Efficacy of generic versus branded diacerein for treatment of knee osteoarthritis: A randomized control trial

Abstract

Background:

Several studies have proved that diacerein effectively treats knee osteoarthritis (OA). All studies used branded diacerein. Recently, generic diacerein has been available in several countries, with limited studies comparing the efficacy of generic and branded diacerein for knee OA treatment.

Methods:

Among 200 eligible patients, 94 were randomized to take a daily 50 mg of generic diacerein (Diaceric®); group A or branded diacerein (Artrodar®); group B for treating mild to moderate knee OA. All patients were assigned 5-visit assessments and followed until 24 weeks. The primary outcome was a visual analog scale (VAS) on the motion. The secondary outcomes were 2 patient-report outcome measures (PROMs): the Western Ontario and McMaster Universities Osteoarthritis (WOMAC) index and the Short Form-12 (SF-12), as well as 3 performance-based measures (PBMs): 5-time sit to stand test (5 × SST), the time up and go test (TUGT), and the 3-minute walk test (3MWT).

Results:

There were 47 patients in group A and 47 in group B, with no patients lost for FU. Among all patients, 79.8% were female with a mean age of 63.2 years in group A and 64.8 years in group B. The Kellgren and Lawrence (KL) grade II was the most common in both groups. There were no differences in all demographic data. At 24-week follow-up (FU), both groups had significantly improved VAS, with a 12-week earlier improvement in the branded diacerein. In addition, the PBMs, including 5 × SST and 3MWT, significantly improved from 12-week FU in both groups, with insignificantly improved WOMAC and SF-12 and no serious adverse events in either group.

Conclusion:

After a 24-week FU, the generic diacerein had similar efficacy as the branded diacerein in significantly improving VAS and PBMs: 5 × SST and 3MWT. However, the latter had a faster statistically improved VAS than the former.

1. Introduction

Osteoarthritis (OA) is the most common form of arthritis characterized by joint pain and stiffness leading to functional decline and loss in participation and quality of life. Among OA, the knee joint is the most involved, and symptomatic OA knee is highly prevalent among people over 60 years old, affecting more than 250 million worldwide.^[1–4] This disease may be known as primary OA from age-related degeneration or secondary OA after trauma around the knee joint.^[5,6] Besides knee OA causing knee symptoms, it can affect other joints in the lower limbs, resulting in changes in gait mechanics with a substantial effect on the range of motion (ROM), coronal motion arc, and moment of the ankle and hip joints. Nowadays, people tend to live longer worldwide, including Thailand. Therefore, the number of OA knee patients will most likely substantially increase. This is concerning, given the functional impairment and disability associated with this condition and its negative toll on the social and economic aspects of our society.

Currently, there are several options for knee OA treatment, including nonoperative and operative treatments.^[7,8] In nonoperative treatment, options range from no medication, such as information/education, lifestyle modification, or exercise program, to pharmacological therapy, including symptomatic slow-acting drugs for osteoarthritis (SYSADOA), hyaluronic injection, non-steroid anti-inflammatory medicines (NSAIDs), and pain killers.

Diacerein, a SYSADOA, is an anthraquinone derivative with a slow onset of efficacy after 2 to 4 weeks of treatment and a carryover effect. It stimulates the production of cartilage growth factors and slows cartilage breakdown, resulting in pain and swelling relief.^[9] While pro-inflammatory cytokines in synovial fluid play an important role in the inflammatory effect in the process of OA, diacerein primarily inhibits the interleukin-1β (IL-1β) system by reducing IL-1β activation, decreasing IL-1 receptor levels on chondrocytes, increasing IL-1 receptor antagonist production, and inhibiting NF-κB activation, ultimately downregulating IL-1 in the synovial fluid of knee OA patients.^[10–12] Due to supporting studies from animal models and clinical trials, especially in knee osteoarthritis, it has become a popular option for pharmacological OA treatment.

Although generic drugs, compared to original products, can lower the treatment cost and result in a well-controlled budget in the national healthcare system in several counties, patients, and physicians may perceive that generic drugs are less effective than their branded counterparts. Therefore, the myths about the efficacy of generic drugs need to be clarified among patients and physicians.^[13,14] Although there are several studies regarding diacerein for knee OA, most studies focused on its efficacy or compared treatment outcomes with other agents.^[15,16] Therefore, the present study aimed to compare the efficacy of the generic and original diacerein for knee OA treatment. Both the generic and original diacerein capsules claim to contain 50 mg of diacerein without any additional components or excipients. The primary outcomes were changes in the visual analog scale (VAS) on motion; the secondary outcomes were changes in 3 performance-based measures (PBMs) and 2 patient-reported outcome measures (PROMs).

