Trial Outcomes & Findings for Dose-finding Study of Intrathecal Paracetamol Administered Immediately Before Spinal Anaesthesia (NCT NCT02654860)

Results Overview

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

Recruitment status

COMPLETED

Study phase

PHASE1/PHASE2

Target enrollment

69 participants

Primary outcome timeframe

In the first 24 hours, in the first 48 hours and at day 7±1

Results posted on

2021-10-27

Participant Flow

Participant milestones

Participant milestones
Measure	60 mg Paracetamol 3% (2 mL) 60 mg Paracetamol 3%. Solution for injection, single administration by Intrathecal route. Paracetamol 3%: Investigate the efficacy and safety of a single intrathecal injection of paracetamol,for post-operative analgesia of hip replacement surgery Hyperbaric Bupivacaine HCl 0.5%: NIMP, spinal anaesthetic before the surgical procedure	90 mg Paracetamol 3% (3 mL) 90 mg Paracetamol 3%. Solution for injection, single administration by Intrathecal route. Paracetamol 3%: Investigate the efficacy and safety of a single intrathecal injection of paracetamol,for post-operative analgesia of hip replacement surgery Hyperbaric Bupivacaine HCl 0.5%: NIMP, spinal anaesthetic before the surgical procedure	120 mg Paracetamol 3% (4mL) 120 mg Paracetamol 3%. Solution for injection, single administration by Intrathecal route. Paracetamol 3%: Investigate the efficacy and safety of a single intrathecal injection of paracetamol,for post-operative analgesia of hip replacement surgery Hyperbaric Bupivacaine HCl 0.5%: NIMP, spinal anaesthetic before the surgical procedure	Phase II Only: 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. Placebo injection containing Saline solution 0.9%: Injection containing sterile solution of Saline Solution 0.9 %. 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. Hyperbaric Bupivacaine HCl 0.5%: NIMP, spinal anaesthetic before the surgical procedure
First Part STARTED	3	3	3	0
First Part COMPLETED	3	3	3	0
First Part NOT COMPLETED	0	0	0	0
Second Part STARTED	15	15	15	15
Second Part COMPLETED	15	15	15	15
Second Part NOT COMPLETED	0	0	0	0

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

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

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	60 mg Paracetamol 3% (2 mL) n=18 Participants 60 mg Paracetamol 3%. Solution for injection, single administration by Intrathecal route. Paracetamol 3%: Investigate the efficacy and safety of a single intrathecal injection of paracetamol,for post-operative analgesia of hip replacement surgery Hyperbaric Bupivacaine HCl 0.5%: NIMP, spinal anaesthetic before the surgical procedure	90 mg Paracetamol 3% (3 mL) n=18 Participants 90 mg Paracetamol 3%. Solution for injection, single administration by Intrathecal route. Paracetamol 3%: Investigate the efficacy and safety of a single intrathecal injection of paracetamol,for post-operative analgesia of hip replacement surgery Hyperbaric Bupivacaine HCl 0.5%: NIMP, spinal anaesthetic before the surgical procedure	120 mg Paracetamol 3% (4mL) n=18 Participants 120 mg Paracetamol 3%. Solution for injection, single administration by Intrathecal route. Paracetamol 3%: Investigate the efficacy and safety of a single intrathecal injection of paracetamol,for post-operative analgesia of hip replacement surgery Hyperbaric Bupivacaine HCl 0.5%: NIMP, spinal anaesthetic before the surgical procedure	Phase II Only: Saline Solution 0.9% n=15 Participants 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. Placebo injection containing Saline solution 0.9%: Injection containing sterile solution of Saline Solution 0.9 %. 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. Hyperbaric Bupivacaine HCl 0.5%: NIMP, spinal anaesthetic before the surgical procedure	Total n=69 Participants Total of all reporting groups
Age, Continuous	66.9 years STANDARD_DEVIATION 6.7 • n=5 Participants	65.1 years STANDARD_DEVIATION 7.9 • n=7 Participants	62.3 years STANDARD_DEVIATION 9.3 • n=5 Participants	65.1 years STANDARD_DEVIATION 7.7 • n=4 Participants	64.8 years STANDARD_DEVIATION 7.9 • n=21 Participants
Sex: Female, Male Female	8 Participants n=5 Participants	13 Participants n=7 Participants	4 Participants n=5 Participants	6 Participants n=4 Participants	31 Participants n=21 Participants
Sex: Female, Male Male	10 Participants n=5 Participants	5 Participants n=7 Participants	14 Participants n=5 Participants	9 Participants n=4 Participants	38 Participants n=21 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants
Race (NIH/OMB) Asian	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants
Race (NIH/OMB) Black or African American	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants
Race (NIH/OMB) White	18 Participants n=5 Participants	18 Participants n=7 Participants	18 Participants n=5 Participants	15 Participants n=4 Participants	69 Participants n=21 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants

PRIMARY outcome

Timeframe: 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

Outcome measures

Outcome measures
Measure	60 mg Paracetamol 3% (2 mL) n=3 Participants 60 mg Paracetamol 3%. Solution for injection, single administration by Intrathecal route. Paracetamol 3%: Investigate the efficacy and safety of a single intrathecal injection of paracetamol,for post-operative analgesia of hip replacement surgery Hyperbaric Bupivacaine HCl 0.5%: NIMP, spinal anaesthetic before the surgical procedure	90 mg Paracetamol 3% (3 mL) n=3 Participants 90 mg Paracetamol 3%. Solution for injection, single administration by Intrathecal route. Paracetamol 3%: Investigate the efficacy and safety of a single intrathecal injection of paracetamol,for post-operative analgesia of hip replacement surgery Hyperbaric Bupivacaine HCl 0.5%: NIMP, spinal anaesthetic before the surgical procedure	120 mg Paracetamol 3% (4mL) n=3 Participants 120 mg Paracetamol 3%. Solution for injection, single administration by Intrathecal route. Paracetamol 3%: Investigate the efficacy and safety of a single intrathecal injection of paracetamol,for post-operative analgesia of hip replacement surgery Hyperbaric Bupivacaine HCl 0.5%: NIMP, spinal anaesthetic before the surgical procedure	Phase II Only: 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. Placebo injection containing Saline solution 0.9%: Injection containing sterile solution of Saline Solution 0.9 %. 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. Hyperbaric Bupivacaine HCl 0.5%: NIMP, spinal anaesthetic before the surgical procedure
Phase 1: Number of Participants With Adverse Events Related, Not Related and Serious Events Related to Paracetamol Adverse event related	0 participants	0 participants	0 participants	—
Phase 1: Number of Participants With Adverse Events Related, Not Related and Serious Events Related to Paracetamol Adverse event not related	1 participants	1 participants	6 participants	—
Phase 1: Number of Participants With Adverse Events Related, Not Related and Serious Events Related to Paracetamol Serious adverse event	0 participants	0 participants	0 participants	—

PRIMARY outcome

Timeframe: 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)

Outcome measures

Outcome measures
Measure	60 mg Paracetamol 3% (2 mL) n=14 Participants 60 mg Paracetamol 3%. Solution for injection, single administration by Intrathecal route. Paracetamol 3%: Investigate the efficacy and safety of a single intrathecal injection of paracetamol,for post-operative analgesia of hip replacement surgery Hyperbaric Bupivacaine HCl 0.5%: NIMP, spinal anaesthetic before the surgical procedure	90 mg Paracetamol 3% (3 mL) n=13 Participants 90 mg Paracetamol 3%. Solution for injection, single administration by Intrathecal route. Paracetamol 3%: Investigate the efficacy and safety of a single intrathecal injection of paracetamol,for post-operative analgesia of hip replacement surgery Hyperbaric Bupivacaine HCl 0.5%: NIMP, spinal anaesthetic before the surgical procedure	120 mg Paracetamol 3% (4mL) n=15 Participants 120 mg Paracetamol 3%. Solution for injection, single administration by Intrathecal route. Paracetamol 3%: Investigate the efficacy and safety of a single intrathecal injection of paracetamol,for post-operative analgesia of hip replacement surgery Hyperbaric Bupivacaine HCl 0.5%: NIMP, spinal anaesthetic before the surgical procedure	Phase II Only: Saline Solution 0.9% n=15 Participants 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. Placebo injection containing Saline solution 0.9%: Injection containing sterile solution of Saline Solution 0.9 %. 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. Hyperbaric Bupivacaine HCl 0.5%: NIMP, spinal anaesthetic before the surgical procedure
Phase 2: Pain Intensity baseline	11.9 units on a scale Standard Deviation 15.5	17.3 units on a scale Standard Deviation 15.6	24.5 units on a scale Standard Deviation 19.5	10.7 units on a scale Standard Deviation 13.4
Phase 2: Pain Intensity 1 hour after anaesthetic	0 units on a scale Standard Deviation 0	0 units on a scale Standard Deviation 0	0 units on a scale Standard Deviation 0	0 units on a scale Standard Deviation 0
Phase 2: Pain Intensity 6 hours after anaesthetic	21.5 units on a scale Standard Deviation 22.2	32.2 units on a scale Standard Deviation 25	20.3 units on a scale Standard Deviation 25.3	42.3 units on a scale Standard Deviation 31.5
Phase 2: Pain Intensity 9 hours after anaesthetic	21.6 units on a scale Standard Deviation 18	13.6 units on a scale Standard Deviation 11.6	17.3 units on a scale Standard Deviation 24	26.3 units on a scale Standard Deviation 22.3
Phase 2: Pain Intensity 12 hours after anaesthetic	13.1 units on a scale Standard Deviation 16.5	10.1 units on a scale Standard Deviation 8.6	11.2 units on a scale Standard Deviation 17.5	17.9 units on a scale Standard Deviation 16.7
Phase 2: Pain Intensity 15 hours after anaesthetic	15.4 units on a scale Standard Deviation 16.7	10.2 units on a scale Standard Deviation 10.2	10.6 units on a scale Standard Deviation 13.8	20.5 units on a scale Standard Deviation 21.5
Phase 2: Pain Intensity 24 hours after anaesthetic	11.4 units on a scale Standard Deviation 10.7	9.5 units on a scale Standard Deviation 8.9	13.6 units on a scale Standard Deviation 14.9	16 units on a scale Standard Deviation 18.3
Phase 2: Pain Intensity 48 hours after anaesthetic	6.1 units on a scale Standard Deviation 8.6	3.2 units on a scale Standard Deviation 6.6	7.7 units on a scale Standard Deviation 12.9	8.7 units on a scale Standard Deviation 11.6
Phase 2: Pain Intensity Discharge	2.5 units on a scale Standard Deviation 3.7	4.1 units on a scale Standard Deviation 4.8	4.8 units on a scale Standard Deviation 6.8	8.0 units on a scale Standard Deviation 9.6

SECONDARY outcome

Timeframe: At 24 and 48 h after anaesthetic IT injection and entire study period, up to 7 days

