CHL.2/01-2014/M

Sintetica SA

Via Penate 5, Mendrisio, Switzerland, 6850

Study Management, CROSS SA, 0041 (0)916300510, corporate@croalliance.com

Study Management, CROSS SA, 0041 (0)916300510, corporate@croalliance.com

No

No

No

Final

24 May 2017

No

Yes

24 May 2017

No

This study evaluate the Non-inferiority evaluation of Test versus Reference product in terms of proportion of subjects with a successful block for distal upper limb surgeries, without any supplementation in the first 45 min (see definitions below), calculated from the time of readiness for surgery (complete sensory block). Successful block: anaesthesia adequate for the surgery (complete sensory block), without any supplementation in the first 45 min (even if surgery lasts for > 45 min), calculated from the time of readiness for surgery (complete sensory block). Supplementation: i.v. premedication or general anaesthesia or pre- or intra-operative systemic analgesia or additional local anaesthetic infiltration

In order to avoid any risk for patients, the following exclusion criteria have been considered: 1.Physical findings: Clinically significant abnormal physical findings which could interfere with the objectives of the study. Contraindications to peripheral nerve block anaesthesia. History of neuromuscular diseases to the upper extremities 2.Axillary status: Axillary local infections, surgical scarring and pathological lymph node enlargement 3.ASA physical status: IV-V 4.Further anaesthesia: Patients anticipated to be requiring further anaesthesia (general or local anaesthesia) 5.Chronic pain syndromes: Patients with chronic pain syndromes (taking opioids, antidepressants, anticonvulsant agents) 6.Allergy: Ascertained or presumptive hypersensitivity to the active principle and/or formulations ingredients; ascertained or presumptive hypersensitivity to the amide and ester-type anaesthetics 7.Diseases: Significant history of renal, hepatic, gastrointestinal, cardiovascular, respiratory, skin, haematological, endocrine or neurological diseases that could interfere with the aim of the study; ascertained psychiatric diseases, sepsis, blood coagulation disorders, insulin dependent diabetes mellitus, terminal kidney failure 8.Medications: Medication known to interfere with the extent of regional blocks (see chloroprocaine and ropivacaine SmPCs) for 2 weeks before the start of the study. Hormonal contraceptives for females were allowed 9.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 10.Drug, alcohol: History of drug or alcohol abuse 11.Pregnancy: Missing or positive pregnancy test at screening, pregnant or lactating women

30 Jan 2015

No

No

Switzerland: 87

Austria: 124

211

124

0

0

0

0

0

0

147

60

4

overall trial (overall period)

Randomised - controlled

All the clinical staff members involved in anaesthesia, surgery and study-related activities (Investigator/co-investigators/study nurses) as well as the patients were blind with respect to the administered treatment. Syringes for injection were prepared out of the operating area by a person not involved in any other study-related activity. Only the person preparing the syringe and the CRA in charge of investigational products' accountability were aware of the administered treatments.

Yes

Chloroprocaine HCl 2%

Solution for injection

Perineural use

Chloroprocaine HCl 2% injection (20 mg/mL)

Ropivacaine HCl 0.75%

Solution for injection

Perineural use

Naropin®, Ropivacaine HCl 0.75% injectable solution (7.5 mg/mL)

overall trial

Enrolled set

All enrolled subjects. This analysis set was used for demographic, baseline and background characteristics

Full Analysis Set (FAS)

all randomised patients who fulfilled the study protocol requirements in terms of study anaesthetics administration. This analysis set was used for sensitivity analyses and secondary efficacy analyses

Per Protocol set (PP)

All randomised patients who fulfilled the study protocol requirements in terms of anaesthetic administration and primary efficacy evaluation, with no major deviations that could affect the primary efficacy results. This analysis set was used for the primary efficacy analysis and secondary efficacy analyses

Safety set

All patients who received at least one dose of the investigational medicinal product. This analysis set was used for the safety analyses

