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Clinical Trial Results:
Prospective, double-blind, randomised trial to assess the efficacy of continuous sciatic/posterior tibial nerve blockade via a neural sheath catheter in lower limb amputees

Summary
EudraCT number	2007-000619-27
Trial protocol	GB
Global end of trial date	30 Apr 2013

Results information
Results version number	v1(current)
This version publication date	27 Dec 2019
First version publication date	27 Dec 2019
Other versions

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

56481676

ISRCTN number

ISRCTN68691928

US NCT number

WHO universal trial number (UTN)

Sponsor organisation name

University Hospitals of Leicester NHS Trust

Sponsor organisation address

Research & Innovation, Trust HQ. Level 3 Balmoral Building. Leicester Royal Infirmary. , Leicester, United Kingdom, LE1 5WW

Public contact

Carolyn Maloney, University Hospitals of Leicester NHS Trust, +44 116 258 4109, carolyn.maloney@uhl-tr.nhs.uk

Scientific contact

Prof. Jonathan Thompson, University Hospitals of Leicester NHS Trust, jt23@le.ac.uk

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Final

Date of interim/final analysis

30 Apr 2013

Is this the analysis of the primary completion data?

Yes

Primary completion date

30 Apr 2013

Global end of trial reached?

Yes

Global end of trial date

30 Apr 2013

Was the trial ended prematurely?

Main objective of the trial

To establish the effects of continuous peri- and post-operative sciatic/posterior tibial nerve blockade using a levobupivacaine infusion via a neural sheath catheter on late stump pain, phantom limb sensations and phantom limb pain.

Protection of trial subjects

All trial subjects (including intervention and control groups) received patient-controlled analgesia with morphine. All patients had access to further escape medication according to the protocol as required

Background therapy

Standardised surgery performed under standardised general anaesthesia

Evidence for comparator

Pain scores, requirements for analgesia, quality of life questionnaires

Actual start date of recruitment

01 Oct 2007

Long term follow-up planned

Yes

Long term follow-up rationale

Scientific research

Long term follow-up duration

12 Months

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

United Kingdom: 90

Worldwide total number of subjects

EEA total number of subjects

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

Recruitment October 2007 to March 2013. Single UK centre

Screening details

All patients admitted to the vascular unit at Leicester Royal Infirmary and planned for major lower limb amputation surgery (due to vascular aetiology) were considered for inclusion

Period 1 title

Recruitment (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator, Data analyst, Assessor

Blinding implementation details

Computer generated randomisation by an independent clinical trials unit

Are arms mutually exclusive

Yes

Intervention group

Arm description

infusion of 0.125% Levobupivacaine at a rate of 8mls h-1 for 96hrs via a neural sheath catheter into the sciatic or posterior tibial nerve for above and below knee amputations respectively.

Arm type

Experimental

Investigational medicinal product name

levobupivacaine 0.125%

Investigational medicinal product code

Other name

Pharmaceutical forms

Infusion

Routes of administration

Perineural use

Dosage and administration details

infusion of 0.125% Levobupivacaine at a rate of 8mls h-1 for 96hrs via a neural sheath catheter into the sciatic or posterior tibial nerve for above and below knee amputations respectively.

placebo control arm

Arm description

infusion of 0.9% saline at a rate of 8mls h-1 for 96hrs via a neural sheath catheter into the sciatic or posterior tibial nerve for above and below knee amputations respectively.

Arm type

Placebo

Investigational medicinal product name

0.9% saline

Investigational medicinal product code

Other name

Pharmaceutical forms

Infusion

Routes of administration

Perineural use

Dosage and administration details

infusion of 0.9% saline at a rate of 8mls h-1 for 96hrs via a neural sheath catheter into the sciatic or posterior tibial nerve for above and below knee amputations respectively.

Number of subjects in period 1	Intervention group	placebo control arm
Started	45	45
Completed	41	40
Not completed	4	5
Adverse event, serious fatal	-	1
Consent withdrawn by subject	1	-
Protocol deviation	3	4

Baseline characteristics

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Reporting group title

Recruitment

Reporting group description

Reporting group values	Recruitment	Total
Number of subjects	90	90
Age categorical
Units: Subjects
In utero	0	0
Preterm newborn infants (gestational age < 37 wks)	0	0
Newborns (0-27 days)	0	0
Infants and toddlers (28 days-23 months)	0	0
Children (2-11 years)	0	0
Adolescents (12-17 years)	0	0
Adults (18-64 years)	27	27
From 65-84 years	48	48
85 years and over	15	15
18 -100	0	0
Adults aged 18-64	0	0
Age continuous
Female
Units: years
median (inter-quartile range (Q1-Q3))	72 (62 to 82)	-
Gender categorical
Male
Units: Subjects
Female	32	32
Male	58	58

End points

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Reporting group title

Intervention group

Reporting group description

infusion of 0.125% Levobupivacaine at a rate of 8mls h-1 for 96hrs via a neural sheath catheter into the sciatic or posterior tibial nerve for above and below knee amputations respectively.