Phase 2: Total morphine use

Outcome measures

Outcome measures
Measure	60 mg Paracetamol 3% (2 mL) n=14 Participants 60 mg Paracetamol 3%. Solution for injection, single administration by Intrathecal route. Paracetamol 3%: Investigate the efficacy and safety of a single intrathecal injection of paracetamol,for post-operative analgesia of hip replacement surgery Hyperbaric Bupivacaine HCl 0.5%: NIMP, spinal anaesthetic before the surgical procedure	90 mg Paracetamol 3% (3 mL) n=13 Participants 90 mg Paracetamol 3%. Solution for injection, single administration by Intrathecal route. Paracetamol 3%: Investigate the efficacy and safety of a single intrathecal injection of paracetamol,for post-operative analgesia of hip replacement surgery Hyperbaric Bupivacaine HCl 0.5%: NIMP, spinal anaesthetic before the surgical procedure	120 mg Paracetamol 3% (4mL) n=15 Participants 120 mg Paracetamol 3%. Solution for injection, single administration by Intrathecal route. Paracetamol 3%: Investigate the efficacy and safety of a single intrathecal injection of paracetamol,for post-operative analgesia of hip replacement surgery Hyperbaric Bupivacaine HCl 0.5%: NIMP, spinal anaesthetic before the surgical procedure	Phase II Only: Saline Solution 0.9% n=15 Participants 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. Placebo injection containing Saline solution 0.9%: Injection containing sterile solution of Saline Solution 0.9 %. 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. Hyperbaric Bupivacaine HCl 0.5%: NIMP, spinal anaesthetic before the surgical procedure
Phase 2: Morphine first 24 hours	14.1 mg Standard Deviation 10.4	12.6 mg Standard Deviation 4.5	22.8 mg Standard Deviation 14.7	14.3 mg Standard Deviation 7.4
Phase 2: Morphine first 48 hours	24.5 mg Standard Deviation 19.7	15.8 mg Standard Deviation 5.1	33.5 mg Standard Deviation 21.5	21 mg Standard Deviation 12.8
Phase 2: Morphine entire study period	24.8 mg Standard Deviation 19.7	15.8 mg Standard Deviation 5.1	33.8 mg Standard Deviation 21.4	21.1 mg Standard Deviation 13

SECONDARY outcome

Timeframe: Postoperative, up to 48 hours after end of surgery

Phase 2: Time to first morphine use (minutes)

Outcome measures

Outcome measures
Measure	60 mg Paracetamol 3% (2 mL) n=15 Participants 60 mg Paracetamol 3%. Solution for injection, single administration by Intrathecal route. Paracetamol 3%: Investigate the efficacy and safety of a single intrathecal injection of paracetamol,for post-operative analgesia of hip replacement surgery Hyperbaric Bupivacaine HCl 0.5%: NIMP, spinal anaesthetic before the surgical procedure	90 mg Paracetamol 3% (3 mL) n=15 Participants 90 mg Paracetamol 3%. Solution for injection, single administration by Intrathecal route. Paracetamol 3%: Investigate the efficacy and safety of a single intrathecal injection of paracetamol,for post-operative analgesia of hip replacement surgery Hyperbaric Bupivacaine HCl 0.5%: NIMP, spinal anaesthetic before the surgical procedure	120 mg Paracetamol 3% (4mL) n=15 Participants 120 mg Paracetamol 3%. Solution for injection, single administration by Intrathecal route. Paracetamol 3%: Investigate the efficacy and safety of a single intrathecal injection of paracetamol,for post-operative analgesia of hip replacement surgery Hyperbaric Bupivacaine HCl 0.5%: NIMP, spinal anaesthetic before the surgical procedure	Phase II Only: Saline Solution 0.9% n=15 Participants 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. Placebo injection containing Saline solution 0.9%: Injection containing sterile solution of Saline Solution 0.9 %. 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. Hyperbaric Bupivacaine HCl 0.5%: NIMP, spinal anaesthetic before the surgical procedure
Phase 2: Time to First Morphine Use	351 minutes Interval 275.0 to 503.0	236 minutes Interval 181.0 to 322.0	318 minutes Interval 184.0 to 415.0	279 minutes Interval 169.0 to 313.0

SECONDARY outcome

Timeframe: Postoperative, up to 48 hours after end of surgery

Phase 2: Need for supplementary analgesia, other than the planned morphine PCA

Outcome measures

Outcome measures
Measure	60 mg Paracetamol 3% (2 mL) n=15 Participants 60 mg Paracetamol 3%. Solution for injection, single administration by Intrathecal route. Paracetamol 3%: Investigate the efficacy and safety of a single intrathecal injection of paracetamol,for post-operative analgesia of hip replacement surgery Hyperbaric Bupivacaine HCl 0.5%: NIMP, spinal anaesthetic before the surgical procedure	90 mg Paracetamol 3% (3 mL) n=15 Participants 90 mg Paracetamol 3%. Solution for injection, single administration by Intrathecal route. Paracetamol 3%: Investigate the efficacy and safety of a single intrathecal injection of paracetamol,for post-operative analgesia of hip replacement surgery Hyperbaric Bupivacaine HCl 0.5%: NIMP, spinal anaesthetic before the surgical procedure	120 mg Paracetamol 3% (4mL) n=15 Participants 120 mg Paracetamol 3%. Solution for injection, single administration by Intrathecal route. Paracetamol 3%: Investigate the efficacy and safety of a single intrathecal injection of paracetamol,for post-operative analgesia of hip replacement surgery Hyperbaric Bupivacaine HCl 0.5%: NIMP, spinal anaesthetic before the surgical procedure	Phase II Only: Saline Solution 0.9% n=15 Participants 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. Placebo injection containing Saline solution 0.9%: Injection containing sterile solution of Saline Solution 0.9 %. 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. Hyperbaric Bupivacaine HCl 0.5%: NIMP, spinal anaesthetic before the surgical procedure
Phase 2: Number of Participants With Need for Supplemental Analgesia	9 Participants	11 Participants	11 Participants	10 Participants