Chloroprocaine

Ropivacaine

Enrolled set

All enrolled subjects. This analysis set was used for demographic, baseline and background characteristics

Full Analysis Set (FAS)

all randomised patients who fulfilled the study protocol requirements in terms of study anaesthetics administration. This analysis set was used for sensitivity analyses and secondary efficacy analyses

Per Protocol set (PP)

All randomised patients who fulfilled the study protocol requirements in terms of anaesthetic administration and primary efficacy evaluation, with no major deviations that could affect the primary efficacy results. This analysis set was used for the primary efficacy analysis and secondary efficacy analyses

Safety set

All patients who received at least one dose of the investigational medicinal product. This analysis set was used for the safety analyses

Non-inferiority evaluation of Test versus Reference product in terms of proportion of patients with a successful block* for distal upper limb surgeries, without any supplementation** (i.e. no general anaesthesia or pre- and intra-operative systemic analgesia and no additional anaesthetic infiltration) in the first 45 min, calculated from the time of readiness for surgery (complete sensory block). *Successful block: anaesthesia adequate for the surgery (complete sensory block), without any supplementation in the first 45 min (even if surgery lasts for > 45 min), calculated from the time of readiness for surgery (complete sensory block). **Supplementation: i.v. premedication or general anaesthesia or pre- or intra-operative systemic analgesia or additional local anaesthetic infiltration.

Primary

at treatment-visit2, day 1 (day of surgery)

The proportion of subjects (FAS set) who achieved a successful block, defined as anaesthesia adequate for the surgery, without any supplementation in the first 45 min from the time of readiness for surgery (see § 9.5.1.2), was 89/98 (90.8%) with Chloroprocaine HCl 2% and 92/99 (92.9%) with Ropivacaine HCl 0.75% (Table 14.2.1.1).

Chloroprocaine v Ropivacaine

209

Pre-specified

Non-inferiority evaluation of Test versus Reference product in terms of proportion of patients with a successful block* for distal upper limb surgeries, without any supplementation** (i.e. no general anaesthesia or pre- and intra-operative systemic analgesia and no additional anaesthetic infiltration) in the first 45 min, calculated from the time of readiness for surgery (complete sensory block). *Successful block: anaesthesia adequate for the surgery (complete sensory block), without any supplementation in the first 45 min (even if surgery lasts for > 45 min), calculated from the time of readiness for surgery (complete sensory block). **Supplementation: i.v. premedication or general anaesthesia or pre- or intra-operative systemic analgesia or additional local anaesthetic infiltration.

Primary

at treatment-visit 2/ day 1 (day of surgery)

The proportion of subjects (PP set) who achieved a successful block, defined as anaesthesia adequate for the surgery, without any supplementation in the first 45 min from the time of readiness for surgery (see § 9.5.1.2), was 89/98 (90.8%) with Chloroprocaine HCl 2% and 92/99 (92.9%) with Ropivacaine HCl 0.75% (Table 14.2.1.1).

Ropivacaine v Chloroprocaine

197

Pre-specified

Time period from completion of the final perineural injection (time 0 h) to achievement of sensory block in the 4 nerve territories

Secondary

at treatment-visit 2/day 1 (day of surgery), up to 1 h after last perineural injection

Time period from completion of the final perineural injection (time 0 h) to achievement of sensory block in the 4 nerve territories

Secondary

at treatment-visit 2/day 1 (day of surgery), up to 1 h after last perineural injection

Ropivacaine v Chloroprocaine

209

Pre-specified

Time period from completion of the final perineural injection (time 0 h) to achievement of motor block

Secondary

at treatment-visit 2/day 1 /day of surgery), up to 1 h after last perineural injection

Time period from completion of the final perineural injection (time 0 h) to achievement of motor block

Secondary

at treatment-visit 2/day 1 /day of surgery), up to 1 h after last perineural injection

Was deemed to have occurred when cold sensation and sensitive perception had returned (if assessable) in at least one nerve territory.

