Spinal Anaesthesia With Chloroprocaine HCl 1% for Elective Lower Limb Procedures of Short Duration.

To evaluate the efficacy of the three Chloroprocaine HCl 1% doses (i.e. D1, D2 and D3) in terms of time to complete regression of spinal block (i.e. end of anaesthesia)

• Chloroprocaine HCl 1% (Drug), also known as Ampres 1%: Intrathecal Route

Primary outcomes

• Time to Regression of Spinal Block [Up to 5 hours after regression of two dermatomers]: When Bromage score returns to 0 and sensitive perception returns to S1 To evaluate the efficacy of the three Chloroprocaine HCI 1% doses (i.e. 30 mg, 40 mg e 50 mg) in terms of time to complete regression of spinal block (i.e. end of anaesthesia) Bromage Score is comprised between 1 and 4 (1 equals Free movement of legs and feet while 4 stands for Unable to move legs or feet)

Secondary outcomes

• Time to Onset of Sensory Block (Corresponding to Readiness for Surgery) [Up to 40 min after spinal injection]: Time period from spinal injection (time 0 h) to achievement of sensory block The evolution of both sensory and motor blocks, including sensory block metameric level, will be evaluated every 2 min until readiness for surgery, every 5 min until the maximum level is reached (two consecutive observations with the same level of sensory block) and then every 5 min until regression of two dermatomers with respect to the maximum level of sensory block.
• Time to Onset of Motor Block [Up to 40 min after spinal injection]: Time period from spinal injection (time 0 h) to achievement of motor block
• Time to Readiness for Surgery [Up to 40 min after spinal injection]: Time period from completion of spinal injection (time 0 h) to achievement of sensory and motor block adequate for surgery, i.e. loss of Pinprick sensation and Bromage's score ≥ 2 at the required metameric level ≥ T12
• Time to Regression of Spinal Block [Up to 1 h and 40 min after readiness for surgery]
• Time to Resolution of Sensory Block to S1(Min) [Up to 5 h after regression of two dermatomers]: Time period from spinal injection (time 0 h) to the time when sensitive perception has returned to S1
• Time to Resolution of Motor Block [Up to 5 h after regression of two dermatomers]: Time period from spinal injection (time 0 h) to the time when the Bromage score has returned to 0 (Bromage Scale comprises from 1 to 4, where 1 equals Free movement of legs and feet while 4 stands for Unable to move legs or feet)
• Time to Unassisted Ambulation [Up to 5 h after regression of two dermatomers]: Time period from spinal injection (time 0 h) to the time when the patient can walk unassisted
• Sensory Block Metameric Level [Up to 5 h after regression of two dermatomers]: Metameric level of sensory block assessed from spinal injection (time 0 h) until regression of sensory block to S1
• Maximum Level of Sensory Block [Up to 1 h and 40 min after readiness for surgery]: Maximum metameric level of sensory block (decreased or absent sensation) achieved
• Time to Maximum Level of Sensory Block [Up to 1 h and 40 min after readiness for surgery]: Time period from spinal injection (Tsp; time 0 h) to the time when the maximum metameric level of sensory block is achieved (consider the time of the first of the two consecutive observations with the same level of sensory block)
• Time to Regression of Two Dermatomers With Respect to the Maximum Level of Sensory Block [Up to 5 h after regression of two dermatomers]: Time period from spinal injection (time 0 h) to the time when the sensory block decrease of two dermatomers with respect to the maximum level of sensory block
• Time to Eligibility for Home Discharge [Expected up to 24 hrs post surgery]: Time period from spinal injection (time 0 h) to the time when the criteria from discharge are met, even if according to the hospital procedures the patient is discharged at a later time
• Time to First Spontaneous Urine Voiding [Expected up to 24 hrs post surgery]: Time period from spinal injection ( time 0 h) to the first time when the patient can pass urine unassisted
• Time to First Post-operative Analgesia [Expected up to 24 hrs post surgery]: Time from spinal injection (time 0 h) to first post-operative analgesia
• Time to Administration of Rescue Anaesthesia or Rescue Analgesia [Expected up to 24 hrs post surgery]
• Concentration of 2-chloro-4-aminobenzoic Acid (CABA) in Plasma [at pre-dose, 5, 10, 30 and 60 min after spinal puncture]
• Excretion of 2-chloro-4-aminobenzoic Acid (CABA) in Urine [at the time of first urine voiding post surgery]: Time period from spinal injection ( time 0 h) to the first time when the patient can pass urine unassisted
• Treatment-emergent Adverse Events (TEAEs) [Up to Day 6 +/- 1 after spinal puncture]: All AEs occurring or worsening after the dose of IMP
• Transient Neurological Symptoms (TNS) [Up to Day 6 +/- 1 after spinal puncture]
• Pain Assessment at the Site of Injection and at the Site of Surgery [Up to Day 6 +/- 1 after spinal puncture]: Number of patients with pain at the site of injection and at the site of surgery
• Heart Rate [Expected up to 24 hrs post surgery]: The following normal ranges Heart Rate parameters will be used: 50-90 beats/min
• Blood Pressure [Expected up to 24 hrs post surgery]: The following normal ranges Systolic and Diastolic Blood Pressure parameters will be used: Systolic Blood Pressure: 100-139 mmHg Diastolic Blood Pressure: 50-89 mmHg
• SpO2 [Expected up to 24 hrs post surgery]: The following normal ranges SpO2 parameters will be used: Peripheral Oxygen Saturation: ≥ 95%

