Clinical Trial Comparing Intravenous and Oral Diclofenac and Pharmacokinetics

Study Overview
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Brief Summary
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NSAIDs are commonly used in the management of acute pain; Diclofenac is one from the same class. It is an amino phenyl acetic acid derivative which inhibits prostaglandin biosynthesis to produce analgesic, antipyretic and anti-inflammatory effect. The drug efficacy and safety in acute pain management has been proved by several studies like in renal colic, post and pre-operative pain management, migraines etc. It's also known to have an opioid-sparing effect. Mode of administration is one of the important factors to consider in a busy emergency room. Perception about the route of administration differs among patients. As believed,injectable have rapid onset, easier to titrate, and patients respond better to them as they consider them stronger than oral medication. Number of trials has compared oral and parenteral NSAIDs. Most found no benefit to the parenteral route. Considering the limitations of the previously done studies like small sample size, heterogeneity in the group of patients enrolled, improper blinding and comparing of two different drugs from the same class. Therefore, aim of the study is to conduct a Double blind randomized clinical trial to assess the clinical efficacy and pharmacokinetic parameters of oral diclofenac compared to intramuscular diclofenac in patients with acute limb injury. In this two group double blind randomized clinical trial, the clinical efficacy and pharmacokinetic parameters among the two groups will be assessed. Eligible patients visiting to HGH-ED, age (above 18 years) with acute limb injury, having moderate to severe pain (defined as pain score of >=4 on Numerical rating scale) will be recruited. With the use of computer generated block randomization, subjects will be allocated to one of the two treatment groups in the ratio of 1:1. Each group will receive either (intramuscular diclofenac / oral placebo) or (oral diclofenac / intramuscular placebo). Among the 300 subjects enrolled for the study, further stratified randomization will be done in order to enroll 20 patients for pharmacokinetic study within the subjects.High-performance liquid chromatography, method will be used for the determination of drug concentration in human plasma, for detailed pharmacokinetics. The pain score will be assessed by using the validated pain scale i.e. Numerical rating scale (NRS). The participants, clinicians and investigators will be masked to treatment assigned and the results will be analyzed by the intention to treat analysis among the two group treatment.

Detailed Description
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This will be a prospective, double blinded, randomized clinical trial, and it will be conducted and reported according to the consolidated standards of reporting trials group 14. Setting: The study will be conducted at Hamad General Hospital Emergency Department (HGH-ED). Since it is the largest tertiary care medical center in the country, having a busy ED with monthly census exceeding 40,000 (approximately 500,000 annually). Patients with acute limb injury are frequently seen in ED. Sample size calculation: 300 patients are required to have a 95% chance of detecting, as significant at the 5%level, a decrease in the primary outcome measure from 70% in the control group to 50% in the experimental group. As for the number of subjects to be enrolled in pharmacokinetic study is directly related to both power and cost of the trial (14)*, we aim a convenience sample of 20 subjects, 10 in each group. Screening and Randomization: All adult patients (age above 18-65 years) presenting with Acute limb injury will be assessed by the available physician initially. Patient's hospital identification number will be put into the study registry. The registry will assure all consecutive patients are screened. Once an eligible patient is identified the physicians will page the research assistant, who will be available in the emergency department from 6 am to 2 pm on week days. After meeting the inclusion criteria and the subject agrees to participate, written consent will be obtained. The enrolled participants will be randomly assigned in a 1:1 ratio, to one of the two groups- either intramuscular diclofenac or oral diclofenac, from the trial packet available in the stock. A computer generated block randomization sequence will be generated and stored with sequential coding known to the clinical pharmacist only. Within the randomized sequence, another stratified randomized sequence will be generated for the 20 subjects to be enrolled for pharmacokinetic trial only during the morning shifts. In case of adverse reaction form will be filled and medical research center will be notified for such event. Intervention: Typical trial packet Syringe A: 3ml solution, diclofenac 75mg or placebo Tablet: 100mg diclofenac tablet or placebo A trial packet will contain one syringe labelled A (3ml) and one tablet labelled B (100mg) in an amber colored zip lock pouch. Each will be labelled with a sticker mentioning a unique code, date of preparation and instructions for administration. Trial packs A B Combination 1 Intramuscular Diclofenac Oral Placebo Combination 2 Oral Diclofenac Intramuscular Placebo Trial packs will be prepared and kept in a locker ready to be used on a daily basis. The team preparing these packets will have no further part in patient treatment or data recording. Dosage Intramuscular Diclofenac will be available in 75mg/3ml concentration for single dose intramuscular administration. Tablet Diclofenac will be available as 100mg tablet for single dose per oral administration. The protocol dictates to administer syringe A (3ml) intramuscular, 100mg tablet labeled B to administer per oral. Data and sample collection: Patient enrolled for pharmacokinetic measurement, will have an intravenous line to obtain blood for routine sampling, a hep- lock will be attached to the line, for the withdrawal of repeated samples. Blood samples will be collected only in weekdays and morning shifts from 6am until 2 pm. 3 ml of blood will be withdrawn at time 0, 5, 10, 15, 20, 25, 30, 45 and 60 minutes. High- performance liquid chromatography method will be used to determine drug in human plasma as the method is potentially considered to be used for detailed pharmacokinetics, pharmacodynamics and bioequivalence studies of diclofenac in humans. Along with blood sampling patient pain score using a numerical rating scale (NRS) will be used to assess the pain, as for the rest of the patients. Pain scores will be recorded at 0, 5, 10, 15, 20, 25, 30, 45 and 60, minutes following administration of analgesia. Patients reported pain scores will be recorded contemporaneously and patient will not be reminded of the previous score. If patients pain does not reduce significantly at the end of 30 minutes after receiving the study drug, a rescue analgesia in the form of morphine will be given 3mg intravenously every 5 minutes until sedation side effects or pain drops to Numerical rating score = or <2.Patient will be discharged as per the advice of the available physician in ED.

