The natural SCI model of canine intervertebral disc herniation: - - PowerPoint PPT Presentation

The natural SCI model of canine intervertebral disc herniation:

Clinical trials of novel therapies

Nick Jeffery BVSc PhD MSc DipECVS DipECVN FRCVS

Why clinical dogs?

Increase confidence to translate from laboratory to clinic

Dogs are amenable to detailed locomotor assessment

Normal dog Injure red d dog

… electrophysiology …

TMMEP SSEP

SCI dog

Detrusor over-reactivity

Normal dog

Fowler et al, 2008

… bladder function …

… high quality MRI…

Clinical veterinary thinking on dogs

Our patients are small(ish) humans

Rat ather er tha han n

Large rats

‘Necessary’?

• Use for determining effects in actual clinical

condition

Heterogeneity: dog patients vary similarly to their human counterparts…

Variability iability in: age, weight, lesion nature, severity, intercurrent disease, genetics….

… which makes detection of beneficial effects more difficult … but more clinically-relevant …

Clin inica ically: lly: Is the intervention sufficiently efficacious to make a meaningful difference to a recipient?

Aim: unbiased measure of intervention effect in chronic clinical canine SCI using an RCT

Recruit cases of chronic (>3 months from injury) clinically complete SCI Control Treatment Randomization

Blinded assessment of primary and secondary

• utcome measures

Pre-defined primary outcome measure = fore-hind coordination

~15-20 years ago…

Lancet Neurology 2006

Trial case selection

• Clinically ‘complete’ injury
• Recovery at a plateau (i.e. >3 months after

SCI)

• Thoracolumbar lesion
• Small dogs
• Usin

ing g very seve vere chronic nic case ses s minimiz nimizes es re required ired sample le size ze

C1 C1-C5 C5 C6 C6-T2 T2 T3 T3-L3 L3 L4 L4-S3 S3

Blinded observer correctly identified 78% transplanted animals

• LR test: P = 0.04

3 months 1 month 2 months 4 months 6 months Cumulative delay (ms)

OEC transplant significantly improves fore-hind coordination

P = 0 0.007

Cont ntrol OEC

Distribution-based calculation (mean change /s.d.) = 0.955

• designated a ‘large effect’ (Cohen, 1977)

SPIN-OFF QUESTIONS FROM OEC TRIAL

What is the best method for cell transplantation? How long do cells survive? What’s the best time to transplant? Should we transplant more than

• nce??

Randomized double-blinded phase II clinical trial of intraspinal chondroitinase ABC in dogs

Why chondroitinase?

• Long history of success in multiple laboratories and multiple species
• Translatable delivery system:

Heat-stabilization by trehalose and slow release from lipid microtubes (Lee et al, 2010)

• Synergistic with physical therapy:
• Can use sham injection for controls

Bradbury et al, 2002 :

Garcia-Alias et al, 2009

Methods

Inject under anesthesia at 2 sites: lesion epicenter and cranial margin of central pattern generator lower motor neuron network

• 200mL at each site (=625mU)

OR Needle puncture of skin

Demographics: chronic disease in middle-aged animals

Age (year) Median (range) 6.0 (0.5 – 14) 6.0 (1 – 13) Weight (Kg) Median (range) 6.3 (2.7 – 20) 6.0 (2.2 – 17) Time interval since injury (months) Median (range) 10.5 (3 – 75) 17 (3 – 89) Chondroitinase Control

Results: primary outcome - coordination

As a group, ChAse dogs have improved coordination 23% improvement from baseline Significant interaction between time and ChAse: P=0.007

Results

3 individual dogs recovered to walk independently

Results: von Frey filament skin sensitivity testing

• Very variable but median score of zero at all time points
• Increase in scores after injection … in BOTH groups
• Fading of sensitivity with time, final results similar to baseline

Results: other adverse events

Contr trol l (8) Treatmen tment t (11)

Mont nth h 0 1 1 – diarr rrhea 1 1 – acted painful nful for 12 hr hr 1 1 – seizure re when recovering ring from GA 1 1 – diarr rrhea 3 3 – reduced d movement nt for r 1-3 days Mont nth 1 1 1 – skin ulceration tion 1 1 – diarr rrhea 1 1 – skin ulceration tion 1 1 – spasms ms in pelvic ic limbs bs 1 1 – diarr rrhea Mont nth 3 1 1 – diarr rrhea 1 1 – UTI 2 2 – UTI Month 6 1 1 – hematuria ria 2 2 – UTI None

Obstacles to translation – where are these therapies now?

• Safety
• Second species confirmation?
• Can delivery system be translated?
• Resilient in the face of clinical heterogeneity?

Clinical dog cases can’t solve everything

• Can’t get verbal feedback on pain etc
• Can’t evaluate fine motor function (CST)
• Some limits on possible interventions (and follow-up)

Remaining translational questions

• What is the relationship between spinal fracture in a car

crash and acute disc extrusion in a dog?

Kaufman et al, 2013 http://www.sci-recovery.org/sci.htm

VERSUS US

Ethical aspect

• Using clinical cases avoids inducing the target disease
• BUT
• If a dog therapy is not the outcome then we are effectively using them as

tools to develop human medicine where they may be harmed but accrue no gains

Where do we go now?

• Do a human clinical trial!
• Increase effectiveness of interventions
• Better delivery
• Greater activity of cells or enzymes
• Make a commercial product for dogs

Acknowledgements

Ravi Bellamkonda Georgia Tech / Duke Nicolas Granger University of London Hilary Hu Texas A&M Bala Pai Georgia Tech