1. Double blinded placebo controlled crossover study of High Frequency SCS
C. Perruchoud, E. Buchser, A Durrer, B. Rutschmann, M. Rosato1,2, N. Bovet, A. Gulve3, M Brookes3, G. Madzinga3 A. Batterham4 and S . Eldabe3
1.Dept of Anaesthesiology and Pain Management Centre for Neuromodulation, Morges. Switzerland
2.Dept of Anaesthesiology and Pain Management University Hospital Center and University of Lausanne Switzerland
3. Dept of Anaesthesiology and Pain Management The James Cook University Hospital Middlesbrough UK
4. University of Teesside Middlesbrough UK

2. Disclosure
Medtronic funded the study and provided the technical support for IPG programming.
No member of Medtronic personnel contributed to the study design, data collection or data analysis.
The study was sponsored by the author’s institutions
E. Buchser, S. Eldabe and C. Perruchoud are Medtronic Consultants

3. Background
Double blinded controlled studies have not been feasible in SCS
In a randomised placebo controlled trial of 12 RA patients Eddicks showed Sub-threshold stimulation (SS) to have an analgesic effect1
High Frequency (HF) stimulation and Burst stimulation produce analgesia without paraesthesias2,3
In this study we aim to compare HF stimulation and Sham Stimulation in a double blind crossover design
Eddicks, S., et al., Thoracic spinal cord stimulation improves functional status and relieves symptoms in patients with refractory angina pectoris: the first placebo-controlled randomised study. Heart, (5): p
De Ridder, D., et al., Burst spinal cord stimulation: toward paresthesia-free pain suppression. Neurosurgery, (5): p
Smet I, Van Buyten JP and Alkaisy A. Successful treatment of low back pain with a novel neurostimulation device. Proceeds of the North American Neuromodulation Society Meeting 2011 Las Vegas

4. Patients and Methods
40 Patients with existing SCS systems (stable pain relief) implanted for low back and or leg pain enrolled at Morges Switzerland and Middlesbrough UK.
Patients Implanted with Restore Advanced/ Ultra/ Sensor and Prime Advanced.
A special study programmer allowed any of the IPGs to deliver the following settings
Frequency of 5'000 Hz continuous stimulation
Pulse width 60 μsec
Amplitude increased gradually to threshold then reduced again to a point where the patient is unable to feel paraesthesias regardless of the position

5. Patient Inclusion PGIC 2 week periods End of Study NS is restarted
Randomisation
Sequence 1
Patient Inclusion
DATA 1
DATA 3
DATA 5
DATA 7 NS
NS to HF
HF to NS
NS to Sham
Sequence 2
DATA 2
DATA 4
DATA 6
DATA 8 NS
NS to Sham
Sham to NS
NS to HF
Visit 1
Visit 2
Visit 3
Visit 4
Visit 5
Normal Stimulation
DATA X
5 Day Data Collection
HF Stimulation 5Khz
Sham
PGIC
2 week periods

6. Randomisation & Blinding
Subjects were randomised to receive sequence 1 or 2 using central randomisation service
Blinding Precautions
Research teams were split into 2 groups of blinded and unblinded personnel with no crossover in personnel
In patients with rechargeable devices we set an IPG current leakage in the sham period to similar level of the current usage during HFSCS
Patients were asked to guess the nature of the treatment they received to test the blinding strength at visits 3 and 5

7. Primary Outcome measure: PGIC
Patient Global Impression of Change (PGIC)
end of each 2-week period. "Since the last visit to the pain clinic my overall pain control is:
very much improved
much improved
minimally improved
no change
minimally worse
much worse
very much worse
A responder is defined as a subject reporting at least a “minimal improvement”, with the point of reference being the last visit under conventional stimulation

8. Study Flow 17 Completed Sequence 1 HF first 40 Patients Consented
Randomized
33 Patients
Analysed
Withdrawn
1 battery failure
1 lead fracture
2 withdrew consent
1 Battery flipping
16 Completed Sequence 2
Sham First
2 patient withdrew consent

9. Results: Sample Baseline Characteristics
Data are mean (SD).

10. Results: Blinding
None of the subjects reported a sensation of paraesthesias in either group
At visit 3, the proportion of patients guessing their therapy group correctly was 15/33 = 45%
At visit 5 the proportion guessed correctly was 18/33 = 55%. 
Neither is significantly different from chance (50%)

11. Results: Patient Global Impression of Change (PGIC)
In sequence 1 (HF first) 9/17 (52.9%) responded to HF vs. 2/17 (11.7%) to sham; a difference of (41.2%)
In sequence 2 (sham first) 5/16 (31.2%) responded to HF vs. 8/16 (50%) to sham; a difference of (18.8%, in favour of sham)
The overall treatment effect (benefit of HF vs. sham) is the average of these two proportions: (0.412 and ) = (11.2%)1.
a responder is defined as a subject reporting at least a ‘minimal improvement’, with the point of reference being the last visit under conventional stimulation)
1. Schouten H, Kester A: A simple analysis of a simple crossover trial with a dichotomous outcome measure. Stat Med 2010; 29:

12. The Period Effect
We observed a substantial period effect, irrespective of treatment received, with 17/33 (51.5%) patients benefiting at Visit 3 versus 7/33 (21.2%) at Visit 5; mean difference in proportions = 30% ( P=0.006).

