|Year : 2013 | Volume
| Issue : 1 | Page : 18-24
A phase III trial evaluating the efficacy and tolerability of nimesulide 1% spray in patients with soft-tissue injuries
Mazharuddin Ali Khan1, Madhusudhan Rao2, Madan M Reddy3, Datta Tamloorker4, Vishesh Gumdal5, Moodahadu S Latha6, Binny Krishnankutty7
1 Department of Orthopedics, Deccan College of Medical Sciences, Hyderabad, India
2 Department of Orthopedics, Mediciti Hospital, Hyderabad, India
3 Department of Orthopedics, Apollo Hospitals, Chennai, India
4 Department of Orthopedics, Dr. V R K Hospital, Hyderabad, India
5 Department of Rheumatology, GVN Medical Centre, Hyderabad, India
6 Global Medical Affairs, Dr. Reddy's Laboratories, Hyderabad, India
7 Department of Pharmacology, Azeezia Medical College, Kollam, India
|Date of Web Publication||22-Mar-2013|
Mazharuddin Ali Khan
Department of Orthopedics, Deccan College of Medical Sciences, Kanchanbagh, Hyderabad
Source of Support: Study was sponsored by Dr. Reddy’s Laboratories Hyderabad, India, Conflict of Interest: Dr. M S Latha, and Dr. Binny, Krishnan Kutty are the employees of Dr. Reddy’s Laboratories Ltd., which is manufacturing Nimesulide spray in India. These authors are stakeholders having financial stakes in Dr. Reddy’s Laboratories Ltd. by means of salary, company stocks or both. Dr. Mazharuddin Ali Khan, Dr. Madhusudhan Rao, Dr. Madan Mohan Reddy, Dr. Dutta Tamloorker and Dr. Vishesh G. do not have any conflict of interest
| Abstract|| |
Aim: To evaluate the efficacy and safety of nimesulide 1% w/w spray in minor soft-tissue injuries in adult Indians through a multicentric, open-labeled, phase III trial.
Materials and Methods: 125 eligible patients, who met the selection criteria and gave written informed consent, were screened, enrolled, and treated with nimesulide 1% spray for seven days. Patients were assessed at baseline, day 1, day 4, and day 8 for efficacy and safety. Primary efficacy variable pain intensity, was measured using a NRS 1-100 mm (numerical rating scale). Secondary efficacy variables were degree of inflammation and edema and degree of functional impairment; overall assessment of efficacy was done by patient (patient global assessment - PGA) and by investigator (investigator global assessment - IGA) on days 4 and 8.
Result: There was a statistically significant reduction in the NRS score, degree of pain, edema (inflammation), and improvement in functional impairment on days 4 and 8 and in serum creatine kinase levels on day 8 in comparison with baseline. Global assessment of efficacy on day 8 was rated as "very good (21%)," "good (67.70%)," and "fair (11.30%)" by investigators and "very good (25%)," "good (58.90%)," and "fair (16.1%)" by patients. Two mild adverse events were reported in two patients, which resolved without any intervention. One (local irritation) was reported as not related, while the other (itching sensation) was probably related to the study drug.
Conclusion: Nimesulide 1% spray was effective with a good safety profile and can be considered is a good alternative to oral analgesic therapy in minor soft-tissue injuries.
Keywords: Global assessment of efficacy, nimesulide spray, NRS score, signs of inflammation, soft-tissue injury
|How to cite this article:|
Khan MA, Rao M, Reddy MM, Tamloorker D, Gumdal V, Latha MS, Krishnankutty B. A phase III trial evaluating the efficacy and tolerability of nimesulide 1% spray in patients with soft-tissue injuries. Int J Crit Illn Inj Sci 2013;3:18-24
|How to cite this URL:|
Khan MA, Rao M, Reddy MM, Tamloorker D, Gumdal V, Latha MS, Krishnankutty B. A phase III trial evaluating the efficacy and tolerability of nimesulide 1% spray in patients with soft-tissue injuries. Int J Crit Illn Inj Sci [serial online] 2013 [cited 2019 Dec 12];3:18-24. Available from: http://www.ijciis.org/text.asp?2013/3/1/18/109414
| Introduction|| |
Musculoskeletal injuries which are usually self-resolving, resulting due to normal daily activities and sports are one of the most common clinical presentations. Nevertheless, they may cause considerable discomfort as a consequence of inflammation, pain, and marked functional limitation, which in severe cases, can cause absence from work and restricting the person from performing routine daily activities. Obesity is a contributing factor and elderly are more prone to these injuries.
