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

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.

Inclusion criteria

Phase 1 and Phase 2:

• Informed consent: signed written informed consent before inclusion in the study
• Sex, age and surgery: male/female 18-80 years (inclusive) old patients, scheduled for hip replacement surgery, with anticipated need for post-operative narcotic analgesia, adequate i.v. access and anticipated hospital stay > 48 hours.
• Body Mass Index (BMI): 18 - 34 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
• Inclusion criteria - Phase 1 only : Age: 18-70 (inclusive) old patients
• Inclusion criteria - Phase 2 only : Age: 18-80 (inclusive) old patients Hospital stay: Patients with anticipated hospital stay > 48 hours

Exclusion criteria

Phase 1 and Phase 2:

• 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
• Pain assessment: anticipated to be unable to make a reliable self-report of pain intensity
• Allergy: ascertained or presumptive hypersensitivity to the active principles (paracetamol and/or amide type anaesthetics) and/or formulations' ingredients or related drugs, opioids, non-steroidal anti-inflammatory drugs; history of anaphylaxis to drugs or allergic reactions in general, which the investigator considers could affect the outcome of the study
• 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 asthma or 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.
• Liver function: Impaired liver function (transaminases > twice upper limit)
• Renal function: Renal dysfunction (creatinine > 2.0 mg/dL)
• Investigative drug studies: participation in the evaluation of any investigational product for 3 months before this study, calculated from the first day of the month following the last visit of the previous study
• Drug, alcohol: history of drug or alcohol abuse. Pre-existing dependence on narcotics or known tolerance to opioids
• 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)]
• Chronic pain syndromes: patients with chronic pain syndromes (taking opioids, anticonvulsant agents or chronic analgesic therapy).
• 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 1 week before the start of the study and during the study. Hormonal contraceptives for females are allowed.
• Phase 2 only - Exclusion criteria Pain assessment: anticipated to be unable to make a reliable self-report of pain intensity