ADIPOSE-DERIVED CELL THERAPY FOR HAND DYSFUNCTION IN PATIENTSWITH SYSTEMIC SCLEROSIS:A RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED TRIAL
Dinesh Khanna1, Paul Caldron2, Richard Mar7n3, Suzanne Kafaja4, Robert Spiera5, Shadi Shahouri6, Ankoor Shah7, Vivien Hsu8, John Ervin9, Robert Simms10, Robyn Domsic11,Virginia Steen12, John Yocum13, Laura Hummers14, Chris Derk15, Maureen Mayes16, Soumya ChaSerjee17, John Varga18, Mark Adams19, John K. Fraser20, , Daniel Furst21

1. University of Michigan; 2. Arizona Arthri7s and Rheumatology Research, PLLC; 3. West Michigan Rheumatology, PLLC; 4. UCLA David Geﬀen School of Medicine; 5. Hospital for Special Surgery, NY; 6. Heartland Research Associates;7. Duke University Medical Center;
8. Robert Wood Johnson Medical School; 9. Center For Pharmaceu7cal Research, ;10. Boston University Medical Center 11. University of PiSsburgh Medical Center; 12. MedStar Georgetown University Hospital; 13. Bap7st Health Center for Clinical Research; 14. Johns Hopkins University;
15. University of Pennsylvania; 16. University of Texas Houston Medical School; 17. Cleveland Clinic; 18. Northwestern University; 19. Central Kentucky Research Associates Inc.; 20. Cytori Therapeu7cs Inc.; 21. 4. UCLA, University of Washington, University of Florence

BackgroundMethods

Raynaud’s Condition Score (RCS):
Improvement from baseline in Raynaud’s Condition
Score at 12 weeks for the ADRC-treated subjects was
greater than that for the placebo group for all
subjects, and for subjects with diffuse and limited SSc(nominal p-values 0.009, 0.09, and 0.022
respectively). The same trends were apparent at 48weeks (all subjects: ADRCs 27% improvement,Placebo 14%; diffuse SSc ADRCs 21%, Placebo 8%;
limited SSc ADRCs 33% Placebo 21%), however,these differences were not associated with nominal pvalues of less than 0.05.
Scleroderma Health Assessment Questionnaire(SHAQ)
The main component of the SHAQ is the validated
HAQ-DI; the mean improvement in the HAQ-DI at 48weeks for subjects treated with ADRCs was greaterthan that for the placebo arm for all groups. Subjects
with diffuse SSc in the treated arm improved by anaverage of 0.21 at 48 weeks compared with a mean of0.04 in the placebo arm (between-group difference=0.17 points; nominal p=0.044). These differenceswere most evident in HAQ-DI domains associatedwith hand use (Figure 2).
Figure 2: Change in HAQ-DI Subscores at 48 weeks: Subjects with Diﬀuse SSc
Improvement From Baseline at 48 weeks

0.40

Placebo
ADRCs

0.35
0.30

Variable
Number of Subjects
Gender (% female)Age (years)
Disease Dura7on (SSc diagnosis) (years)
Dura7on Since Raynaud’s Onset (years)
Diﬀuse SSc Subtype (%)
Subjects with Digital Ulcers at Baseline

All PaQents
16

p=0.029p=0.441412

p=0.34

p=0.30p=0.28108642

ADRC: n=48; Placebo: n=400

p=0.008

p=0.11116

p=0.102p=0.069

1412p=0.09

108642ADRC: n=32; Placebo: n=1900

6 12 18 24 30 36 42 48
Time ARer Treatment (weeks)

ADRCs

p=0.63

Placebop=0.45p=0.4214p=0.66

p=0.7212108642ADRC: n=16; Placebo: n=2100

6 12 18 24 30 36 42 48
Time ARer Treatment (weeks)

06 12 18 24 30 36 42 48
Time ARer Treatment (weeks)

All

Placebo

ADRCs

All

Placebo

ADRCs

All

Placebo

ADRCs

Baseline

42.1±11.4

39.3±10.5

Baseline

43.6±11.5

40.7±9.4

Baseline

40.7±11.4

36.4±12.3

Responder Analysis: Subjects with Diffuse SSc
Responder rates based on assumed thresholds of change >9.5 for the CHFS[1] and change ≥0.125 (morethan slight improvement) and change >0.25 (more than mild improvement) for the HAQ-DI[1,2] showed that
only 16% (3/19) of subjects with diffuse SSc in the placebo arm responded in both the CHFS and HAQ-DI
compared with 52% (16/31) of subjects in the treated arm (nominal p=0.0163; Figures 3 and 4).
Figure 3: Improvement in CHFS and HAQ-DI at 48 weeks
Placebo

1.5

Figure 4: Percent Responders in ADRC and Placebo Groups

MCID for CHFS (>9)

Treated1.00.5MCID for HAQ-DI (>0.125)

0.0-20-1001020Placebo

703040506060ADRCs

p=0.020
p=0.042p=0.0163
p=0.035

50

40

30

2010-0.5

0ADRC: n=32; Placebo: n=19

CHFS (>9.5)

0.25
0.20

-1.00.15

ADRCPlacebo
4840
85% (40/48) 88% (35/40)
54±952±1212.7 ±7.9 y 13.3 ± 8.9 y
14.7 ± 9.5 y 15.4 ± 10.5 y
67% (32/48) 48% (19/40)
35%33%

Limited Disease
Improvement From Baseline

16Diﬀuse Disease

Percent Responders at 48w (%)

Key Secondary End Points

Table 1: Demographics of Subjects Enrolled in the STAR Trial

Figure 1: Change Over Baseline in Cochin Hand FuncQon Scale

Improvement From Baseline

Cochin Hand Function Scale (CHFS):
The primary endpoint was change in the CHFS at 24
and 48 weeks after treatment. Data for subjects withdiffuse SSc indicate an early and sustained
improvement in CHFS for subjects treated withADRCs that was greater than that for subjects in theplacebo group (Figure 1). This difference approachedstatistical signiFicance at 48 weeks (p=0.0689).

