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Clinical Trial Results:
A Multicenter, Randomized, Double-Blind, Parallel-Group, Active-Control, Dose-Ranging Study to Evaluate the Safety, Efficacy, and Comparative Systemic Bioavailability of a Single Administration of SKY0402 via Local Infiltration for Prolonged Postoperative Analgesia in Subjects Undergoing Total Knee Arthroplasty

Summary
EudraCT number	2007-005115-26
Trial protocol	CZ AT DE DK
Global end of trial date	03 Jul 2008

Results information
Results version number	v1(current)
This version publication date	24 Jun 2022
First version publication date	24 Jun 2022
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

SKY0402-C-208

ISRCTN number

US NCT number

NCT00485693

WHO universal trial number (UTN)

Sponsor organisation name

Pacira Pharmceuticals, Inc.

Sponsor organisation address

5 Sylvan Way, Parsippany, United States, 07054

Public contact

Clinical Operations, Pacira Pharmaceuticals, Inc., +1 858-625-2424, medinfo@pacira.com

Scientific contact

Clinical Operations, Pacira Pharmaceuticals, Inc., +1 858-625-2424, medinfo@pacira.com

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

25 Nov 2008

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

03 Jul 2008

Was the trial ended prematurely?

Main objective of the trial

The main objective of the trial is to evaluate four dose levels of SKY0402, compared with bupivacaine HCl, with respect to the extent and duration of the analgesic effect achieved by a single administration of the study drug via local infiltration.

Protection of trial subjects

Prior to enrolling subjects into this study, the study site obtained the approval of a properly constituted Institutional Review Board (IRB) or Independent Ethics Committee (IEC). This study was conducted in accordance with the clinical research guidelines established by Title 21 CFR, Parts 50, 54, 56, and 312 and the ICH GCP.

Background therapy

Evidence for comparator

Actual start date of recruitment

03 Oct 2007

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Czechia: 41

Country: Number of subjects enrolled

United States: 97

Worldwide total number of subjects

138

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

Screening details

Inclusion: Male or Female >/= 18 and </=75, scheduled to undergo primary unilateral TKA under general anesthesia, ASA class 1-3. Exclusion: use of long-acting opioid medication within 3 days, or any opioid medication within 24 hours, concurrent painful physical condition

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator, Monitor, Data analyst, Carer, Assessor

Blinding implementation details

Blinded and unblinded Monitors were employed. Site specific blinding plans were created.

Are arms mutually exclusive

Yes

SKY0402 150mg

Arm description

Arm type

Experimental

Investigational medicinal product name

SKY0402

Investigational medicinal product code

Other name

Pharmaceutical forms

Injection/infusion

Routes of administration

Infiltration

Dosage and administration details

SKY0402 150mg/10mL + 0.9% NaCl 50mL for a total volume of 60mL

SKY0402 300mg

Arm description

Arm type

Experimental

Investigational medicinal product name

SKY0402

Investigational medicinal product code

Other name

Pharmaceutical forms

Injection/infusion

Routes of administration

Infiltration

Dosage and administration details

SKY0402 300mg/20mL + 0.9% NaCl 40mL for a total volume of 60mL

SKY0402 450 mg

Arm description

Arm type

Experimental

Investigational medicinal product name

SKY0402

Investigational medicinal product code

Other name

Pharmaceutical forms

Injection/infusion

Routes of administration

Infiltration

Dosage and administration details

SKY0402 450mg/30mL + 0.9% NaCl 30mL for a total volume of 60mL

SKY0402 600mg

Arm description

Arm type

Experimental

Investigational medicinal product name

SKY0402

Investigational medicinal product code

Other name

Pharmaceutical forms

Injection/infusion

Routes of administration

Infiltration

Dosage and administration details

SKY0402 600mg/40mL + 0.9% NaCl 20mL for a total volume of 60mL

0.25% Bupivacaine HCl 150mg

Arm description

Arm type

Active comparator

Investigational medicinal product name

0.25% Bupivacaine HCl 150mg

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Infiltration

Dosage and administration details

0.25% Bupivacaine HCl (Marcaine 0.25% with epinephrine 1:200,000) 150mg

Number of subjects in period 1	SKY0402 150mg	SKY0402 300mg	SKY0402 450 mg	SKY0402 600mg	0.25% Bupivacaine HCl 150mg
Started	27	25	26	25	35
Completed	27	25	26	24	32
Not completed	0	0	0	1	3
Adverse event, serious fatal	-	-	-	-	1
Consent withdrawn by subject	-	-	-	-	2
Adverse event, non-fatal	-	-	-	1	-