13. Conclusions I
This is the first double blinded RCT in spinal cord stimulation
We showed a minimal advantage of HF over sham as a proportion of 11.2% ( P=0.30).
We showed a substantial period effect with a greater proportion of responders at visit 3 versus visit 5 (difference = 30% P=0.006).
Both VAS & EQ-5D show the same consistent pattern of period effect (NS differences)

14. Conclusions II
At settings used, HF offers small advantage over sham. Only the order of the treatment in the sequence, dictates a significant effect
We believe this period effect to be related to patient expectation, or a “study” effect.
Study Limitation
These findings cannot be extrapolated to other stimulation frequencies/modes applied for a longer duration of time on stimulation naïve patients
We applied sub-threshold amplitudes; stimulation above sensory threshold may have been unpleasant and resulted in ublinding
The short duration of HFSCS and sham may have allowed a carry over effect of conventional SCS to play a significant role
Cathode position

15. Prof. A. Batterham Teesside University
Thank you
Middlesbrough Team
A Gulve
G. Madzinga
F. Garner
S. West
M. Brookes
S. Eldabe
Morges Team
C. Perruchoud
A Durrer,
B. Rutschmann,
M. Rosato
N. Bovet
E. Buchser
Prof. A. Batterham Teesside University

16. Thank You Morges Team Middlesbrough Team C. Perruchoud A Durrer,
B. Rutschmann,
M. Rosato
E. Buchser
Middlesbrough Team
A Gulve
G. Madzinga
F Garner
S. West
M. Brookes
S. Eldabe
Prof. A. Batterham Teesside University

17. Sample Size and statistical methods
Using methods proposed by Schouten and Kester1, we estimated that a sample of 38 patients was required to have 90% power (2P=0.05) detect a difference in the proportion of patients responding to treatment in HF vs. sham of 25%
Statistical analysis
PGIC :methods of Schouten and Kester, in which the treatment difference (HFSCS-sham) for each of the two treatment sequences is computed and then averaged.
Pain VAS and EQ5-D index analysed using a conventional within-subjects model accounting for the period effect and utilizing the baseline scores before each treatment (visits 2 and 4) in an ANCOVA model
1. Schouten H, Kester A: A simple analysis of a simple crossover trial with a dichotomous outcome measure. Stat Med 2010; 29:

18. Secondary Outcome measures
Pain VAS
mean pain VAS on the HF treatment was 4.35 cm vs cm on the sham (P=0.82).
Irrespective of treatment received, the mean VAS in the first treatment period (visit 3) was 3.99 cm vs cm in the second period (Visit 5) ; difference (visit 3 minus visit 5) = cm (95% CI, to 0.14 cm; P=0.11).
Visit 3
VAS 3.99
Visit 5
VAS 4.63

19. Secondary Outcome Measures
Mean EQ5D-index on the HF treatment was vs on the sham; difference (HF minus sham) = (95% CI, to 0.135; P=0.78).
Mean EQ5-D index was at visit 3 vs at Visit 5; difference (visit 3 minus visit 5) = (95% CI, to 0.196 ; P=0.19).
Visit 3
EQ5D 0.51
Visit 5
EQ5D 0.432

20. Subsequent Visits
Paraesthesia / pain mapping – estimated % of paraesthesia coverage
Concomitant pain medication assessment
Non drug treatments assessment
Stimulation settings
Pain Intensity VAS score
PGIC questionnaire
EQ-5D questionnaire
Blinding Check ‘which type of therapy do you think you are receiving and why?’
Patients asked if they have felt paraesthesia at any point during the blinded phase
Adverse Event and Serious Adverse Event assessment

21. The Period Effect

22. Results: Responder Graph

23. Data collected Baseline assessment
Demographic data (age, weight and height)
Type of stimulator and leads
Lead position (tip and midline)
Paraesthesia / pain mapping – estimated % of paraesthesia coverage
Diagnosis and medical history
Duration of pain
Location of pain
Concomitant pain medication
Non drug treatments
Stimulation settings
Physical and neurological examination