Sex: All, ages: 18 Years to 65 Years

Inclusion Criteria:

1. Sex, age and surgery: male/female patients, 18-65 years old, scheduled for short duration (less than 40 min) lower limb surgery requiring ≥ T12 metameric level of sensory block
2. Body Mass Index (BMI): 18 - 32 kg/m2 inclusive
3. ASA physical status: I-II
4. Informed consent: signed written informed consent before inclusion in the study 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: III-V
3. Further anaesthesia: patients expected to require further anaesthesia
4. Allergy: ascertained or presumptive hypersensitivity to the active principle and/or formulations ingredients; ascertained or presumptive hypersensitivity to the ester type and major anaesthetics
5. 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 or other neuropathies.
6. 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
7. Drug, alcohol: history of drug or alcohol abuse
8. Blood donation: blood donations in the 3 months before this study
9. Pregnancy and lactation: missing or positive pregnancy test at screening, pregnant or lactating women
10. Chronic pain syndromes: patients with chronic pain syndromes (taking opioids, antidepressants, anticonvulsant agents or chronic analgesic therapy) 11. Medications: medication known to interfere with the extent of spinal blocks for 2 weeks before the start of the study. Hormonal contraceptives for females are allowed.

Participant flow

Outcome results

• Time to Regression of Spinal Block (Primary), Mean, minutes: 3 mL Chloroprocaine HCl 1% 40.8 +/- 12.1; 4 mL Chloroprocaine HCl 1% 39.4 +/- 12.5; 5 mL Chloroprocaine HCl 1% 41.5 +/- 13.9
• Time to Onset of Sensory Block (Corresponding to Readiness for Surgery) (Secondary), Mean, minutes: 3 mL Chloroprocaine HCl 1% 5.4 +/- 3; 4 mL Chloroprocaine HCl 1% 6.6 +/- 3.4; 5 mL Chloroprocaine HCl 1% 4.8 +/- 2
• Time to Onset of Motor Block (Secondary), Mean, minutes: 3 mL Chloroprocaine HCl 1% 6.3 +/- 3.2; 4 mL Chloroprocaine HCl 1% 6 +/- 3.3; 5 mL Chloroprocaine HCl 1% 4.4 +/- 2.3
• Time to Readiness for Surgery (Secondary), Mean, minutes: 3 mL Chloroprocaine HCl 1% 8 +/- 4.1; 4 mL Chloroprocaine HCl 1% 7.9 +/- 4.7; 5 mL Chloroprocaine HCl 1% 5.3 +/- 2
• Time to Regression of Spinal Block (Secondary), Mean, hours: 3 mL Chloroprocaine HCl 1% 1.761 +/- 0.348; 4 mL Chloroprocaine HCl 1% 2.127 +/- 0.457; 5 mL Chloroprocaine HCl 1% 2.229 +/- 0.379
• Time to Resolution of Sensory Block to S1(Min) (Secondary), Mean, hours: 3 mL Chloroprocaine HCl 1% 1.761 +/- 0.348; 4 mL Chloroprocaine HCl 1% 2.127 +/- 0.457; 5 mL Chloroprocaine HCl 1% 2.195 +/- 0.386
• Time to Resolution of Motor Block (Secondary), Mean, hours: 3 mL Chloroprocaine HCl 1% 2.662 +/- 0.789; 4 mL Chloroprocaine HCl 1% 3.361 +/- 1.120; 5 mL Chloroprocaine HCl 1% 3.213 +/- 0.856
• Time to Unassisted Ambulation (Secondary), Mean, hours: 3 mL Chloroprocaine HCl 1% 2.662 +/- 0.789; 4 mL Chloroprocaine HCl 1% 3.361 +/- 1.120; 5 mL Chloroprocaine HCl 1% 3.213 +/- 0.856
