Double blinded placebo controlled crossover study of High Frequency SCS

1.Dept of Anaesthesiology and Pain Management Centre for Neuromodulation, Morges. Switzerland2.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 UK4. University of Teesside Middlesbrough UK

C. Perruchoud, E. Buchser, A Durrer, B. Rutschmann, M. Rosato1,2, N. Bovet, A. Gulve3, M Brookes3, G. Madzinga3 A. Batterham4 and S .

Eldabe3

Disclosureo Medtronic funded the study and provided the

technical support for IPG programming. o No member of Medtronic personnel contributed

to the study design, data collection or data analysis.

o The study was sponsored by the author’s institutions

o E. Buchser, S. Eldabe and C. Perruchoud are Medtronic Consultants

Backgroundo Double blinded controlled studies have not been

feasible in SCS o In a randomised placebo controlled trial of 12 RA

patients Eddicks showed Sub-threshold stimulation (SS) to have an analgesic effect1

o High Frequency (HF) stimulation and Burst stimulation produce analgesia without paraesthesias2,3

o In this study we aim to compare HF stimulation and Sham Stimulation in a double blind crossover design 1. 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, 2007. 93(5): p. 585-90.2. De Ridder, D., et al., Burst spinal cord stimulation: toward paresthesia-free pain suppression. Neurosurgery, 2010. 66(5): p.

986-90.3. 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

Patients and Methodso 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

DATA 1 DATA 3 DATA 5 DATA 7

NS NS to HF HF to NS NS to Sham

DATA 2

NS

DATA 6

DATA 4

NS to Sham Sham to NS

DATA 8

NS to HF

RandomisationEnd of Study

NS is restarted

Patie

nt In

clus

ion

Visit 1 Visit 2 Visit 3 Visit 4 Visit 5

2 week periods

Normal StimulationHF Stimulation 5KhzSham

DATA X 5 Day Data Collection

Sequence 1

Sequence 2

PGIC

Randomisation & Blindingo Randomisation

Subjects were randomised to receive sequence 1 or 2 using central randomisation service

o 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

Primary Outcome measure: PGICo 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

40 Patients Consented

2 patient withdrew consent

38 Patients Randomized

5 Withdrawn1 battery failure 1 lead fracture2 withdrew consent1 Battery flipping

33 Patients Analysed

17 Completed Sequence 1

HF first

16 Completed Sequence 2

Sham First

Study Flow

Results: Sample Baseline Characteristics

Data are mean (SD).

Results: Blindingo None of the subjects reported a sensation of

paraesthesias in either group

o At visit 3, the proportion of patients guessing their therapy group correctly was 15/33 = 45%

o At visit 5 the proportion guessed correctly was 18/33 = 55%. 

o Neither is significantly different from chance (50%)

Results: Patient Global Impression of Change (PGIC)

o In sequence 1 (HF first) 9/17 (52.9%) responded to HF vs. 2/17 (11.7%) to sham; a difference of (41.2%)

o 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)

o The overall treatment effect (benefit of HF vs. sham) is the average of these two proportions: (0.412 and -0.188) = 0.112 (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: 193-8.

Seq 1 HF First

Seq 2 Sham First

0%10%20%30%40%50%60%

HFSham

The Period Effecto 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).

Treatment Proposed First Treatment Proposed Last02468

1012141618

HFShamTotal

Conclusions Io This is the first double blinded RCT in spinal cord

stimulationo We showed a minimal advantage of HF over

sham as a proportion of 11.2% ( P=0.30). o We showed a substantial period effect with a

greater proportion of responders at visit 3 versus visit 5 (difference = 30% P=0.006).

o Both VAS & EQ-5D show the same consistent pattern of period effect (NS differences)

Conclusions IIo At settings used, HF offers small advantage over sham.

Only the order of the treatment in the sequence, dictates a significant effect

o We believe this period effect to be related to patient expectation, or a “study” effect.

o 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

Thank you

Morges TeamC. PerruchoudA Durrer, B. Rutschmann,M. RosatoN. BovetE. Buchser

Middlesbrough TeamA GulveG. MadzingaF. GarnerS. WestM. BrookesS. Eldabe Prof. A. Batterham Teesside University

Thank Youo Morges Team

C. Perruchoud A Durrer, B. Rutschmann, M. Rosato E. Buchser

o Middlesbrough Team A Gulve G. Madzinga F Garner S. West M. Brookes S. Eldabe

• Prof. A. Batterham Teesside University

Sample Size and statistical methods o Sample size

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%

o 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: 193-8.

Secondary Outcome measureso Pain VAS

mean pain VAS on the HF treatment was 4.35 cm vs. 4.26 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. 4.63 cm in the second period (Visit 5) ; difference (visit 3 minus visit 5) = -0.64 cm (95% CI, -1.41 to 0.14 cm; P=0.11).

Visit 3VAS 3.99

Visit 5VAS 4.63

Secondary Outcome Measureso Mean EQ5D-index on the HF treatment was 0.480

vs. 0.463 on the sham; difference (HF minus sham) = 0.017 (95% CI, -0.101 to 0.135; P=0.78).

o Mean EQ5-D index was 0.510 at visit 3 vs. 0.432 at Visit 5; difference (visit 3 minus visit 5) = 0.078 (95% CI, -0.041 to 0.196 ; P=0.19).

Visit 3EQ5D 0.51

Visit 5EQ5D 0.432

The Period Effect

Sequence 1 HF First Sequence 2 Sham First0%

10%

20%

30%

40%

50%

60%

HFSham