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

Overview

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%.

Full Title of Study: “Dose-finding Study of Intrathecal Paracetamol Administered Immediately Before Spinal Anaesthesia With Chloroprocaine HCl 1% for Elective Knee Procedures of Short Duration”

Study Type

  • Study Type: Interventional
  • Study Design
    • Allocation: Randomized
    • Intervention Model: Parallel Assignment
    • Primary Purpose: Supportive Care
    • Masking: Triple (Participant, Investigator, Outcomes Assessor)
  • Study Primary Completion Date: October 22, 2019

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).

Interventions

  • Drug: 30 mg Paracetamol 3% (1 mL)
    • Single administration by intrathecal injection just before spinal anaesthesia. The injection will be performed according to the hospital procedures. For the intrathecal injection of Paracetamol followed by the intrathecal injection of the anaesthetic, two needles will be used: one introducer needle, which will serve to introduce the second needle through the skin, plus one intrathecal Pencil point needle (27-G or 25-Gauge or Reganesth or Nizell needle) to which the first syringe containing Paracetamol will be attached first, followed by the second syringe with the anaesthetic. In this way only one intrathecal puncture will be performed. Lumbar puncture will be done according to the standard hospital procedures.
  • Drug: 60 mg Paracetamol 3% (2 mL)
    • Single administration by intrathecal injection just before spinal anaesthesia. The injections will be performed according to the hospital procedures. For the intrathecal injection of Paracetamol followed by the intrathecal injection of the anaesthetic, two needles will be used: one introducer needle, which will serve to introduce the second needle through the skin, plus one intrathecal Pencil point needle (27-G or 25-Gauge or Reganesth or Nizell needle) to which the first syringe containing Paracetamol will be attached first, followed by the second syringe with the anaesthetic. In this way only one intrathecal puncture will be performed. Lumbar puncture will be done according to the standard hospital procedures.
  • Drug: 90 mg Paracetamol 3% (3 mL)
    • Single administration by intrathecal injection just before spinal anaesthesia. The injections will be performed according to the hospital procedures. For the intrathecal injection of Paracetamol followed by the intrathecal injection of the anaesthetic, two needles will be used: one introducer needle, which will serve to introduce the second needle through the skin, plus one intrathecal Pencil point needle (27-G or 25-Gauge or Reganesth or Nizell needle) to which the first syringe containing Paracetamol will be attached first, followed by the second syringe with the anaesthetic. In this way only one intrathecal puncture will be performed. Lumbar puncture will be done according to the standard hospital procedures.
  • Drug: Placebo, 0.9% saline solution
    • Single administration by intrathecal injection just before spinal anaesthesia. The injections will be performed according to the hospital procedures. For the intrathecal injection of Placebo followed by the intrathecal injection of the anaesthetic, two needles will be used: one introducer needle, which will serve to introduce the second needle through the skin, plus one intrathecal Pencil point needle (27-G or 25-Gauge or Reganesth or Nizell needle) to which the first syringe containing Placebo will be attached first, followed by the second syringe with the anaesthetic. In this way only one intrathecal puncture will be performed. Lumbar puncture will be done according to the standard hospital procedures.
  • Drug: NIMP: Chloroprocaine HCl 1% (10 mg/mL), solution for injection
    • Immediately after intrathecal administration of the Paracetamol dose or Placebo, all patients will receive a single intrathecal dose of Chloroprocaine HCl 1% according to the Summary of Product Characteristics indications. Time interval between the 2 administrations should not exceed 2 min.

Arms, Groups and Cohorts

  • Experimental: D1
    • 30 mg Paracetamol 3% (1 mL), solution for injection, single dose by intrathecal injection (IT)
  • Experimental: D2
    • 60 mg Paracetamol 3% (2 mL), solution for injection, single dose by intrathecal injection (IT)
  • Experimental: D3
    • 90 mg Paracetamol 3% (3 mL), solution for injection, single dose by intrathecal injection (IT)
  • Placebo Comparator: P
    • Placebo, 0.9% saline solution (1 mL, 2 mL or 3 mL), solution for injection, single dose by intrathecal injection (IT)

Clinical Trial Outcome Measures

Primary Measures

  • Pain intensity at rest evaluated using a 0-100 mm VAS
    • Time Frame: Up to 24 hours after injection
    • 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

