Sodium Thiosulfate for Treatment of Calcinosis Associated With Juvenile and Adult Dermatomyositis

An Open-label Study of Sodium Thiosulfate for Treatment of Calcinosis Associated With Juvenile and Adult Dermatomyositis

Status

Completed

Phases

Phase 2Phase 3

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT03267277

Enrollment

Registered

2017-08-30

Start date

2017-10-05

Completion date

2023-11-09

Last updated

2024-11-26

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Dermatomyositis, Idiopathic Inflammatory Myopathies

Keywords

Calcinosis, Dermatomyositis, Juvenile Dermatomyositis, Idiopathic Inflammatory Myopathies, Sodium Thiosulfate

Brief summary

Background: Dermatomyositis (DM) and juvenile dermatomyositis (JDM) cause inflammation in the muscles. People with DM and JDM can develop calcium deposits in places they should not, known as calcinosis. Calcinosis can be painful and cause disabilities and other problems. Researchers want to learn more about calcinosis to find treatments for it. Objective: To test if sodium thiosulfate (STS) can treat people with DM with calcinosis. Eligibility: People ages 7 and older who have moderate or severe calcinosis. They must have stable DM and calcium deposits in the torso or at least 2 limbs. Design: Participants will be screened with: * Medical history * Physical exam * Muscle strength and function tests * Blood and urine tests Participants will have several visits: * 7-day pre-treatment visit about 10 weeks before starting STS * Treatment visits over 10 weeks. They will get STS 3 times a week through IV infusion. They may be hospitalized the whole time. If they tolerate the drug, they may be discharged at certain times. During these times, they will return for the infusions. * 3- to 5-day post-treatment visits 24 weeks and 62 weeks after starting STS. Visits may include repeats of screening tests and: * Questionnaires * Scans: They lie in a machine that takes pictures of the body. They may be injected with a radioactive agent. * Durometry: A small instrument applies pressure on the skin or exposed calcinosis. * Measurements of blood flow in the arms and fingernail blood vessels * Photographs of the skin * Kidney ultrasound * Tests of kidney function * Calcinosis aspiration: A needle placed into areas of calcinosis removes liquid.

Detailed description

Calcinosis, a serious complication of dermatomyositis, involves deposition of calcium (carbonate apatite) in soft tissue, and can result in negative impacts on quality of life and physical function. To date, there are no known effective therapies that are approved for the treatment of dermatomyositis-associated calcinosis, and there is no consensus within the medical community on the optimum treatment strategy for this often-debilitating condition. A few reports in the literature describe treatment successes with a variety of therapeutics; however, these data are from anecdotal reports or case series and thus provide limited scientific evidence of effectiveness. Recently published reports as well as personal observations within our group have suggested that intravenous sodium thiosulfate treatment may benefit calcinosis patients. In order to gather more robust data on the utility of this medication in the treatment of calcinosis associated with adult and juvenile dermatomyositis, we propose to evaluate its effects in the context of a prospective clinical trial. We plan to enroll participants at a single center into a single-arm, open-label study, with the overall objective of evaluating the efficacy and safety of intravenous sodium thiosulfate use in patients with moderate to severe extensive calcinosis associated with juvenile and adult dermatomyositis. The study will enroll a maximum of 18 participants over 4 years into the full study, but up to 250 patients may screen for study entry. Eligible patients will be age 7 or older, and will have extensive calcinosis (defined as calcinosis involving the torso or 2 extremities) and moderate to severe calcinosis (indicated by a calcinosis activity visual analogue scale score of greater than or equal to 3.5 cm out of 10 cm). Two separate evaluations performed at the NIH prior to initiation of therapy will be used as baseline data to compare in a pairwise manner to the change in assessments following treatment with sodium thiosulfate, with all other medications remaining stable. Study treatment will be 16 g/m2 sodium thiosulfate administered 3 times weekly over a period of 10 weeks at the NIH. Subjects who complete 10 weeks of treatment or reach the primary end point by week 6 will be considered completers. Following the treatment period, all participants will return to the NIH for evaluations at weeks 24 and 62. The primary outcome will be change in calcinosis activity visual analogue scale score from week 0 to week 10 on therapy, compared to the baseline change in calcinosis activity visual analogue scale score from week -10 to week 0 pre-treatment. Secondary measures will evaluate safety and changes in components of the Calcinosis Assessment Tool, clinical assessments of calcinosis, Mawdsley Calcinosis Questionnaire, quality of life, functional disability, muscle testing (manual and quantitative), laboratory parameters (muscle enzymes, inflammatory markers, and endothelial activation markers), gene expression, calcification pathogenesis, time to improvement, and imaging. Myositis disease activity and damage will also be assessed by validated measures. A number of research studies will be incorporated into this clinical trial in an attempt to understand the immunologic markers associated with calcification in dermatomyositis as well as the immunologic effects of sodium thiosulfate treatment.

