Clinical Trial Results:
Intrathecal morphine administration for minimally invasive pancreatic surgery: A double blind, prospective randomized placebo-controlled trial.
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Summary
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EudraCT number |
2021-002625-20 |
Trial protocol |
BE |
Global end of trial date |
07 Feb 2025
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Results information
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Results version number |
v1(current) |
This version publication date |
10 Apr 2025
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First version publication date |
10 Apr 2025
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Other versions |
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Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
SC052021
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
- | ||
WHO universal trial number (UTN) |
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Sponsors
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Sponsor organisation name |
UZ Leuven
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Sponsor organisation address |
HERESTRAAT 49, Leuven, Belgium, 3000
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Public contact |
Research Anesthesiology, University Hospitals Leuven, +32 16344270, steve.coppens@uzleuven.be
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Scientific contact |
Research Anesthesiology, University Hospitals Leuven, +32 16344270, steve.coppens@uzleuven.be
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
18 Feb 2025
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
01 Apr 2024
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Global end of trial reached? |
Yes
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Global end of trial date |
07 Feb 2025
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Was the trial ended prematurely? |
No
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General information about the trial
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Main objective of the trial |
To test the efficacy of intrathecal morphine after minimally invasive pancreatic surgery
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Protection of trial subjects |
The Investigator and the Participating Site(s) (as applicable) shall treat all information and data relating to the Trial disclosed to them as confidential and shall not disclose such information to any third parties or use such information for any purpose other than the objectives of the Trial as described in this protocol. The collection, processing and disclosure of personal data, such as participant health and medical information is subject to compliance with applicable laws and regulations regarding personal data protection and the processing of personal data.
The Investigator will maintain all source documents and completed (e)CRFs that support the data collected from each Trial participant, and will maintain a Trial Master File (TMF)/Investigator Site File (ISF) containing all Trial documents as specified in ICH-GCP E6(R2) Chapter 8 entitled “Essential Documents for the Conduct of a Clinical Trial”, and as specified by applicable regulatory requirement(s).
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Background therapy |
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Evidence for comparator |
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Actual start date of recruitment |
04 Oct 2021
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
No
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
Belgium: 128
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Worldwide total number of subjects |
128
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EEA total number of subjects |
128
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
73
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From 65 to 84 years |
55
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85 years and over |
0
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Recruitment
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Recruitment details |
Patients will be recruited by the principal investigator or co-investigator. Detailed background information will be given about the study and any question brought forward by the patient will be answered. Each eligible patient willing to participate will sign a written informed consent before any particular study procedure. | |||||||||
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Pre-assignment
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Screening details |
- 18-80 years of age - Body Mass Index (BMI) ≤ 40 kg/m2 - Patient is able to give informed consent - Patient understands the use of morphine PCIA - Patient is scheduled for elective minimal invasive pancreatic surgery - ASA I-IV | |||||||||
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Period 1
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Period 1 title |
Surgery (overall period)
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Is this the baseline period? |
Yes | |||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Double blind | |||||||||
Roles blinded |
Subject, Investigator, Monitor, Assessor | |||||||||
Blinding implementation details |
Patients will be randomized using a computer-generated permuted block randomization sequence (variable block-size, 1:1 allocation). Allocation concealment will be ensured by enclosing assignments in sealed, opaque, sequentially numbered envelopes which will be opened before surgery at the holding area. The study nurse will than prepare the trial medication (see above). If for any reason, either due to perioperative complications or logistic reasons, a patient is withdrawn from the elective pancr
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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ITM (intrathecal morphine) | |||||||||
Arm description |
Before induction of anesthesia, the patient is positioned in the upright position. The skin of the lumbar region will be disinfected with chlorhexidine 0.5%. After careful identification of the lumbar interspace at level L3-L4 or L4-L5 and local anesthesia infiltration with 5 ml lidocaine 1%, an introducer will be inserted via which a 27G Whitacre needle, Pencan© (B.Braun Bethlehem, Pennsylvania, USA) will be advanced until identification of the subarachnoid space. Correct needle placement will be verified by observing spontaneous cerebrospinal fluid (CSF) reflux. After careful aspiration of CSF, the trial medication will be injected. After injection of 1 ml, a second careful aspiration of CSF will confirm further appropriate needle placement. In case of a difficult puncture on 2 levels (L3-L4; L4-L5), a 25G Whitacre needle may be used. ITM dose up 4 µg/kg will be administered + bupivacaine 0.5% | |||||||||
