Intrathecal Paracetamol Before Spinal Anaesthesia With Chloroprocaine HCl 1% for Short Knee Procedures

Phase 2

Completed

Conditions: Pain, Postoperative

Interventions: Drug: 30 mg Paracetamol 3% (1 mL)
Drug: 60 mg Paracetamol 3% (2 mL)
Drug: 90 mg Paracetamol 3% (3 mL)
Drug: Placebo, 0.9% saline solution

Registration Number: NCT03428230

Lead Sponsor: Sintetica SA

Brief Summary: This is a phase II, single centre, randomised, parallel-group, double-blind, three doses, placebo-controlled, exploratory efficacy and safety study. The objective of this study is to investigate the efficacy and safety of a single intrathecal injection of Paracetamol 3% (30 mg/mL) administered at 3 doses to 3 active treatment groups, as compared to placebo, for post-operative analgesia in knee procedures up to 40 min duration performed under spinal anaesthesia with Chloroprocaine HCl 1%.

Detailed Description: Eligible patients undergoing elective short-duration knee procedures up to 40 min duration will be randomised into 4 treatment groups (15 patients per group) to receive either one of the 3 single doses of Paracetamol 3% (D1: 30 mg, D2: 60 mg, D3: 90 mg) or the placebo solution (P: 0.9% saline solution) by intrathecal injection (IT), according to the randomised, parallel-group design.

Immediately after IT paracetamol or placebo administration, all patients will receive a single IT dose of Chloroprocaine HCl 1% (Non-investigational medicinal product, NIMP) according to the Summary of Product Characteristics indications. The time interval between paracetamol IT and chloroprocaine IT injections should not exceed 2 min.

The study will include a screening phase (Visit 1, Day -21/-1), a treatment phase (IMP IT administration, anaesthesia and surgical procedure: Visit 2, Day 1) and a follow-up phase including an observation period (Visit 3), a final visit and two follow-ups (24 h post-dose and day 7±1).

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 60

Inclusion Criteria

Informed consent: signed written informed consent before inclusion in the study
Sex, age and surgery: male/female patients, 18-80 years old (inclusive), scheduled for short duration (up to 40 min) knee procedures
Body Mass Index (BMI): 18 - 32 kg/m2 inclusive
ASA physical status: I-III
Full comprehension: ability to comprehend the full nature and purpose of the study, including possible risks and side effects; ability to co-operate with the investigator and to comply with the requirements of the entire study.

Exclusion Criteria

Physical findings: clinically significant abnormal physical findings which could interfere with the objectives of the study. Contraindications to spinal anaesthesia. History of neuromuscular diseases to the lower extremities
ASA physical status: IV-V
Further anaesthesia: patients expected to require further anaesthesia
Allergy: ascertained or presumptive hypersensitivity to the active principles (paracetamol and/or ester type anaesthetics) and/or formulations' ingredients or related drugs, non-steroidal anti-inflammatory drugs and/or opioid derivatives; history of anaphylaxis to drugs or allergic reactions in general, which the investigator considers could affect the outcome of the study
Chronic pain syndromes: patients with chronic pain syndromes taking opioids, anticonvulsant agents or chronic analgesic therapy
Pain assessment: patients anticipated to be unable to make a reliable self-report of pain intensity
Diseases: significant history of renal, hepatic, gastrointestinal, cardiovascular, respiratory, skin, haematological, endocrine or neurological diseases that may interfere with the aim of the study; ascertained psychiatric and neurological diseases, sepsis, blood coagulation disorders, severe cardiopulmonary disease, thyroid disease, diabetes, other neuropathies, history or evidence of heart failure. History of severe head trauma that required hospitalisation, intracranial surgery or stroke within the previous 30 days, or any history of intracerebral arteriovenous malformation, cerebral aneurism or CNS mass lesion
Medications: medication known to interfere with the extent of spinal blocks for 2 weeks before the start of the study. Paracetamol formulations, other than the investigational product, for 2 weeks before the start of the study and during the study. Hormonal contraceptives for females are allowed. Anti-hypotensive, anti-bradycardia (e.g. ephedrine, atropine, Ringer's solution), anti-haemetic and anti-nausea medications will be allowed
Investigative drug studies: participation in the evaluation of any investigational product for 3 months before this study. The 3-month interval is calculated as the time between the first calendar day of the month that follows the last visit of the previous study and the first day of the present study
Drug, alcohol: history of drug or alcohol abuse according to the Investigator's opinion
Pregnancy and lactation: positive pregnancy test at screening (if applicable), pregnant or lactating women [The pregnancy test will be performed to all fertile women and to all women up to 55 years old, if not in proven menopause (available laboratory test confirming menopause or surgically sterilised)]

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
30 mg Paracetamol 3% (1 mL)	30 mg Paracetamol 3% (1 mL)	30 mg Paracetamol 3% (1 mL), solution for injection, single dose by intrathecal injection (IT)
60 mg Paracetamol 3% (2 mL)	60 mg Paracetamol 3% (2 mL)	60 mg Paracetamol 3% (2 mL), solution for injection, single dose by intrathecal injection (IT)
90 mg Paracetamol 3% (3 mL)	90 mg Paracetamol 3% (3 mL)	90 mg Paracetamol 3% (3 mL), solution for injection, single dose by intrathecal injection (IT)
Placebo, 0.9% saline solution	Placebo, 0.9% saline solution	Placebo, 0.9% saline solution (1 mL, 2 mL or 3 mL), solution for injection, single dose by intrathecal injection (IT)