Interventions

DRUGSodium Thiosulfate

Sodium thiosulfate is a calcium chelator

Study design

Allocation

Intervention model

SINGLE_GROUP

Primary purpose

TREATMENT

Masking

NONE

Eligibility

Sex/Gender

ALL

Age

7 Years to No maximum

Healthy volunteers

Inclusion criteria

* INCLUSION CRITERIA: 1. At least 7 years of age 2. Meets Bohan and Peter criteria, as modified by the International Myositis Assessment and Clinical Studies Group (IMACS), for probable or definite DM or JDM 3. Has extensive calcinosis, defined as calcinosis involving at least 2 extremities or the torso 4. Has moderate to severe calcinosis, defined as having a calcinosis activity visual analogue scale score of greater than or equal to 3.5 cm out of 10 cm 5. Is willing and able to comply with the requirements of the protocol and to undergo all testing 6. Can have IV access established to receive study infusions 7. Myositis disease activity is stable\* 8. Medications for myositis are stable for at least 6 weeks prior to study entry\*\* 9. Men and women of reproductive potential must agree to use a reliable form of birth control during the 62-week duration of the study 10. Subjects or their legal guardian must sign a written informed consent * Stable myositis disease activity will be defined by physician global and patient/parent global VAS that are \<4 cm, as well as creatine kinase (CK), lactate dehydrogenase (LDH), aldolase, aspartate aminotransferase (AST), and alanine aminotransferase (ALT) that are less than or equal to 2X upper limit of normal (ULN). * If a patient has a medication for myositis changed in this window for reasons besides their myositis activity and has returned to their baseline medication use prior to enrollment they will still be eligible.

Exclusion criteria

1. Is pregnant or breastfeeding 2. Has known allergies to sodium thiosulfate, any of its components, or dextrose 3. Has severe myositis disease activity as defined by patient/parent or physician global activity visual analogue scale score \>4 cm out of 10 cm 4. Has had an escalation of immunosuppressive therapy in the 2 months prior to enrollment for the purpose of treating active myositis disease activity, including the addition of a new agent to treat the patients underlying disease or an increase in dose of an existing medication used to treat the patient's disease (other than an adjustment for weight or body surface area in children) 5. Has a malignancy or had a malignancy within 5 years of diagnosis of their DM (except for benign skin lesions or basal cell carcinoma) 6. Known or suspected history of alcohol or drug abuse in the 6 months prior to study enrollment 7. Has systemic lupus erythematosus, scleroderma, or a condition other than DM that is associated with calcinosis as a complication 8. Has had a change in medications used specifically for calcinosis in the 2 months prior to enrollment, including but not limited to alendronate, etidronate, pamidronate, probenecid, colchicine, diltiazem, thalidomide, and aluminum hydroxide 9. Has used probenecid, diltiazem, aluminum hydroxide, or hydrochlorothiazide in the 2 months prior to enrollment 10. Has currently or has a history of any of the following: heart failure, renal impairment (GFR less than 30 representing severe renal disease), liver disease (Child-Pugh class C), arrhythmias (that are symptomatic or are concerning for progression to symptomatic arrhythmias), or recurrent kidney stones (more than one episode of symptomatic kidney stones separated by at least 1 month), or QT prolongation, or hypocalcemia, or metabolic acidosis, or hypotension 11. Has severe osteoporosis or has had a bone fracture within a year prior to enrollment. For adults, severe osteoporosis as defined by the World Health Organization (WHO) as bone mineral density (BMD) 2.5 standard deviations below that of a young, normal adult (T-score at or below -2.5 and one or more fractures). For individuals, less than age 18, severe osteoporosis as defined by the First Pediatric Consensus Development Conference as a Z-score below -2 and one or more fractures. 12. Has a psychiatric illness or medical non-compliance that the study team feels will make the patient unlikely to complete the study 13. Has dysphagia where non-oral feeding alternatives are needed. 14. Requires supplemental oxygen therapy 15. Has \>3 episodes of cellulitis requiring IV antibiotics related to calcinosis within a year prior to enrollment or cellulitis within 1 month of enrollment 16. Previously received or currently receiving sodium thiosulfate by any route 17. Is on an oral prednisone dose of more than 1mg/kg/day or other oral corticosteroid equivalent. 18. Is taking any concomitant medications that are thought to alter sodium thiosulfate s effects or pharmacokinetics. Once patients have met all other inclusion criteria and no other