• Sensory Block Metameric Level (Secondary), Number, participants: 3 mL Chloroprocaine HCl 1% 0; 4 mL Chloroprocaine HCl 1% 2; 5 mL Chloroprocaine HCl 1% 2
• Maximum Level of Sensory Block (Secondary), Number, participants: 3 mL Chloroprocaine HCl 1% 0; 4 mL Chloroprocaine HCl 1% 2; 5 mL Chloroprocaine HCl 1% 2
• Time to Maximum Level of Sensory Block (Secondary), Mean, minutes: 3 mL Chloroprocaine HCl 1% 0.224 +/- 0.14; 4 mL Chloroprocaine HCl 1% 0.235 +/- 0.077; 5 mL Chloroprocaine HCl 1% 0.234 +/- 0.098
• Time to Regression of Two Dermatomers With Respect to the Maximum Level of Sensory Block (Secondary), Mean, hours: 3 mL Chloroprocaine HCl 1% 0.687 +/- 0.361; 4 mL Chloroprocaine HCl 1% 0.851 +/- 0.468; 5 mL Chloroprocaine HCl 1% 0.695 +/- 0.290
• Time to Eligibility for Home Discharge (Secondary), Mean, hours: 3 mL Chloroprocaine HCl 1% 3.021 +/- 1.012; 4 mL Chloroprocaine HCl 1% 3.545 +/- 1.281; 5 mL Chloroprocaine HCl 1% 3.530 +/- 0.887
• Time to First Spontaneous Urine Voiding (Secondary), Mean, hours: 3 mL Chloroprocaine HCl 1% 2.530 +/- 0.761; 4 mL Chloroprocaine HCl 1% 3.361 +/- 1.120; 5 mL Chloroprocaine HCl 1% 3.067 +/- 0.755
• Time to First Post-operative Analgesia (Secondary), Mean, hours: 3 mL Chloroprocaine HCl 1% 8.186 +/- 10.815; 4 mL Chloroprocaine HCl 1% 2.928 +/- 1.228; 5 mL Chloroprocaine HCl 1% 2.988 +/- 1.167
• Time to Administration of Rescue Anaesthesia or Rescue Analgesia (Secondary), Mean, hours: 3 mL Chloroprocaine HCl 1% 0.717 +/- 0.397; 4 mL Chloroprocaine HCl 1% 0.315 +/- 0.049; 5 mL Chloroprocaine HCl 1% 0 +/- 0
• Concentration of 2-chloro-4-aminobenzoic Acid (CABA) in Plasma (Secondary), Mean, minutes: 3 mL Chloroprocaine HCl 1% 16.127 +/- 20.108; 4 mL Chloroprocaine HCl 1% 20.411 +/- 23.037; 5 mL Chloroprocaine HCl 1% 24.887 +/- 20.340
• Excretion of 2-chloro-4-aminobenzoic Acid (CABA) in Urine (Secondary), Mean, ng/mL: 3 mL Chloroprocaine HCl 1% 1217.7 +/- 627.8; 4 mL Chloroprocaine HCl 1% 1827.9 +/- 904.1; 5 mL Chloroprocaine HCl 1% 2103.5 +/- 1537.5
• Treatment-emergent Adverse Events (TEAEs) (Secondary), Number, participants: 3 mL Chloroprocaine HCl 1% 14; 4 mL Chloroprocaine HCl 1% 13; 5 mL Chloroprocaine HCl 1% 13
• Transient Neurological Symptoms (TNS) (Secondary), Number, participants: 3 mL Chloroprocaine HCl 1% 0; 4 mL Chloroprocaine HCl 1% 0; 5 mL Chloroprocaine HCl 1% 0
• 4 more outcome measures not shown.

Adverse events

Time frame: 7 days

Other adverse events by term

• Results publication: Ghisi D, Boschetto G, Spinelli AM, Giannone S, Frugiuele J, Ciccarello M, Bonarelli S. Spinal anaesthesia with Chloroprocaine HCl 1% for elective lower limb procedures of short duration: a prospective, randomised, observer-blind study in adult patients. BMC Anesthesiol. 2021 Feb 20;21(1):58. doi: 10.1186/s12871-021-01279-9. PMID 33610175

• Study Protocol (PDF, 2014-10-03)
• Statistical Analysis Plan (PDF, 2016-02-02)

• Stefano MD Bonarelli, Principal investigator, Istituto Ortopedico Rizzoli, SC Anestesia e Terapia Intensiva post-operatoria e del dolore IOR-IRCCS

NIH grants: 2014