| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| MedDRA Classification |
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
To evaluate the analgesic efficacy of 1g of i.v. paracetamol versus i.v. placebo,
administered every 6h, as measured by the reduction of the 24-hour cumulative dose of PCA tramadol in the treatment of postoperative pain following total hip arthroplasty. |
|
| E.2.2 | Secondary objectives of the trial |
1) To evaluate the analgesic efficacy of 1g of i.v. paracetamol compared to i.v. placebo, administered every 6h, as measured by pain intensity scores and pain intensity differences from baseline, cumulative doses of tramadol over each 6-hour interval, number of boluses demanded and self-administered by the subject over each 6-hour interval and over the 24-hour period, time elapsed between the first drug administration and the PCA tramadol start, total concomitant opioid use over the whole study period (72h) and subject’s global evaluation of efficacy in the treatment of postoperative pain following total hip arthroplasty over a 24-hour study period.
2) To evaluate the general safety of 1g of i.v. paracetamol compared to i.v. placebo,
administered every 6h, as assessed by adverse events (AE) reporting, level of sedation, incidence of postoperative nausea and vomiting (PONV), vital signs and laboratory tests measurements in the treatment of postoperative pain. |
|
| E.2.3 | Trial contains a sub-study | Information not present in EudraCT |
| E.3 | Principal inclusion criteria |
1) Subject is willing to participate in the study and sign the informed consent.
2) All subjects must have the ability to read and understand the study procedures and the use of the pain scales, must be able to operate a PCA device and to
communicate meaningfully with the study observer and staff.
3) In-patients with ASA risk class I, II or III according to the American Society of
Anaesthesiologist (Appendix 1).
4) Subjects undergoing total hip arthroplasty and prepared for PCA during the
anesthetic consultation.
5) Surgery conducted under standardized spinal anesthesia and presenting a
Modified Bromage Score equal to 2 (almost complete block), after arrival in the
PACU.
6) Body mass index (BMI) greater than or equal to 19 and less than or equal to 35
7) Men or women (not nursing and not pregnant) at least 18 years of age but no
greater than 80 years old.
Women of childbearing potential (WOCBP) must be using an adequate method of
contraception to avoid pregnancy throughout the study and for up to 4 weeks after the study in such a manner that the risk of pregnancy is minimized.
8) Subject free of any contra-indication to the study drugs, or excipients, the rescue
medication and to the standardized anesthesia protocol.
9) Subjects free of other painful physical conditions which, in the opinion of the
investigator, may confound quantifying postoperative pain resulting from hip
arthroplasty. |
|
| E.4 | Principal exclusion criteria |
1) WOCBP who are unwilling or unable to use an acceptable method to avoid
pregnancy for the entire study period and for up to 4 weeks after the study.
2) WOCBP using a prohibited contraceptive method
3) Women who are pregnant or breastfeeding.
4) Women with a positive pregnancy test on enrollment or prior to study drug
administration.
5) Subject for whom the spinal anesthesia was converted to general anesthesia
during the procedure.
6) Subject who needs simultaneously any additional surgery procedures unrelated to
hip arthroplasty during the same session.
7) Subject scheduled for early reintervention or reinstrumentation, i.e. within 60
days of the initial procedure or less.
8) Subject with abnormally high perioperative blood loss at risk of hypovolemia
during the postoperative period.
9) Subject with known or suspected history of alcohol or drug abuse.
10) Subject with psychiatric disease or medical conditions which in the opinion of the
investigator may invalidate subject ability to communicate with the investigator or
to comply with the study procedures.
11) Subject having a history of complete non-response to either paracetamol,
NSAID’s or tramadol when seeking pain relief; subjects having previously
required more than usual doses of analgesics for comparable surgical procedures.
12) Subject with any known significant medical disease(s) or condition(s) that in the
investigator´s judgement could compromise the subject´s ability to communicate
with the study staff or contraindicate study participation.
13) Impaired liver function (transaminases > 3 x upper limit of normal range).
14) Advanced renal dysfunction (creatinine > 2.0 mg/dL or 170 µmol/L) or subject at risk for renal failure due to volume depletion.
15) Subject with coagulation alterations.
16) Any additional laboratory abnormality which, in the investigator´s opinion would
contraindicate study participation.
17) Respiratory insufficiency or severe cardiac insufficiency not stabilized by therapy.
18) Chronic malnutrition.
19) Subject with raised intracranial pressure or convulsions.
20) Known hypersensitivity or contraindications to study drugs or related compounds, rescue medication, standardized anaesthesia or to inactive ingredients of the study medication.
21) Subject who has taken NSAIDs within 8 hours (48 h for long acting NSAIDs)
before administration of the study medications, any analgesic drug within the 12 hours (48 h for long acting drugs) prior to administration of the study medications
or any medication that, in the opinion of the Investigator, would be expected to
confound the analgesic responses.
22) Subject who is taking any concomitant treatments (i.e. sedatives, hypnotics,
anxiolytics, anti-depressant drugs, tranquilizers) which could potentially confound
the quantification of analgesia.
23) Subject treated with MAO inhibitors or whose treatment with these has been
stopped less than 10 days prior to surgery; subject treated with corticosteroids or
whose treatment with these has been stopped less than 7 days prior surgery.
24) Subject treated with agents known to affect microsomal enzymes (such as
rifampicin, barbiturates, izoniazid, anticonvulsants, zidovudine, and tricyclic
antidepressants), and/or agents which could affect the analgesic response (such as
neuroleptic agents, clonidine and anti-psychotic agents) except as indicated in the
standardized anesthesia protocol.
25) Subject treated with anticoagulants (except for heparin 5000 UI).
26) Prisoners or subjects who are compulsorily detained (involuntarily incarcerated)
for treatment of either a psychiatric or physical (e.g., infectious disease) illness
must not be enrolled into this study.
27) Subject participating in any other clinical study or having done so in the previous
60 days.
28) Subject previously included in the study. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary efficacy criterion will be the 24-hour cumulative dose of PCA tramadol
requested over the 24-hour study period in the treatment of postoperative pain following total hip arthroplasty.
Other criteria for evaluation of efficacy will include:
- Cumulative doses of tramadol over the 6-hour intervals: 0h-6h, 6h-12h, 12h-18h, 18h-24h.
- Number of boluses demanded and self-administered by the subjects over each 6-hour interval and over the 24-hour study period.
- Time elapsed between the first study drug administration (T0) and the PCA tramadol start.
- Total concomitant opioid use (whatever the type and route of administration) over the whole study period (72H).
- Pain intensity scores (at rest and during mobilization) and pain intensity differences
from baseline (at rest) assessed on a 4-point verbal scale (VS) and on a 100 mm
visual analogue scale (VAS) at regular time-intervals.
- Subject´s global evaluation of efficacy (4-point VS)
The criteria for evaluation of safety will include:
- Number of AEs in each treatment group.
- Number and percentage of subjects presenting at least one AE.
- Level of sedation (5-point VS)
- Incidence of PONV
- Number of subjects requiring anti-emetic and total dose of anti-emetic administered
over the 24-hour study period.
- Vital signs.
- Laboratory safety tests. |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Information not present in EudraCT |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | Yes |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
| E.8.7 | Trial has a data monitoring committee | Information not present in EudraCT |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
| |
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | |
| E.8.9.1 | In the Member State concerned months | 9 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial months | 9 |
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