Design outcomes

Primary

Measure	Time frame	Description
Change in Calcinosis Activity Visual Analogue Scale Score	Week 10 minus week 0 (on therapy) and week 0 minus week -10 (baseline)	Calcinosis activity is defined by the metabolic activity and the inflammation associated with calcinosis. In evaluating calcinosis activity, the study physicians take into account the change in extent of calcinosis and the location of calcinosis lesions, the consistency and texture of calcinosis lesions, the presence of erythema surrounding calcinosis lesion, and any pain associated with the calcinosis lesions. A 10 cm visual analogue scale (VAS) was scored by a physician with a vertical line on the scale marking calcinosis activity where 0 cm indicates no evidence of calcinosis, and 10 cm mark indicates severe calcinosis activity. The change in calcinosis activity VAS score from week 0 to week 10 on therapy was compared to the change in calcinosis activity VAS score from week -10 to week 0 on baseline therapy. The baseline score was calculated by taking the week 0 score minus the week -10 score. The on therapy score was calculated by taking the week 10 score minus the week 0 score.

Secondary

Measure	Time frame	Description
Change in Quality of Life Measured by the 36-Item Short Form Health Survey (SF-36) Score: General Health Domain	Week -10 to 0 (pre-treatment); Week 0 to 10 (on treatment); Week 24 to 62 (post-treatment)	36-Item Short Form Health Survey (SF-36) is a 36-item patient-reported survey of patient health status that consists of eight scaled scores, which are the weighted sums of the questions in their section. Each scale is directly transformed into a 0-100 scale. The Change in quality of life measured was assessed using the general health domain of SF-36. The higher the score the less disability. The change in quality of life using the SF-36 general health domain was measured as the mean difference in scores between time points.
Improvement of Calcinosis Lesions Measured by the Change in Mawdsley Calcinosis Questionnaire (MCQ) Score	Week -10 to 0 (pre-treatment); Week 0 to 10 (on treatment); Week 24 to 62 (post-treatment)	The Mawdsley Calcinosis Questionnaire (MCQ) is a 17-item questionnaire scale that measures the severity and impact of calcinosis. Each item is scored on 11-point scale of 0 to 10. Total score is the the average of the cumulative measure ranging from 0-10. Higher score indicates worse severity and impact of calcinosis. Improvement of calcinosis lesions was measured by the MCQ. The change in score was measured as the mean difference between time points.
Change in Quality of Life Measured by Skindex-29 Score	Week -10 to 0 (pre-treatment); Week 0 to 10 (on treatment); Week 24 to 62 (post-treatment)	The Skindex-29 scale is 29-item questionnaire that measures the quality of life. Each item is scored 0 (Never) to 4 (All the time). All responses are transformed to a linear scale of 100, varying from 0 (no effect) to 100 (effect experienced all the time) and overall score is the mean of the responses. Higher score indicates more severe impact on quality of life. The change in quality of life was measured as the mean difference in Skindex-29 scores between time points.
Change in Muscle Strength Over Time Measured by Manual Muscle Test-8 (MMT-8) Score	Week -10 to 0 (pre-treatment); Week 0 to 10 (on treatment); Week 24 to 62 (post-treatment)	Manual Muscle Test-8 (MMT-8) is a measure of muscle strength. The MMT-8 uses a 10-point scale to score each muscle group, with 0 indicating extreme weakness and 10 indicating normal strength. The scores for each muscle group are then added together to get a total score ranging from 0 to 80, with higher scores indicating greater muscle strength. Change in muscle strength over time was measured as the mean difference in MMT-8 scores between time points.
Change in Quality of Life Measured by the Child Health Questionnaire-Parent Form 50 (CHQ-PF50): Physical Function Domain	Week -10 to 0 (pre-treatment); Week 0 to 10 (on treatment)	The Child Health Questionnaire-Parent Form 50 (CHQ-PF50) is a 50-item survey with 14 domains that parents complete to assess their child's physical and mental well-being. The change in quality of life was measured by the physical functioning domain score on the CHQ-PF50. The CHQ-PF50 physical functioning domain scale was transformed to 0 to 100 score with higher score indicating better health or more positive functioning. The change in quality of life using the CHQ-PF50 score was measured as the mean difference in scores between time points.
Change in Myositis Activity Measured by Physician Global Activity (PGA)	Week -10 to 0 (pre-treatment); Week 0 to 10 (on treatment); Week 24 to 62 (post-treatment)	The Physician Global Activity (PGA) is an index that uses a 10-cm Visual Analog Scale (VAS) to score a patient's disease activity. Higher score indicates more activity. Change in myositis activity was measured as the mean difference in disease activity scores between time points.
Change in Myositis Damage Measured by Physician Global Damage (PGD)	Week -10 to 0 (pre-treatment); Week 0 to 10 (on treatment); Week 24 to 62 (post-treatment)	The Physician Global Damage (PGD) is an index that uses a 10-cm Visual Analog Scale (VAS) to score a patient's disease damage. Higher score indicates more global damage. Change in myositis damage was measured as the mean difference in disease damage scores between time points.
Change in Total Percent Body Surface Area (BSA) Involved With Calcinosis	Week -10 to 0 (pre-treatment); Week 0 to 10 (on treatment); Week 24 to 62 (post-treatment)	Total percent of body surface area (BSA) involved with calcinosis was measured by physician assessment. Improvement of calcinosis lesions was measured as the mean difference in total percent of BSA scores between time points
Change in Muscle Strength Over Time Measured by Quantitative Muscle Assessment (QMA): Hip Abductor Muscle	Week -10 to 0 (pre-treatment); Week 0 to 10 (on treatment); Week 24 to 62 (post-treatment)	Quantitative muscle assessment (QMA) tests how much force participant can be exerted by the hip abductor muscle. It is measured as the kilograms of force produced. Higher score indicates more force. Change in hip abductor muscle strength over time was measured by the quantitative muscle assessment (QMA) as the mean difference in QMA scores between time points.

Countries

United States

Participant flow

Recruitment details

15 participants were consented but one participant was a screen failure so was not enrolled to the treatment phase of the study.

Participants by arm

Arm	Count
Treatment Participants received intravenous sodium thiosulfate 16 g/m\^2 three times weekly for 10 weeks	14
Total	14

Withdrawals & dropouts

Period	Reason	FG000
Overall Study	Withdrawal by Subject	1

Baseline characteristics

Characteristic	Treatment
Age, Categorical <=18 years	4 Participants
Age, Categorical >=65 years	0 Participants
Age, Categorical Between 18 and 65 years	10 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	3 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	11 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants
Race (NIH/OMB) Asian	1 Participants
Race (NIH/OMB) Black or African American	4 Participants
Race (NIH/OMB) More than one race	2 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants
Race (NIH/OMB) White	7 Participants
Sex: Female, Male Female	10 Participants
Sex: Female, Male Male	4 Participants

Adverse events

Event type	EG000 affected / at risk
deaths Total, all-cause mortality	0 / 14
other Total, other adverse events	14 / 14
serious Total, serious adverse events	6 / 14

Outcome results

Primary

Change in Calcinosis Activity Visual Analogue Scale Score

Calcinosis activity is defined by the metabolic activity and the inflammation associated with calcinosis. In evaluating calcinosis activity, the study physicians take into account the change in extent of calcinosis and the location of calcinosis lesions, the consistency and texture of calcinosis lesions, the presence of erythema surrounding calcinosis lesion, and any pain associated with the calcinosis lesions. A 10 cm visual analogue scale (VAS) was scored by a physician with a vertical line on the scale marking calcinosis activity where 0 cm indicates no evidence of calcinosis, and 10 cm mark indicates severe calcinosis activity. The change in calcinosis activity VAS score from week 0 to week 10 on therapy was compared to the change in calcinosis activity VAS score from week -10 to week 0 on baseline therapy. The baseline score was calculated by taking the week 0 score minus the week -10 score. The on therapy score was calculated by taking the week 10 score minus the week 0 score.

Time frame: Week 10 minus week 0 (on therapy) and week 0 minus week -10 (baseline)