Arm type |
Experimental | |||||||||
Investigational medicinal product name |
morphine
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Injection
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Routes of administration |
Intrathecal use
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Dosage and administration details |
4 µg/kg with a maximum dose of 200 µg if patient > 75 years
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Investigational medicinal product name |
bupivacaine
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Injection
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Routes of administration |
Intrathecal use
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Dosage and administration details |
0,125 mg/kg hyperbaric bupivacaine intrathecal morphine
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Arm title
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Spinal placebo | |||||||||
Arm description |
Before induction of anesthesia, the patient is positioned in the upright position. The skin of the lumbar region will be disinfected with chlorhexidine 0.5%. After careful identification of the lumbar interspace at level L3-L4 or L4-L5 and local anesthesia infiltration with 5 ml lidocaine 1%, an introducer will be inserted via which a 27G Whitacre needle, Pencan© (B.Braun Bethlehem, Pennsylvania, USA) will be advanced until identification of the subarachnoid space. Correct needle placement will be verified by observing spontaneous cerebrospinal fluid (CSF) reflux. After careful aspiration of CSF, the trial medication will be injected. After injection of 1 ml, a second careful aspiration of CSF will confirm further appropriate needle placement. In case of a difficult puncture on 2 levels (L3-L4; L4-L5), a 25G Whitacre needle may be used. Placebo Nacl 0.9% + bupivacaine 0.5% will be injected | |||||||||
Arm type |
Placebo | |||||||||
Investigational medicinal product name |
bupivacaine
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Injection
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Routes of administration |
Intrathecal use
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Dosage and administration details |
- The control group will receive placebo (saline 0.9 % ) and 0,125 mg /kg hyperbaric bupivacaine 0.5 % (total volume: 4ml).
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Baseline characteristics reporting groups
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Reporting group title |
ITM (intrathecal morphine)
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Reporting group description |
Before induction of anesthesia, the patient is positioned in the upright position. The skin of the lumbar region will be disinfected with chlorhexidine 0.5%. After careful identification of the lumbar interspace at level L3-L4 or L4-L5 and local anesthesia infiltration with 5 ml lidocaine 1%, an introducer will be inserted via which a 27G Whitacre needle, Pencan© (B.Braun Bethlehem, Pennsylvania, USA) will be advanced until identification of the subarachnoid space. Correct needle placement will be verified by observing spontaneous cerebrospinal fluid (CSF) reflux. After careful aspiration of CSF, the trial medication will be injected. After injection of 1 ml, a second careful aspiration of CSF will confirm further appropriate needle placement. In case of a difficult puncture on 2 levels (L3-L4; L4-L5), a 25G Whitacre needle may be used. ITM dose up 4 µg/kg will be administered + bupivacaine 0.5% | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Spinal placebo
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Reporting group description |
Before induction of anesthesia, the patient is positioned in the upright position. The skin of the lumbar region will be disinfected with chlorhexidine 0.5%. After careful identification of the lumbar interspace at level L3-L4 or L4-L5 and local anesthesia infiltration with 5 ml lidocaine 1%, an introducer will be inserted via which a 27G Whitacre needle, Pencan© (B.Braun Bethlehem, Pennsylvania, USA) will be advanced until identification of the subarachnoid space. Correct needle placement will be verified by observing spontaneous cerebrospinal fluid (CSF) reflux. After careful aspiration of CSF, the trial medication will be injected. After injection of 1 ml, a second careful aspiration of CSF will confirm further appropriate needle placement. In case of a difficult puncture on 2 levels (L3-L4; L4-L5), a 25G Whitacre needle may be used. Placebo Nacl 0.9% + bupivacaine 0.5% will be injected | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Subject analysis sets
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Subject analysis set title |
ITM
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Subject analysis set type |
Intention-to-treat | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set description |
Morphine consumption at 24 and 48 hours
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Subject analysis set title |
Spinal placebo
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Subject analysis set type |
Intention-to-treat | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set description |
morphine consumption over 24 and 48 hours
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End points reporting groups
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Reporting group title |
ITM (intrathecal morphine)
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Reporting group description |
Before induction of anesthesia, the patient is positioned in the upright position. The skin of the lumbar region will be disinfected with chlorhexidine 0.5%. After careful identification of the lumbar interspace at level L3-L4 or L4-L5 and local anesthesia infiltration with 5 ml lidocaine 1%, an introducer will be inserted via which a 27G Whitacre needle, Pencan© (B.Braun Bethlehem, Pennsylvania, USA) will be advanced until identification of the subarachnoid space. Correct needle placement will be verified by observing spontaneous cerebrospinal fluid (CSF) reflux. After careful aspiration of CSF, the trial medication will be injected. After injection of 1 ml, a second careful aspiration of CSF will confirm further appropriate needle placement. In case of a difficult puncture on 2 levels (L3-L4; L4-L5), a 25G Whitacre needle may be used. ITM dose up 4 µg/kg will be administered + bupivacaine 0.5% | ||
