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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03428230
Recruitment Status : Completed
First Posted : February 9, 2018
Last Update Posted : November 21, 2019
Sponsor:
Collaborator:
Cross Research S.A.
Information provided by (Responsible Party):
Sintetica SA

Brief Summary:
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%.

Condition or disease Intervention/treatment Phase
Pain, Postoperative Drug: 30 mg Paracetamol 3% (1 mL) Drug: 60 mg Paracetamol 3% (2 mL) Drug: 90 mg Paracetamol 3% (3 mL) Drug: Placebo, 0.9% saline solution Drug: NIMP: Chloroprocaine HCl 1% (10 mg/mL), solution for injection Phase 2

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).

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 60 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: Eligible patients will be randomised into four treatment groups (15 patients/group) to receive either one of the three single doses of Paracetamol 3% (30 mg, 60 mg, 90 mg) or placebo solution (1 mL, 2 mL, 3 mL) according to the randomised, parallel-group design.
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Masking Description: The study will be double-blind. Neither the Investigator/co-investigators/study nurses involved in the clinical study procedures, nor will the patients be aware of the administered treatment. At the site, syringes for injection will then be prepared by a person not involved in any other study-related activities where a bias is possible.
Primary Purpose: Supportive Care
Official Title: Dose-finding Study of Intrathecal Paracetamol Administered Immediately Before Spinal Anaesthesia With Chloroprocaine HCl 1% for Elective Knee Procedures of Short Duration
Actual Study Start Date : August 6, 2018
Actual Primary Completion Date : October 22, 2019
Actual Study Completion Date : October 22, 2019

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: D1
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.

Experimental: D2
60 mg Paracetamol 3% (2 mL), solution for injection, single dose by intrathecal injection (IT)
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: 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.

Experimental: D3
90 mg Paracetamol 3% (3 mL), solution for injection, single dose by intrathecal injection (IT)
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: 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.

Placebo Comparator: P
Placebo, 0.9% saline solution (1 mL, 2 mL or 3 mL), solution for injection, single dose by intrathecal injection (IT)
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.




Primary Outcome Measures :
  1. 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 Outcome Measures :
  1. 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

  2. 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

  3. 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.


  4. 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)

  5. 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)

  6. Total amount of analgesic 1 consumption [ Time Frame: Up to 24 hours after surgery ]
    Amount of Ketorolac i.v. [Toradol] 30 mg administered

  7. Total amount of analgesic 2 consumption [ Time Frame: Up to 24 hours after surgery ]
    Amount of Tramadol i.v. 1 mg/kg administered

  8. 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 ]
  9. 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 ]
  10. 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 ]
  11. Proportion of patients requiring level 1 analgesia from surgery end until eligibility for home discharge [ Time Frame: Up to 24 hours after surgery ]
  12. Proportion of patients requiring level 2 analgesia from surgery end until eligibility for home discharge [ Time Frame: Up to 24 hours after surgery ]
  13. Time to first supplementary analgesia, other than the planned level 1 or 2 analgesia [ Time Frame: Up to 24 hours after surgery ]
  14. Proportion of patients requiring supplementary analgesia, other than the planned level 1 or 2 analgesia [ Time Frame: Up to 24 hours after surgery ]
  15. Time to rescue anaesthesia [ Time Frame: Up to 1 hour after injection ]
  16. Proportion of patients requiring rescue anaesthesia [ Time Frame: Up to 1 hour after injection ]
  17. 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.

  18. Maximum level of sensory block [ Time Frame: Intraoperative ]
  19. Time to maximum level of sensory block [ Time Frame: Intraoperative ]
  20. 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.

  21. Time to unassisted ambulation [ Time Frame: Up to 24 hours after injection ]
  22. Time to first spontaneous urine voiding [ Time Frame: Up to 24 hours after injection ]
  23. Time to eligibility for home discharge [ Time Frame: Up to 24 hours after injection ]

Other Outcome Measures:
  1. Treatment-emergent adverse events throughout the study [ Time Frame: From immediately after the signature of the informed consent up to day 7±1 (i.e. 6±1 days after analgesic/anaesthetic IT injection and surgery) ]
  2. Incidence of neurological complications including TNS at 24 h post-dose and at day 7±1 [ Time Frame: From anaesthetic intrathecal injection up to day 7±1 (i.e. 6±1 days after analgesic/anaesthetic IT injection and surgery) ]


Information from the National Library of Medicine

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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:

  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)]

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): NCT03428230


Locations
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Switzerland
Department of Anaesthesiology, Clinica Ars Medica
Gravesano, Switzerland, 6929
Sponsors and Collaborators
Sintetica SA
Cross Research 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: NCT03428230    
Other Study ID Numbers: PAR.3-01-2017
CRO-17-133 ( Other Identifier: CROSS Research S.A. )
First Posted: February 9, 2018    Key Record Dates
Last Update Posted: November 21, 2019
Last Verified: November 2019

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Pain, Postoperative
Postoperative Complications
Pathologic Processes
Pain
Neurologic Manifestations
Signs and Symptoms
Acetaminophen
Anesthetics
Chloroprocaine
Procaine
Pharmaceutical Solutions
Central Nervous System Depressants
Physiological Effects of Drugs
Analgesics, Non-Narcotic
Analgesics
Sensory System Agents
Peripheral Nervous System Agents
Antipyretics
Anesthetics, Local