Baseline characteristics

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Reporting group title

SKY0402 150mg

Reporting group description

Reporting group title

SKY0402 300mg

Reporting group description

Reporting group title

SKY0402 450 mg

Reporting group description

Reporting group title

SKY0402 600mg

Reporting group description

Reporting group title

0.25% Bupivacaine HCl 150mg

Reporting group description

Reporting group values	SKY0402 150mg	SKY0402 300mg	SKY0402 450 mg	SKY0402 600mg	0.25% Bupivacaine HCl 150mg	Total
Number of subjects	27	25	26	25	35	138
Age categorical
Units: Subjects
Adults (18-64 years)	16	15	16	11	21	79
From 65-84 years	11	10	10	14	14	59
Not Recorded	0	0	0	0	0	0
Gender categorical
Units: Subjects
Female	14	12	15	20	24	85
Male	13	13	11	5	11	53
not recorded	0	0	0	0	0	0

End points

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Reporting group title

SKY0402 150mg

Reporting group description

Reporting group title

SKY0402 300mg

Reporting group description

Reporting group title

SKY0402 450 mg

Reporting group description

Reporting group title

SKY0402 600mg

Reporting group description

Reporting group title

0.25% Bupivacaine HCl 150mg

Reporting group description

Primary: Area under the curve (AUC) of the numeric rating scale (NRS) with activity (NRS-A) pain intensity scores through postoperative Day 4

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End point title

Area under the curve (AUC) of the numeric rating scale (NRS) with activity (NRS-A) pain intensity scores through postoperative Day 4

End point description

The subject’s pain intensity was to be assessed with activity (NRS-A) after actively flexing the involved knee to the maximum flexion point possible. The subject was asked to respond to the following question: “On a scale of 0 to 10, where 0 = no pain and 10 = worst possible pain, how much pain did you have while bending your knee?”

End point type

Primary

End point timeframe

0 to 96 hours

End point values	SKY0402 150mg	SKY0402 300mg	SKY0402 450 mg	SKY0402 600mg	0.25% Bupivacaine HCl 150mg
Number of subjects analysed	27	25	26	25	35
Units: Units on a scale*hours
arithmetic mean (standard deviation)	20.7 ± 5.4	19.5 ± 5.3	18.8 ± 5.3	19.1 ± 4.4	20.4 ± 3.9

Primary Efficacy Analysis: NRS-A AUC through Day 4

Comparison groups

SKY0402 150mg v SKY0402 300mg v SKY0402 450 mg v SKY0402 600mg v 0.25% Bupivacaine HCl 150mg

Number of subjects included in analysis

138

Analysis specification

Pre-specified

Analysis type

P-value

= 0.8198 ^[1]

Method

ANOVA

Parameter type

Adjusted Mean

Confidence interval

level

95%

Variability estimate

Standard error of the mean

Notes
[1] - P-Values per arm: 150mg=0.8198; 300mg=0.4827; 450mg=0.1926; 600mg=0.3125

Secondary: Number of participants with Adverse Events or Serious Adverse Events through 30 days

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End point title

Number of participants with Adverse Events or Serious Adverse Events through 30 days

End point description

End point type

Secondary

End point timeframe

Up to 30 days

End point values	SKY0402 150mg	SKY0402 300mg	SKY0402 450 mg	SKY0402 600mg	0.25% Bupivacaine HCl 150mg
Number of subjects analysed	27	25	26	25	35
Units: Participants	23	19	16	25	29

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

Adverse events (AEs) were recorded through Day 8; serious adverse events (SAEs) were recorded through Day 36.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