Reporting group title

placebo control arm

Reporting group description

infusion of 0.9% saline at a rate of 8mls h-1 for 96hrs via a neural sheath catheter into the sciatic or posterior tibial nerve for above and below knee amputations respectively.

Primary: Presence or absence of significant phantom limb pain

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End point title

Presence or absence of significant phantom limb pain

End point description

End point type

Primary

End point timeframe

6 months after intervention

End point values	Intervention group	placebo control arm
Number of subjects analysed	30	32
Units: number	7	8

chi squared test

Comparison groups

Intervention group v placebo control arm

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other

P-value

< 0.05

Method

Chi-squared

Confidence interval

Adverse events

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Timeframe for reporting adverse events

6 months

Assessment type

Systematic

Dictionary name

OED

Dictionary version

Reporting group title

experimental

Reporting group description

Reporting group title

Placebo

Reporting group description

Serious adverse events	experimental	Placebo
Total subjects affected by serious adverse events
subjects affected / exposed	22 / 41 (53.66%)	24 / 43 (55.81%)
number of deaths (all causes)	7	6
number of deaths resulting from adverse events	7	6
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Lung cancer metastatic
subjects affected / exposed	1 / 41 (2.44%)	0 / 43 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Brain Tumour
subjects affected / exposed	1 / 41 (2.44%)	0 / 43 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Vascular disorders
Deep vein thrombosis postoperative
subjects affected / exposed	0 / 41 (0.00%)	1 / 43 (2.33%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Lower limb ischemia
subjects affected / exposed	3 / 41 (7.32%)	1 / 43 (2.33%)
occurrences causally related to treatment / all	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 2	0 / 1
Ischaemic small bowel
subjects affected / exposed	1 / 41 (2.44%)	0 / 43 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
femoral and iliac vein thrombosis
subjects affected / exposed	1 / 41 (2.44%)	0 / 43 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
CVA
subjects affected / exposed	0 / 41 (0.00%)	1 / 43 (2.33%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Saddle embolus
subjects affected / exposed	1 / 41 (2.44%)	0 / 43 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
messenteric vascular occlusion
subjects affected / exposed	0 / 41 (0.00%)	1 / 43 (2.33%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Surgical and medical procedures
Revision of amputation
Additional description: Below knee to above knee amputations
subjects affected / exposed	7 / 41 (17.07%)	5 / 43 (11.63%)
occurrences causally related to treatment / all	0 / 7	0 / 5
deaths causally related to treatment / all	0 / 0	0 / 0
loop colostomy
subjects affected / exposed	0 / 41 (0.00%)	1 / 43 (2.33%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
SMA Embolectomy
subjects affected / exposed	0 / 41 (0.00%)	1 / 43 (2.33%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Amputation
Additional description: Vascular insufficiency left AKA
subjects affected / exposed	0 / 41 (0.00%)	1 / 43 (2.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
left CFA endarterectomy and a left profundaplasty
subjects affected / exposed	1 / 41 (2.44%)	0 / 43 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Angioplasty
subjects affected / exposed	1 / 41 (2.44%)	0 / 43 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Amputation of toes
Additional description: Debridement and amputation of 1st,2nd and 3rd toes
subjects affected / exposed	1 / 41 (2.44%)	0 / 43 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
iliac and profunda thrombectomy
subjects affected / exposed	1 / 41 (2.44%)	0 / 43 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
axillo femoral bypass.
subjects affected / exposed	1 / 41 (2.44%)	0 / 43 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Right hemicolectomy
subjects affected / exposed	0 / 41 (0.00%)	1 / 43 (2.33%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Reproductive system and breast disorders
Recto vaginal fistula
subjects affected / exposed	1 / 41 (2.44%)	0 / 43 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Exacerbation COPD
subjects affected / exposed	2 / 41 (4.88%)	0 / 43 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pulmonary oedema
subjects affected / exposed	0 / 41 (0.00%)	1 / 43 (2.33%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	1 / 41 (2.44%)	1 / 43 (2.33%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
pulmonary embolism
subjects affected / exposed	1 / 41 (2.44%)	0 / 43 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
pulmonary nodules
Additional description: possible lung metastasis
subjects affected / exposed	1 / 41 (2.44%)	0 / 43 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Chest Infection
subjects affected / exposed	1 / 41 (2.44%)	0 / 43 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Psychiatric disorders
Dementia
subjects affected / exposed	2 / 41 (4.88%)	0 / 43 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 2	0 / 0
disassociation disorder
subjects affected / exposed	1 / 41 (2.44%)	0 / 43 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
delirium
subjects affected / exposed	1 / 41 (2.44%)	0 / 43 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Confusional state
subjects affected / exposed	0 / 41 (0.00%)	4 / 43 (9.30%)
