Clinical Trial Results:
Neodolpasse® Infusion Solution versus diclofenac 75 mg infusion in the treatment of postoperative pain after elective knee surgery - an exploratory placebo-controlled clinical study to investigate the analgesic properties of the combination of diclofenac and orphenadrine versus diclofenac alone.
|
Summary
|
|
EudraCT number |
2016-001056-22 |
Trial protocol |
AT |
Global end of trial date |
20 May 2019
|
|
Results information
|
|
Results version number |
v1(current) |
This version publication date |
11 Sep 2020
|
First version publication date |
11 Sep 2020
|
Other versions |
|
Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
|
|||
|
Trial identification
|
|||
Sponsor protocol code |
NDOL-001-2016
|
||
|
Additional study identifiers
|
|||
ISRCTN number |
- | ||
US NCT number |
- | ||
WHO universal trial number (UTN) |
- | ||
|
Sponsors
|
|||
Sponsor organisation name |
University Clinic for Anaesthesiology, Medical Univerity Vienna
|
||
Sponsor organisation address |
Währinger Gürtel 18-20, Vienna, Austria, 1090
|
||
Public contact |
Principle Investigator, University Clinic for Anaesthesiology, Medical Univerity Vienna, 0043 140400 41030, oliver.kimberger@meduniwien.ac.at
|
||
Scientific contact |
Principle Investigator, University Clinic for Anaesthesiology, Medical Univerity Vienna, 0043 140400 41030, oliver.kimberger@meduniwien.ac.at
|
||
|
Paediatric regulatory details
|
|||
Is trial part of an agreed paediatric investigation plan (PIP) |
No
|
||
Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
|
||
Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
|
||
|
Results analysis stage
|
|||
Analysis stage |
Final
|
||
Date of interim/final analysis |
20 Feb 2020
|
||
Is this the analysis of the primary completion data? |
No
|
||
Global end of trial reached? |
Yes
|
||
Global end of trial date |
20 May 2019
|
||
Was the trial ended prematurely? |
No
|
||
|
General information about the trial
|
|||
Main objective of the trial |
Trial objective is to investigate the use of additional analgesic medication via PCA during the first 24 hours postoperatively.
|
||
Protection of trial subjects |
The local and systemic tolerability and safety of the clinical study medications was assessed, as were possible neurological side effects using the Delirium Detection Score 2h and 24h after the first infusion. Overall pharmacological safety of the infusion solution was assessed via laboratory safety values. All patients were provided with a PCA as postoperative rescue pain medication. Consequently the possibility of an inadequate postoperative pain treatment in the study patients was very low, even in the placebo group. In case of PONV standard of care treatment with ondansetron was established. Furthermore, pregnancy was ruled out via a pregnancy test (hCG) in female patients prior to enrollment in this study.
|
||
Background therapy |
Included were patients receiving elective cruciate ligament surgery. Patients received a standard of care total intravenous anesthesia consisting of an induction with propofol, remifentanil and, if relaxation required, rocuronium followed by a maintenance with remifentanil and propofol. PCA was established after the patient awoke, containing 20 mg hydromorphone in 50 ml saline solution. | ||
Evidence for comparator |
A multimodal approach including opiates and nonsteroidal anti-inflammatory drugs (NSAIDs), coxibs or paracetamol (acetaminophen) as well as an around-the-clock regimen of NSAIDs, coxibs, or paracetamol (acetaminophen) is standard of care. Intravenous diclofenac has an established role in the treatment of acute and chronic pain as well as in postoperative pain and has been in use for several decades in Europe. Placebos are typically used as controls for the active treatment under investigation in RCTs. | ||
Actual start date of recruitment |
01 Oct 2016
|
||
Long term follow-up planned |
No
|
||
Independent data monitoring committee (IDMC) involvement? |
Yes
|
||
|
Population of trial subjects
|
|||
Number of subjects enrolled per country |
|||
Country: Number of subjects enrolled |
Austria: 72
|
||
Worldwide total number of subjects |
72
|
||
EEA total number of subjects |
72
|
||
Number of subjects enrolled per age group |
|||
In utero |
0
|
||
Preterm newborn - gestational age < 37 wk |
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) |
72
|
||
From 65 to 84 years |
0
|
||
85 years and over |