Reporting group title |
Spinal placebo
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Reporting group description |
Before induction of anesthesia, the patient is positioned in the upright position. The skin of the lumbar region will be disinfected with chlorhexidine 0.5%. After careful identification of the lumbar interspace at level L3-L4 or L4-L5 and local anesthesia infiltration with 5 ml lidocaine 1%, an introducer will be inserted via which a 27G Whitacre needle, Pencan© (B.Braun Bethlehem, Pennsylvania, USA) will be advanced until identification of the subarachnoid space. Correct needle placement will be verified by observing spontaneous cerebrospinal fluid (CSF) reflux. After careful aspiration of CSF, the trial medication will be injected. After injection of 1 ml, a second careful aspiration of CSF will confirm further appropriate needle placement. In case of a difficult puncture on 2 levels (L3-L4; L4-L5), a 25G Whitacre needle may be used. Placebo Nacl 0.9% + bupivacaine 0.5% will be injected | ||
Subject analysis set title |
ITM
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Subject analysis set type |
Intention-to-treat | ||
Subject analysis set description |
Morphine consumption at 24 and 48 hours
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Subject analysis set title |
Spinal placebo
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Subject analysis set type |
Intention-to-treat | ||
Subject analysis set description |
morphine consumption over 24 and 48 hours
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End point title |
Morphine consumption 24 hours | ||||||||||||||||||||
End point description |
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End point type |
Primary
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End point timeframe |
Assessed 24 hours post-intubation
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Statistical analysis title |
Primary outcome | ||||||||||||||||||||
Statistical analysis description |
ITM versus Spinal placebo
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Comparison groups |
ITM (intrathecal morphine) v Spinal placebo v ITM v Spinal placebo
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Number of subjects included in analysis |
256
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||||||||||
P-value |
≤ 0.05 | ||||||||||||||||||||
Method |
t-test, 2-sided | ||||||||||||||||||||
Confidence interval |
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End point title |
Next 24 hour morphine consumption | ||||||||||||||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
48 hour morphine consumption
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Statistical analysis title |
Key secondary outcome | ||||||||||||||||||||
Comparison groups |
ITM (intrathecal morphine) v Spinal placebo v ITM v Spinal placebo
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Number of subjects included in analysis |
256
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||||||||||
P-value |
≤ 0.05 | ||||||||||||||||||||
Method |
t-test, 2-sided | ||||||||||||||||||||
Confidence interval |
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Adverse events information
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Timeframe for reporting adverse events |
From enrolment until time of discharge from hospital
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Assessment type |
Systematic | |||||||||||||||||||||||||||||||||||||||||||||
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Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | |||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
27
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Reporting groups
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Reporting group title |
ITM (intrathecal morphine)
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Reporting group description |
Intrathecal morphine | |||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Placebo Spinal
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Reporting group description |
- | |||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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| Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
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03 Aug 2022 |
1) At current our inclusion rate is lagging behind. This is partially due to restrictive exclusion criteria. We envisioned more adverse events in patients with severe liver function disorders, however most adverse events are surgically related, and parameter changes are more related to pancreatic disease. There was also concern that tumor surgery would be more complex (and more conversion to open surgery) in patients with high bilirubin levels, however rigorous pre-operative check-up is more important here. Furthermore, our initial showed us this is not the case. Liver function disease which affects our clotting parameters remains a strict exclusion criterion of course. (Page 13,21)
2) Our renal function exclusion criterion has also been lowered to GFR < 30 to match more closely clinical decision making in hospital when to adjust morphine (Page 13, 21). (Adjusted trial flow chart with specific mention of GFR < 30 mL/min as exclusion criterion)
3) Secondly, recent literature indicates minimal invasive laparoscopic surgery (laparoscopic, robotic or partial) has same postoperative pain issues. (Reference 6 added to protocol, all subsequent references changed number) To increase recruitment and to speed up the evaluation of intrathecal morphine it seemed wise to include other minimal invasive pancreatic surgery procedures. Therefor title and subsequent acronym was changed as reference was added. The title of our RCT will change to “Intrathecal morphine administration for minimally invasive pancreatic surgery: A double blind, prospective randomized placebo-controlled trial”, added abbreviation for minimal invasive pancreatic surgery (mips on page 7) (page 1, 2, 11, 14, 27 and all pages containing original title)
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Interruptions (globally) |
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| Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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| Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
| None reported | |||
