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Clinical Trial Results:
Perioperative Analgesia for Knee Arthroplasty: A prospective randomised controlled trial

Summary
EudraCT number	2013-002439-10
Trial protocol	GB
Global end of trial date	30 Nov 2016

Results information
Results version number	v1(current)
This version publication date	22 Sep 2017
First version publication date	22 Sep 2017
Other versions
Summary report(s)	PAKA study report

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

PAKA-33601-AS117013

ISRCTN number

ISRCTN60611146

US NCT number

WHO universal trial number (UTN)

Sponsor organisation name

University of Warwick

Sponsor organisation address

Clifford Bridge Road, Coventry, United Kingdom, CV2 2DX

Public contact

PAKA Trial, University of Warwick Clifford Bridge Road Coventry, 02476 968629,

Scientific contact

PAKA Trial, University of Warwick Clifford Bridge Road Coventry, 02476 968629,

Sponsor organisation name

University Hospitals Coventry and Warwickshire

Sponsor organisation address

Clifford Bridge Road, Coventry , United Kingdom, CV2 2DX

Public contact

PAKA trial, UHCW, paka@warwick.ac.uk

Scientific contact

PAKA trial, UHCW, paka@warwick.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

20 Jan 2017

Is this the analysis of the primary completion data?

Yes

Primary completion date

30 Nov 2015

Global end of trial reached?

Yes

Global end of trial date

30 Nov 2016

Was the trial ended prematurely?

Main objective of the trial

The aim of this study is to determine if there a difference in patient reported pain prior to physiotherapy on the first post operative day between patients managed with local knee injections (peri-articular),compared to the standard treatment (femoral nerve block),following a total knee replacement.

Protection of trial subjects

The study was approved by a Research Ethics Committee and received authorisation from the Medicines and Healthcare Products Regulatory Authority. Patients received verbal and written information prior to consenting to the trial and had the time to consider their participation and opportunity to ask questions. Patient data were anonymised to ensure information was kept confidential. Identifiable information was kept separately in a secure location

Background therapy

Evidence for comparator

Actual start date of recruitment

01 Oct 2013

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

United Kingdom: 262

Worldwide total number of subjects

262

EEA total number of subjects

262

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

181

85 years and over

Subject disposition

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Recruitment details

Participants were recruited from the University Hospitals Coventry and Warwickshire NHS trust, Hospital of St. Cross, Rugby from March 2014 to November 2015. All those undergoing primary unilateral TKA were eligible.

Screening details

Participants listed for a unilateral knee replacement who attended a pre-op physiotherapy class at Rugby St Cross were screened for the study. Out of the 802 participants screened, 360 were excluded due to ineligibility, 234 were eligible but not recruited to the study, 264 recruited and 262 were randomised to the study.

Period 1 title

Overall trial (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind ^[1]

Roles blinded

Subject, Monitor, Data analyst, Carer, Assessor

Blinding implementation details

Due to the nature of the study it is not possible for the surgeon to be blinded to the treatment options. Both Groups will have a standardised dressing applied and for the peri-articular injection Group this will be part of normal standard of care. Outcome data will be collected by a research associate and an independent clinical physiotherapist that are blinded to the treatment options. Furthermore, the trial statistician will be blinded to the intervention groups throughout.

Are arms mutually exclusive

Yes

FNB arm

Arm description

Femoral Nerve Block

Arm type

Active comparator

Investigational medicinal product name

30 ml (75mg) of levobupivacaine hydrochloride 0.25%.

Investigational medicinal product code

Other name

Pharmaceutical forms

Concentrate and solvent for solution for injection/infusion

Routes of administration

Intramuscular and intravenous use

Dosage and administration details

Under aseptic conditions, the femoral artery will be palpated immediately below the inguinal ligament and nerve stimulation will be used to identify the femoral nerve just lateral to the artery. Once the femoral nerve has been identified the block may be performed in the routine manner using 30 ml (75mg) of levobupivacaine hydrochloride 0.25%. The precise technique used will be noted on trial documentation.

PI arm

Arm description

Periarticular injection

Arm type

Experimental

Investigational medicinal product name

peri-articular infiltration

Investigational medicinal product code

Other name

Pharmaceutical forms

Concentrate and solvent for solution for injection

Routes of administration

Intramuscular and intravenous use

Dosage and administration details

The peri-articular infiltration of multi-modal agents will involve the preparation of two 50ml syringes each containing 30ml (75mg) of levobupivacaine hydrochloride 0.25% injection, 0.5ml (5mg) morphine sulphate injection, 0.5ml (15mg) ketorolac trometamol injection and 0.25ml of 1:1000 adrenaline then diluted with 0.9% saline to make a mixture containing a total volume of 50ml. Adrenaline is added to the mixture to reduce blood loss after the operation. Each syringe will be prepared for immediate use and not stored.