0
|
||
|
|||||||||||||||||||||||||||||||||
|
Recruitment
|
|||||||||||||||||||||||||||||||||
Recruitment details |
Patients undergoing elective cruciate ligament surgery at the general hospital of Vienna and who meet all enrollment criteria received detailed oral information about the study as well as a patient information leaflet. The patients were given amble time (but at minimum 24 hours) for consideration before enrollment in the study. | ||||||||||||||||||||||||||||||||
|
Pre-assignment
|
|||||||||||||||||||||||||||||||||
Screening details |
enrollment criteria: Age 18 to ≤ 85 years, No analgesics within 48 hours prior to surgery (surgery-related medication excluded), Absence of congestive heart failure classes 2 or higher (NYHA), Absence of ischemic heart disease, Absence of cerebro-vascular disease, Absence of risk factors for card. vasc. events ( e.g. aHT, DM II) | ||||||||||||||||||||||||||||||||
|
Pre-assignment period milestones
|
|||||||||||||||||||||||||||||||||
Number of subjects started |
72 | ||||||||||||||||||||||||||||||||
Intermediate milestone: Number of subjects |
Registration, Randomisation: 72
|
||||||||||||||||||||||||||||||||
Number of subjects completed |
72 | ||||||||||||||||||||||||||||||||
|
Period 1
|
|||||||||||||||||||||||||||||||||
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 |
Patients were randomized pre-surgery using the web-based randomizer provided by the Institute for Medical Informatics, Statistics and Documentation, Medical University Graz.(https://www.randomizer.at/) to one of the three study arms. The study arms were numbered 1, 2, 3 and received according study medications, provided and labelled in accordance with the requirements of the AMG by the hospital pharmacy. Unblinding of the groups occured after conclusion of the study.
|
||||||||||||||||||||||||||||||||
|
Arms
|
|||||||||||||||||||||||||||||||||
Are arms mutually exclusive |
Yes
|
||||||||||||||||||||||||||||||||
|
Arm title
|
investigational medicinal products | ||||||||||||||||||||||||||||||||
Arm description |
Patients in this arm received the investigational product containing 75 mg diclofenac and 30 mg orphenadrine citrate as active ingredients in 250 ml saline solution | ||||||||||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||||||||||
Investigational medicinal product name |
Neodolpasse® Infusion Solution (250 mL)
|
||||||||||||||||||||||||||||||||
Investigational medicinal product code |
|||||||||||||||||||||||||||||||||
Other name |
diclofenac and orphenadrine
|
||||||||||||||||||||||||||||||||
Pharmaceutical forms |
Solution for infusion
|
||||||||||||||||||||||||||||||||
Routes of administration |
Intravenous drip use
|
||||||||||||||||||||||||||||||||
Dosage and administration details |
A single bottle (250 mL) of the investigational product contained 75 mg diclofenac and 30 mg orphenadrine citrate as active ingredients.
Total treatment durationwas less than 24 hours. Each patient received two (2) infusions. The first infusion of investigational medicinal product was administered directly after fixation of the graft replacement. The second infusion was started after an interval of 8 hours +/- 30 minutes counted from the start of the first infusion. Both were administered as an intravenous drip.
|
||||||||||||||||||||||||||||||||
|
Arm title
|
Active comparator | ||||||||||||||||||||||||||||||||
Arm description |
Patients in this arm received the active comparator | ||||||||||||||||||||||||||||||||
Arm type |
Active comparator | ||||||||||||||||||||||||||||||||
Investigational medicinal product name |
Diclofenac
|
||||||||||||||||||||||||||||||||
Investigational medicinal product code |
|||||||||||||||||||||||||||||||||
Other name |
|||||||||||||||||||||||||||||||||
Pharmaceutical forms |
Solution for infusion
|
||||||||||||||||||||||||||||||||
Routes of administration |
Intravenous drip use
|
||||||||||||||||||||||||||||||||
Dosage and administration details |
A single bottle (250 mL) of the active comparator product contains 75 mg diclofenac as active ingredient. Total treatment duration was less than 24 hours. Each patient received two (2) infusions. The first infusion of comparator was administered directly after fixation of the graft replacement. The second infusion was started after an interval of 8 hours +/- 30 minutes counting from the start of the first infusion. The comparator was provided as an intravenous drip.