Primary Outcome Measures

Name	Time	Method
Pain Intensity at Rest Evaluated Using a 0-100 mm VAS	Pain intensity at rest evaluated using a 0-100 mm VAS at baseline (within 30 min before NIMP IT injection, 0 h), 1, 1.25, 1.5, 1.75, 2 h after NIMP IT injection, then every 30 min after NIMP IT injection until eligibility for home discharge.	The study primary efficacy measures will be the VAS scores at each predefined time-point after the anaesthetic intrathecal injection until eligibility for home discharge ( VAS scale is 0-100 mm, where 0 is no pain and 100 is maximum pain)

Secondary Outcome Measures

Name	Time	Method
Pain at Rest AUCt1-t2	Up to 4 hours after injection	AUC t1-t2 is defined as the area under the pain intensity curve at the specified time-intervals
Pain at Rest AUClast	Up to 24 hours after injection	AUClast is defined as the area under the pain intensity curve from 0 h up to the last assessment time
Time to First Postoperative Analgesia (Level 1 or 2)	Up to 24 hours after surgery	Postoperatively, patients will be administered an analgesic as needed. Post-operative analgesia could include Ketorolac i.v. \[Toradol\] 30 mg (level 1 analgesia) and/or Tramadol i.v. 1 mg/kg (level 2 analgesia). The administered analgesic (level 1 or 2), analgesic dose and intake frequency will be decided according to the reported surgery-related pain intensity. Post-operatively, patients were administered an analgesic, as needed. Post-operative analgesia could include Ketorolac i.v. \[Toradol\] 30 mg (level 1 analgesia) and/or Tramadol i.v. 1 mg/kg (level 2 analgesia).
Partecipants to Received Level 1 Analgesia	from surgery day to 24 hours after surgery	Partecipants to received Ketorolac i.v. \[Toradol\] 30 mg administration (level 1 analgesia)
Partecipants Received Level 2 Analgesia	from surgery day to 24 hours after surgery	Partecipants received Tramadol i.v. 1 mg/kg administration (level 2 analgesia)
Total Number of Partecipants Receiving Analgesic 1	From surgery day to 24 hours after surgery	Total number of partecipants receiving Ketorolac i.v. \[Toradol\] 30 mg
Total Number of Partecipants Receiving Analgesic 2	from surgery day to 24 hours after surgery	Total Number of Partecipants Receiving Tramadol i.v. 1 mg/kg
Percentage of Patients Requiring Analgesia in the First 2 h After Surgery End	Form surgery day to 2 hours after surgery end	Percentage of patients requiring analgesia (level 1 or level 2) in the first 2 h after surgery end
Percentage of Patients Requiring Analgesia in the First 4 h After Surgery End	from surgery day to 4 hours after surgery end	Percentage of patients requiring analgesia (level 1 or level 2) in the first 4 h after surgery end
Percentage of Patients Requiring Analgesia From Surgery End Until Eligibility for Discharge	from surgery day to 24 hours after surgery	Percentage of patients requiring analgesia (level 1 or level 2) from surgery end until eligibility for home discharge
Percentage of Patients Requiring Supplementary Analgesia, Other Than the Planned Level 1 or 2 Analgesia	from surgery day to 24 hours after surgery	Percentage of patients requiring supplementary analgesia, other than the planned level 1 or 2 analgesia
Time to Sensory Block	Intraoperative	Time to maximum level of sensory block (bilateral Pinprick test using a 20-G hypodermic needle)
Percentage of Patients Requiring Level 1 Analgesia From Surgery End Until Eligibility for Discharge	from surgery day to 24 hours after surgery	Percentage of patients requiring level 1 analgesia from surgery end until eligibility for home discharge
Percentage of Patients Requiring Level 2 Analgesia From Surgery End Until Eligibility for Discharge	from surgery day to 24 hours after surgery	Percentage of Patients Requiring Level 2 Analgesia From Surgery End Until Eligibility for Home Discharge
Percentage of Patients Requiring Rescue Anaesthesia	from surgery day to 1 hour after injection	Percentage of patients requiring rescue anaesthesia
Time to Onset of Spinal Block (i.e. Time to Readiness for Surgery)	Up to 20 minutes after injection	Spinal block/Readiness for surgery is defined as the presence of an adequate motor block (Bromage's score ≥ 2) and loss of Pinprick sensation, according to the Investigator's opinion. Time to readiness for surgery is defined as the time from the spinal injection (time 0 h) to achievement of readiness for surgery.
Maximum Sensory Block	Intraoperative	Maximum level of sensory block
Time to Regression of Spinal Block	Up to 4 hours after injection	Time period from spinal injection to the complete regression of sensory block to S1.
Time to Ambulation	Up to 24 hours after injection	Time to unassisted ambulation
Time to First Urine	Up to 24 hours after injection	Time to first spontaneous urine voiding
Time to Eligibility for Discharge	Up to 24 hours after injection	Time to eligibility for home discharge