Notes
[1] - The roles blinded appear to be inconsistent with a double blind trial.
Justification: The Trial is patient and assessor blinded. It was not possible to blind the surgeons, as detailed in the Blinding implementation details section

Number of subjects in period 1	FNB arm	PI arm
Started	131	131
Primary outcome	113 ^[2]	117 ^[3]
Completed	124	127
Not completed	7	4
Adverse event, serious fatal	1	1
Consent withdrawn by subject	1	-
Lost to follow-up	5	3

Notes
[2] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
Justification: The number of subjects completed was the number of patients who received the TKR surgery and randomized to this group. However, due to reasons outlined in the reporting paper, the primary outcome was missed for a number of participants. These patients had not withdrawn, and many provided subsequent follow up data
[3] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
Justification: The number of subjects completed was the number of patients who received the TKR surgery and randomized to this group. However, due to reasons outlined in the reporting paper, the primary outcome was missed for a number of participants. These patients had not withdrawn, and many provided subsequent follow up data

Baseline characteristics

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Reporting group title

FNB arm

Reporting group description

Femoral Nerve Block

Reporting group title

PI arm

Reporting group description

Periarticular injection

Reporting group values	FNB arm	PI arm	Total
Number of subjects	131	131	262
Age categorical
Units: Subjects
In utero			0
Preterm newborn infants (gestational age < 37 wks)			0
Newborns (0-27 days)			0
Infants and toddlers (28 days-23 months)			0
Children (2-11 years)			0
Adolescents (12-17 years)			0
Adults (18-64 years)			0
From 65-84 years			0
85 years and over			0
Age continuous
Participant age at baseline
Units: years
arithmetic mean (standard deviation)	68.2 ± 10	68.7 ± 9.6	-
Gender categorical
Units: Subjects
Female	80	77	157
Male	51	54	105

End points

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Reporting group title

FNB arm

Reporting group description

Femoral Nerve Block

Reporting group title

PI arm

Reporting group description

Periarticular injection

Subject analysis set title

FNB

Subject analysis set type

Intention-to-treat

Subject analysis set description

Femoral nerve block

Subject analysis set title

Subject analysis set type

Intention-to-treat

Subject analysis set description

Periarticular infiltration

Primary: Differences between allocation groups on the VAS pain score prephysiotherapy on the first day postoperatively

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End point title

Differences between allocation groups on the VAS pain score prephysiotherapy on the first day postoperatively

End point description

End point type

Primary

End point timeframe

Pre-physiotherapy on the first day postoperatively

End point values	FNB arm	PI arm
Number of subjects analysed	113	117
Units: mm
arithmetic mean (standard deviation)	44.1 ± 23	43.2 ± 24.6

Primary analysis

Statistical analysis description

The main analysis will investigate differences in the primary outcome measure, the VAS pain score pre-physiotherapy on the first day postoperatively, between the two treatment groups (single injection femoral nerve block and multimodal periarticular injection) on an intention-to-treat basis.

Comparison groups

FNB arm v PI arm

Number of subjects included in analysis

230

Analysis specification

Pre-specified

Analysis type

superiority ^[1]

P-value

= 0.77

Method

t-test, 2-sided

Parameter type

Mean difference (net)

Point estimate

-0.9

Confidence interval

level

95%

sides

2-sided

lower limit

-5.3

upper limit

7.2

Notes
[1] - A power calculation a priori detailed that 262 participants would be needed, based on a MCID of 12mm with a standard deviation of 30mm

Adverse events

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Timeframe for reporting adverse events

Six weeks from randomization (day of surgery)

Assessment type

Non-systematic

Dictionary name

MedDRA

Dictionary version

10.0

Reporting group title

FNB arm

Reporting group description

Femoral Nerve Block

Reporting group title

PI arm

Reporting group description

Periarticular injection

Notes
[1] - There are no non-serious adverse events recorded for these results. It is expected that there will be at least one non-serious adverse event reported.
Justification: No AEs are reported as the number of AEs observed did not meet the 5% frequency reporting criterion.