2. Methods

2.1. Study design

This was a single-center, prospective, double-blinded, randomized controlled trial (RCT), approved by our institutional reviewed board (IRB) (COA No. 0536/2024 and IRB No. 0637/65) and was registered on the website of thaiclinicaltrials.org (TCTR20240514004). The study was conducted from October 2022 to December 2023. Participants and outcome assessors were blinded to the group allocations, and 1 co-investigator giving medication to the patient at each visit was blinded. All patients provided signed informed consent before the study. Participants were randomly assigned to 2 groups at a 1:1 ratio, using a randomization list generated with validated computer software in simple random sampling.

2.2. Patient selection

Patients aged 50 years or more who had been diagnosed with knee OA according to the criteria of the American College of Rheumatology,^[17] with radiographic grading of I to III by the Kellgren and Lawrence (KL) classification^[18] and knee pain on motion of at least 40 mm from a 100-mm VAS, were enrolled in the study.

Patients were excluded from the study if any of the following criteria were present: secondary OA; previous surgery on the affected knee or surgery planned within the subsequent 6 months; lower limb surgery within the last 6 months; radiographic grade IV by the KL classification; being treated with SYSADOA within 6 months or intraarticular injection (corticosteroids, hyaluronic acid) within 3 months before the enrollment; severe gastrointestinal disorders; persistent diarrhea (>3 times/24 hours) or laxative use; concomitant severe medical illness or significant co-morbidity precluding aerobic exercise at 50% to 60% maximum heart rate.

2.3. Treatment protocol

The study treatment regimen comprised either 1 capsule of branded diacerein (Artrodar®, TRB Pharma, Buenos Aires, Argentina) containing 50 mg of diacerein or 1 capsule of generic diacerein (Diaceric®, Millimed BF, Chiangrai, Thailand) containing 50 mg of diacerein. All participants were instructed to take 2 capsules daily for 24 weeks.

Participants were removed from the study if it was not in the subject’s best interest to continue the study evaluated by the principal investigator, such as a change of treatment plan to surgery, inability to tolerate the drug’s side effects, or failure to maintain the required application frequency.

2.4. Clinical outcomes

All patients were assigned 5-visit assessments, during which all patients were evaluated for all investigated parameters and followed until 24 weeks. At baseline before taking diacerein (week 0), patients were assessed for pain on motion using a 0- to 100-mm VAS, 2 PROMs using the Western Ontario and McMaster Universities Osteoarthritis (WOMAC) index and the Short Form-12 (SF-12), and 3 PBMs using the 5-time sit to stand test (5×SST), the time up and go test (TUGT), and the 3-min walk test (3MWT). During the follow-up (FU) in the 6th week, 12th week, and 24th week, all patients were again evaluated for VAS, PROMs, and PBMs. All parameters were compared to baseline values and compared between both groups.

2.5. Sample size and statistical analysis

The sample size was calculated based on the VAS difference. A 10 mm out of 100-mm reduction in VAS for pain on motion was considered the minimum difference to be detected between both groups,^[19] with a standard deviation (SD) of 19.3, based on the study by Pelletier et al.^[20] An α of 5% and a power of study (1-β) of 80% were used. Forty-seven participants were required in each of the 2 groups. Therefore, the total number of participants was 94. Data were presented as numbers and percentages for categorical variables and mean ± SD for continuous variables. Pearson’s chi-square or Fisher exact test was used to compare categorical variables. For continuous variables, a Student t test was used to compare parametric data. A comparison of the percentage of patients with increased, decreased, or stable VAS was performed using the chi-square test. One-way repeated measure ANOVA was conducted to assess the effect of time on the change in VAS, PBMs, and PROMs in each group. We assumed this study was a non-inferiority trial; therefore, a 1-sided P-value < .05 was considered statistically significant.

3. Results

3.1. Studied patients and baseline characteristics

Among 200 Thai patients assessed for eligibility, 106 were excluded from the study due to unmet criteria. The remaining 94 patients were randomized into group A: generic diacerein in 47 patients and group B: branded diacerein in 47. No patient failed to FU or complete all tests according to the studied protocol; therefore, all patients completed the study. The disposition of the patients is provided in Figure 1.

Figure 1.

CONSORT flow diagram of the studied group. CONSORT = Consolidated Standards of Reporting Trails.

The patients were predominantly female (79.8%), with a mean age of 63.2 years in group A and 64.8 years in group B. Most group A and B patients had radiographic grade II according to the KL classification (61.7% and 53.1%, respectively). The baseline characteristics of both groups A and B were not significantly different in all parameters, as shown in Table 1.

Table 1.

Demographic data of patients in groups A and B.