|
||||||||||||||||||||||||||||||||
|
Arm title
|
placebo | ||||||||||||||||||||||||||||||||
Arm description |
patients in this arm received a placebo infusion. | ||||||||||||||||||||||||||||||||
Arm type |
Placebo | ||||||||||||||||||||||||||||||||
Investigational medicinal product name |
Placebo
|
||||||||||||||||||||||||||||||||
Investigational medicinal product code |
|||||||||||||||||||||||||||||||||
Other name |
|||||||||||||||||||||||||||||||||
Pharmaceutical forms |
Solution for infusion
|
||||||||||||||||||||||||||||||||
Routes of administration |
Intravenous drip use
|
||||||||||||||||||||||||||||||||
Dosage and administration details |
Physiologic saline infusion (250 mL). Total treatment duration was less than 24 hours. Each patient in this arm received two (2) infusions. The first infusion of placebo was administered directly after fixation of the graft replacement. The second infusion was started after an interval of 8 hours +/- 30 minutes counting from the start of the first infusion. The placebo was administered as an intravenous drip.
|
||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||
|
Baseline characteristics reporting groups
|
|||||||||||||||||||||||||||||||||||||
Reporting group title |
Overall study
|
||||||||||||||||||||||||||||||||||||
Reporting group description |
- | ||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||
|
|||
|
End points reporting groups
|
|||
Reporting group title |
investigational medicinal products
|
||
Reporting group description |
Patients in this arm received the investigational product containing 75 mg diclofenac and 30 mg orphenadrine citrate as active ingredients in 250 ml saline solution | ||
Reporting group title |
Active comparator
|
||
Reporting group description |
Patients in this arm received the active comparator | ||
Reporting group title |
placebo
|
||
Reporting group description |
patients in this arm received a placebo infusion. | ||
|
|||||||||||||||||
End point title |
mean dose of hydromorphone required via PCA in the first 2h | ||||||||||||||||
End point description |
|||||||||||||||||
End point type |
Primary
|
||||||||||||||||
End point timeframe |
2h after surgery
|
||||||||||||||||
|
|||||||||||||||||
Statistical analysis title |
ANOVA for mean dose of hydromorphon 2h | ||||||||||||||||
Comparison groups |
Active comparator v placebo v investigational medicinal products
|
||||||||||||||||
Number of subjects included in analysis |
65
|
||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||
Analysis type |
superiority | ||||||||||||||||
P-value |
= 0.737 | ||||||||||||||||
Method |
ANOVA | ||||||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||||||
Confidence interval |
|||||||||||||||||
level |
95% | ||||||||||||||||
sides |
2-sided
|
||||||||||||||||
lower limit |
1.2732 | ||||||||||||||||
upper limit |
1.7053 | ||||||||||||||||
Variability estimate |
Standard deviation
|
||||||||||||||||
Dispersion value |
0.8718
|
||||||||||||||||
|
|||||||||||||||||
End point title |
total dose of hydromorphone required via PCA (24h) | ||||||||||||||||
End point description |
|||||||||||||||||
End point type |
Primary
|
||||||||||||||||
End point timeframe |
24h post-surgery
|
||||||||||||||||
|
|||||||||||||||||
Statistical analysis title |
ANOVA for mean dose of hydromorphon 24h | ||||||||||||||||
Comparison groups |
investigational medicinal products v Active comparator v placebo
|
||||||||||||||||
Number of subjects included in analysis |
65
|
||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||
Analysis type |
|||||||||||||||||
P-value |
= 0.188 | ||||||||||||||||
Method |
ANOVA | ||||||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||||||
Confidence interval |
|||||||||||||||||
level |
95% | ||||||||||||||||
sides |
2-sided
|
||||||||||||||||
lower limit |
4.3378 | ||||||||||||||||
upper limit |
6.0991 | ||||||||||||||||
Variability estimate |
Standard deviation
|
||||||||||||||||
Dispersion value |
3.55417
|
||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
Adverse events information
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Timeframe for reporting adverse events |
48h post-surgery
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Adverse event reporting additional description |
The local and systemic tolerability and safety of the clinical study medications was assessed, as were possible neurological side effects using the Delirium Detection Score 2h and 24h after the first infusion. Overall pharmacological safety of the infusion solution was assessed via laboratory safety values.
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
Dictionary used for adverse event reporting
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
22.1
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
Reporting groups
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
investigational medicinal products
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group description |
Patients in this arm received the investigational product containing 75 mg diclofenac and 30 mg orphenadrine citrate as active ingredients in 250 ml saline solution | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Active comparator
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group description |
Patients in this arm received the active comparator | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
placebo
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group description |
patients in this arm received a placebo infusion. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Frequency threshold for reporting non-serious adverse events: 1% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||
Substantial protocol amendments (globally) |
|||
| Were there any global substantial amendments to the protocol? No | |||
Interruptions (globally) |
|||
| Were there any global interruptions to the trial? No | |||
Limitations and caveats |
|||
| Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
| None reported | |||