SECONDARY outcome

Timeframe: 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

Outcome measures

Outcome measures
Measure	60 mg Paracetamol 3% (2 mL) n=15 Participants 60 mg Paracetamol 3%. Solution for injection, single administration by Intrathecal route. Paracetamol 3%: Investigate the efficacy and safety of a single intrathecal injection of paracetamol,for post-operative analgesia of hip replacement surgery Hyperbaric Bupivacaine HCl 0.5%: NIMP, spinal anaesthetic before the surgical procedure	90 mg Paracetamol 3% (3 mL) n=15 Participants 90 mg Paracetamol 3%. Solution for injection, single administration by Intrathecal route. Paracetamol 3%: Investigate the efficacy and safety of a single intrathecal injection of paracetamol,for post-operative analgesia of hip replacement surgery Hyperbaric Bupivacaine HCl 0.5%: NIMP, spinal anaesthetic before the surgical procedure	120 mg Paracetamol 3% (4mL) n=15 Participants 120 mg Paracetamol 3%. Solution for injection, single administration by Intrathecal route. Paracetamol 3%: Investigate the efficacy and safety of a single intrathecal injection of paracetamol,for post-operative analgesia of hip replacement surgery Hyperbaric Bupivacaine HCl 0.5%: NIMP, spinal anaesthetic before the surgical procedure	Phase II Only: Saline Solution 0.9% n=15 Participants 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. Placebo injection containing Saline solution 0.9%: Injection containing sterile solution of Saline Solution 0.9 %. 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. Hyperbaric Bupivacaine HCl 0.5%: NIMP, spinal anaesthetic before the surgical procedure
Phase 2: Morphine-related Adverse Events	1 Participants	6 Participants	1 Participants	6 Participants

SECONDARY outcome

Timeframe: Intraoperative

Time period from completion of spinal injection (time 0 h) to achievement of sensory and motor block adequate for surgery.

Outcome measures

Outcome measures
Measure	60 mg Paracetamol 3% (2 mL) n=15 Participants 60 mg Paracetamol 3%. Solution for injection, single administration by Intrathecal route. Paracetamol 3%: Investigate the efficacy and safety of a single intrathecal injection of paracetamol,for post-operative analgesia of hip replacement surgery Hyperbaric Bupivacaine HCl 0.5%: NIMP, spinal anaesthetic before the surgical procedure	90 mg Paracetamol 3% (3 mL) n=15 Participants 90 mg Paracetamol 3%. Solution for injection, single administration by Intrathecal route. Paracetamol 3%: Investigate the efficacy and safety of a single intrathecal injection of paracetamol,for post-operative analgesia of hip replacement surgery Hyperbaric Bupivacaine HCl 0.5%: NIMP, spinal anaesthetic before the surgical procedure	120 mg Paracetamol 3% (4mL) n=15 Participants 120 mg Paracetamol 3%. Solution for injection, single administration by Intrathecal route. Paracetamol 3%: Investigate the efficacy and safety of a single intrathecal injection of paracetamol,for post-operative analgesia of hip replacement surgery Hyperbaric Bupivacaine HCl 0.5%: NIMP, spinal anaesthetic before the surgical procedure	Phase II Only: Saline Solution 0.9% n=15 Participants 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. Placebo injection containing Saline solution 0.9%: Injection containing sterile solution of Saline Solution 0.9 %. 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. Hyperbaric Bupivacaine HCl 0.5%: NIMP, spinal anaesthetic before the surgical procedure
Phase 2: Time to Readiness for Surgery	9 minutes Interval 5.0 to 16.0	10 minutes Interval 4.0 to 10.0	10 minutes Interval 5.0 to 11.0	8 minutes Interval 5.0 to 12.0

SECONDARY outcome

Timeframe: 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)

Outcome measures

Outcome measures
Measure	60 mg Paracetamol 3% (2 mL) n=15 Participants 60 mg Paracetamol 3%. Solution for injection, single administration by Intrathecal route. Paracetamol 3%: Investigate the efficacy and safety of a single intrathecal injection of paracetamol,for post-operative analgesia of hip replacement surgery Hyperbaric Bupivacaine HCl 0.5%: NIMP, spinal anaesthetic before the surgical procedure	90 mg Paracetamol 3% (3 mL) n=15 Participants 90 mg Paracetamol 3%. Solution for injection, single administration by Intrathecal route. Paracetamol 3%: Investigate the efficacy and safety of a single intrathecal injection of paracetamol,for post-operative analgesia of hip replacement surgery Hyperbaric Bupivacaine HCl 0.5%: NIMP, spinal anaesthetic before the surgical procedure	120 mg Paracetamol 3% (4mL) n=15 Participants 120 mg Paracetamol 3%. Solution for injection, single administration by Intrathecal route. Paracetamol 3%: Investigate the efficacy and safety of a single intrathecal injection of paracetamol,for post-operative analgesia of hip replacement surgery Hyperbaric Bupivacaine HCl 0.5%: NIMP, spinal anaesthetic before the surgical procedure	Phase II Only: Saline Solution 0.9% n=15 Participants 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. Placebo injection containing Saline solution 0.9%: Injection containing sterile solution of Saline Solution 0.9 %. 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. Hyperbaric Bupivacaine HCl 0.5%: NIMP, spinal anaesthetic before the surgical procedure
Phase 2:Maximum Level of Sensory Block T1	0 participants	0 participants	0 participants	0 participants
Phase 2:Maximum Level of Sensory Block T2	0 participants	0 participants	0 participants	0 participants
Phase 2:Maximum Level of Sensory Block T3	0 participants	0 participants	0 participants	0 participants
Phase 2:Maximum Level of Sensory Block T4	0 participants	2 participants	0 participants	1 participants
Phase 2:Maximum Level of Sensory Block T5	2 participants	1 participants	0 participants	0 participants
Phase 2:Maximum Level of Sensory Block T6	4 participants	4 participants	3 participants	3 participants
Phase 2:Maximum Level of Sensory Block T7	1 participants	2 participants	1 participants	6 participants
Phase 2:Maximum Level of Sensory Block T8	7 participants	7 participants	10 participants	28 participants
Phase 2:Maximum Level of Sensory Block T9	0 participants	2 participants	0 participants	2 participants
Phase 2:Maximum Level of Sensory Block T10	2 participants	0 participants	1 participants	0 participants
Phase 2:Maximum Level of Sensory Block T11	1 participants	0 participants	0 participants	0 participants

