Neodolpasse® Infusion Solution Versus Diclofenac 75 mg Infusion in the Treatment of Postoperative Pain After Elective Knee Surgery

Neodolpasse® Infusion Solution Versus Diclofenac 75 mg Infusion in the Treatment of Postoperative Pain After Elective Knee Surgery - an Exploratory Placebo-controlled Clinical Study to Investigate the Analgesic Properties of the Combination of Diclofenac and Orphenadrine Versus Diclofenac Alone.

The clinical study is planned as a double-blind, randomised, placebo-controlled, parallel-group, single-centre exploratory clinical study with the aim to investigate the analgesic efficacy of the Neodolpasse® Infusion Solution in comparison to a 75 mg diclofenac only infusion. Included will be Patients receiving elective cruciate ligament surgery. The effectiveness will be measured by the use of additional analgesic medication via PCA during the first 24 hours postoperatively as well as by using a Visual Analogue Scale (VAS). Furthermore the local and systemic tolerability and safety of the clinical study medications (i.e. Neodolpasse® Infusion Solution and 75 mg diclofenac only infusion) will be assessed.

The clinical study is planned as a double-blind, randomised, treatment-controlled, parallel-group, single-centre exploratory clinical study with the aim to investigate the analgesic efficacy of the Neodolpasse® Infusion Solution in comparison to a 75 mg diclofenac only infusion.

Patients who meet the inclusion and exclusion criteria will be enrolled to the clinical study and receive an enrolment number. The enrolment number will be a 4-digit number where the leftmost position will be zero ("0"). Enrolled patients will receive enrolment numbers starting at 0001, 0002, and so forth.

Only patients who were successfully randomized after surgery will continue the study protocol. All other patients will be regarded as screening failures. Successfully randomized patients will receive two infusions over 60 - 90 minutes with a time interval of 8 hours each during the first 24 hours postoperatively. All patients will be provided with a PCA device and will be allowed on demand analgetics as postoperative rescue medication. Consequently the possibility of an inadequate postoperative pain treatment in the study patients is very low.

Anaesthesia will be induced with propofol (1.0-2.5 mg/kg), remifentanil (1 mcg/kg over minimum of 30s) and rocuronium (0.6mg/kg) and subsequently maintained with remifentail (0.25 - 1 mcg/kg/min), and sevoflurane. During skin suture, 7.5 mg piritramid will be administered. No nitrous oxide will be administered.

No other narcotics, analgesics, or sedatives than those described herein will be allowed. In case the surgical procedure mandates the use of additional and/or other narcotics, analgesics, or sedatives it shall be up to the investigator to decide on further treatment. However, in such case the patient will not be randomized and will be regarded as screening failure.

Randomization of the study patient takes place post-surgery as soon as the patient is able to cooperate adequatey. Ability to cooperate is defined as successful VAS assessment. At this time point the patient will be randomized and assigned her/his final randomisation number. The final randomisation number will be a 4-digit number where the leftmost position indicating the type of knee surgery performed. Patient undergoing surgery for cruciate ligament repair will receive randomisation numbers starting at 1001, 1002, and so forth. Patients undergoing knee replacement surgery will receive randomisation numbers starting at 2001, 2002, and so forth.

The first infusion of the investigational medicinal product will be started immediately after randomization. PCA will be established as soon as possible after the start of the first infusion of the investigational medicinal product but not later than 30 min after the start of the first infusion of the investigational medicinal product. A one-way PCA device (Vygon PCA-System) will be used. The PCA system is independent from any power supply and therefore both safe and reliable. The PCA system contains 20 mg Hydal® (hydromorphone) in 50 mL solvent. The PCA system parameters are fixed to a single bolus volume of 0.5 mL thus delivering 0.2 mg hydromorphone per bolus which equates to 2.0 mg piritramide or 1.5 mg morphine. Lock-out period of the PCA system used is fixed to 5 min.

All bolus injections will be recorded and added to the cumulative analgesic doses delivered by PCA.

Inclusion Criteria:

• Elective cruciate ligament surgery
• Confirmed patient suitability for planned surgery
• Legally valid signed written informed consent provided
• Female patients are confirmed non-pregnant (negative pregnancy test) or not breast feeding
• Adequate renal function defined by a creatinine value lower than 1.80 mg/dL for male and ower than 1.50 mg/dL for female patients
• No known intolerabilities or hypersensitivities to any part of the IMP / control medication
• No reoperation/revision within 6 months after the initial surgery
• Absence of history of abuse of analgesics or other drug
• No analgesics within 48 hours prior to surgery (surgery-related medication excluded)
• No current / recent (within 4 weeks prior to enrolment) experimental treatment
• No current / recent (within 4 weeks prior to enrolment) participation in another clinical study
• No foreseeable difficulties with regard to protocol compliance
• No known hypersensibility against the active ingredients diclofenac, orphenadrine, remifentanil, propofol, rocuronium, and hydromorphone
• No known hypersensibility against the other ingredients of the investigational medicinal product
• Absence of congestive heart failure classes 2 or higher according to the NYHA classification
• Absence of ischemic heart disease
• Absence of peripheral arterial occlusive disease
• Absence of cerebro-vascular disease
• Absence of significant risk factors for cardiovascular events (e.g., hypertension, hyperlipidaemia, type-2 diabetes, moderate smoking defined as consumation of 11 cigarettes or more per day)

exclusion criteria

• Major complications during surgery possibly leading to problems in the handling of the PCA or subsequently with the experimental treatment
• Intolerable adverse events or any serious adverse event
• Severe violation of the clinical study protocol
• Withdrawal of patient informed consent