Clinical Trial Comparing Intravenous and Oral Diclofenac and Pharmacokinetics

NCT ID: NCT03472339

Last Updated: 2018-03-22

Basic Information

• Recruitment Status: UNKNOWN
• Clinical Phase: PHASE4
• Total Enrollment: 300 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2018-01-15
• Study Completion Date: 2018-04-15

Brief Summary

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

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.

Conditions

Pain Management; Limb Injury

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: DOUBLE

Study Groups

Group A

diclofenac sodium75 mg, intravenously, once

Group Type: EXPERIMENTAL

Diclofenac Sodium

Intervention Type: DRUG

Group A-Intramuscular diclofenac sodium+oral placebo Group B-Oral diclofenac sodium+ intramuscular placebo

Group B

diclofenac sodium 100 mg, orally, once

Group Type: ACTIVE_COMPARATOR

Diclofenac Sodium

Intervention Type: DRUG

Group A-Intramuscular diclofenac sodium+oral placebo Group B-Oral diclofenac sodium+ intramuscular placebo

Interventions

Diclofenac Sodium

Group A-Intramuscular diclofenac sodium+oral placebo Group B-Oral diclofenac sodium+ intramuscular placebo

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

1. Healthy volunteers

2. Adult patients above 18-65 years of age.

3. Patients with soft tissue injury/ cut wounds

4. Pain score more than or equal to 4 on NRS.

5. Patients weight more than or equal to 50kgs.

6. If treating physician approves patient participation in the study.

7. Not on any medication.

Exclusion Criteria

1. Received any analgesic within last 12 hours, on the day of visit to ED.

2. Patients with fractures

3. Allergic to diclofenac.

4. Cardio-vascular disease, renal impairment, stroke or any other co-morbidity / chronic illness.

5. Pregnancy / Nursing

6. Peptic ulcers

7. Bleeding disorders

8. liver disease

9. Bronchial asthma

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 65 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

Hamad Medical Corporation

INDUSTRY

Sponsor Role: lead

Responsible Party

Dr. Isma Qureshi

Academic Research Associate

Responsibility Role: PRINCIPAL_INVESTIGATOR

Locations

Isma Qureshi

Doha, , Qatar

Site Status: RECRUITING

Countries

Qatar

Facility Contacts

Isma Qureshi

Role: primary

iqureshi@hamad.qa

44390985

References

Derry P, Derry S, Moore RA, McQuay HJ. Single dose oral diclofenac for acute postoperative pain in adults. Cochrane Database Syst Rev. 2009 Apr 15;(2):CD004768. doi: 10.1002/14651858.CD004768.pub2.

Reference Type: BACKGROUND

PMID: 19370609 (View on PubMed)

Marret E, Kurdi O, Zufferey P, Bonnet F. Effects of nonsteroidal antiinflammatory drugs on patient-controlled analgesia morphine side effects: meta-analysis of randomized controlled trials. Anesthesiology. 2005 Jun;102(6):1249-60. doi: 10.1097/00000542-200506000-00027.

Reference Type: BACKGROUND

PMID: 15915040 (View on PubMed)

Pathan SA, Mitra B, Straney LD, Afzal MS, Anjum S, Shukla D, Morley K, Al Hilli SA, Al Rumaihi K, Thomas SH, Cameron PA. Delivering safe and effective analgesia for management of renal colic in the emergency department: a double-blind, multigroup, randomised controlled trial. Lancet. 2016 May 14;387(10032):1999-2007. doi: 10.1016/S0140-6736(16)00652-8. Epub 2016 Mar 16.

Reference Type: BACKGROUND

PMID: 26993881 (View on PubMed)

Gan TJ, Daniels SE, Singla N, Hamilton DA, Carr DB. A novel injectable formulation of diclofenac compared with intravenous ketorolac or placebo for acute moderate-to-severe pain after abdominal or pelvic surgery: a multicenter, double-blind, randomized, multiple-dose study. Anesth Analg. 2012 Nov;115(5):1212-20. doi: 10.1213/ANE.0b013e3182691bf9. Epub 2012 Aug 10.

Reference Type: BACKGROUND

PMID: 22886837 (View on PubMed)

Turturro MA, Paris PM, Seaberg DC. Intramuscular ketorolac versus oral ibuprofen in acute musculoskeletal pain. Ann Emerg Med. 1995 Aug;26(2):117-20. doi: 10.1016/s0196-0644(95)70138-9.

Reference Type: BACKGROUND

PMID: 7618770 (View on PubMed)

Ucar R, Biyik M, Ucar E, Polat I, Cifci S, Ataseven H, Demir A. Rectal or intramuscular diclofenac reduces the incidence of pancreatitis afterendoscopic retrograde cholangiopancreatography. Turk J Med Sci. 2016 Jun 23;46(4):1059-63. doi: 10.3906/sag-1502-104.

Reference Type: BACKGROUND

PMID: 27513404 (View on PubMed)

Other Identifiers

16413/16

Identifier Type: -

Identifier Source: org_study_id