13.0

Reporting group title

SKY0402 150mg

Reporting group description

Reporting group title

SKY0402 300mg

Reporting group description

Reporting group title

SKY0402 450 mg

Reporting group description

Reporting group title

SKY0402 600mg

Reporting group description

Reporting group title

0.25% Bupivacaine HCl 150mg

Reporting group description

Serious adverse events	SKY0402 150mg	SKY0402 300mg	SKY0402 450 mg	SKY0402 600mg	0.25% Bupivacaine HCl 150mg
Total subjects affected by serious adverse events
subjects affected / exposed	0 / 27 (0.00%)	1 / 25 (4.00%)	2 / 26 (7.69%)	2 / 25 (8.00%)	3 / 35 (8.57%)
number of deaths (all causes)	0	0	0	0	1
number of deaths resulting from adverse events					0
Injury, poisoning and procedural complications
Post procedural haemorrhage
subjects affected / exposed	0 / 27 (0.00%)	1 / 25 (4.00%)	0 / 26 (0.00%)	0 / 25 (0.00%)	0 / 35 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Nervous system disorders
Sedation
subjects affected / exposed	0 / 27 (0.00%)	0 / 25 (0.00%)	0 / 26 (0.00%)	1 / 25 (4.00%)	0 / 35 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Haematemesis
subjects affected / exposed	0 / 27 (0.00%)	0 / 25 (0.00%)	1 / 26 (3.85%)	0 / 25 (0.00%)	0 / 35 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Hypoxia
subjects affected / exposed	0 / 27 (0.00%)	0 / 25 (0.00%)	0 / 26 (0.00%)	1 / 25 (4.00%)	0 / 35 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pulmonary embolism
subjects affected / exposed	0 / 27 (0.00%)	0 / 25 (0.00%)	0 / 26 (0.00%)	0 / 25 (0.00%)	1 / 35 (2.86%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
Respiratory depression
subjects affected / exposed	0 / 27 (0.00%)	0 / 25 (0.00%)	1 / 26 (3.85%)	0 / 25 (0.00%)	0 / 35 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Psychiatric disorders
Bipolar disorder
subjects affected / exposed	0 / 27 (0.00%)	0 / 25 (0.00%)	0 / 26 (0.00%)	1 / 25 (4.00%)	0 / 35 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Renal and urinary disorders
Cystitis haemorrhagic
subjects affected / exposed	0 / 27 (0.00%)	0 / 25 (0.00%)	0 / 26 (0.00%)	1 / 25 (4.00%)	0 / 35 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
Infections and infestations
Bronchitis
subjects affected / exposed	0 / 27 (0.00%)	0 / 25 (0.00%)	0 / 26 (0.00%)	0 / 25 (0.00%)	1 / 35 (2.86%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Haematoma infection
subjects affected / exposed	0 / 27 (0.00%)	0 / 25 (0.00%)	0 / 26 (0.00%)	0 / 25 (0.00%)	1 / 35 (2.86%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0

