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

Study Overview
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Brief Summary
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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%.

Detailed Description
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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).

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

Conditions
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Pain, Postoperative

Intervention / Treatment
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* 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


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Informed consent: signed written informed consent before inclusion in the study Sex, age and surgery: male/female patients, 18-80 years old (inclusive), scheduled for short duration (up to 40 min) knee procedures Body Mass Index (BMI): 18 - 32 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. Exclusion Criteria: 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 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 Chronic pain syndromes: patients with chronic pain syndromes taking opioids, anticonvulsant agents or chronic analgesic therapy Pain assessment: patients anticipated to be unable to make a reliable self-report of pain intensity 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 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 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 Drug, alcohol: history of drug or alcohol abuse according to the Investigator's opinion 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)]

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Supportive Care
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional 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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 30 mg Paracetamol 3% (1 mL)<br>30 mg Paracetamol 3% (1 mL), solution for injection, single dose by intrathecal injection (IT) | Drug: 30 mg Paracetamol 3% (1 mL)<br>* 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.<br>Drug: NIMP: Chloroprocaine HCl 1% (10 mg/mL), solution for injection<br>* 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.<br>* Other names: Ampres 1%;|
| Experimental: 60 mg Paracetamol 3% (2 mL)<br>60 mg Paracetamol 3% (2 mL), solution for injection, single dose by intrathecal injection (IT) | Drug: 60 mg Paracetamol 3% (2 mL)<br>* 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.<br>Drug: NIMP: Chloroprocaine HCl 1% (10 mg/mL), solution for injection<br>* 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.<br>* Other names: Ampres 1%;|
| Experimental: 90 mg Paracetamol 3% (3 mL)<br>90 mg Paracetamol 3% (3 mL), solution for injection, single dose by intrathecal injection (IT) | Drug: 90 mg Paracetamol 3% (3 mL)<br>* 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.<br>Drug: NIMP: Chloroprocaine HCl 1% (10 mg/mL), solution for injection<br>* 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.<br>* Other names: Ampres 1%;|
| Placebo Comparator: Placebo, 0.9% saline solution<br>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<br>* 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.<br>* Other names: physiological solution;Drug: NIMP: Chloroprocaine HCl 1% (10 mg/mL), solution for injection<br>* 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.<br>* Other names: Ampres 1%;|

What is the study measuring?
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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 |