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

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

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%.

Study Overview

• Status: Completed
• Conditions: Pain, Postoperative
• Intervention / Treatment: Drug: 30 mg Paracetamol 3% (1 mL); Drug: NIMP: Chloroprocaine HCl 1% (10 mg/mL), solution for injection; Drug: 60 mg Paracetamol 3% (2 mL); Drug: 90 mg Paracetamol 3% (3 mL); Drug: Placebo, 0.9% saline solution

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).

• Study Type: Interventional
• Enrollment (Actual): 60
• Phase: Phase 2

Contacts and Locations

Study Locations

• Switzerland
  • Gravesano, Switzerland, 6929
    • Department of Anaesthesiology, Clinica Ars Medica

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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)]

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Supportive Care
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 30 mg Paracetamol 3% (1 mL); 30 mg Paracetamol 3% (1 mL), solution for injection, single dose by intrathecal injection (IT)	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: 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.; Other Names: Ampres 1%
Experimental: 60 mg Paracetamol 3% (2 mL); 60 mg Paracetamol 3% (2 mL), solution for injection, single dose by intrathecal injection (IT)	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.; Other Names: Ampres 1%; 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.
Experimental: 90 mg Paracetamol 3% (3 mL); 90 mg Paracetamol 3% (3 mL), solution for injection, single dose by intrathecal injection (IT)	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.; Other Names: Ampres 1%; 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.
Placebo Comparator: 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)	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.; Other Names: Ampres 1%; 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.; Other Names: physiological solution

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pain Intensity at Rest Evaluated Using a 0-100 mm VAS	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)	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.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pain at Rest AUCt1-t2	AUC t1-t2 is defined as the area under the pain intensity curve at the specified time-intervals	Up to 4 hours after injection
Pain at Rest AUClast	AUClast is defined as the area under the pain intensity curve from 0 h up to the last assessment time	Up to 24 hours after injection
Time to First Postoperative Analgesia (Level 1 or 2)	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).	Up to 24 hours after surgery
Partecipants to Received Level 1 Analgesia	Partecipants to received Ketorolac i.v. [Toradol] 30 mg administration (level 1 analgesia)	from surgery day to 24 hours after surgery
Partecipants Received Level 2 Analgesia	Partecipants received Tramadol i.v. 1 mg/kg administration (level 2 analgesia)	from surgery day to 24 hours after surgery
Total Number of Partecipants Receiving Analgesic 1	Total number of partecipants receiving Ketorolac i.v. [Toradol] 30 mg	From surgery day to 24 hours after surgery
Total Number of Partecipants Receiving Analgesic 2	Total Number of Partecipants Receiving Tramadol i.v. 1 mg/kg	from surgery day to 24 hours after surgery
Percentage of Patients Requiring Analgesia in the First 2 h After Surgery End	Percentage of patients requiring analgesia (level 1 or level 2) in the first 2 h after surgery end	Form surgery day to 2 hours after surgery end
Percentage of Patients Requiring Analgesia in the First 4 h After Surgery End	Percentage of patients requiring analgesia (level 1 or level 2) in the first 4 h after surgery end	from surgery day to 4 hours after surgery end
Percentage of Patients Requiring Analgesia From Surgery End Until Eligibility for Discharge	Percentage of patients requiring analgesia (level 1 or level 2) from surgery end until eligibility for home discharge	from surgery day to 24 hours after surgery
Percentage of Patients Requiring Level 1 Analgesia From Surgery End Until Eligibility for Discharge	Percentage of patients requiring level 1 analgesia from surgery end until eligibility for home discharge	from surgery day to 24 hours after surgery
Percentage of Patients Requiring Level 2 Analgesia From Surgery End Until Eligibility for Discharge	Percentage of Patients Requiring Level 2 Analgesia From Surgery End Until Eligibility for Home Discharge	from surgery day to 24 hours after surgery
Percentage of Patients Requiring Supplementary Analgesia, Other Than the Planned Level 1 or 2 Analgesia	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 Rescue Anaesthesia	Percentage of patients requiring rescue anaesthesia	from surgery day to 1 hour after injection
Time to Onset of Spinal Block (i.e. Time to Readiness for Surgery)	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.	Up to 20 minutes after injection
Maximum Sensory Block	Maximum level of sensory block	Intraoperative
Time to Sensory Block	Time to maximum level of sensory block (bilateral Pinprick test using a 20-G hypodermic needle)	Intraoperative
Time to Regression of Spinal Block	Time period from spinal injection to the complete regression of sensory block to S1.	Up to 4 hours after injection
Time to Ambulation	Time to unassisted ambulation	Up to 24 hours after injection
Time to First Urine	Time to first spontaneous urine voiding	Up to 24 hours after injection
Time to Eligibility for Discharge	Time to eligibility for home discharge	Up to 24 hours after injection

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Neurological Complications Including TNS	Number of Participants with Neurological Complications Including TNS at 24 h post-dose and at day 7±1	From anaesthetic intrathecal injection up to day 7±1 (i.e. 6±1 days after analgesic/anaesthetic IT injection and surgery)

Collaborators and Investigators

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

Study record dates

Study Major Dates

• Study Start (Actual): August 6, 2018
• Primary Completion (Actual): October 22, 2019
• Study Completion (Actual): October 22, 2019

Study Registration Dates

• First Submitted: January 23, 2018
• First Submitted That Met QC Criteria: February 8, 2018
• First Posted (Actual): February 9, 2018

Study Record Updates

• Last Update Posted (Actual): June 24, 2021
• Last Update Submitted That Met QC Criteria: June 1, 2021
• Last Verified: June 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Postoperative Complications; Pain; Neurologic Manifestations; Pain, Postoperative; Physiological Effects of Drugs; Central Nervous System Depressants; Peripheral Nervous System Agents; Analgesics; Sensory System Agents; Anesthetics; Analgesics, Non-Narcotic; Antipyretics; Anesthetics, Local; Acetaminophen; Pharmaceutical Solutions; Chloroprocaine
• Other Study ID Numbers: PAR.3-01-2017; CRO-17-133 (Other Identifier: CROSS Research S.A.)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No