occurrences causally related to treatment / all	0 / 0	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0
Psychosis postoperative
subjects affected / exposed	1 / 41 (2.44%)	0 / 43 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Depression
subjects affected / exposed	1 / 41 (2.44%)	0 / 43 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Injury, poisoning and procedural complications
Fall
subjects affected / exposed	0 / 41 (0.00%)	1 / 43 (2.33%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Cardiac disorders
Myocardial infarction
subjects affected / exposed	0 / 41 (0.00%)	1 / 43 (2.33%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Cardiac arrest
subjects affected / exposed	0 / 41 (0.00%)	1 / 43 (2.33%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
SVT
subjects affected / exposed	0 / 41 (0.00%)	1 / 43 (2.33%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
ECG changes
subjects affected / exposed	0 / 41 (0.00%)	1 / 43 (2.33%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
IHD
subjects affected / exposed	1 / 41 (2.44%)	0 / 43 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Gastrointestinal disorders
PR Bleeding
subjects affected / exposed	1 / 41 (2.44%)	0 / 43 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Vomiting
Additional description: admitted with 24hr history of vomiting
subjects affected / exposed	0 / 41 (0.00%)	1 / 43 (2.33%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
small bowel ischaemia
subjects affected / exposed	1 / 41 (2.44%)	0 / 43 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Haematemesis due to severe eosophagitis
subjects affected / exposed	0 / 41 (0.00%)	1 / 43 (2.33%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hepatobiliary disorders
Hepatic encephalopathy
subjects affected / exposed	0 / 41 (0.00%)	1 / 43 (2.33%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Elevated Liver function tests
subjects affected / exposed	0 / 41 (0.00%)	1 / 43 (2.33%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Skin and subcutaneous tissue disorders
Cellulitis
subjects affected / exposed	1 / 41 (2.44%)	1 / 43 (2.33%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Erythema
Additional description: right leg
subjects affected / exposed	0 / 41 (0.00%)	1 / 43 (2.33%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Ulcer
Additional description: Non healing leg Ulcer
subjects affected / exposed	0 / 41 (0.00%)	1 / 43 (2.33%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
peri orbital swelling
subjects affected / exposed	0 / 41 (0.00%)	1 / 43 (2.33%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Stage 3 pressure sore
subjects affected / exposed	0 / 41 (0.00%)	1 / 43 (2.33%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Endocrine disorders
Hypoglycaemia
subjects affected / exposed	0 / 41 (0.00%)	1 / 43 (2.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Hairline pelvic fracture
Additional description: Fall leading to fracture
subjects affected / exposed	1 / 41 (2.44%)	0 / 43 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Bakers Cyst
subjects affected / exposed	0 / 41 (0.00%)	1 / 43 (2.33%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Infections and infestations
Amputation wound infection
subjects affected / exposed	1 / 41 (2.44%)	6 / 43 (13.95%)
occurrences causally related to treatment / all	0 / 1	0 / 6
deaths causally related to treatment / all	0 / 0	0 / 0
Infected Axillo femoral graft
subjects affected / exposed	1 / 41 (2.44%)	0 / 43 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Venous ulceration infection
subjects affected / exposed	1 / 41 (2.44%)	1 / 43 (2.33%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Infected axillo femoral graft
subjects affected / exposed	1 / 41 (2.44%)	0 / 43 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pressure sore infection
subjects affected / exposed	0 / 41 (0.00%)	1 / 43 (2.33%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 0%

Non-serious adverse events	experimental	Placebo
Total subjects affected by non serious adverse events
subjects affected / exposed	6 / 41 (14.63%)	4 / 43 (9.30%)
Gastrointestinal disorders
nausea and vomiting
subjects affected / exposed	6 / 41 (14.63%)	4 / 43 (9.30%)
occurrences all number	1	1

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Were there any global substantial amendments to the protocol? No

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

None reported

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Clinical trials

Clinical Trial Results:
Prospective, double-blind, randomised trial to assess the efficacy of continuous sciatic/posterior tibial nerve blockade via a neural sheath catheter in lower limb amputees

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Presence or absence of significant phantom limb pain

Primary: Presence or absence of significant phantom limb pain

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

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Clinical trials

Clinical Trial Results: Prospective, double-blind, randomised trial to assess the efficacy of continuous sciatic/posterior tibial nerve blockade via a neural sheath catheter in lower limb amputees

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Presence or absence of significant phantom limb pain

Primary: Presence or absence of significant phantom limb pain

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Clinical Trial Results:
Prospective, double-blind, randomised trial to assess the efficacy of continuous sciatic/posterior tibial nerve blockade via a neural sheath catheter in lower limb amputees