Injury to ligament is classified in to three grades.
Grade I: tearing of only few fibers of the ligament characterized by pain with little or no requirement of immobilization and the patient usually can return to work within 10 days.
Grade II: tearing of third to almost all fibers of ligament, characterized by instability and requiring 2-4 weeks of immobilization.
Grade III: complete tear of ligament with tendency to give away, requiring a surgical repair.
Van Rijn et al. have reported a rapid decrease in pain within the first 2 weeks in case of acute ankle sprains. There have been reports of persisting pain in 5-33% of patients, even after one year full recovery was reported in 36%-85% within three years. 
Nonsteroidal anti-inflammatory drugs (NSAIDs) have often been used to facilitate improvement in symptoms such as pain, functional impairment, and swelling  than the conventional treatment of RICE (rest, ice, compression, and elevation).  Oral preparations of NSAIDs have the disadvantage of causing adverse events (AEs).  Topical preparations are preferred for their rapid onset of action, ease of administration, less systemic absorption and thus less AEs. 
Many topical preparations of NSAIDs are used as analgesics in nonserious arthritic conditions and/or soft-tissue injuries. A topical formulation brings the drug directly to the site of action, thereby increasing its local bioavailability, avoiding hepatic and gut first pass metabolism, thus minimizing systemic exposure and exerting its therapeutic activities locally without significant absorption in the blood. These are preferred in soft-tissue musculoskeletal disorders such as sprains, strains, tendinitis, bursitis, and other minor traumatic lesions due to their potential advantages. 
Topical nimesulide is available in our country as a gel preparation for local application in the treatment of a variety of painful inflammatory conditions including those associated with sprains, strains, tendinitis, tenosynovitis, and low back pain.  Its anti-inflammatory action has been found to be higher in comparison with diclofenac or piroxicam gels.  Greater analgesic action of nimesulide has been observed as compared to diclofenac when both were applied topically on the skin as gel formation. On the most important derived variable in the assessment of analgesic effect viz., total pain relief, nimesulide gel induced significantly greater and also faster analgesic effect as measured at 15, 30, and 120 min post-treatment. 
Against this backdrop, we conducted a clinical trial of efficacy and tolerability of nimesulide 1% w/w spray in the treatment of minor traumatic lesions of soft tissues.
| Materials and Methods|| |
One hundred and twenty five eligible patients from five centres, who met selection criteria, were screened, enrolled, and treated with nimesulide 1% w/w spray.
This was a prospective, open, multicentric, phase III trial conducted in India with an objective to assess the efficacy and tolerability of nimesulide spray, an aerosol formulation containing nimesulide 1% w/w in the treatment of minor traumatic lesions of soft tissues.
| Materials and Methods|| |
This study was conducted in accordance with Good Clinical Practices and the Declaration of Helsinki. The protocol, statement of informed consent, and other study related documents were approved by Drugs Controller General of India and the Institutional Ethics committees' prior to the initiation of study. Written informed consent was obtained from each subject prior to entry into the study, in compliance with Schedule Y.
Eligible adult patients aged between 16 and 60 years with a clinical diagnosis of minor traumatic lesions of soft tissues (bruises, sprains, strains, tendinitis, and tenosynovitis) were included in the study. Those with history of hypersensitivity to aspirin and/or other NSAID's, active peptic ulcer disease, major hepatic, renal, and hematological disease were excluded. Those who consumed aspirin and otherNSAID's, systemic/local corticosteroids within one week of commencing the study, with injuries requiring immobilization, orthopedic/surgical intervention, skin disease that was either local to the site of application, and intermittent, or intercurrent medical conditions requiring the use of NSAID's preparations were also excluded from the study. Pregnant or lactating women were not screened.
Enrolled patients were treated with nimesulide 1% spray for seven days. During the study period, patients visited the site at baseline, day 1, day 4, and day 8 (end of study visit) and were assessed for efficacy and AEs at each visit.
