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

Study Overview
=================
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.

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

Conditions
-----------------
Dermatomyositis, Idiopathic Inflammatory Myopathies

Intervention / Treatment
-----------------
* Drug: Sodium Thiosulfate


Participation Criteria
=================
Eligibility Criteria
-----------------
INCLUSION CRITERIA: At least 7 years of age Meets Bohan and Peter criteria, as modified by the International Myositis Assessment and Clinical Studies Group (IMACS), for probable or definite DM or JDM Has extensive calcinosis, defined as calcinosis involving at least 2 extremities or the torso 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 Is willing and able to comply with the requirements of the protocol and to undergo all testing Can have IV access established to receive study infusions Myositis disease activity is stable* Medications for myositis are stable for at least 6 weeks prior to study entry** Men and women of reproductive potential must agree to use a reliable form of birth control during the 62-week duration of the study 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: Is pregnant or breastfeeding Has known allergies to sodium thiosulfate, any of its components, or dextrose Has severe myositis disease activity as defined by patient/parent or physician global activity visual analogue scale score >4 cm out of 10 cm 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) Has a malignancy or had a malignancy within 5 years of diagnosis of their DM (except for benign skin lesions or basal cell carcinoma) Known or suspected history of alcohol or drug abuse in the 6 months prior to study enrollment Has systemic lupus erythematosus, scleroderma, or a condition other than DM that is associated with calcinosis as a complication 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 Has used probenecid, diltiazem, aluminum hydroxide, or hydrochlorothiazide in the 2 months prior to enrollment 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 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. Has a psychiatric illness or medical non-compliance that the study team feels will make the patient unlikely to complete the study Has dysphagia where non-oral feeding alternatives are needed. Requires supplemental oxygen therapy Has >3 episodes of cellulitis requiring IV antibiotics related to calcinosis within a year prior to enrollment or cellulitis within 1 month of enrollment Previously received or currently receiving sodium thiosulfate by any route Is on an oral prednisone dose of more than 1mg/kg/day or other oral corticosteroid equivalent. 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 exclusion criteria this criteria will be checked. A PharmD will evaluate the patient's current medication list for medications with the potential for interaction with sodium thiosulfate. Methodology is as follows: He or she will perform a search in two individual validated medication interaction software programs. He or she will also perform a literature search via PubMed for case reports of interactions with sodium thiosulfate. As an additional safeguard, the PharmD will evaluate the medication list utilizing principles of pharmacology and pharmacokinetics to attempt to identify any potential interactions not yet documented in the literature. Has any health conditions that, in the opinion of the investigator, significantly increase the risk of taking sodium thiosulfate or participating in any of the study procedures Weighs less than 26 kilograms.** Has a regimen of pulse steroids or IVIG that is at an interval besides every 1, 2, or 5 weeks. Has a chronic infection that makes assessment of muscle disease difficult including, but not limited to, hepatitis, HIV, HTLV 1, and HTLV 2. Has had a severe complication of diabetes in the past year prior to enrollment. Anemia with a HgB less than 10 at time of screening or deemed to be too low to safely complete study by hematology consult team. We will attempt to enroll patients at a weight greater than 28 kg as these patients will be able to obtain all lab work for the study. Patients weighing 26 to 28 kg will only be able to obtain some of the research blood work. Patients less than 26 kg of body weight will be unable to obtain all safety labs, so will not be able to enroll.

Ages Eligible for Study
-----------------
Minimum Age: 7 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment<br>Patient will be assessed for 10 weeks off treatment and then will receive 10 weeks of treatment. They will return at weeks 24 and 52 for safety and sustainability of efficacy assessments. | Drug: Sodium Thiosulfate<br>* Sodium thiosulfate is a calcium chelator<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in calcinosis severity visual analogue scale score from week 0 to week 10 on therapy, compared to the baseline change in calcinosis severity visual analogue scale score from week -10 to week 0 pre-treatment. | Our primary hypothesis is that participants treated with sodium thiosulfate will experience greater improvement in calcinosis activity as assessed by a change in the calcinosis visual analogue scale (VAS) score after treatment, compared with any change in calcinosis activity VAS score during the observation period prior to treatment with sodium thiosulfate. | Week 6, week 10, week 24, week 62 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Validation of the Calcinosis Assessment Tool |  | week -10, Week 6, week 10, week 24, week 62 | 
| Incidence and severity of adverse events, including laboratory abnormalities, over time |  | Week 6, week 10, week 24, week 62 | 
| Improvement of calcinosis lesions, assessed by Calcinosis Assessment Tool, durometry measurements, photography, and imaging studies |  | week -10, Week 6, week 10, week 24, week 62 | 
| Improvement in or stabilization of myositis activity and damage, as assessed by the IMACS core set measures |  | week -10, Week 6, week 10, week 24, week 62 | 
| Greater improvement in quality of life score (CHQ-PF50 for children, SF-36 for adults) from Week 0 to Week 10, compared with any change in quality of life score observed during the pre-treatment period (from Week -10 to Week 0). |  | week -10, Week 6, week 10, week 24, week 62 | 
| Changes in gene expression, measured by RNA and protein analyses (e.g., to evaluate changes due to therapy, or differences between responders and non-responders to therapy) |  | week -10, Week 6, week 10, week 24, week 62 | 
| Changes in functional disability over time, measured by CHAQ/HAQ, CMAS/AMAT/Myositis Functional Index, and physical therapy-related assessments (e.g., range of motion, 6-minute walk, timed up and go, sit to stand, Motor Functional Measure (MFM)) |  | week -10, Week 6, week 10, week 24, week 62 | 
| Changes in components of quality of life over time, as measured by quality of life questionnaires (e.g., SF-36, CHQ-PF50, PROMIS, Skindex-29) |  | week -10, Week 6, week 10, week 24, week 62 | 
| Change in muscle strength over time, measured by manual and quantitative muscle testing |  | week -10, Week 6, week 10, week 24, week 62 | 
| Assessment of imaging modalities to assess change in calcinosis (CT, DEXA, MRI, PET) |  | week -10, Week 6, week 10, week 24, week 62 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Calcinosis, Dermatomyositis, Juvenile Dermatomyositis, Idiopathic Inflammatory Myopathies, Sodium Thiosulfate