Presented by Murray Baron, MD at the Scleroderma Patient Education Conference, hosted by the Scleroderma Foundation Greater Chicago Chapter on Saturday, October 12, 2019 in Chicago, IL. For more about the foundation visit scleroderma.org/chicago.

1. Clinical Trials in Scleroderma
Murray Baron, MD
Chicago 2019

2. • Kathleen Dennis-Aren, MPH, CHES
• Assistant Manager of Clinical Research
Programs
• Research Project Manager
• Northwestern University, Division of
Rheumatology

4. Is this (nintendanib or Ofev) the first
treatment?
• NO
• Not the first treatment but it is the first APPROVED
treatment for ANY aspect of scleroderma, not just lung
disease, except for drugs approved for pulmonary
hypertension
• Other treatments currently on the market and in use
for scleroderma (not pulmonary hypertension) :
– mycophenolate (Cellcept or Myfortic)
– Rituximab (Rituxin)
– Possibly tocilizumab (Actemra)
– Cyclophosphamide (procytox)

5. SCLERODERMA IS AN AUTOIMMUNE
DISEASE
• The current theory is that first there is an
abnormality f the immune system which leads
to inflammation
• And then the inflammation leads to fibrosis
(scarring)

6. Inflammation

7. The redness and swelling you see in inflammation are
because of more blood flowing to that area with
leakage of fluid from the blood vessels and movement
of white blood cells out of the vessel into the tissue

9. Fibrosis = Scar tissue

10. Fibrosis = Scar Tissue

12. Punch biopsy

13. Treatment – How ?
• Interfere with the immune system which
theoretically should decrease the fibrosis
(scarring)
• Use drugs that directly can stop the fibroblasts
from laying down more collagen which makes
up the fibrotic (scar) tissue

14. How are studies done?
• Why can’t you just take a new medicine and
see if it works?
• What does it even mean to “see if it works”?

15. How most studies are done – your
regulators, the FDA, require that
studies must be done this way before
they approve a drug
• Randomized – important?
• double-blind – important?
• placebo-controlled – important?
• parallel-group trial that may be performed in
many countries – important?

16. Patients
• AGE – for adults usually at least 18 years of
age
• DISEASE DURATION - How long the patients in
the trial have had scleroderma - onset of the
first non-Raynaud’s symptom within XX years
before screening – note how this affects you
• OTHER disease related CRITERIA – e.g may
require certain skin score (not too high and
not too low)– so just a tiny amount of disease
OR too severe disease would mean not
accepted –how might this affect you?

17. • Can you be on other meds – e.g does trial
allow some prednisone, perhaps at a dose of
up to 10 mg per day
• Does it allow immunosuppressive drugs eg
mycophenolate or methotrexate perhaps at a
stable dose for at least 6 months could
participate – good news – means you can
remain on these drugs if they might be helping
– many studies of new immunosuppressives
excluded people on these meds

18. Excluded if..
• significant pulmonary hypertension ?
• history of scleroderma renal crisis ?
• Patients who had undergone hematopoietic
stem cell transplantation or planned to do so
within the next year were excluded
• Too severe lung disease
• Factors which may lead to you not being
compliant

19. • So remember that when you see the results,
they only apply to patients who met all
inclusion criteria and none of the exclusion
criteria.
• If the drug is used in ANY other circumstance
(which it will be undoubtedly), we really do
not know what effect it would have
• Could work better, worse or have more side
effects

20. End points
• This is how we would decide if the drug worked
• There is usually a primary end point and secondary
endpoints
• It is the primary one that gets a trial approved or not
• secondary end points are important but they don’t
count for approval even if they show benefit
• E.g if reduction in skin score is the primary endpoint
and the trial fails to show that the drug did that BUT
lung function improved on the drug better than on
placebo, the drug will not be approved
• A good result of a secondary endpoint will never get a
drug approved. That’s the way studies are designed.

21. • Efficacy endpoints are measures intended to
reflect the effects of a drug.
• They include assessments of clinical events
(e.g., mortality, stroke, pulmonary
exacerbation, venous thromboembolism),
• patient symptoms (e.g., pain, dyspnea,
depression),
• measures of function (e.g., ability to walk or
exercise),
• or surrogates (eg BP) of these events or
symptoms.

22. Why not multiple primary endpoints?
• The more endpoints you measure, the higher
the chance of finding at least one that looks
like it is meaningful but it really is not
• We will come back to what meaningful means

23. Secondary endpoints
• Secondary endpoints may be used to support
the primary endpoint(s) and/or demonstrate
additional effects.
• In all cases, when an effect on the primary
endpoint is shown, the secondary endpoints
can be examined and may contribute
important supportive information about a
drug’s effectiveness.

24. • Positive results on the secondary endpoints
can be interpreted only if there is first a
demonstration of a treatment effect on the
primary endpoint family.

25. How many patients should be included
in a trial
• The sample size of a study is generally chosen
to provide a reasonably high power to show a
treatment effect if an effect of a specified size
is in fact present.
• In some cases, multiple aspects of a disease
may appropriately be combined into a single
endpoint, but subsequent analysis of the
components is generally important for an
adequate understanding of the drug’s effect.