Secondary Measures

  • Pain at rest AUCt1-t2
    • Time Frame: Up to 4 hours after injection
    • AUCt1-t2 is defined as the area under the pain intensity curve at the specified time-intervals
  • Pain at rest AUClast
    • Time Frame: 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)
    • Time Frame: 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.
  • Time to level 1 analgesia
    • Time Frame: Up to 24 hours after surgery
    • Time to Ketorolac i.v. [Toradol] 30 mg administration (level 1 analgesia)
  • Time to level 2 analgesia
    • Time Frame: Up to 24 hours after surgery
    • Time to Tramadol i.v. 1 mg/kg administration (level 2 analgesia)
  • Total amount of analgesic 1 consumption
    • Time Frame: Up to 24 hours after surgery
    • Amount of Ketorolac i.v. [Toradol] 30 mg administered
  • Total amount of analgesic 2 consumption
    • Time Frame: Up to 24 hours after surgery
    • Amount of Tramadol i.v. 1 mg/kg administered
  • Proportion of patients requiring analgesia (level 1 or level 2) in the first 2 h after surgery end
    • Time Frame: Up to 2 hours after surgery end
  • Proportion of patients requiring analgesia (level 1 or level 2) in the first 4 h after surgery end
    • Time Frame: Up to 4 hours after surgery end
  • Proportion of patients requiring analgesia (level 1 or level 2) from surgery end until eligibility for home discharge
    • Time Frame: Up to 24 hours after surgery
  • Proportion of patients requiring level 1 analgesia from surgery end until eligibility for home discharge
    • Time Frame: Up to 24 hours after surgery
  • Proportion of patients requiring level 2 analgesia from surgery end until eligibility for home discharge
    • Time Frame: Up to 24 hours after surgery
  • Time to first supplementary analgesia, other than the planned level 1 or 2 analgesia
    • Time Frame: Up to 24 hours after surgery
  • Proportion of patients requiring supplementary analgesia, other than the planned level 1 or 2 analgesia
    • Time Frame: Up to 24 hours after surgery
  • Time to rescue anaesthesia
    • Time Frame: Up to 1 hour after injection
  • Proportion of patients requiring rescue anaesthesia
    • Time Frame: Up to 1 hour after injection
  • Time to onset of spinal block (i.e. time to readiness for surgery)
    • Time Frame: 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 level of sensory block
    • Time Frame: Intraoperative
  • Time to maximum level of sensory block
    • Time Frame: Intraoperative
  • Time to regression of spinal block
    • Time Frame: Up to 4 hours after injection
    • Time period from spinal injection to the complete regression of sensory block to S1.
  • Time to unassisted ambulation
    • Time Frame: Up to 24 hours after injection
  • Time to first spontaneous urine voiding
    • Time Frame: Up to 24 hours after injection
  • Time to eligibility for home discharge
    • Time Frame: Up to 24 hours after injection

Participating in This Clinical Trial

Inclusion Criteria

1. Informed consent: signed written informed consent before inclusion in the study

2. Sex, age and surgery: male/female patients, 18-80 years old (inclusive), scheduled for short duration (up to 40 min) knee procedures

3. Body Mass Index (BMI): 18 – 32 kg/m2 inclusive

4. ASA physical status: I-III

5. 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

1. 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

2. ASA physical status: IV-V

3. Further anaesthesia: patients expected to require further anaesthesia

4. 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

5. Chronic pain syndromes: patients with chronic pain syndromes taking opioids, anticonvulsant agents or chronic analgesic therapy

6. Pain assessment: patients anticipated to be unable to make a reliable self-report of pain intensity

7. 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

8. 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

9. 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

10. Drug, alcohol: history of drug or alcohol abuse according to the Investigator's opinion

11. 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)]

Gender Eligibility: All

Minimum Age: 18 Years

Maximum Age: 80 Years

Are Healthy Volunteers Accepted: No

Investigator Details

  • Lead Sponsor
    • Sintetica SA
  • Collaborator
    • Cross Research S.A.
  • Provider of Information About this Clinical Study
    • Sponsor
  • Overall Official(s)
    • Claudio Camponovo, MD, Principal Investigator, Department of Anaesthesiology, Clinica Ars Medica, Via Cantonale, CH-6929 Gravesano, Switzerland

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