Clinical variables	Group A: generic diacerein	Group B: branded diacerein	P-value
	(Diaceric®)	(Artrodar®)
	(n = 47)	(n = 47)
Age (yr)	63.2 ± 9.3	64.8 ± 8.0	.072
Gender (Female), n (%)	39 (82.9%)	36 (76.6%)	.445
Height (m)	1.58 ± 0.07	1.59 ± 0.09	.723
Weight (kg)	65.7 ± 13.3	66.3 ± 12.6	.676
BMI (kg/m2)	26.10 ± 4.54	26.10 ± 4.02	.987
KL grading, n (%)
Grade I	6 (12.8%)	4 (8.5%)	.285
Grade II	29 (61.7%)	25 (53.1%)	.211
Grade III	12 (25.5%)	18 (38.4%)	.381

BMI = body mass index, KL = kellgren and lawrence radiographic classification.

3.2. Clinical results

At the 24th week, the mean VAS on motion, which gradually decreased from baseline until the final FU, became significantly different in both groups; however, group B had improved considerably VAS beginning from the 12th week. At the final FU, the VAS in groups A and B reduced from an average (±SD) of 44 ± 28 and 50 ± 29 to 31 ± 23 and 34 ± 22, respectively (P = .002 and P = .000), as shown in Table 2.

Table 2.

Comparing VAS on motion from baseline to final follow-up between groups A and B.

VAS on motion	Group A: generic diacerein (Diaceric®)			Group B: branded diacerein (Artrodar®)			P-value between groups
	Mean ± SD	95% CI	P-value within group	Mean ± SD	95% CI	P-value within group
Week 0 (Baseline)	44 ± 28	36 to 53	−	50 ± 29	41 to 58	−	.401
Week 6	47 ± 24	40 to 55	.465	46 ± 29	38 to 55	.415	.879
Week 12	37 ± 20	31 to 44	.078	38 ± 25	31 to 45	.004*	.817
Week 24	31 ± 23	24 to 39	.002*	34 ± 22	28 to 41	.000*	.610

CI = confidence of interval, SD = standard deviation, VAS = visual analog scale.

*P < .05.

Among 3 PBMs, both groups had significantly improved 5 × SST from 12-week FU and continued to 24-week FU, with no statistical difference, as shown in Table 3. The TUGT in both groups had no significant improvement from baseline until 24-week FU, with no difference between groups, as shown in Table 4. Similar to 5 × SST, significantly improved 3MWT in both groups was recognized from 12-week FU, as shown in Table 5.

Table 3.

Comparing 5-time sit to stand test from baseline to final follow-up between groups A and B.

5 × SST	Group A: generic diacerein (Diaceric®)			Group B: branded diacerein (Artrodar®)			P-value between groups
	Mean ± SD	95% CI	P-value within group	Mean ± SD	95% CI	P-value within group
Week 0 (baseline)	18.01 ± 5.53	16.26 to 19.67	−	18.83 ± 6.20	16.97 to 20.69	−	.523
Week 6	17.39 ± 6.35	15.39 to 19.40	.285	18.09 ± 6.21	16.23 to 19.96	.184	.607
Week 12	16.49 ± 5.00	14.91 to 18.06	.009*	17.45 ± 5.70	15.74 to 19.16	.013*	.408
Week 24	16.60 ± 4.78	15.09 to 18.11	.015*	17.53 ± 5.87	15.77 to 19.30	.020*	.421

5 × SST = 5-time sit to stand test, CI = confidence of interval, SD = standard deviation.

*P < .05.

Table 4.

Comparing time up and go test from baseline to final follow-up between groups A and B.

TUGT	Group A: generic diacerein (Diaceric®)			Group B: branded diacerein (Artrodar®)			P-value between groups
	Mean ± SD	95% CI	P-value within group	Mean ± SD	95% CI	P-value within group
Week 0 (baseline)	9.64 ± 2.77	8.81 to 10.51	−	10.78 ± 3.57	9.71 to 11.86	−	.103
Week 6	9.36 ± 2.99	8.42 to 10.31	.375	10.61 ± 4.64	9.22 to 12.01	.567	.146
Week 12	9.16 ± 2.46	8.38 to 9.94	.123	10.52 ± 4.16	9.27 to 11.77	.372	.072
Week 24	9.20 ± 2.34	8.46 to 9.94	.159	10.36 ± 4.93	8.88 to 11.84	.153	.174

CI = confidence of interval, SD = standard deviation, TUGT = time up and go test.

Table 5.

Comparing 3-minute walk test from baseline to final follow-up between groups A and B.

3MWT	Group A: generic diacerein (Diaceric®)			Group B: branded diacerein (Artrodar®)			P-value between groups
	Mean ± SD	95% CI	P-value within group	Mean ± SD	95% CI	P-value within group
Week 0 (baseline)	172.44 ± 35.68	161.18 to 183.70	−	166.40 ± 36.57	155.41 to 177.39	−	.441
Week 6	173.51 ± 35.88	162.19 to 184.84	.393	166.60 ± 37.27	155.40 to 177.80	.868	.384
Week 12	175.02 ± 33.17	164.56 to 185.49	.040*	168.91 ± 35.72	158.18 to 179.64	.037*	.415
Week 24	176.73 ± 32.31	166.53 to 186.93	.001*	170.80 ± 35.88	160.02 to 181.58	.000*	.424

3MWT = 3-minite walk test, CI = confidence of interval, SD = standard deviation.