Serious adverse events	FNB arm	PI arm
Total subjects affected by serious adverse events
subjects affected / exposed	26 / 127 (20.47%)	37 / 131 (28.24%)
number of deaths (all causes)	1	1
number of deaths resulting from adverse events	0	0
Surgical and medical procedures
Admission to manage pain
subjects affected / exposed	1 / 127 (0.79%)	1 / 131 (0.76%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Admission to remove skin clips
subjects affected / exposed	0 / 127 (0.00%)	1 / 131 (0.76%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Knee instability undergoing revision
subjects affected / exposed	0 / 127 (0.00%)	1 / 131 (0.76%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
General disorders and administration site conditions
Admission no cause found
subjects affected / exposed	0 / 127 (0.00%)	1 / 131 (0.76%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
General malaise
Additional description: General malaise - No cause found
subjects affected / exposed	1 / 127 (0.79%)	0 / 131 (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
Chest infection
subjects affected / exposed	6 / 127 (4.72%)	2 / 131 (1.53%)
occurrences causally related to treatment / all	0 / 6	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Exacerbation of asthma
subjects affected / exposed	1 / 127 (0.79%)	0 / 131 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pulmonary embolism
subjects affected / exposed	1 / 127 (0.79%)	0 / 131 (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
cement syndrome
Additional description: Cement syndrome (perioperative hypotension)
subjects affected / exposed	0 / 127 (0.00%)	1 / 131 (0.76%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Morphine overdose
subjects affected / exposed	0 / 127 (0.00%)	1 / 131 (0.76%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Cardiac disorders
Death
subjects affected / exposed	1 / 127 (0.79%)	1 / 131 (0.76%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 1	0 / 1
Nervous system disorders
Foot drop
subjects affected / exposed	0 / 127 (0.00%)	1 / 131 (0.76%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Blood and lymphatic system disorders
Symptomatic anaemia requiring blood transfusion
subjects affected / exposed	1 / 127 (0.79%)	3 / 131 (2.29%)
occurrences causally related to treatment / all	0 / 1	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Gastrointestinal disorders
Bleeding gastric ulcer
subjects affected / exposed	0 / 127 (0.00%)	2 / 131 (1.53%)
occurrences causally related to treatment / all	0 / 0	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Gastroenteritis
subjects affected / exposed	0 / 127 (0.00%)	1 / 131 (0.76%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Small bowel obstruction
subjects affected / exposed	0 / 127 (0.00%)	1 / 131 (0.76%)
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
Pressure sore
subjects affected / exposed	1 / 127 (0.79%)	0 / 131 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Superficial wound infection
subjects affected / exposed	6 / 127 (4.72%)	9 / 131 (6.87%)
occurrences causally related to treatment / all	0 / 6	0 / 9
deaths causally related to treatment / all	0 / 0	0 / 0
Wound haematoma
subjects affected / exposed	0 / 127 (0.00%)	1 / 131 (0.76%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Renal and urinary disorders
Acute kidney injury
subjects affected / exposed	3 / 127 (2.36%)	6 / 131 (4.58%)
occurrences causally related to treatment / all	3 / 3	6 / 6
deaths causally related to treatment / all	0 / 0	0 / 0
Urinary retention
subjects affected / exposed	0 / 127 (0.00%)	2 / 131 (1.53%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Urinary tract infection
subjects affected / exposed	0 / 127 (0.00%)	2 / 131 (1.53%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Back pain
subjects affected / exposed	1 / 127 (0.79%)	0 / 131 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Reduced early ROM
Additional description: Reduced early ROM requiring manipulation
subjects affected / exposed	2 / 127 (1.57%)	2 / 131 (1.53%)
occurrences causally related to treatment / all	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Infections and infestations
Deep wound infection undergoing revision
subjects affected / exposed	0 / 127 (0.00%)	1 / 131 (0.76%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Metabolism and nutrition disorders
Dehydration
subjects affected / exposed	1 / 127 (0.79%)	0 / 131 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 5%

Non-serious adverse events	FNB arm	PI arm
Total subjects affected by non serious adverse events
subjects affected / exposed	0 / 127 (0.00%)	0 / 131 (0.00%)

More information

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Were there any global substantial amendments to the protocol? Yes

26 Aug 2014

Removal of temperature monitoring of trial drugs; inclusion of DN4 as a secondary outcome

13 Jun 2015

Addition of 12 month follow up point

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.

The study involved only one centre in the NHS, although the trial included different surgeons and anaesthetists

http://www.ncbi.nlm.nih.gov/pubmed/28663395

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Clinical trials

Clinical Trial Results:
Perioperative Analgesia for Knee Arthroplasty: A prospective randomised controlled trial

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Differences between allocation groups on the VAS pain score prephysiotherapy on the first day postoperatively

Primary: Differences between allocation groups on the VAS pain score prephysiotherapy on the first day postoperatively

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

Online references

More information

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Clinical trials

Clinical Trial Results: Perioperative Analgesia for Knee Arthroplasty: A prospective randomised controlled trial

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Differences between allocation groups on the VAS pain score prephysiotherapy on the first day postoperatively

Primary: Differences between allocation groups on the VAS pain score prephysiotherapy on the first day postoperatively

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

Online references

More information

Clinical Trial Results:
Perioperative Analgesia for Knee Arthroplasty: A prospective randomised controlled trial