SECONDARY outcome

Timeframe: Intraoperative

Time to maximum level of sensory block

Outcome measures

Outcome measures
Measure	60 mg Paracetamol 3% (2 mL) n=15 Participants 60 mg Paracetamol 3%. Solution for injection, single administration by Intrathecal route. Paracetamol 3%: Investigate the efficacy and safety of a single intrathecal injection of paracetamol,for post-operative analgesia of hip replacement surgery Hyperbaric Bupivacaine HCl 0.5%: NIMP, spinal anaesthetic before the surgical procedure	90 mg Paracetamol 3% (3 mL) n=15 Participants 90 mg Paracetamol 3%. Solution for injection, single administration by Intrathecal route. Paracetamol 3%: Investigate the efficacy and safety of a single intrathecal injection of paracetamol,for post-operative analgesia of hip replacement surgery Hyperbaric Bupivacaine HCl 0.5%: NIMP, spinal anaesthetic before the surgical procedure	120 mg Paracetamol 3% (4mL) n=15 Participants 120 mg Paracetamol 3%. Solution for injection, single administration by Intrathecal route. Paracetamol 3%: Investigate the efficacy and safety of a single intrathecal injection of paracetamol,for post-operative analgesia of hip replacement surgery Hyperbaric Bupivacaine HCl 0.5%: NIMP, spinal anaesthetic before the surgical procedure	Phase II Only: Saline Solution 0.9% n=15 Participants 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. Placebo injection containing Saline solution 0.9%: Injection containing sterile solution of Saline Solution 0.9 %. 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. Hyperbaric Bupivacaine HCl 0.5%: NIMP, spinal anaesthetic before the surgical procedure
Phase 2: Time to Sensory Block	18 minutes Interval 13.0 to 20.0	15 minutes Interval 9.0 to 20.0	15 minutes Interval 13.0 to 20.0	17 minutes Interval 10.0 to 23.0

SECONDARY outcome

Timeframe: 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

Outcome measures

Outcome measures
Measure	60 mg Paracetamol 3% (2 mL) n=15 Participants 60 mg Paracetamol 3%. Solution for injection, single administration by Intrathecal route. Paracetamol 3%: Investigate the efficacy and safety of a single intrathecal injection of paracetamol,for post-operative analgesia of hip replacement surgery Hyperbaric Bupivacaine HCl 0.5%: NIMP, spinal anaesthetic before the surgical procedure	90 mg Paracetamol 3% (3 mL) n=15 Participants 90 mg Paracetamol 3%. Solution for injection, single administration by Intrathecal route. Paracetamol 3%: Investigate the efficacy and safety of a single intrathecal injection of paracetamol,for post-operative analgesia of hip replacement surgery Hyperbaric Bupivacaine HCl 0.5%: NIMP, spinal anaesthetic before the surgical procedure	120 mg Paracetamol 3% (4mL) n=15 Participants 120 mg Paracetamol 3%. Solution for injection, single administration by Intrathecal route. Paracetamol 3%: Investigate the efficacy and safety of a single intrathecal injection of paracetamol,for post-operative analgesia of hip replacement surgery Hyperbaric Bupivacaine HCl 0.5%: NIMP, spinal anaesthetic before the surgical procedure	Phase II Only: Saline Solution 0.9% n=15 Participants 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. Placebo injection containing Saline solution 0.9%: Injection containing sterile solution of Saline Solution 0.9 %. 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. Hyperbaric Bupivacaine HCl 0.5%: NIMP, spinal anaesthetic before the surgical procedure
Phase 2: Time to Regression of Spinal Block	285 minutes Interval 260.0 to 345.0	246 minutes Interval 228.0 to 280.0	265 minutes Interval 245.0 to 303.0	280 minutes Interval 232.0 to 302.0

SECONDARY outcome

Timeframe: at screening, at baseline (before the spinal injection) and at end of the study (Day 6).

Systolic and Diastolic Blood Pressure (mmHg)

Outcome measures

Outcome measures
Measure	60 mg Paracetamol 3% (2 mL) n=15 Participants 60 mg Paracetamol 3%. Solution for injection, single administration by Intrathecal route. Paracetamol 3%: Investigate the efficacy and safety of a single intrathecal injection of paracetamol,for post-operative analgesia of hip replacement surgery Hyperbaric Bupivacaine HCl 0.5%: NIMP, spinal anaesthetic before the surgical procedure	90 mg Paracetamol 3% (3 mL) n=15 Participants 90 mg Paracetamol 3%. Solution for injection, single administration by Intrathecal route. Paracetamol 3%: Investigate the efficacy and safety of a single intrathecal injection of paracetamol,for post-operative analgesia of hip replacement surgery Hyperbaric Bupivacaine HCl 0.5%: NIMP, spinal anaesthetic before the surgical procedure	120 mg Paracetamol 3% (4mL) n=15 Participants 120 mg Paracetamol 3%. Solution for injection, single administration by Intrathecal route. Paracetamol 3%: Investigate the efficacy and safety of a single intrathecal injection of paracetamol,for post-operative analgesia of hip replacement surgery Hyperbaric Bupivacaine HCl 0.5%: NIMP, spinal anaesthetic before the surgical procedure	Phase II Only: Saline Solution 0.9% n=15 Participants 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. Placebo injection containing Saline solution 0.9%: Injection containing sterile solution of Saline Solution 0.9 %. 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. Hyperbaric Bupivacaine HCl 0.5%: NIMP, spinal anaesthetic before the surgical procedure
Phase 2: Vital Signs systolic Blood Pressure at screening	137 mmHg Standard Deviation 20.4	144.6 mmHg Standard Deviation 20.5	148.5 mmHg Standard Deviation 14.7	147.7 mmHg Standard Deviation 15.7
Phase 2: Vital Signs systolic Blood Pressure at baseline	145.5 mmHg Standard Deviation 13.6	146.3 mmHg Standard Deviation 19.2	138.7 mmHg Standard Deviation 10.5	144.8 mmHg Standard Deviation 12.3
Phase 2: Vital Signs systolic Blood Pressure at end of the study (day6)	130 mmHg Standard Deviation 14.6	130.3 mmHg Standard Deviation 11.3	133.5 mmHg Standard Deviation 10.2	138.1 mmHg Standard Deviation 14.5
Phase 2: Vital Signs Diastolic Blood Pressure at screening	87.1 mmHg Standard Deviation 11.3	85.7 mmHg Standard Deviation 7	90.9 mmHg Standard Deviation 8.2	87 mmHg Standard Deviation 5.1
Phase 2: Vital Signs Diastolic Blood Pressure at baseline	83 mmHg Standard Deviation 8.8	78.9 mmHg Standard Deviation 10.3	77.8 mmHg Standard Deviation 10	85.9 mmHg Standard Deviation 5.8
Phase 2: Vital Signs Diastolic Blood Pressure at end of the study (day6)	79.5 mmHg Standard Deviation 10.8	78.2 mmHg Standard Deviation 7.5	79 mmHg Standard Deviation 6.8	83.1 mmHg Standard Deviation 9.3

