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

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.

- 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).

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, 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 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.

19. 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

20. Weighs less than 26 kilograms.**

21. Has a regimen of pulse steroids or IVIG that is at an interval besides every 1, 2, or
5 weeks.

22. Has a chronic infection that makes assessment of muscle disease difficult including,
but not limited to, hepatitis, HIV, HTLV 1, and HTLV 2.

23. Has had a severe complication of diabetes in the past year prior to enrollment.

24. 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.