Primary efficacy variable was pain intensity which was measured on day 1, day 4, and day 8 using a NRS 1-100 mm (numerical rating scale). 
Secondary efficacy variables were degree of inflammation and edema (graded 0 -absence of pain to grade 3 - severe pain) and degree of functional impairment (grade 0 - no stiffness with full range of movement to grade 4 - complete fixation).  Overall assessment of efficacy was done separately by patient -patient global assessment (PGA) and by investigator - investigator global assessment (IGA), using a rating scale with ordinal assessments, on days 4 and 8.
Baseline characteristics of the study population were described by considering all patients enrolled into the trial. Evaluations of safety parameters were considered on a per protocol basis in patients who have completed one week therapy.
All patients who completed at least one follow-up visit (day 4) were considered as last observation carried forward (LOCF) population. This was used to handle the drop out in the study. Evaluation of efficacy parameters was done on ITT (intention to treat) basis. The data of the visit 2 were carried forward to the last visit (day 8) and analyzed.
Paired t test, Wilcoxon-signed rank test, and one-way ANOVA test with post-hoc Bonferroni test were used in this study for analysis.
Primary Efficacy Assessment - Pain intensity was compared using paired t test.
Secondary Efficacy Assessments - Degree of pain intensity, edema (inflammation), and degree of functional impairment were analyzed and compared using Wilcoxon signed-rank test.
IGA and PGA were reported descriptively.
All biochemical parameters were analyzed using paired t-test technique.
The analysis was done using the licensed Statistics/Data Analysis software Stata tm version 10. (Stata Corp, College Station, TX) © 1984-2008.
| Results|| |
One hundred and twenty five patients of both gender (males = 43.2% and females = 56.8%), aged between 18 and 60 years were enrolled in the study with a mean age of 36.68 years (±11.46 SD), median 35, minimum 18, and maximum of 60 years. One hundred and twenty patients completed one week therapy [Figure 1]. Five patients dropped out of the study.The details of the primary diagnosis are summarized in [Table 1].
| Efficacy Results|| |
Primary efficacy analysis
There was a statistically significant reduction (P < 0.001) in the NRS score on day 4 (41.73 ± 10.99) and day 8 (end of therapy 16.98 ± 11.93) as compared to baseline (63.68 ± 15.45) indicating a reduction in the severity of pain [Figure 2]. A statistically significant difference (P < 0.001) was observed on day 4 (mean =21.95) and day 8 (mean =46.70) when compared to baseline.
Secondary efficacy analysis
Degree of pain, edema (inflammation), and functional impairment on days 4 and 8 were significantly reduced in comparison with baseline.
There was statistically significant (P < 0.001) reduction in the pain intensity on days 4 and 8 as compared to baseline [Figure 3].
At base line visit, 124 patients had pain and by the end of the study 37 (29.84%) patients were relieved of pain and 84 (67.7%) had only mild pain [Figure 4].
Of 35 patients with severe pain at baseline, 33 (94.2%) had no/mild pain at the end of the study. Of 54 patients with moderate pain at the screening, 53 (98.15%) had no/mild pain at the end of the study.
Degree of inflammation
There was a statistically significant reduction (P < 0.001) in the degree of inflammation and edema on days 4 and 8 as compared to baseline [Figure 5].
At base line, inflammation and edema were present in 110 patients and by end of the study, 91 (82.72%) were relieved of these symptoms [Table 2].
|Table 2: Change in response in pain, edema, and impairment of function from screening to end of study|
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There was a statistically significant reduction (P < 0.001) in the degree of functional impairment on days 4 and 8 as compared to baseline [Figure 6].
|Figure 6: Change in mean functional impairment scale during different visits|
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Of 121 patients with functional impairment at enrollment, 77.69% had no functional impairment at the end of the study. Only 30 (24.79%) patients had some degree of functional impairment of which 28 (93.33%) had grade 1 and two (6.66%) patients had grade 2 degree of impairment showing a significant improvement in degree of impairment [Figure 7].
Global assessment of efficacy at the end of therapy was rated as "very good (21%)," "good (67.70%)," and "fair (11.30%)" by the investigator [Figure 8] and was rated as "very good (25%)," "good (58.90%)," and "fair (16.1%)" by the patients.
Paracetamol 500 mg was given as rescue medication to four (3.33%) patients.