Secondary

at treatment-visit 2/day 1, up to 12 hrs after surgery

Was deemed to have occurred when cold sensation and sensitive perception had returned (if assessable) in at least one nerve territory.

Secondary

at treatment-visit 2/day 1, up to 12 hrs after surgery

Was deemed to have occurred when motor score was ≥ 3 in at least one nerve territory.

Secondary

at treatment-visit 2/day 1, up to 12 hrs after surgery

Was deemed to have occurred when motor score was ≥ 3 in at least one nerve territory.

Secondary

at treatment-visit 2/day 1, up to 12 hrs after surgery

Time from completion of the final perineural injection (time 0 h) to administration of the first rescue anaesthesia or analgesia (supplementation) (if applicable) NOTE: 0 was entered as results. According to the CSR, NC (not calculated) was the correct answer, not possible to enter.

Secondary

45 min from the time of readiness of surgery

Time from completion of the final perineural injection (time 0 h) to administration of the first rescue anaesthesia or analgesia (supplementation) (if applicable) NOTE: 0 was entered as results. According to the CSR, NC (not calculated) was the correct answer, not possible to enter.

Secondary

45 min from the time of readiness of surgery

Time from completion of the final perineural injection (time 0 h) to the first post-operative analgesia. NOTE: For Chloroprocaine: Lower limit of the confidence interval was 200.0, upper was NC (not calculated). For avoiding error, 0 (zero) was entered for both. For Ropivacaine: Lower limit of the confidence interval was 783.0, upper was NC (not calculated). For avoiding error, 0 (zero) was entered for both

Secondary

From surgery day to 24 hrs post surgery

Time from completion of the final perineural injection (time 0 h) to the first post-operative analgesia NOTE: For Chloroprocaine: Lower limit of the confidence interval was 205.0, upper was NC (not calculated). For avoiding error, 0 (zero) was entered for both. For Ropivacaine: Lower limit of the confidence interval was 822.0, upper was NC (not calculated). For avoiding error, 0 (zero) was entered for both

Secondary

From surgery day to 24 hrs post surgery

Time from completion of the final perineural injection (time 0 h) to the time when the criteria for discharge were met, even if, according to the hospital procedures, the patient was discharged from the hospital at a later time

Secondary

from surgery day to 24h post surgery

Time from completion of the final perineural injection (time 0 h) to the time when the criteria for discharge were met, even if, according to the hospital procedures, the patient was discharged from the hospital at a later time

Secondary

from surgery day to 24h post surgery

Number of Treatment-emergent Adverse Events (TEAEs) occurring or worsening after the first dose of IMP

Secondary

from surgery day to day 6 +/- 1 after surgery

Number of patients with Neurological Symptoms (e.g. paraesthesia, motor function problems and pain at the injection site) Following syntomps have been investigated: Burning Tingling Pins and needles sensation (for category title, summarized as "pins sensation") Pricking Aching Numbness Hypoesthesia Pain surgery site At Day 7±1, pain at surgery site was not evaluated and diffuse hair loss, headache and Itching were evaluated.

Secondary

from surgery day to day 6 +/- 1 after surgery

for safety assessment The following normal ranges Heart Rate parameters will be used: 50-90 beats/min

Secondary

from surgery day to 24 hrs post surgery

for safety assessment. 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

Secondary

from surgery day to 24 hrs post surgery

for safety assessment. The following normal ranges SpO2 parameters will be used: Peripheral Oxygen Saturation: ≥ 95%

Secondary

from surgery day to 24 hrs post surgery

from Visit 1 - Screening to Telephonic Follow-up (from Days -14/1 to Day 7±1)

AEs monitored from the screening visit, immediately after informed consent signature, up to the telephonic follow-up. Particular attention was given to systemic and local toxicity symptoms, neurological symptoms (e.g. paraesthesia, motor function problems and pain at the injection site) and allergic reactions. NO SAE occurred.

20.1

Chloroprocaine

Ropivacaine

Safety Set