SECONDARY outcome

Timeframe: at screening, at baseline until the end of the study (Day 6)

record the concomitant medications intaked during the study

Outcome measures

Outcome measures
Measure	60 mg Paracetamol 3% (2 mL) n=15 Participants 60 mg Paracetamol 3%. Solution for injection, single administration by Intrathecal route. Paracetamol 3%: Investigate the efficacy and safety of a single intrathecal injection of paracetamol,for post-operative analgesia of hip replacement surgery Hyperbaric Bupivacaine HCl 0.5%: NIMP, spinal anaesthetic before the surgical procedure	90 mg Paracetamol 3% (3 mL) n=15 Participants 90 mg Paracetamol 3%. Solution for injection, single administration by Intrathecal route. Paracetamol 3%: Investigate the efficacy and safety of a single intrathecal injection of paracetamol,for post-operative analgesia of hip replacement surgery Hyperbaric Bupivacaine HCl 0.5%: NIMP, spinal anaesthetic before the surgical procedure	120 mg Paracetamol 3% (4mL) n=15 Participants 120 mg Paracetamol 3%. Solution for injection, single administration by Intrathecal route. Paracetamol 3%: Investigate the efficacy and safety of a single intrathecal injection of paracetamol,for post-operative analgesia of hip replacement surgery Hyperbaric Bupivacaine HCl 0.5%: NIMP, spinal anaesthetic before the surgical procedure	Phase II Only: Saline Solution 0.9% n=15 Participants 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. Placebo injection containing Saline solution 0.9%: Injection containing sterile solution of Saline Solution 0.9 %. 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. Hyperbaric Bupivacaine HCl 0.5%: NIMP, spinal anaesthetic before the surgical procedure
Phase2: Concomitant Medications heparin group	15 participants	15 participants	15 participants	15 participants
Phase2: Concomitant Medications Second-generation cephalosporins	15 participants	15 participants	15 participants	15 participants
Phase2: Concomitant Medications Solutions affecting the electrolyte balance	15 participants	15 participants	15 participants	15 participants
Phase2: Concomitant Medications Direct factor Xa inhibi	15 participants	15 participants	14 participants	15 participants
Phase2: Concomitant Medications Amino acids	14 participants	13 participants	12 participants	15 participants
Phase2: Concomitant Medications propofol	11 participants	13 participants	13 participants	14 participants
Phase2: Concomitant Medications Adrenergic and dopaminergic agents	10 participants	11 participants	12 participants	12 participants
Phase2: Concomitant Medications Propionic acid derivatives	7 participants	8 participants	10 participants	6 participants
Phase2: Concomitant Medications Pyrazolones	4 participants	7 participants	11 participants	9 participants
Phase2: Concomitant Medications Acetic acid derivatives and related substances	6 participants	7 participants	8 participants	8 participants
Phase2: Concomitant Medications Osmotically acting laxatives	1 participants	3 participants	6 participants	3 participants
Phase2: Concomitant Medications Proton pump inhibitors	2 participants	4 participants	4 participants	3 participants
Phase2: Concomitant Medications Serotonin (5HT3) antagonists	1 participants	6 participants	2 participants	4 participants
Phase2: Concomitant Medications Benzodiazepine derivatives	2 participants	0 participants	4 participants	2 participants
Phase2: Concomitant Medications ANTIEMETICS AND ANTINAUSEANTS	1 participants	2 participants	1 participants	3 participants
Phase2: Concomitant Medications Other opioids	1 participants	1 participants	1 participants	2 participants
Phase2: Concomitant Medications Platelet aggregation inhibitors excl. heparin	1 participants	1 participants	0 participants	1 participants
Phase2: Concomitant Medications Angiotensin II antagonists,	1 participants	1 participants	0 participants	0 participants
Phase2: Concomitant Medications Natural opium alkaloids	0 participants	0 participants	1 participants	1 participants

