Dose-finding Study of Intrathecal Paracetamol Administered Immediately Before Spinal Anaesthesia

Phase 1

Completed

Conditions: Phase 1: Pain Management
Phase 2: Pain Management

Interventions: Drug: Paracetamol 3%
Drug: Placebo injection containing Saline solution 0.9%
Drug: Hyperbaric Bupivacaine HCl 0.5%

Registration Number: NCT02654860

Lead Sponsor: Sintetica SA

Brief Summary: Two-part study of intrathecal paracetamol administered immediately before spinal anaesthesia in patients scheduled for hip replacement surgery

Detailed Description: This is a prospective, single centre, two-part, three doses study. Part 1 is a Phase I, three cohorts, dose-ascending, open-label, safety study. Part 2 is a Phase II, randomised, parallel-group, double-blind, placebo-controlled, exploratory efficacy and safety study The objective of the study is to investigate the efficacy and safety of a single intrathecal injection of paracetamol, administered at 3 doses to 3 active treatment groups, as compared to placebo solution, for post-operative analgesia of hip replacement surgery performed under spinal anaesthesia. Patients scheduled for hip replacement surgery will be randomised into 4 treatment groups (15 patients per group) to receive either one of the 3 single doses of paracetamol 3% (D1: 60 mg, D2: 90 mg, D3: 120 mg) or placebo solution (P: saline solution) by intrathecal (IT) injection. Immediately after paracetamol or placebo IT administration, all patients will receive a single IT dose of Hyperbaric Bupivacaine HCl 0.5% (12.5 mg for ≤ 160 cm-tall patients and 15 mg for \> 160 cm-tall patients). The time interval between paracetamol IT and bupivacaine IT administrations should not exceed 2 min.

The study will include a screening phase (Visit 1, Days -21/1), a treatment phase (paracetamol IT administration, anaesthesia and surgical procedure: Visit 2, Day 1) and a follow-up phase including an observation period (Visit 3, from Day 1 after surgery until discharge, a final visit (at discharge) and a follow-up (day 6±1). Pain at rest will be assessed at screening and on visit 2 at baseline (0 h), 1, 2, 3, 6, 9, 12, 15, 18, 21, 24, 27, 30, 33, 36, 39, 42, 45 and 48 h after anaesthetic IT injection and at discharge, using a 0-100 mm VAS.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 69

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
60 mg Paracetamol 3% (2 mL)	Paracetamol 3%	60 mg Paracetamol 3%. Solution for injection, single administration by Intrathecal route.
60 mg Paracetamol 3% (2 mL)	Hyperbaric Bupivacaine HCl 0.5%	60 mg Paracetamol 3%. Solution for injection, single administration by Intrathecal route.
90 mg Paracetamol 3% (3 mL)	Paracetamol 3%	90 mg Paracetamol 3%. Solution for injection, single administration by Intrathecal route.
90 mg Paracetamol 3% (3 mL)	Hyperbaric Bupivacaine HCl 0.5%	90 mg Paracetamol 3%. Solution for injection, single administration by Intrathecal route.
120 mg Paracetamol 3% (4mL)	Paracetamol 3%	120 mg Paracetamol 3%. Solution for injection, single administration by Intrathecal route.
120 mg Paracetamol 3% (4mL)	Hyperbaric Bupivacaine HCl 0.5%	120 mg Paracetamol 3%. Solution for injection, single administration by Intrathecal route.
Phase II Only: Saline solution 0.9%	Placebo injection containing Saline solution 0.9%	Placebo, 0.9%. Solution for injection , single administration by route Intrathecal (2 mL, 3 mL and 4 mL) Study part 2 will be placebo-controlled. Each patient will be allocated to a treatment arm (one of the three paracetamol doses or placebo) according to a computer-generated randomisation list.
Phase II Only: Saline solution 0.9%	Hyperbaric Bupivacaine HCl 0.5%	Placebo, 0.9%. Solution for injection , single administration by route Intrathecal (2 mL, 3 mL and 4 mL) Study part 2 will be placebo-controlled. Each patient will be allocated to a treatment arm (one of the three paracetamol doses or placebo) according to a computer-generated randomisation list.

Primary Outcome Measures

Name	Time	Method
Phase 2: Pain Intensity	baseline (0 h), 1, 6, 9, 12, 15, 24, and 48 h after anaesthetic IT injection and at discharge	Phase 2: Pain intensity at rest evaluated as VAS scores ( 0-100 mm visual analogue scale : 0 is the absence pain and 100 is the maximum pain sensation)
Phase 1: Number of Participants With Adverse Events Related, Not Related and Serious Events Related to Paracetamol	In the first 24 hours, in the first 48 hours and at day 7±1	Phase 1: Number of participants with treatment evaluation and confirmation of the safety of the three doses of paracetamol 3% solution administered in the total number of patients enrolled

Secondary Outcome Measures

Name	Time	Method
Phase 2: Number of Participants With Need for Supplemental Analgesia	Postoperative, up to 48 hours after end of surgery	Phase 2: Need for supplementary analgesia, other than the planned morphine PCA
Phase 2: Morphine-related Adverse Events	up to 24 hours after surgery, up to 48 hours	Percentage of subjects experiencing during the study the morphine-related adverse events pre-specified in the protocol
Phase 2:Maximum Level of Sensory Block	Intraoperative	Sensorial block will be verified by bilateral Pinprick test using a 20-G hypodermic needle and will be recorded. Pinprick sensation will be scored as being present (score 1) or absent (score 0). Onset of sensory block is defined as an absent touch sensation (score 0)
Phase 2: ECG	screening, baseline and end of study (Day 6±1)	Electrocardiography is the process of producing an electrocardiogram (ECG), it is a graph of voltage versus time of the electrical activity of the heart using electrodes placed on the skin.
Phase 2: Morphine	At 24 and 48 h after anaesthetic IT injection and entire study period, up to 7 days	Phase 2: Total morphine use
Phase 2: Time to First Morphine Use	Postoperative, up to 48 hours after end of surgery	Phase 2: Time to first morphine use (minutes)
Phase 2: Time to Sensory Block	Intraoperative	Time to maximum level of sensory block
Phase 2: Time to Readiness for Surgery	Intraoperative	Time period from completion of spinal injection (time 0 h) to achievement of sensory and motor block adequate for surgery.
Phase 2: Time to Regression of Spinal Block	from readiness for surgery,then every 10 min until the maximum level is reached (two consecutive observations with the same level of sensory block) and then every 30 min until regression of spinal block	Time period from spinal injection (time 0 h) to the time when the Bromage score returns to 0 and sensitive perception returns to S1. Bromage scale: I - Free movement of legs and feet II - Just able to flex knees with free movement of feet III - Unable to flex knees, but with free movement of feet IV - Unable to move legs or feet
Phase 2: Vital Signs	at screening, at baseline (before the spinal injection) and at end of the study (Day 6).	Systolic and Diastolic Blood Pressure (mmHg)
Phase 2: SpO2	at screening, at baseline (before the spinal injection) and at the end of the study (day 6)	Oxygen saturation is the fraction of oxygen-saturated hemoglobin relative to total hemoglobin (unsaturated + saturated) in the blood.
Phase2: Concomitant Medications	at screening, at baseline until the end of the study (Day 6)	record the concomitant medications intaked during the study