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

Non-serious adverse events	SKY0402 150mg	SKY0402 300mg	SKY0402 450 mg	SKY0402 600mg	0.25% Bupivacaine HCl 150mg
Total subjects affected by non serious adverse events
subjects affected / exposed	23 / 27 (85.19%)	19 / 25 (76.00%)	16 / 26 (61.54%)	25 / 25 (100.00%)	29 / 35 (82.86%)
Injury, poisoning and procedural complications
Anaemia postoperative
subjects affected / exposed	7 / 27 (25.93%)	4 / 25 (16.00%)	2 / 26 (7.69%)	0 / 25 (0.00%)	7 / 35 (20.00%)
occurrences all number	7	4	2	0	7
Vascular disorders
Hypotension
subjects affected / exposed	6 / 27 (22.22%)	6 / 25 (24.00%)	2 / 26 (7.69%)	7 / 25 (28.00%)	12 / 35 (34.29%)
occurrences all number	6	6	2	7	14
Hypertension
subjects affected / exposed	1 / 27 (3.70%)	0 / 25 (0.00%)	2 / 26 (7.69%)	0 / 25 (0.00%)	1 / 35 (2.86%)
occurrences all number	1	0	2	0	1
Cardiac disorders
Tachycardia
subjects affected / exposed	4 / 27 (14.81%)	5 / 25 (20.00%)	2 / 26 (7.69%)	7 / 25 (28.00%)	4 / 35 (11.43%)
occurrences all number	4	5	2	7	4
Bradycardia
subjects affected / exposed	0 / 27 (0.00%)	1 / 25 (4.00%)	0 / 26 (0.00%)	2 / 25 (8.00%)	1 / 35 (2.86%)
occurrences all number	0	1	0	2	1
Nervous system disorders
Dizziness
subjects affected / exposed	3 / 27 (11.11%)	3 / 25 (12.00%)	0 / 26 (0.00%)	7 / 25 (28.00%)	6 / 35 (17.14%)
occurrences all number	3	3	0	7	6
Somnolence
subjects affected / exposed	6 / 27 (22.22%)	2 / 25 (8.00%)	3 / 26 (11.54%)	0 / 25 (0.00%)	1 / 35 (2.86%)
occurrences all number	6	2	3	0	1
Headache
subjects affected / exposed	2 / 27 (7.41%)	1 / 25 (4.00%)	2 / 26 (7.69%)	0 / 25 (0.00%)	2 / 35 (5.71%)
occurrences all number	2	1	2	0	2
Lethargy
subjects affected / exposed	1 / 27 (3.70%)	2 / 25 (8.00%)	1 / 26 (3.85%)	3 / 25 (12.00%)	0 / 35 (0.00%)
occurrences all number	1	2	1	3	0
Hypoaesthesia
subjects affected / exposed	2 / 27 (7.41%)	0 / 25 (0.00%)	0 / 26 (0.00%)	1 / 25 (4.00%)	0 / 35 (0.00%)
occurrences all number	2	0	0	1	0
General disorders and administration site conditions
Pyrexia
subjects affected / exposed	9 / 27 (33.33%)	11 / 25 (44.00%)	8 / 26 (30.77%)	10 / 25 (40.00%)	11 / 35 (31.43%)
occurrences all number	9	11	8	10	11
Oedema peripheral
subjects affected / exposed	8 / 27 (29.63%)	7 / 25 (28.00%)	2 / 26 (7.69%)	13 / 25 (52.00%)	11 / 35 (31.43%)
occurrences all number	8	7	2	13	11
Fatigue
subjects affected / exposed	1 / 27 (3.70%)	0 / 25 (0.00%)	2 / 26 (7.69%)	2 / 25 (8.00%)	4 / 35 (11.43%)
occurrences all number	1	0	2	2	4
Asthenia
subjects affected / exposed	2 / 27 (7.41%)	1 / 25 (4.00%)	0 / 26 (0.00%)	2 / 25 (8.00%)	1 / 35 (2.86%)
occurrences all number	2	1	0	2	1
Chills
subjects affected / exposed	0 / 27 (0.00%)	2 / 25 (8.00%)	0 / 26 (0.00%)	1 / 25 (4.00%)	0 / 35 (0.00%)
occurrences all number	0	2	0	1	0
Blood and lymphatic system disorders
haemorrhagic anaemia
subjects affected / exposed	2 / 27 (7.41%)	2 / 25 (8.00%)	0 / 26 (0.00%)	12 / 25 (48.00%)	6 / 35 (17.14%)
occurrences all number	2	2	0	12	6
Anaemia
subjects affected / exposed	0 / 27 (0.00%)	2 / 25 (8.00%)	2 / 26 (7.69%)	5 / 25 (20.00%)	2 / 35 (5.71%)
occurrences all number	0	2	2	5	2
Gastrointestinal disorders
Nausea
subjects affected / exposed	12 / 27 (44.44%)	8 / 25 (32.00%)	9 / 26 (34.62%)	19 / 25 (76.00%)	23 / 35 (65.71%)
occurrences all number	13	8	9	20	25
Constipation
subjects affected / exposed	10 / 27 (37.04%)	11 / 25 (44.00%)	3 / 26 (11.54%)	12 / 25 (48.00%)	13 / 35 (37.14%)
occurrences all number	10	11	3	12	13
Vomiting
subjects affected / exposed	6 / 27 (22.22%)	2 / 25 (8.00%)	4 / 26 (15.38%)	4 / 25 (16.00%)	6 / 35 (17.14%)
occurrences all number	6	2	4	4	6
Dyspepsia
subjects affected / exposed	1 / 27 (3.70%)	0 / 25 (0.00%)	0 / 26 (0.00%)	2 / 25 (8.00%)	1 / 35 (2.86%)
occurrences all number	12	0	0	2	1
Skin and subcutaneous tissue disorders
Pruritus
subjects affected / exposed	3 / 27 (11.11%)	3 / 25 (12.00%)	1 / 26 (3.85%)	3 / 25 (12.00%)	6 / 35 (17.14%)
occurrences all number	3	3	1	3	6
Blister
subjects affected / exposed	1 / 27 (3.70%)	3 / 25 (12.00%)	0 / 26 (0.00%)	0 / 25 (0.00%)	1 / 35 (2.86%)
occurrences all number	1	3	0	0	1
Musculoskeletal and connective tissue disorders
Muscle spasms
subjects affected / exposed	4 / 27 (14.81%)	2 / 25 (8.00%)	0 / 26 (0.00%)	0 / 25 (0.00%)	3 / 35 (8.57%)
occurrences all number	4	2	0	0	3
Joint swelling
subjects affected / exposed	1 / 27 (3.70%)	0 / 25 (0.00%)	1 / 26 (3.85%)	3 / 25 (12.00%)	1 / 35 (2.86%)
occurrences all number	1	0	1	3	1
Pain in extremity
subjects affected / exposed	2 / 27 (7.41%)	0 / 25 (0.00%)	1 / 26 (3.85%)	2 / 25 (8.00%)	1 / 35 (2.86%)
occurrences all number	2	0	1	2	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

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Area under the curve (AUC) of the numeric rating scale (NRS) with activity (NRS-A) pain intensity scores through postoperative Day 4

Primary: Area under the curve (AUC) of the numeric rating scale (NRS) with activity (NRS-A) pain intensity scores through postoperative Day 4

Secondary: Number of participants with Adverse Events or Serious Adverse Events through 30 days

Secondary: Number of participants with Adverse Events or Serious Adverse Events through 30 days

Adverse events

Adverse events

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Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

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