26. Endpoints in scleroderma trials
• Let’s concentrate on studies that want to
show a global effect on disease – this would
not apply to a pulmonary hypertension study
or to study of a drug aimed a digital ulcers
• We want to know if the drug helps the overall
disease

27. • The commonest outcome used is the modified
Rodnan skin score - mRSS

28. • The assumption is that improvement or less
worsening of the skin score is associated with
similar changes in other organs
• Probably true

29. The American College of
Rheumatology provisional
Composite Response Index for
clinical trials in early diffuse
cutaneous Systemic Sclerosis
CRISS

30. • a binary outcome of improved/not improved
– Evaluate if a patient has meet criterion for new organ
involvement = NOT-IMPROVED.
– patient is assigned a probability score of 0.0
– For remaining patients, calculate probability based on
change in 5 measures over 1 year
• MRSS,
• FVC%,
• HAQ-DI,
• Pt global
• MD global assessment
• Each patient is assigned a probability score between
0.0-1.0
• A score of > 0.6 (60%) = improved

31. • The CRISS is new and we don’t really yet know
if it is a meaningful endpoint – but it is now
being used in at least one trial as the primary
outcome

32. How do we know if a difference
between 2 groups of patients is real or
just by chance?
• “Significance tests were two-sided, with an alpha value
of 0.05” – what the heck is this?
• Lets say you give a food supplement to 13 year old girls
to decide if it helps them grow
• 100 girls get the supplement and 100 don’t
• At the start the average height of the girls is 4 feet.
• After 1 year, regular food girls are an average of 4‘2”
tall and supplement girls are 4’3” tall.
• Did the supplement help?

33. • And if the drug was shown to be ‘active’
biologically eg the 1” difference is real, is that
difference meaningful to patients?
• Is taking a supplement for a year worthwhile
for a 1” gain in height, on average?
• What if 10% have side effects severe enough
to warrant stopping the supplement?
• What if it costs $20,000/year?
• What about height gain over 5 years?? Can
we project? If you knew that the average gain
over 5 years would be 5”, would you feel
different? Can we know that?

34. Let’s look at one important study
Think about primary and secondary
outcomes

35. Tocilizumab (Actemra)
• Recently completed a study in which the
outcome was improvement of skin
• multicentre, randomised, double-blind,
placebo-controlled, two-arm, parallel-group,
phase 3 clinical trial conducted at many
hospitals across continents

36. inclusion
• 18 years of age or older
• less than 5 years since their first non-Raynaud’s sign or
symptom
• mRSS score of 15 to 40
• Active disease: defined as at least one of the following
features at screening:
– increase ≥3 in mRSS units compared with the last visit
within the previous 1 to 6 months or new-onset SSc within
1 year before screening,
– involvement of one new body area with ≥2 mRSS units or
two new body areas with ≥1 mRSS,
– documentation of worsening skin thickening (patients
with new-onset SSc only), or ≥1 tendon friction rub plus C-
reactive protein (CRP)level ≥10 mg/L, erythrocyte
sedimentation rate (ESR) ≥28 mm/hour or platelet count
≥330 × 103/µL.

37. • randomly assigned 1:1 to receive weekly
double-blind injections of subcutaneous TCZ
162 mg or PBO for 48 weeks
• The primary end point was difference in mean
change in mRSS from baseline to week 48 for
TCZ vs PBO.
• Key secondary end points were change from
baseline in percent predicted FVC at week 48
and time to treatment failure

38. Results:
• 210 randomly assigned patients
• baseline mean values were
– age 48 years,
– SSc duration 23 months,
– mRSS 20.4,
– percent predicted FVC 82.1% - how does this
effect FVC results?
– PBO, 106; TCZ, 104

39. Change from baseline in mRSS
At week 48, the primary end point (change in mRSS) was not met but improved
numerically (PBO, -4.41; TCZ, -6.14). 9.8% of the time this difference could have
been by chance with no real difference between the 2 groups

40. Change from baseline in FVC
The difference in mean change from baseline in FVC at week 48 was 167 mL in favor
of TCZ. There is a 95% chance that the real change lies between 83 – 250 ml

41. But remember….
• If you were going to test the drug to see if it
prevents deterioration in lung function, would
you select patients the same way for the
study??

42. Side effects
• serious adverse events were reported by 17%
of PBO patients and 13% of TCZ patients
• serious infections were reported by 7% and
2% of patients, respectively

43. Nintedanib trial - Skin?
• change from baseline in modified Rodnan skin
score at week 52 was −2.17 in the nintedanib
group and −1.96 in the placebo group
• Real or chance?
• (difference, −0.21; 95% CI; −0.94 to 0.53).

44. How o find current trials
• Clinicaltrials.gov

45. What about the patient experience
in a trial?

46. Clinical Trials at Northwestern: The Basics
• Current and pending SSc trials focus on skin
disease, lung disease (ILD), and Raynauds
• Prior to enrollment in clinical trials, patients must
see one of our SSc physicians for a standard of
care visit (billed to insurance) to ensure they are a
good candidate for trials
• Study visits are held in Rheumatology clinic or our
clinical research unit, depending on the study
• Most studies involve blood draws, skin scores,
vitals, physical exams, urinalysis, pulmonary
function testing (PFTs), and electrocardiograms

47. What to expect as a trial participant
• Screening period – may take several weeks to determine eligibility
• Length of trials is typically 6 months to 1 year
– Some trials offer open label extension, where you can decide to
continue to participate in the study for an additional year or two
(study drug given, no placebo)
• Study visits can last from about 1 hour to 7 hours
• Frequent communication with study staff
• Often cannot request records related to your study visits until after
trial has ended
• Reimbursement for travel and sometimes hotels depending on the
study, the sponsor, and/or how far away you live. Keep your
receipts!
• Stipends typically offered (often $50 or $75 depending on length of
visits)
• Some sponsors will plan travel for you, if needed

48. Expectations of patients in trials
• Keep close track of symptoms and medication
changes
• Notify study team of all symptoms, new
diagnoses, planned procedures, and
medication changes (yes, even supplements!)
• If you’re taking pills, must return bottles at
each visit (both empty and partial)
• Take and store study drug as instructed

49. Questions?