Improvement in HAQ-DI at 48 weeks

Primary End Point

Adipose tissue collected by a small volume liposuction
was processed with the Celution® System (CytoriTherapeutics Inc.) to prepare ADRCs for immediatesubcutaneous administration under local anesthesia.
Subjects with signiFicant impairment of hand function(baseline Cochin Hand Function Scale [CHFS] >20
points; scale 0-90) were randomized (1:1) to receive
ADRCs (4x106 per Finger) or a visually-matchedplacebo into all Fingers of each hand. Safety wasassessed throughout the trial. EfFicacy was evaluated at
multiple time points over 48 weeks using the CHFS,
SHAQ, and other patient-reported and quantitative
assessments of hand function.

Improvement From Baseline

Hand dysfunction is almost universal in systemicsclerosis (SSc). There is no approved treatment for thisindication. Adipose-Derived Regenerative Cells (ADRCs)
are a population of cells isolated from a patient’s
adipose tissue. Preclinical studies and a 12-patient,
open-label pilot clinical trial have suggested that ADRCs
have the capacity to reduce inFlammation, improve
vascularity, and thereby, improve hand function. TheSTAR Trial was a 88-patient, 19-center prospective,
double-blind, randomized, controlled trial to to test thishypothesis.

Demographics

HAQ-DI (>0.125) HAQ-DI (>0.25)

CHFS (9.5) andHAQ-DI (0.125)

DeﬁniQon of Responder

Improvement in CHFS at 48 weeks

0.10

Safety

0.05
0.00
-0.05
-0.10

HAQ-DI Domain

Exploratory End Points
Improvement from baseline at 48 weeks that was
greater for the ADRC-treated arm than for the placebo
arm was also evident in other endpoints. For EQ-5Dand Patient Global Score these changes wereassociated with a nominal p-value of less than 0.05. Nochanges favoring the placebo arm approached or
achieved nominal p-values of less than 0.05 (Table 2).
Table 2: Improvement from Baseline for Other Endpoints
at 48 weeks in Subjects with Diﬀuse SSc
Parameter

Group Nominal
Placebo
ADRCs
Favored p-value-0.09 ± 0.02 0.04 ± 0.12 ADRCs 0.0112

EQ-5D 3L
Pa7ent Global SSc Ac7vity-0.16 ± 1.8 1.03 + 2.81 ADRCs
Score
Physician Global SSc Ac7vity-0.05 ± 1.75 0.61 ± 1.54 ADRCs
Score
1st Corner Distance (mm)1.0 ± 14.24.4 ± 18.3 ADRCs
2nd-4th Corner Distance (mm)-2.0 ± 12.0 9.2 ± 28.2 ADRCs
Grip Strength (right hand; kg)
2.1 ± 11.9
0.5 ± 12.5 Placebo
Pinch Strength (right hand; kg) -0.22 ± 2.63 0.16 ± 3.28 ADRCs
MRSS (hand only)-1.5 ± 4.2-0.7 + 2.3 Placebo
References:
1. STAR data set for subjects with diffuse SSc
2. Khanna et al (2005) Ann Rheum Dis 2006;65:1325–1329

0.0152
0.169
0.484
0.107
0.679
0.673
0.506

Table 3: Summary of Most Common Adverse Events Reported

The procedure was well-tolerated; 6 subjects
reported serious adverse events [1 ADRC (2.1%); 5
placebo (12.5%)] with no SAEs in the hand and nodeaths. Adverse events affecting at least 5% ofsubjects in either the ADRC or placebo group areshown in Table 3. The overall rate of adverse
events was very similar for both groups. Notabledifferences were observed between treatmentgroups in the percentage of subjects who
experienced peripheral vascular related events andthose with calcinosis. Peripheral vascular events(e.g., hypertension, hypotension, digital infarction,and worsening of Raynaud’s phenomenon) wereobserved in 6 of the 40 placebo treated subjects(15.0%), compared with none of the 48 ADRCtreated subjects. Similarly, calcinosis was observedin 5 of 40 (12.5% of subjects in the placebo groupcompared with 1 of 48 (2.1%) in the ADRC group.

Preferred Term
Any Adverse Event
Localized infec7on
Skin ulcer
Upper respiratory tract infec7on
Calcinosis
Diarrhea
Rash
Limb injury
AnemiaNauseaArthralgia
Celluli7s
Pain in extremity
Hypoesthesia

Placebo (%)
81.3
15.0
15.0
15.0
12.5
10.0
7.5
7.5
7.57.5
5.0
5.0
2.5
0.0

ADRCs (%)
82.5
6.3
8.3
20.8
2.1
6.3
0.0
0.0
0.0
4.2
6.3
8.3
6.3
8.3

ITT Data Set; all subjects irrespecNve of SSc subtype
Events occurring in at least 5% of either ADRC or placebo group
Preferred Terms are listed in decreasing order of frequency based on the placebo group

Conclusions
Treatment with ADRCs was safe. While not meeting the primary endpoint for all SSc patients, the STAR trial
revealed strong signals of efFicacy. In particular, improvement over baseline at 3 months was greater for theADRC treatment group than for placebo for the CHFS, RCS, and HAQ-DI scores for the entire ITT group. Forsubjects with diffuse SSc, improvements from baseline at 48 weeks in the ADRC group that were greaterthan those in the placebo group and associated with nominal p-values of less than 0.05 were evident forseveral key parameters including CHFS, HAQ-DI, EQ-5D, and Patient Global Assessment of SSc activity.