Official Title
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A Randomized Double-blinded Trial Comparing the Clinical Efficacy and Pharmacokinetic Parameters of Oral Diclofenac and Intramuscular Diclofenac in Patients With Acute Limb Injuries

Conditions
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Pain Management, Limb Injury

Intervention / Treatment
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* Drug: Diclofenac Sodium


Participation Criteria
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Eligibility Criteria
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Eligible patients are those adults (age at least 18years), presenting to HGH-ED with complaints of acute limb injury, initially evaluated by the physician. Inclusion criteria: Healthy volunteers Adult patients above 18-65 years of age. Patients with soft tissue injury/ cut wounds Pain score more than or equal to 4 on NRS. Patients weight more than or equal to 50kgs. If treating physician approves patient participation in the study. Not on any medication. Exclusion criteria: Received any analgesic within last 12 hours, on the day of visit to ED. Patients with fractures Allergic to diclofenac. Cardio-vascular disease, renal impairment, stroke or any other co-morbidity / chronic illness. Pregnancy / Nursing Peptic ulcers Bleeding disorders liver disease Bronchial asthma

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Double blind randomized trial
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group A<br>diclofenac sodium75 mg, intravenously, once | Drug: Diclofenac Sodium<br>* Group A-Intramuscular diclofenac sodium+oral placebo Group B-Oral diclofenac sodium+ intramuscular placebo<br>|
| Active Comparator: Group B<br>diclofenac sodium 100 mg, orally, once | Drug: Diclofenac Sodium<br>* Group A-Intramuscular diclofenac sodium+oral placebo Group B-Oral diclofenac sodium+ intramuscular placebo<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Difference in proportion of patients achieving 50% pain reduction | The primary outcome is defined as the proportion of patients achieving pain reduction by 50% at 30 minutes following analgesia administration. | 30 mins | 
| the mean difference in plasma concentration for two drugs | Cmax - Peak plasma concentration and Time curve | 60 mins | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| proportion of patients achieving pain reduction of >=2 Numerical Rating Scale( which is a numeric scale where respondent selects a whole number from 0 to 10, where 0 means no pain and 10 means worst pain) from the initial score | to assess proportion of patients who could achieve minimal significant pain reduction | at 30 mins | 
| Rescue analgesia | proportion of patients requiring a rescue analgesia after 30 min in each group | after 30 mins | 
| Adverse events | the number of adverse events in each group | 2 hours | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Acute limb injury, Diclofenac, pain management