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	60 mg Paracetamol 3% (2 mL) n=15 Participants 60 mg Paracetamol 3%. Solution for injection, single administration by Intrathecal route. Paracetamol 3%: Investigate the efficacy and safety of a single intrathecal injection of paracetamol,for post-operative analgesia of hip replacement surgery Hyperbaric Bupivacaine HCl 0.5%: NIMP, spinal anaesthetic before the surgical procedure	90 mg Paracetamol 3% (3 mL) n=15 Participants 90 mg Paracetamol 3%. Solution for injection, single administration by Intrathecal route. Paracetamol 3%: Investigate the efficacy and safety of a single intrathecal injection of paracetamol,for post-operative analgesia of hip replacement surgery Hyperbaric Bupivacaine HCl 0.5%: NIMP, spinal anaesthetic before the surgical procedure	120 mg Paracetamol 3% (4mL) n=15 Participants 120 mg Paracetamol 3%. Solution for injection, single administration by Intrathecal route. Paracetamol 3%: Investigate the efficacy and safety of a single intrathecal injection of paracetamol,for post-operative analgesia of hip replacement surgery Hyperbaric Bupivacaine HCl 0.5%: NIMP, spinal anaesthetic before the surgical procedure	Phase II Only: Saline Solution 0.9% n=15 Participants 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. Placebo injection containing Saline solution 0.9%: Injection containing sterile solution of Saline Solution 0.9 %. 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. Hyperbaric Bupivacaine HCl 0.5%: NIMP, spinal anaesthetic before the surgical procedure
Phase 2: SpO2 screening	97.93 Oxygen Saturation percentage Standard Deviation 0.59	98 Oxygen Saturation percentage Standard Deviation 0.53	98.27 Oxygen Saturation percentage Standard Deviation 0.70	97.80 Oxygen Saturation percentage Standard Deviation 0.77
Phase 2: SpO2 baseline	97.27 Oxygen Saturation percentage Standard Deviation 1.03	97.07 Oxygen Saturation percentage Standard Deviation 1.03	97.33 Oxygen Saturation percentage Standard Deviation 1.18	96.87 Oxygen Saturation percentage Standard Deviation 1.36
Phase 2: SpO2 end of the study (day 6)	97.73 Oxygen Saturation percentage Standard Deviation 1.03	97.53 Oxygen Saturation percentage Standard Deviation 0.83	97.8 Oxygen Saturation percentage Standard Deviation 0.77	97.6 Oxygen Saturation percentage Standard Deviation 0.74

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	60 mg Paracetamol 3% (2 mL) n=15 Participants 60 mg Paracetamol 3%. Solution for injection, single administration by Intrathecal route. Paracetamol 3%: Investigate the efficacy and safety of a single intrathecal injection of paracetamol,for post-operative analgesia of hip replacement surgery Hyperbaric Bupivacaine HCl 0.5%: NIMP, spinal anaesthetic before the surgical procedure	90 mg Paracetamol 3% (3 mL) n=15 Participants 90 mg Paracetamol 3%. Solution for injection, single administration by Intrathecal route. Paracetamol 3%: Investigate the efficacy and safety of a single intrathecal injection of paracetamol,for post-operative analgesia of hip replacement surgery Hyperbaric Bupivacaine HCl 0.5%: NIMP, spinal anaesthetic before the surgical procedure	120 mg Paracetamol 3% (4mL) n=15 Participants 120 mg Paracetamol 3%. Solution for injection, single administration by Intrathecal route. Paracetamol 3%: Investigate the efficacy and safety of a single intrathecal injection of paracetamol,for post-operative analgesia of hip replacement surgery Hyperbaric Bupivacaine HCl 0.5%: NIMP, spinal anaesthetic before the surgical procedure	Phase II Only: Saline Solution 0.9% n=15 Participants 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. Placebo injection containing Saline solution 0.9%: Injection containing sterile solution of Saline Solution 0.9 %. 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. Hyperbaric Bupivacaine HCl 0.5%: NIMP, spinal anaesthetic before the surgical procedure
Phase 2: ECG screening · normal	10 Participants	9 Participants	11 Participants	11 Participants
Phase 2: ECG screening · Abnormal, Not Clinically Significant	5 Participants	6 Participants	4 Participants	4 Participants
Phase 2: ECG screening · Abnormal, Clinically Significant	0 Participants	0 Participants	0 Participants	0 Participants
Phase 2: ECG baseline · normal	13 Participants	11 Participants	11 Participants	12 Participants
Phase 2: ECG baseline · Abnormal, Not Clinically Significant	2 Participants	4 Participants	4 Participants	3 Participants
Phase 2: ECG baseline · Abnormal, Clinically Significant	0 Participants	0 Participants	0 Participants	0 Participants
Phase 2: ECG end of study · normal	12 Participants	13 Participants	11 Participants	12 Participants
Phase 2: ECG end of study · Abnormal, Not Clinically Significant	3 Participants	2 Participants	4 Participants	3 Participants
Phase 2: ECG end of study · Abnormal, Clinically Significant	0 Participants	0 Participants	0 Participants	0 Participants

Adverse Events

60 mg Paracetamol 3% (2 mL)

Serious events: 0 serious events

Other events: 8 other events

Deaths: 0 deaths

90 mg Paracetamol 3% (3 mL)

Serious events: 0 serious events

Other events: 10 other events

Deaths: 0 deaths

120 mg Paracetamol 3% (4mL)

