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

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ClinicalTrials.gov Identifier: NCT02654860
Recruitment Status : Completed
First Posted : January 13, 2016
Last Update Posted : March 13, 2019
Sponsor:
Collaborator:
Cross S.A.
Information provided by (Responsible Party):
Sintetica SA

Brief Summary:

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.


Condition or disease Intervention/treatment Phase
Phase 1: Pain Management Phase 2: Pain Management Drug: Paracetamol 3% Drug: Placebo injection containing Saline solution 0.9% Drug: Hyperbaric Bupivacaine HCl 0.5% Phase 1 Phase 2

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 69 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: 4 arms for Phase II only
Masking: Double (Participant, Investigator)
Masking Description: Phase II only
Primary Purpose: Supportive Care
Official Title: Two-part Study of Intrathecal Paracetamol Administered Immediately Before Spinal Anaesthesia in Patients Scheduled for Hip Replacement Surgery
Study Start Date : November 2016
Actual Primary Completion Date : February 2019
Actual Study Completion Date : February 2019

Arm Intervention/treatment
Experimental: 60 mg Paracetamol 3% (2 mL)
60 mg Paracetamol 3%. Solution for injection, single administration by Intrathecal route.
Drug: Paracetamol 3%
Investigate the efficacy and safety of a single intrathecal injection of paracetamol,for post-operative analgesia of hip replacement surgery

Drug: Hyperbaric Bupivacaine HCl 0.5%
NIMP, spinal anaesthetic before the surgical procedure

Experimental: 90 mg Paracetamol 3% (3 mL)
90 mg Paracetamol 3%. Solution for injection, single administration by Intrathecal route.
Drug: Paracetamol 3%
Investigate the efficacy and safety of a single intrathecal injection of paracetamol,for post-operative analgesia of hip replacement surgery

Drug: Hyperbaric Bupivacaine HCl 0.5%
NIMP, spinal anaesthetic before the surgical procedure

Experimental: 120 mg Paracetamol 3% (4mL)
120 mg Paracetamol 3%. Solution for injection, single administration by Intrathecal route.
Drug: Paracetamol 3%
Investigate the efficacy and safety of a single intrathecal injection of paracetamol,for post-operative analgesia of hip replacement surgery

Drug: Hyperbaric Bupivacaine HCl 0.5%
NIMP, spinal anaesthetic before the surgical procedure

Placebo Comparator: 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.
Drug: 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.

Drug: Hyperbaric Bupivacaine HCl 0.5%
NIMP, spinal anaesthetic before the surgical procedure




Primary Outcome Measures :
  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 [ Time Frame: In the first 24 hours, in the first 48 hours and at day 7±1 ]
  2. Phase 2: Pain intensity at rest evaluated as VAS scores [ Time Frame: screening,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 ]

Secondary Outcome Measures :
  1. Phase 2: Total morphine use [ Time Frame: In the first 24 hours, in the first 48 hours ]
  2. Phase 2: Time to first morphine use [ Time Frame: Postoperative, up to 48 hours after end of surgery ]
  3. Phase 2: Need for supplementary analgesia, other than the planned morphine PCA [ Time Frame: Postoperative , up to 48 hours after end of surgery ]
  4. Phase 2:Morphine-related adverse events [ Time Frame: up to 24 hours after surgery, up to 48 hours ]
  5. Phase 2: Time to readiness for surgery [ Time Frame: Intraoperative ]
    Time period from completion of spinal injection (time 0 h) to achievement of sensory and motor block adequate for surgery.

  6. Phase 2:Maximum level of sensory block [ Time Frame: 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)

  7. Phase 2: Time to maximum level of sensory block [ Time Frame: Intraoperative ]
  8. Phase 2: Time to regression of spinal block [ Time Frame: 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

  9. Phase 2: Treatment-emergent adverse events, including morphine-related adverse events and transient neurological symptoms (TNS) [ Time Frame: up to 24 hours,up to 48 hours ]
  10. Phase 2: Vital signs [ Time Frame: up to 24 hours,up to 48 hours ]
  11. Phase2: Concomitant medications [ Time Frame: up to 24 hours,up to 48 hours ]
  12. Phase 2: SpO2 [ Time Frame: up to 24 hours,up to 48 hours ]
  13. Phase 2: Routine safety laboratory tests at screening and final visit. Blood cell count [ Time Frame: On day 2 ]
  14. Phase 2: ECG [ Time Frame: up to 24 hours,up to 48 hours ]


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Ages Eligible for Study:   18 Years to 80 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02654860


Locations
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Switzerland
Claudio Camponovo
Gravesano, Lugano, Switzerland, CH-6929
Sponsors and Collaborators
Sintetica SA
Cross S.A.
Investigators
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Principal Investigator: Claudio Camponovo, MD Department of Anaesthesiology,Clinica Ars Medica,Via Cantonale, CH-6929 Gravesano, Switzerland

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Responsible Party: Sintetica SA
ClinicalTrials.gov Identifier: NCT02654860     History of Changes
Other Study ID Numbers: PAR.3/02-2015
First Posted: January 13, 2016    Key Record Dates
Last Update Posted: March 13, 2019
Last Verified: March 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Additional relevant MeSH terms:
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Pharmaceutical Solutions
Bupivacaine
Acetaminophen
Anesthetics, Local
Anesthetics
Central Nervous System Depressants
Physiological Effects of Drugs
Sensory System Agents
Peripheral Nervous System Agents
Analgesics, Non-Narcotic
Analgesics
Antipyretics