Evaluation of Intravenous Ibuprofen (Arginate)-Tramadol Hydrochloride Combination for Analgesic Efficacy in Acute Severe Postoperative Pain: A Phase III Study

The primary objective of this Phase III, double-blind, randomized, placebo- and active treatment-controlled clinical trial is to evaluate the **analgesic efficacy** of a fixed-dose combination of ibuprofen (arginate)-tramadol hydrochloride 400-37.5 mg, administered intravenously every 4 hours, in patients experiencing acute severe postoperative pain. The study aims to determine if this combination achieves non-inferior pain control at 4 hours compared to the administration of 100 mg of tramadol alone and provides superior pain control compared to placebo. This is clinically relevant as it may offer an effective alternative for managing severe postoperative pain, potentially improving patient outcomes and reducing reliance on higher doses of single analgesics.

Secondary objectives include: - Assessing whether the combination achieves non-inferior pain control at 8 hours compared to tramadol alone and better control than placebo. - Evaluating the Numeric Pain Scale (NRS) score and Pain Intensity Differences (PID) at 4 and 8 hours post-treatment. - Determining the time to first pain relief and the time to administration of rescue medication. - Calculating the percentage of responders to each treatment and the percentage of patients using rescue medication within the first 8 hours. - Assessing the total amount of rescue medication used by each treatment group. - Evaluating the safety and tolerability of each study treatment.

The clinical trial involves a study population comprising both **male** and **female** participants aged 18 years and older, with a **body mass index** ranging from 18.5 to less than 40 kg/m². The participants are individuals scheduled for specific surgical procedures, including myomectomy, hysterectomy, oophorectomy, cholecystectomy, haemorrhoidectomy, or tonsillectomy, due to benign conditions. The trial includes patients with an American Society of Anesthesiologists (ASA) anaesthesia risk score of I or II, indicating a generally healthy status with mild systemic disease. Participants are required to have a Numeric Rating Scale (NRS) for pain score of 6 or higher post-surgery to qualify for randomization. The sponsor has not provided information regarding the total number of participants in the study. The trial does not focus on a vulnerable population, and no specific lifestyle considerations such as diet or physical activity are highlighted in the selection criteria.

The clinical trial is a **Phase III**, double-blind, randomized, placebo- and active treatment-controlled study designed to evaluate the analgesic efficacy and safety of a combination of **ibuprofen (arginate)** and **tramadol hydrochloride** administered intravenously to patients experiencing acute severe postoperative pain. The trial aims to determine whether this fixed-dose combination achieves non-inferior pain control compared to the administration of tramadol alone and better pain control than placebo. The study is expected to run from August 2023 to June 2025.

Participants will be randomly assigned to receive either the investigational combination, tramadol alone, or a placebo. The trial will include several key visits: an initial screening visit to confirm eligibility, followed by the administration of the study medication post-surgery. Pain intensity will be measured using the Numeric Rating Scale at baseline and at regular intervals up to 8 hours post-administration. The primary endpoint is the Sum of Pain Intensity Differences from the start of administration to 4 hours (SPID0-4h). Secondary endpoints include pain intensity differences at various time points, time to first pain relief, and the use of rescue medication.

Participants are expected to be involved in the study for a maximum of one day, corresponding to the duration of the treatment period. Conditions that may lead to early termination from the study include the inability to comply with study procedures or the occurrence of adverse events that necessitate withdrawal. The trial will ensure the safety of participants through regular monitoring of vital signs and documentation of any adverse events. The study is conducted under strict adherence to ethical guidelines, with informed consent obtained from all participants prior to their inclusion in the trial.

The clinical trial involves the administration of **Ibuprofen (arginate)-Tramadol HCl** 400-37.5 mg/100 ml solution for infusion. This experimental medication is provided in the form of a **solution for infusion** and is administered via **intravenous infusion**. The maximum daily dose is 200 ml, with a total dose not exceeding 200 ml over a treatment period of one day. The primary objective is to evaluate the analgesic efficacy and safety of this combination in patients experiencing acute severe postoperative pain.

**Tramal 50 mg, Injektionslösung** is used as a comparator treatment in the study. It is a **solution for injection** containing **tramadol hydrochloride** and is administered through **intravenous infusion**. The maximum daily dose is 200 mg, with a total dose not exceeding 200 mg over a one-day treatment period. This comparator aims to assess the non-inferiority of the experimental medication in pain control.

**Morphine Hydrochloride** is included as an auxiliary treatment. It is provided as an **injectable solution** and administered via **IV infusion**. The maximum daily dose is 30 mg, with a total dose not exceeding 30 mg over a one-day treatment period. This auxiliary treatment is used to support the evaluation of the experimental medication's efficacy.

**Fisiológico B.Braun 0,9% Solución para perfusión** serves as a placebo in the trial. It is a **solution for injection/infusion** containing **sodium chloride** and is administered through **intravenous infusion**. The maximum daily dose is 200 ml, with a total dose not exceeding 200 ml over a one-day treatment period. The placebo is used to ensure the double-blind nature of the trial.

**Isotone NaCl-Lösung ASmedic** is listed in the trial documentation but lacks specific details regarding its pharmaceutical form, active substance, and administration route. It is not actively used in the trial as a treatment or comparator.

The efficacy of the clinical trial will be assessed using both primary and secondary endpoints. The primary endpoint is the **Sum of Pain Intensity Differences (SPID)** from the start of administration to 4 hours (SPID0-4h), measured using the Numeric Rating Scale for Pain at baseline, 1 hour, 2 hours, 3 hours, and 4 hours. Secondary endpoints include the SPID from the start of administration to 8 hours (SPID0-8h), pain intensity measured at various time points up to 8 hours, and pain intensity difference (PID) at 4 and 8 hours from the start of administration. Additional secondary endpoints involve the time to first pain relief, responder rate, percentage of patients using rescue medication, time to first administration of rescue medication, and total rescue medication use within 8 hours.

These efficacy parameters will be collected and analyzed at specified time points, including baseline, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, and 8 hours after the start of treatment. The Numeric Rating Scale for Pain will be utilized as the primary tool for measuring pain intensity. The trial aims to determine whether the fixed-dose combination of ibuprofen (arginate)-tramadol hydrochloride achieves non-inferior pain control compared to tramadol alone and superior pain control compared to placebo. The trial is designed to provide a comprehensive assessment of the analgesic efficacy of the treatment regimen in patients with acute severe postoperative pain.