Clinical trial NCT02654860: Dose-finding Study of Intrathecal Paracetamol Administered Immediately Before Spinal Anaesthesia
Official title: Two-part Study of Intrathecal Paracetamol Administered Immediately Before Spinal Anaesthesia in Patients Scheduled for Hip Replacement Surgery
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Phase 1: Pain Management
Phase 2: Pain Management
Lead sponsor: Sintetica SA
Sponsor class: INDUSTRY
Collaborators: name: Cross S.A.
First posted: 2016-01-13
Enrollment: 69
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: 4 arms for Phase II only
Primary purpose: SUPPORTIVE_CARE

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.

Eligibility criteria: 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

Primary outcomes:
measure: Phase 1: Number of Participants With Adverse Events Related, Not Related and Serious Events Related to Paracetamol
timeFrame: In the first 24 hours, in the first 48 hours and at day 7±1
measure: Phase 2: Pain Intensity
timeFrame: baseline (0 h), 1, 6, 9, 12, 15, 24, and 48 h after anaesthetic IT injection and at discharge
Secondary outcomes:
measure: Phase 2: Morphine
timeFrame: At 24 and 48 h after anaesthetic IT injection and entire study period, up to 7 days
measure: Phase 2: Time to First Morphine Use
timeFrame: Postoperative, up to 48 hours after end of surgery
measure: Phase 2: Number of Participants With Need for Supplemental Analgesia
timeFrame: Postoperative, up to 48 hours after end of surgery
measure: Phase 2: Morphine-related Adverse Events
timeFrame: up to 24 hours after surgery, up to 48 hours
measure: Phase 2: Time to Readiness for Surgery
timeFrame: Intraoperative
measure: Phase 2:Maximum Level of Sensory Block
timeFrame: Intraoperative
measure: Phase 2: Time to Sensory Block
timeFrame: Intraoperative
measure: Phase 2: Time to Regression of Spinal Block
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
measure: Phase 2: Vital Signs
timeFrame: at screening, at baseline (before the spinal injection) and at end of the study (Day 6).
measure: Phase2: Concomitant Medications
timeFrame: at screening, at baseline until the end of the study (Day 6)
measure: Phase 2: SpO2
timeFrame: at screening, at baseline (before the spinal injection) and at the end of the study (day 6)
measure: Phase 2: ECG
timeFrame: screening, baseline and end of study (Day 6±1)
Other outcomes:
Locations:
city: Gravesano
country: Switzerland
facility: Claudio Camponovo
state: Lugano
Study officials:
affiliation: Department of Anaesthesiology,Clinica Ars Medica,Via Cantonale, CH-6929 Gravesano, Switzerland
name: Claudio Camponovo, MD
role: PRINCIPAL_INVESTIGATOR
References: