Polmacoxib 2mg in patients with mild to moderate idiopathic osteoarthritis of hip/knee-a randomized, double-anonymous study

ABSTRACT

Aim

Polmacoxib, a new COX-2 inhibitor with carbonic anhydrase (CA) inhibitory action, is expected to help minimize the adverse effects associated with other NSAIDs, like GI (gastrointestinal) and CV (cardiovascular) system- related issues. The comparative efficacy and safety of polmacoxib 2 mg (manufactured by Hetero Labs Limited) versus celecoxib 200 mg (manufactured by Hetero Labs Limited) were assessed in this randomized, double-anonymous, clinical study in Indian adult patients diagnosed with idiopathic osteoarthritis (OA) of the

Patients & Methodology

18 years and older patients of either sex, clinically and radiographically diagnosed idiopathic knee or hip OA were randomized to receive either polmacoxib or celecoxib in a 1:1 ratio. All patients were assessed with various pain measuring scales and recorded the scores at the end of weeks 3 and 6.

Conclusion

The data for all the pain assessment scores were analyzed, and polmacoxib was found to be a non-inferior therapeutic agent compared to celecoxib in terms of safety and efficacy.

(https://ctri.nic.in/CTRI/2022/05/042923)

A NEW PAIN RELIEF MEDICATION – CLINICAL STUDY IN INDIAN PATIENTS WITH OSTEOARTHRITIS - PLAIN LANGUAGE SUMMARY

Gastric and cardiovascular system- related issues are the expected unwanted effects with the use of pain killers. Polmacoxib, a new drug for pain with dual action and lesser side effects, is expected to help in minimizing the unwanted effects like with other NSAIDs. The efficacy and safety of polmacoxib versus celecoxib were assessed in this clinical study in Indian adult patients with osteoarthritis (OA) of the hip or knee with no known reason. Adult male and female patients with knee or hip OA were taken into the study, polmacoxib or celecoxib were given to the patients in equal ratio, after obtaining a consent, which explains about the untoward effects of the treatment drugs and other study details. The severity of the pain in all the patients was estimated with standard pain measuring scales and recorded the scores at the end of weeks 3 and 6. Conclusion: The data for all the pain assessment scores were analyzed, and polmacoxib was found to be a non-inferior therapeutic agent compared to celecoxib in terms of safety and efficacy.

1. Introduction

Degeneration of articular cartilage is the indicative of advanced stage of osteoarthritis (OA), resulting in disability. In the population of elderly patients aged 60 and older, 10% have reported mobility-related disabilities attributed to osteoarthritis (OA). This condition is characterized by joint pain that worsens with activity and improves with rest, as well as stiffness, which can lead to a decline in functional abilities. These clinical manifestations are generally confirmed by further radiographic techniques.

Approximately 50% of the 50-year-old population of the USA suffers from arthritis, and of them about 30% of obese adults are arthritic patients. Osteoarthritis is the most commonly occurring type of arthritis [1]. The main goals of treatment for osteoarthritis (OA) are to manage pain and enhance functionality, as there is currently no cure for the condition. Various treatment strategies are available, including physical exercise, weight management, joint care, surgical interventions, and pain medication. Among these, pain-relieving drugs, particularly non-steroidal anti-inflammatory drugs (NSAIDs), serve as the cornerstone of treatment. Traditional NSAIDs act as nonselective inhibitors of cyclooxygenase enzymes, targeting both COX-1 and COX-2, which play a crucial role in the processes of inflammation and pain [2,3]. COX-1 plays a crucial role in the synthesis of prostaglandins and is believed to safeguard the gastrointestinal mucosa, whereas COX-2 expression rises in response to inflammation and is implicated in the mechanisms of both inflammation and pain. [4,5]. Traditional NSAIDs are associated with a high risk of dyspepsia, hemorrhage of the GIT, ulceration, or gastrointestinal (GI) perforation, including serious GI diseases [6].

Selective COX-2 inhibition can exhibit the inflammatory effect and will not interfere with COX-1 enzyme synthesis, which favors protective prostaglandin synthesis, reducing damage to the GI tract. Celecoxib is a highly selective COX-2 inhibitor that has been shown to decrease gastrointestinal adverse events (AEs) when compared to traditional NSAIDs. [7,8]. Although gastrointestinal-related adverse events (AEs) were reduced, certain COX-2 inhibitors exhibited cardiovascular AEs that were specific to individual compounds rather than a common effect associated with all COX inhibitors. [9]. Therefore, research for further alternate COX-2 inhibitors with reduced cardiac complications was required.

Polmacoxib (CG100649; Acelex), a new COX-2 inhibitor, was approved in South Korea in February 2015 for treating OA [10,11]. Unlike other NSAIDs, polmacoxib inhibits the COX-2 and binds to carbonic anhydrase (CA) with high affinity [12]. Polmacoxib, a dual inhibitor of COX-2 and human CA, does not inhibit COX-2 in CA- rich tissues (i.e., CVS), but fully inhibits COX-2 in CA-deficient tissues (i.e., inflamed joints).

Although there had been clinical studies on polmacoxib, there has been no known Indian clinical trials till date. This randomized, multicentric, parallel, double-anonymized, single-controlled, comparative phase III clinical trial was aimed to evaluate the efficacy and safety of polmacoxib 2 mg versus celecoxib 200 mg in Indian patients with idiopathic (primary) OA of hip/knee. Celecoxib 200 mg is approved for osteoarthritis of hip/knee, hence selected as active comparator to evaluate non-inferiority of polmacoxib 2 mg over 6 weeks of treatment period.

2. Methodology

This research was carried out in compliance with the good clinical practice (GCP) standards established by the Central Drugs Standard Control Organization (CDSCO), the New Drugs and Clinical Trials Rules (2019), the Indian Council of Medical Research (ICMR), the ethical guidelines for biomedical research involving human subjects as outlined in the Declaration of Helsinki (2013), the International Conference on Harmonization guidelines (ICH-GCP E6), relevant regulatory requirements, and applicable standard operating procedures (SOPs). The study was registered with the Clinical Trials Registry of India (CTRI/2022/05/042923). All study-related procedures and assessments were conducted only after securing informed consent from each participant.

2.1. Study design

This was a randomized, multicentric, parallel, double-anonymous, two-arm, active-controlled, comparative study. It comprised a screening phase of two weeks, a treatment phase of six weeks, and a safety follow-up phase of two weeks. Patients were evaluated for study eligibility based on the inclusion and exclusion criteria and were randomized as per the sequence set, in a 1:1 ratio between the polmacoxib (2 mg) and celecoxib (200 mg) arms.

2.2. Study participants

Adult male or female patients aged 18 years and above with clinical and radiographic diagnosis of idiopathic (primary) knee or hip OA as per the American College of Rheumatology criteria; chronic OA pain for ≥3 months; WOMAC pain score in the index joint ≥ 2 at screening and baseline; VAS recording of ≥40 mm; grade ≥ 2 of Kellgren-Lawrence system of OA classification; and willing to share written, signed, and dated informed consent to participate in the clinical trial were included in the study from 15 tertiary care trauma and orthopedic centers throughout India (EC approval details are provided as supplementary data) from July 2022 to Jan 2023 (demographic and baseline characteristics are given in Table 1).

Table 1.

Demographics and baseline characteristics – all patients.

Characteristics		Polmacoxib 2mg N = 147 n (%)	Celecoxib 200mg N = 147 n (%)	Overall N = 294 n (%)	Polmacoxib 2mg Vs Celecoxib 200mg (p-values**)
Gender, n (%) [a]					0.5383
Female		94 (63.95)	100 (68.03)	194 (65.99)
Male		53 (36.05)	47 (31.97)	100 (34.01)
Age (Year) [b]					0.7358
Mean ± SD		51.57±10.92	51.12±11.86	51.35±11.38
Height (Cm) [b]					0.6424
Mean ± SD		159.05±8.46	159.51±8.42	159.28±8.43
Weight (Kg) [b]					0.9867
Mean ± SD		63.98±9.98	63.96±10.95	63.97±10.46
BMI (kg/m2]) [b]					0.7789
Mean ± SD		25.31±3.54	25.18±4.18	25.24±3.87
BSA (m2) [b]					0.6779
Mean ± SD		1.66±0.15	1.67±0.18	1.66±0.16
Ethnicity, n (%) [a]					0.4115
Hispanic/Latino		0 (0)	2 (1.36)	2 (0.68)
Not Hispanic/Latino		135 (91.84)	136 (92.52)	271 (92.18)
Unknown		12 (8.16)	9 (6.12)	21 (7.14)
Race, n (%) [a]					0.7873
Asian		147 (100)	147 (100)	294 (100)
WOMAC Score Details
Pain Subscale [#]		13.32	13.24	13.28	0.8107
Physical Function Subscale [#]		4.71	4.84	4.77	0.4755
Stiffness Subscale [#]		46.40	45.59	46.00	0.4552
Visual Analogue Scale For Pain Score (VAS) [#]		62.59	61.64	62.12	0.5810
Study Joints
Knee-Right		87 (59.18)	79 (53.74)	166 (56.46)
Knee-Left		60 (40.82)	70 (47.62)	130 (44.22)
Hip-Right		2 (1.36)	3 (2.04)	5 (1.70)
Hip-Left		2 (1.36)	3 (2.04)	5 (1.70)
Stiffness < 30 minutes [*]		114 (77.55)	121 (82.31)	235 (79.93)	0.2314
Is Patient having chronic pain for ≥ 3 month from OA [*]		146 (99.32)	146 (99.32)	292 (99.32)	1.0000
Age > 50 [*]		81 (55.10)	74 (50.34)	155 (52.72)	0.4834
Kellgren-Lawrence OA Classification Grade	Garde 0	0 (0)	0 (0)	0 (0)	0.9029
	Grade 1	0 (0)	0 (0)	0 (0)
	Grade 2	90 (61.22)	92 (62.59)	182 (61.90)
	Grade 3	53 (36.05)	50 (34.01)	103 (35.03)
	Grade 4	4 (2.72)	5 (3.40)	9 (3.06)

Abbreviation: SD, standard deviation.

[a] p-values are obtained by performing Fisher’s exact test.

[b] p-values are obtained by performing T-test.

*p-values are obtained by performing Fisher’s Exact Test.

^#p-values are obtained by performing T-test; Grade 0 (None): Definite absence of x-ray changes of osteoarthritis; Grade 1 (Doubtful): Doubtful joint space narrowing and possible osteophytic lipping; Grade 2 (Minimal): Definite osteophytes and possible joint space narrowing; Grade 3 (Moderate): Moderate multiple osteophytes, definite narrowing of joint space and some sclerosis and possible deformity of bone ends; Grade 4 (Severe): Large osteophytes, marked narrowing of joint space, severe sclerosis and definite deformity of bone ends.

2.3. Interventions

Patients were administered either polmacoxib 2 mg or celecoxib 200 mg (manufactured by Hetero Labs Limited) once daily orally after breakfast for 6 weeks. All patients were given anonymized study medication once randomized and were asked to take study medication at home from next day onwards.

2.4. Study outcome measures and endpoints

At week 6, the alteration in the WOMAC pain subscale from the baseline was evaluated and regarded as an indicator of the primary outcome. The secondary outcome measures included the change in the WOMAC pain subscale from baseline to week 3, the total WOMAC OA score, the WOMAC subscales for physical function and stiffness, pain evaluated using the VAS scale, as well as the global assessments from both the subjects and physicians, along with the mini osteoarthritis knee and hip quality of life from baseline to week 6.

The effectiveness was assessed using the WOMAC-OA index questionnaire. The 5-point Likert scale version of the WOMAC-OA index was used in this study. It has 24 mandatory and 3 optional questions covering pain, stiffness and difficulty functional aspects. WOMAC-OA index questionnaire was administered at baseline, week 3, and 6. Global assessments were performed by subject and physician (SGA & PGA) based on a 7-point Likert scale, assessing the overall pain during the past week. SGA and PGA assessments were done at weeks 3 and 6. The VAS scale utilized a range from 0 mm, indicating no pain, to 100 mm, representing extreme pain. Patients were instructed to indicate their level of pain by marking a vertical line on this scale, reflecting their pain experience over the preceding week. Patient’s pain was assessed by using VAS scale (0-100 mm) at week 3 and 6. The mini-OAKHQOL is composed of five dimensions (subscales): physical activities, mental health, pain, social support, social functioning, sexual life, professional life, and the apprehension of becoming dependent. Each item was evaluated on a numerical rating scale ranging from 0 to 10, and the average score for each dimension was calculated. Patients were asked to complete the OAKHQOL questionnaire at weeks 3 and 6.

The safety investigations included hematology, serum biochemistry, urine analysis, pregnancy test at screening and at week 6. A total of 12 lead ECG at screening, baseline, week 3 and week 6, serology tests (HIV, HCV, and HBV) at screening, X-ray of the index joint (AP and lateral view) at screening, physical examination, and assessments of vital signs, including body temperature, blood pressure, respiratory rate, and heart rate, were conducted. Adverse events, encompassing both serious and non-serious occurrences, were documented throughout the duration of the study.

The primary data from all the study centers were recorded in electronic case report forms (eCRF), and site personnel were trained to take care for entering all the requested data into the eCRF.

2.5. Sample size

Sample size was calculated for the primary efficacy end point of change in WOMAC pain subscale score from baseline to week 6. At least 132 evaluable patients in each group were required to show non-inferiority of polmacoxib to celecoxib with 90% power, 11 units of standard deviation, 2.5% level of significance and −2 (−10%) of non-inferiority margin. Considering 10% of dropout rate, 294 were enrolled in 1:1 treatment allocation ratio (i.e., polmacoxib − 147 and celecoxib − 147, demographic details are given in Figure 1).

Figure 1.

Patient disposition.

2.6. Randomisation

The randomization sequence was generated by permuted and variable block randomization method using the latest version of SAS® statistical software (version 9.4, SAS Institute Inc., USA). Anonymized labels were generated with unique kit numbers assigned to each carton. After ensuring the eligibility criteria of the study subjects, a unique patient ID was allotted to all the study participants and the treatment was given as per the randomization schedule.

2.7. Anonymizing

Study treatment was anonymized with respect to their contents. All patients, site team including investigator, laboratory personnel, CRO team including operations and data entry teams were anonymized till the database lock.

2.8. Statistical methods

Individuals who were administered a minimum of one dose of the study medication were classified within the safety population. The intent-to-treat (ITT) population encompassed all randomized participants who satisfied the inclusion and exclusion criteria, received at least one dose of the study medication, and attended at least one post-baseline assessment of the index joint. The per-protocol (PP) population consisted of all randomized subjects who received the study medication and successfully completed the study in accordance with the protocol, without any significant protocol violations. The demographic and baseline characteristics were summarized for continuous variables, including age and height, by reporting the mean, standard deviation, median, and range. For categorical variables such as sex and race, frequencies were provided. A t-test was employed to compare the continuous variables, while Fisher’s exact test was utilized to assess the proportions of males and females.

Mean changes from baseline to later visits both primary and secondary endpoints were observed, along with the relevant statistical information. The primary endpoint was summarized and compared across treatment groups using the ANCOVA test. A significance level of p < 0.05 was established for all statistical tests conducted, with no adjustments made for multiple comparisons. Estimates of the treatment effect, including both point estimates and interval estimates with 95% confidence limits, were also presented. Adverse events (AEs) and adverse drug reactions (ADRs) were categorized by system organ class (SOC) and preferred terms, utilizing the Medical Dictionary for Regulatory Activities Terminology (MedDRA). The occurrence rates of serious adverse events (SAEs), ADRs, and AEs were analyzed across the treatment groups through Fischer’s exact test.

3. Results

3.1. Patient disposition

Overall, 294 patients enrolled in a 1:1 ratio in the two study arms and received study medication. At the end of the study, 8 patients were excluded from the PP population due to being lost to follow-up (3 patients from the polmacoxib 2 mg arm and 4 patients from the celecoxib 200 mg arm) and withdrawn consent (1 patient from the polmacoxib 2 mg arm). The remaining 286 patients completed the study. 294 patients (147 patients each in polmacoxib 2 mg and celecoxib 200 mg arms) were considered the safety population; 288 patients (144 patients each in polmacoxib 2 mg and celecoxib 200 mg arms) were considered the ITT population; and 286 patients (143 patients each in polmacoxib 2 mg and celecoxib 200 mg arms) were the PP patients.

3.2. Efficacy

WOMAC pain score decreased from 13.24 at baseline to 8.22 (mean difference 4.88; p = <0.0001) at week 6 in the polmacoxib group compared to 13.29 to 8.47 (mean difference 4.49; p = <0.0001) in the celecoxib group in ITT population and 13.37 to 8.22 (mean difference 4.90; p = <0.0001) in the polmacoxib group compared to 13.29 to 8.46 (mean difference 4.50; p = <0.0001) in PP population (Figure 2(a) and Table 2). The difference in change in mean WOMAC pain subscale score was 0.37 (95% CI −0.33, 1.07; p = 0.2950) in ITT population and 0.38 (95% CI −0.32,1.08) in PP population. The upper limit of one-sided 97.5% CI (1.07 in ITT & 1.08 in PP) of the difference in WOMAC pain subscale score between polmacoxib 2 mg and celecoxib 200 mg lies within the defined non- inferiority margin of 2 units.

Figure 2.

(a) Change in WOMAC OA pain subscale Score; (b) WOMAC-OA pain, stiffness and physical function subscale scores.

Table 2.

Change in the Mean WOMAC Pain Subscale score from baseline to week 3 and week 6.

Population	Visit	Statistics	Polmacoxib 2mg	Celecoxib 200mg	Statistics	Polmacoxib 2mg Vs Celecoxib 200mg
ITT Population	Week 3	Mean difference	2.83	2.56	Mean difference	0.27
		Std. Error	0.20	0.17	Std. Error	0.26
		Min/Max	−2.000/10.000	−2.000/10.000	95% CI	[−0.23,0.78]
		p-Value [a]	<0.0001	<0.0001	p-Value [a]	0.2877
	Week 6	Mean difference	4.88	4.49	Mean difference	0.37
		Std. Error	0.25	0.25	Std. Error	0.35
		Min/Max	−1.000/12.000	−1.000/11.000	95% CI	[−0.33,1.07]
		p-Value [a]	<0.0001	<0.0001	p-Value [a]	0.2950
PP Population	Week 3	Mean difference	2.83	2.55	Mean difference	0.28
		Std. Error	0.20	0.17	Std. Error	0.26
		Min/Max	−2.000/10.000	−2.000/10.000	95% CI	[−0.23,0.79]
		p-Value [a]	<0.0001	<0.0001	p-Value [a]	0.2744
	Week 6	Mean difference	4.90	4.50	Mean difference	0.38
		Std. Error	0.25	0.25	Std. Error	0.36
		Min/Max	−1.000/12.000	−1.000/11.000	95% CI	[−0.32, 1.08]
		p-Value [a]	<0.0001	<0.0001	p-Value [a]	0.2863

[a] P-values are obtained by performing Paired T-test.

Figure 2(b) explains the decrease of WOMAC-OA total score from baseline to week 3 and week 6 in both polmacoxib and celecoxib groups. Apart from pain subscale score, physical function and stiffness scores decreased from baseline to week 3 and week 6 similarly in both the groups.

The VAS pain scale score decreased from baseline (62.37 in ITT & 62.47 in PP) to week 3 (50.19 in ITT & 50.17 in PP) and week 6 (40.58 in ITT & 40.49 in PP). The difference in VAS score decreases from baseline to Week 3 (ITT − 0.17, 95% CI −2.96, 3.29; p = 0.9173 & PP − 0.15, 95% CI −2.99, 3.30;p = 0.9242) and Week 6 (ITT − 0.50, 95% CI −3.33, 4.33; p = 0.7971 & PP − 0.49, 95% CI −3.35, 4.33;p = 0.8009) were similar for polmacoxib 2 mg and celecoxib 200 mg over 6 weeks of treatment (Figure 3).

Figure 3.

Summary of pain score measured by VAS.

After a duration of 3 weeks, polmacoxib demonstrated SGA scores that were comparable to those of celecoxib, reflecting similar enhancements in the signs and symptoms of osteoarthritis (Figure 4(a,b)). Additionally, polmacoxib showed PGA scores that were on par with celecoxib, suggesting similar improvements regarding osteoarthritis signs and symptoms (Figure 4(c,d)). Patients quality of life, measured by using Mini Osteoarthritis Knee and Hip Quality of Life (OAKHQOL) (Figure 5), improved over 6 weeks of treatment in both Polmacoxib 2 mg group and Celecoxib 200 mg group. Physical function, mental health, pain and social support aspects of OAKHQOL have shown better improvement compared other parameters such as sexual life, social functioning, professional life and fear of dependency.

Figure 4.

(a,b) Summary of subjects global assessment (SGA) at week 3 and week 6; C&D summary of physicians global assessment (PGA) at week 3 and week 6.

Figure 5.

Mini osteoarthritis knee and hip quality of life (OAKHQOL) score from baseline to week 3 and week 6.

3.3. Safety

A total of 294 patients were included in the safety population of the present study, comprising 147 patients from each treatment arm.

Overall, 40 AEs were reported by 39 patients, 18 (12.24%) in the polmacoxib 2 mg arm and 21 (14.29%) in the celecoxib 200 mg arm (Table 3). The most frequently reported AEs were from the gastrointestinal disorders (14 AEs in polmacoxib group and 15 AEs in celecoxib group). Abdominal pain was the most common AE, reported in 8 instances (3 AEs from polmacoxib 2 mg and 5 AEs from the celecoxib 200 mg arm); followed by dyspepsia, reported in 7 instances (3 AEs in the polmacoxib 2 mg arm and 4 AEs in the celecoxib 200 mg arm).

Table 3.

Summary of adverse events.

Description	Polmacoxib 2mg N=147 n (%) E	Celecoxib 200mg N=147 n (%) E
Any AE	18 (12.24) 18	21 (14.29) 22
Any TEAEs	18 (12.24) 18	21 (14.29) 22
Any Serious TEAEs	0 (0) 0	0 (0) 0
Any TEAEs due to Study Drug	13 (8.84) 13	17 (11.56) 17
Any Serious TEAES due to Study Drug	0 (0) 0	0 (0) 0
Any Fatal/Life-Threatening due to Study Drug	0 (0) 0	0 (0) 0
Any Grade 1 TEAEs	13 (8.84) 13	17 (11.56) 18
Any Grade 2 TEAEs	5 (3.40) 5	4 (2.72) 4
Any TEAEs leading Withdrawal/Discontinuation from the Study	0 (0) 0	0 (0) 0
Any TEAEs leading treatment with Concomitant Medication	7 (4.76) 7	14 (9.52) 15
TEAEs Outcome
Improved/Recovery	1 (0.68) 2	0 (0) 0
Resolved with Sequelae	3 (2.04) 3	0 (0) 0
Resolved without Sequelae	14 (9.52) 14	21 (14.29) 22

The AEs reported in the present study were mild in severity (grades 1–2 severity), and none of them were assessed as serious AEs. Thirty (10.20%) AEs were assessed as related to the study drugs (13 AEs in the polmacoxib group and 17 AEs in the celecoxib group), while 10 AEs were assessed as being not related to study treatments (5 AEs each in the two treatment arms). None of the AEs required the withdrawal of patients from the study. Twenty-one patients from the study required treatment with concomitant medication due to AEs: 7 patients (4.76%) from polmacoxib 2 mg and 14 patients (9.52%) from celecoxib 200 mg arms. No SAEs were reported in this study, and no abnormal lab reports were observed during the study treatment period. Table 4 explains the treatment emergent adverse events with onset during treatment.

Table 4.

Treatment-emergent adverse events with onset during treatment period – safety population.

System Organ Class Preferred Term	Polmacoxib 2mg N=147 n (%) E	Celecoxib 200mg N=147 n (%) E
Any Treatment-Emergent Adverse Event	18 (12.24) 18	21 (14.29) 22
Gastrointestinal disorders	14 (9.52) 14	15 (10.20) 15
Abdominal pain	3 (2.04) 3	5 (3.40) 5
Abdominal pain upper	4 (2.72) 4	1 (0.68) 1
Diarrhoea	3 (2.04) 3	2 (1.36) 2
Dyspepsia	3 (2.04) 3	4 (2.72) 4
Gastritis	1 (0.68) 1	1 (0.68) 1
Gastrooesophageal reflux disease	0 0	1 (0.68) 1
Hyperchlorhydria	0 0	1 (0.68) 1
Oral mucosal eruption	14 (9.52) 14	15 (10.20) 15
Vomiting	3 (2.04) 3	5 (3.40) 5
General disorders and administration site conditions	3 (2.04) 3	3 (2.04) 4
Face oedema	1 (0.68) 1	1 (0.68) 1
Oedema peripheral	1 (0.68) 1	0 0
Pyrexia	1 (0.68) 1	2 (1.36) 3
Infections and infestations	0 0	1 (0.68) 1
Rhinitis	0 0	1 (0.68) 1
Nervous system disorders	0 0	2 (1.36) 2
Headache	0 0	2 (1.36) 2
Respiratory, thoracic and mediastinal disorders	1 (0.68) 1	0 0
Rhinitis allergic	1 (0.68) 1	0 0

Adverse events are classified by System Organ Class and Preferred Term as defined by MedDRA (version 25.0).

• Each patient will only be counted once per Preferred Term and once per System Organ Class.
• Treatment-Emergent Adverse Events are defined as those that occur after starting the study medication.
• E: Number of treatment emergent adverse events.

Each patient will only be counted once per Preferred Term and once per System Organ Class.

Treatment-Emergent Adverse Events are defined as those that occur after starting the study medication.

E: Number of treatment emergent adverse events.

4. Discussion

In this study, polmacoxib was evaluated for its safety and efficacy in Indian patients, with an intention to minimize the risk associated with most of the NSAIDs. After 6 weeks of treatment, patients were asked to provide their score index for pain, stiffness, and physical function using a well-defined, globally agreeable questionnaire for assessing the severity of OA. Treatment effects were confirmed by various sensitivity analyses, including PP population and observed cases without imputation for missing values.

The mean change in WOMAC pain subscale scores over a 6-week period showed a difference of 0.37 (95% CI, −0.33 to 1.07, p = 0.2950) between polmacoxib and celecoxib in the intention-to-treat (ITT) analysis, and a difference of 0.38 (95% CI, −0.32 to 1.08, p = 0.2863) in the per-protocol (PP) analysis. Notably, the upper confidence interval remained within the pre-defined non-inferiority margin of 2. Following a three-week treatment period, patients receiving polmacoxib demonstrated higher PGA scores than those treated with celecoxib. These results indicate that polmacoxib 2 mg offers quick alleviation of osteoarthritis signs and symptoms, potentially exhibiting a quicker onset of action compared to celecoxib.Lee M et al (2017) [13] reported a difference of 0.6 ± 0.79 (−0.9 to 2.2) in ITT and 0.3 ± 0.92 (−1.5 to 2.1) in PP population in WOMAC pain score (11-point Likert version). Our study has shown higher rates of “much improved” or “very much improved” by week 6 in the polmacoxib (72.92%) and celecoxib (70.13%) compared to polmacoxib (16.7%), celecoxib (12.1%) groups in Lee M et al (2017) [13].

About 10% of patients from both the groups reported GI related AEs. Less than 5% of the study participants reported non-GI AEs that occurred within the first two weeks of the therapy and most of them recovered within a week without any intervention. Based on the 6 weeks long study, polmacoxib was said to be well-tolerated with an acceptable safety profile, which is comparable to celecoxib. However, a long-term study is required to ascertain more safety information. Polmacoxib and celecoxib had shown similar safety profiles like other COX-2 inhibitors and a reduced incidences of GI related AEs were observed, compared to other NSAIDs [7].

The limitation of this study includes, no placebo arm was used to test the comparator’s sensitivity, short treatment period of 6 weeks and most of the patients included were of knee OA. Additional long-term follow-up is required to confirm the long-term efficacy and safety of polmacoxib, including its CV safety profile. This study included patients from Indian subcontinent only. Larger studies with diverse populations are needed to standardize these findings to different populations. In addition, the results of this study were limited to knee joint OA only due to very low enrollment of patients with hip joint OA.

5. Conclusion

Polmacoxib 2 mg demonstrated a positive tolerance profile and proved to be non-inferior in efficacy when compared to celecoxib during a six-week treatment period in an Indian cohort with osteoarthritis (OA). This medication may represent a viable analgesic alternative, presenting fewer gastrointestinal side effects than traditional nonsteroidal anti-inflammatory drugs commonly prescribed for OA.

Correction Statement

This article has been corrected with minor changes. These changes do not impact the academic content of the article.

Funding Statement

Sponsorship for this study was provided by Hetero Labs Limited, Hyderabad, India.

Article highlights

Methodology

• A randomized, multicentric, parallel, double-blind, two-arm, active-controlled, comparative study was conducted in adult patients of either sex aged 18 years and above with clinical and radiographic diagnosis of idiopathic (primary) knee or hip OA as per theAmerican College of Rheumatology criteria.

• WOMAC pain subscale, WOMAC-OAindex, Global assessments were performed by subject and physician (SGA &PGA) based on a 7-point Likert scale, assessing the overall pain at weeks 3 and 6.Results

• Overall, 294 patients enrolled in a 1:1 ratio in the two study arms and received study medication.

• At the end of the study, 8 patients were excluded from the PP population due to being lost to follow-up (3 patients from the polmacoxib 2 mg arm (ITT 144; PP 143) and 4 patients from the celecoxib 200 mg arm (144 ITT; 143 PP)) and withdrawn consent (1 patient from the polmacoxib 2 mg arm).Efficacy

• A mean change of 4.88(p = <0.0001) was observed in WOMAC pain score from baseline to week 6 in thepolmacoxib group compared to 4.49 (p = <0.0001) in the celecoxib group in ITTpopulation; and in PP population, a mean difference of 4.90 (p = <0.0001) in the polmacoxib group compared to 4.50 (p = <0.0001) of celecoxib group, were observed.Safety

• Of 40 AEs reported, 30 AEs were assessed as related to the study drugs (13 AEs in the polmacoxib (4.76%patients required concomitant medication) group and 17 AEs in the celecoxib(9.52% patients required concomitant medication) group, while 10 AEs (5 in each group) were assessed as being not related to study treatments.Conclusion

• These results indicate thatpolmacoxib 2 mg demonstrated a positive tolerance profile and proved to benon-inferior in efficacy when compared to celecoxib during a six-week treatment period in an Indian cohort with osteoarthritis (OA).

• Polmacoxib was well-tolerated with an acceptable safety profile, which is comparable to celecoxib.

Disclosure statement

The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Ethical declaration

This research was carried out in compliance with the good clinical practice (GCP) standards established by the Central Drugs Standard Control Organization (CDSCO), the New Drugs and Clinical Trials Rules (2019), the Indian Council of Medical Research (ICMR), the ethical guidelines for biomedical research involving human subjects as outlined in the Declaration of Helsinki (2013), the International Conference on Harmonization guidelines (ICH-GCP E6), relevant regulatory requirements, and applicable standard operating procedures (SOPs). The study was registered with the Clinical Trials Registry of India (CTRI/2022/05/042923). (EC approval details are provided as supplementary data). All study-related procedures and assessments were conducted only after securing written informed consent from each participant.

Supplementary material

Supplemental data for this article can be accessed online at https://doi.org/10.1080/17581869.2024.2427944

Author contributions

Shubhadeep Sinha: Conceptualization, Methodology, Review and Edit of the manuscript, Supervision. Tadikonda Bhavani Prasad: Methodology, Investigation, and Resources. Bhaskar Konatham: Methodology, Investigation, and Resources. Sreenivasa Chary Sriramadasu: Methodology, Conceptualization, Formal analysis, statistical analysis, Manuscript review and Editing. Arnab Karmakar: Methodology, Investigation, and Resources. Arun Kumar Sharma: Methodology, Investigation, and Resources. Rakesh Verma: Methodology, Investigation, and Resources. Mohan Reddy Bandi: Methodology, Project Admin, Resources. Muralidhar Panapakam: Data curation, Formal analysis, statistical analysis and reviewing of the manuscript. Srinivas Reddy Devireddy: Writing Original draft, editing, review, Visualization and literature search. Srinivas Reddy Devireddy and Shubhadeep Sinha act as the guarantor of the manuscript.

Data availability statement

The participants of this study did not give written consent for their data to be shared publicly, so due to the sensitive nature of the research supporting data is not available.