Summary of AEs
Two AEs were reported in two patients in the study and both were mild in severity. One event (local irritation) was not related to nimesulide spray while the other (itching sensation) was probably related. AEs are summarized in [Table 3].
Both the AEs were observed with the first use of the drug which resolved spontaneously, without any intervention.
Clinical laboratory tests were performed for each patient prior to the start of therapy (at screening) and at the end of study (day 8).
There was a statistically significant reduction (P = 0.0094) in serum creatine kinase levels at the end of therapy in comparison with baseline. Reduction in lymphocyte and RBC counts though found to be statistically significant, were clinically insignificant [Table 4].
|Table 4: Dispersion of laboratory parameters at baseline and end of study visit|
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| Discussion|| |
NSAIDs are the first line of treatment in the management of musculoskeletal injuries. Administration of systemic NSAIDs is associated with AEs mainly dyspeptic symptoms which limits its use especially in elderly patients. Topical application of analgesics is useful to obtain the desired optimal therapeutic response with minimal adverse effects and is recommended by National Institute for Health & Clinical Excellence (NICE) guidelines prior to oral therapy, when possible.  Nimesulide relatively Cox-2 selective NSAID, has been used frequently by the physicians in the management of acute pain as it is associated with less gastric effects. Topical preparations of nimesulide have been found to be effective for acute pain in earlier studies. , Sengupta et al. have observed that topical nimesulide exhibited greater analgesic activity in human volunteers compared to that of piroxicam, diclofenac, and placebo.  Better symptomatic relief in terms of pain and inflammation in acute musculoskeletal injuries was observed with topical nimesulide when compared to piroxicam and diclofenac gel. This study also showed that topical nimesulide had superior efficacy and tolerability. 
Literature search did not provide information on nimesulide 1% spray as this formulation is being introduced for the first time. The result of our study was comparable to the previous studies done with topical nimesulide.
In our study, NRS assessment, severity of pain, degree of inflammation, and functional impairment were assessed to evaluate efficacy of topically applied nimesulide 1% spray. Of the 124 patients who had pain of various grades at baseline showed statistically significant reduction in the pain severity at the end of therapy, which is similar to that reported in clinical trial conducted by Dhaon et al. in 1998.  Inflammation and edema were relieved totally in 83.8% patients at the end therapy, which is similar to the findings of the study by Dhaon et al. in 2000 (86.87%). 
Gupta et al. and Dhaon et al., have also reported good results in terms of analgesia and improvement in physical functions after topical application of nimesulide gel.
IGA and PGA were rated as good by both investigators (88.7%) and patients (83.9%), which is comparable to the earlier study (data on file) done with nimesulide spray by Dr. Reddy's Laboratory in 2002.
Laboratory assessments done at baseline and at the end of study did not reveal significant changes except for creatinine kinase. Statistically significant reduction in the serum creatine levels observed in our study could be attributed to the healing of injuries.
Two mild AEs reported in this study, without any serious adverse events, indicate that the drug was well tolerated among our study population. Overall treatment compliance was very good inferring that this formulation is well accepted by the patients and enhances the treatment adherence.
| Conclusion|| |
Local application of NSAIDs has shown to possess benefic therapeutic effects with minimal systemic effects, thus having an advantage over oral dosage forms. As there is safety concern for oral NSAIDs, topical application is more welcome in the management of soft-tissue injuries. Ease of application associated with rapid relief of symptoms will enhance patient compliance.
The results of our study indicate that there was a significant symptomatic improvement in pain, inflammation, and functional impairment, following treatment with nimesulide 1% spray. The results also show that there is an early onset of response which benefits the patient. The regimen has also been found to be well tolerated. In conclusion, nimesulide 1% spray is a good alternative to oral NSAID therapy in case of minor traumatic lesions of soft tissues.
| Acknowledgement|| |
This study was supported by Dr. Reddy's Laboratories Ltd., Hyderabad, India. We acknowledge Dr. Paul AD for his valuable guidance. We thank Dr. Ruchi Dhall for supervision and Mr. M Alim, CRA for monitoring this trial; we extend our special thanks to Mrs. Seetha for her contribution in data entry.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7], [Figure 8]
[Table 1], [Table 2], [Table 3], [Table 4]