Serious events: 0 serious events

Other events: 13 other events

Deaths: 0 deaths

Phase II Only: Saline Solution 0.9%

Serious events: 0 serious events

Other events: 11 other events

Deaths: 0 deaths

Serious adverse events

Adverse event data not reported

Other adverse events

Additional Information

Dr.Elisabetta Donati, Corporate Director Scientific Affairs

Sintetica SA

Phone: +41.91.640.42.50

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Measure	60 mg Paracetamol 3% (2 mL) n=18 participants at risk 60 mg Paracetamol 3%. Solution for injection, single administration by Intrathecal route. Paracetamol 3%: Investigate the efficacy and safety of a single intrathecal injection of paracetamol,for post-operative analgesia of hip replacement surgery Hyperbaric Bupivacaine HCl 0.5%: NIMP, spinal anaesthetic before the surgical procedure	90 mg Paracetamol 3% (3 mL) n=18 participants at risk 90 mg Paracetamol 3%. Solution for injection, single administration by Intrathecal route. Paracetamol 3%: Investigate the efficacy and safety of a single intrathecal injection of paracetamol,for post-operative analgesia of hip replacement surgery Hyperbaric Bupivacaine HCl 0.5%: NIMP, spinal anaesthetic before the surgical procedure	120 mg Paracetamol 3% (4mL) n=18 participants at risk 120 mg Paracetamol 3%. Solution for injection, single administration by Intrathecal route. Paracetamol 3%: Investigate the efficacy and safety of a single intrathecal injection of paracetamol,for post-operative analgesia of hip replacement surgery Hyperbaric Bupivacaine HCl 0.5%: NIMP, spinal anaesthetic before the surgical procedure	Phase II Only: Saline Solution 0.9% n=15 participants at risk 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. Placebo injection containing Saline solution 0.9%: Injection containing sterile solution of Saline Solution 0.9 %. 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. Hyperbaric Bupivacaine HCl 0.5%: NIMP, spinal anaesthetic before the surgical procedure
Injury, poisoning and procedural complications procedural nausea	5.6% 1/18 • Number of events 1 • Clinical study duration (7 days)	38.9% 7/18 • Number of events 7 • Clinical study duration (7 days)	16.7% 3/18 • Number of events 3 • Clinical study duration (7 days)	33.3% 5/15 • Number of events 5 • Clinical study duration (7 days)
Injury, poisoning and procedural complications postprocedural constipation	0.00% 0/18 • Clinical study duration (7 days)	16.7% 3/18 • Number of events 3 • Clinical study duration (7 days)	33.3% 6/18 • Number of events 6 • Clinical study duration (7 days)	26.7% 4/15 • Number of events 4 • Clinical study duration (7 days)
Injury, poisoning and procedural complications urinary retention postoperative	5.6% 1/18 • Number of events 1 • Clinical study duration (7 days)	0.00% 0/18 • Clinical study duration (7 days)	22.2% 4/18 • Number of events 4 • Clinical study duration (7 days)	6.7% 1/15 • Number of events 1 • Clinical study duration (7 days)
Injury, poisoning and procedural complications procedural vomiting	0.00% 0/18 • Clinical study duration (7 days)	11.1% 2/18 • Number of events 2 • Clinical study duration (7 days)	5.6% 1/18 • Number of events 1 • Clinical study duration (7 days)	6.7% 1/15 • Number of events 1 • Clinical study duration (7 days)
Injury, poisoning and procedural complications joint dislocation	0.00% 0/18 • Clinical study duration (7 days)	5.6% 1/18 • Number of events 1 • Clinical study duration (7 days)	0.00% 0/18 • Clinical study duration (7 days)	0.00% 0/15 • Clinical study duration (7 days)
Vascular disorders hypotension	33.3% 6/18 • Number of events 6 • Clinical study duration (7 days)	16.7% 3/18 • Number of events 3 • Clinical study duration (7 days)	44.4% 8/18 • Number of events 8 • Clinical study duration (7 days)	33.3% 5/15 • Number of events 5 • Clinical study duration (7 days)
Cardiac disorders bradycardia	0.00% 0/18 • Clinical study duration (7 days)	5.6% 1/18 • Number of events 1 • Clinical study duration (7 days)	5.6% 1/18 • Number of events 1 • Clinical study duration (7 days)	6.7% 1/15 • Number of events 1 • Clinical study duration (7 days)
Cardiac disorders atrial fibrillation	0.00% 0/18 • Clinical study duration (7 days)	0.00% 0/18 • Clinical study duration (7 days)	0.00% 0/18 • Clinical study duration (7 days)	6.7% 1/15 • Number of events 1 • Clinical study duration (7 days)
Gastrointestinal disorders dyspespsia	5.6% 1/18 • Number of events 1 • Clinical study duration (7 days)	0.00% 0/18 • Clinical study duration (7 days)	5.6% 1/18 • Number of events 1 • Clinical study duration (7 days)	0.00% 0/15 • Clinical study duration (7 days)
Gastrointestinal disorders epigastric disconfrort	0.00% 0/18 • Clinical study duration (7 days)	5.6% 1/18 • Number of events 1 • Clinical study duration (7 days)	0.00% 0/18 • Clinical study duration (7 days)	0.00% 0/15 • Clinical study duration (7 days)
Nervous system disorders headache	5.6% 1/18 • Number of events 1 • Clinical study duration (7 days)	5.6% 1/18 • Number of events 1 • Clinical study duration (7 days)	16.7% 3/18 • Number of events 3 • Clinical study duration (7 days)	0.00% 0/15 • Clinical study duration (7 days)
Musculoskeletal and connective tissue disorders back pain	0.00% 0/18 • Clinical study duration (7 days)	5.6% 1/18 • Number of events 1 • Clinical study duration (7 days)	0.00% 0/18 • Clinical study duration (7 days)	0.00% 0/15 • Clinical study duration (7 days)
Psychiatric disorders insomnia	0.00% 0/18 • Clinical study duration (7 days)	0.00% 0/18 • Clinical study duration (7 days)	5.6% 1/18 • Number of events 1 • Clinical study duration (7 days)	0.00% 0/15 • Clinical study duration (7 days)
Skin and subcutaneous tissue disorders prupritus	5.6% 1/18 • Number of events 1 • Clinical study duration (7 days)	0.00% 0/18 • Clinical study duration (7 days)	0.00% 0/18 • Clinical study duration (7 days)	0.00% 0/15 • Clinical study duration (7 days)
Surgical and medical procedures antiementic supportive care	0.00% 0/18 • Clinical study duration (7 days)	0.00% 0/18 • Clinical study duration (7 days)	0.00% 0/18 • Clinical study duration (7 days)	6.7% 1/15 • Number of events 1 • Clinical study duration (7 days)
Investigations Haemoglobin decreased	0.00% 0/18 • Clinical study duration (7 days)	0.00% 0/18 • Clinical study duration (7 days)	5.6% 1/18 • Number of events 1 • Clinical study duration (7 days)	0.00% 0/15 • Clinical study duration (7 days)
Investigations Red blood cell count decreased	0.00% 0/18 • Clinical study duration (7 days)	0.00% 0/18 • Clinical study duration (7 days)	5.6% 1/18 • Number of events 1 • Clinical study duration (7 days)	0.00% 0/15 • Clinical study duration (7 days)