Effects of Sodium Thiosulfate on Vascular Calcification in End-Stage Renal Disease: A Pilot Study of Feasibility, Safety and Efficacy: Am J Nephrol 2011;33:131-138
- Sodium thiosulfate delays the progression of coronary artery calcification in haemodialysis patients -Nephrol. Dial. Transplant. (2010) 25(6): 1923-1929 first published online January 18, 2010 doi:10.1093/ndt/gfp755
Publications
None provided.- HRPO 07-0331
Study Results
Participant Flow
| Recruitment Details | Patients treated with chronic hemodialysis for ESRD at 2 Washington University units were recruited to undergo a battery of cardiovascular tests including CT quantitation (MDCT) of vascular calcification and possible treatment with sodium thiosulfate (see Am J Nephrol 2011;33:131-138) |
|---|---|
| Pre-assignment Detail | All patients with a coronary artery calcium score of greater than 50 Angstrom scores were begun on treatment with sodium thiosulfate after each dialysis for 5 months and the battery of cardiovascular tests were repeated in those who completed the 5 months of treatment. |
| Arm/Group Title | Sodium Thiosulfate |
|---|---|
| Arm/Group Description | Treatment with sodium thiosulfate after each dialysis for 5 months and the battery of cardiovascular tests were repeated in those who completed the 5 months of treatment.subjects with high coronary artery calcium scores. |
| Period Title: Overall Study | |
| STARTED | 37 |
| COMPLETED | 22 |
| NOT COMPLETED | 15 |
Baseline Characteristics
| Arm/Group Title | Sodium Thiosulfate |
|---|---|
| Arm/Group Description | Treatment with sodium thiosulfate after each dialysis for 5 months and the battery of cardiovascular tests were repeated in those who completed the 5 months of treatment.subjects with high coronary artery calcium scores. |
| Overall Participants | 48 |
| Age (Count of Participants) | |
| <=18 years |
0
0%
|
| Between 18 and 65 years |
24
50%
|
| >=65 years |
24
50%
|
| Age (years) [Mean (Standard Deviation) ] | |
| Mean (Standard Deviation) [years] |
59
(10)
|
| Sex: Female, Male (Count of Participants) | |
| Female |
18
37.5%
|
| Male |
30
62.5%
|
| Region of Enrollment (participants) [Number] | |
| United States |
48
100%
|
Outcome Measures
| Title | Change in Annualized Coronary Calcium Volume Score After Treatment With Sodium Thiosulfate. |
|---|---|
| Description | We will compare the annualized coronary calcium volume score obtained at the baseline CT of the coronary arteries with another CT obtained of the same coronary arteries following 5 months of sodium thiosulfate treatment. |
| Time Frame | 5 months |
Outcome Measure Data
| Analysis Population Description |
|---|
| This is a feasibility study and all eligible participants were invited to participate. Out of the 48 participates that started, but only 22 completed. |
| Arm/Group Title | Sodium Thiosulfate |
|---|---|
| Arm/Group Description | Treatment with sodium thiosulfate after each dialysis for 5 months |
| Measure Participants | 22 |
| Geometric Mean (Standard Deviation) [mm3/year] |
6.6
(9.7)
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Sodium Thiosulfate |
|---|---|---|
| Comments | This was a pilot study without a control group. There were no power calculations (see manuscript). | |
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.001 |
| Comments | Coronary calcium score after treatment compared to baseline | |
| Method | Wilcoxon (Mann-Whitney) | |
| Comments | ||
| Method of Estimation | Estimation Parameter | Mean Difference (Final Values) |
| Estimated Value | 9.2 | |
| Confidence Interval |
(2-Sided) 95% to |
|
| Parameter Dispersion |
Type: Standard Deviation Value: 0.987 |
|
| Estimation Comments | ||
Adverse Events
| Time Frame | 5 months | |
|---|---|---|
| Adverse Event Reporting Description | ||
| Arm/Group Title | Sodium Thiosulfate | |
| Arm/Group Description | Treatment with sodium thiosulfate after each dialysis for 5 months and the battery of cardiovascular tests were repeated in those who completed the 5 months of treatment.subjects with high coronary artery calcium scores. | |
All Cause Mortality |
||
| Sodium Thiosulfate | ||
| Affected / at Risk (%) | # Events | |
| Total | / (NaN) | |
Serious Adverse Events |
||
| Sodium Thiosulfate | ||
| Affected / at Risk (%) | # Events | |
| Total | 2/37 (5.4%) | |
| Blood and lymphatic system disorders | ||
| Death due to sepsis | 1/37 (2.7%) | 1 |
| Renal and urinary disorders | ||
| Death due to retroperitoneal bleed | 1/37 (2.7%) | 1 |
Other (Not Including Serious) Adverse Events |
||
| Sodium Thiosulfate | ||
| Affected / at Risk (%) | # Events | |
| Total | 5/37 (13.5%) | |
| Gastrointestinal disorders | ||
| Nausea | 5/37 (13.5%) | |
Limitations/Caveats
More Information
Certain Agreements
All Principal Investigators ARE employed by the organization sponsoring the study.
There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Results Point of Contact
| Name/Title | James Delmez, MD |
|---|---|
| Organization | Washington University School of Medicine |
| Phone | 314 362 7207 |
| jdelmez@dom.wustl.edu |
- HRPO 07-0331