*P < .05.

Regarding the PROMs, both groups gradually insignificantly improved their WOMAC and SF-12 scores from baseline until 24-week FU; however, Table 6 shows no statistical changes.

Table 6.

Comparing patient-report outcome measures from baseline to final follow-up between groups A and B.

Patient report outcome measures	Group A: Generic diacerein (Diaceric®)			Group B: Branded diacerein (Artrodar®)			P-value between groups
	Mean ± SD	95% CI	P-value within group	Mean ± SD	95% CI	P-value within group
WOMAC score
Week 0 (baseline)	41.44 ± 18.32	35.66 to 47.22	−	41.96 ± 20.87	35.68 to 48.23	−	.904
Week 6	38.54 ± 15.96	33.50 to 43.58	.215	40.82 ± 22.35	34.11 to 47.54	.611	.590
Week 12	39.24 ± 17.97	33.57 to 44.92	.348	38.11 ± 22.77	31.27 to 44.95	.086	.800
Week 24	37.95 ± 19.00	31.95 to 43.95	.136	37.60 ± 24.15	30.35 to 44.85	.052	.941
SF-12 score
Week 0 (baseline)	74.80 ± 16.35	69.64 to 79.96	−	75.41 ± 17.15	70.26 to 80.56	−	.866
Week 6	77.64 ± 17.36	72.16 to 83.12	.131	75.48 ± 17.25	70.30 to 80.66	.967	.564
Week 12	76.77 ± 16.57	71.54 to 82.00	.294	76.96 ± 18.81	71.31 to 82.62	.387	.961
Week 24	77.42 ± 17.11	72.02 to 82.83	.164	76.15 ± 18.46	70.60 to 81.70	.680	.742

CI = confidence of interval, SD = standard deviation, SF-12 = short form-12, WOMAC = Western Ontario and McMaster Universities Osteoarthritis.

No serious adverse events occurred in either group, and there were no significant differences between both groups during the treatment period; however, in group A, 3 patients reported recurrent mild transient diarrhea during early treatment, while 1 presented mild gastrointestinal discomfort. All 4 patients completed all FUs without drug discontinuation.

4. Discussion

The present RCT study compared the efficacy of a daily 50 mg of generic (Diaceric®) and branded (Artrodar®) diacerein for treating mild to moderate knee OA. At 24-week FU, both groups had significantly improved VAS, with a 12-week earlier improvement in the branded diacerein. In addition, the PBMs, including 5 × SST and 3MWT, significantly improved from 12-week FU in both groups, with insignificantly improved WOMAC and SF-12 and no serious adverse events in either group.

The literature demonstrated that diacerein reduces the production of interleukin-1β (IL-1β) by reducing the production of IL-1 converting enzyme and increasing the production of IL-1 receptor antagonist (IL-1R).^[9,10,20,21] The meta-analysis showed that diacerein has efficacy in the symptomatic treatment of knee and hip OA; however, its main adverse event was diarrhea.^[10,11,21] Compared to anti-inflammatory drugs, a recent clinical study has demonstrated that diacerein was non-inferior to celecoxib in pain and stiffness reduction.^[15] In the present study, patients receiving either generic or branded diacerein for knee OA exhibited similar improvements in VAS on motion, agreeing with results from previous studies.^[16,20] The significantly improved 5 × SST and 3MWT from 12-week FU of both groups reflected that the decreased VAS following the treatment provided patients more ability to perform specific functional performance tests. At the same time, other knee OA symptoms, such as stiffness, might not gain adequate benefit to improve the WOMAC and SF-12 scores significantly. As both PROMs gradually improved at all points of FU, it could be possible that continued treatment for a more extended period may provide significant improvement.

While healthcare treatment costs increase worldwide, including in our country, high-quality generic medicines may be cheaper, especially in treating chronic diseases like knee OA. Generally, generic drugs should contain active pharmaceutical ingredients like original drugs, and bioequivalence studies should determine the interchangeability between both agents.^[22,23] In contrast, impaired efficacy of generic drugs may lead to unintentionally increased doses and duration of treatment with unsatisfactory results.^[24] Several generic drugs have recently become available in several countries at a competitive price, with a wide range of efficacy and the expectation of increasing marketing share from branded drugs. Therefore, RCT studies must compare the clinical efficacy of generic and branded drugs and focus on target medicines to provide transparent information.

Usually, the cost of treatment using the generic drug is lower than the original, with a variation of definite differences depending on the individual national healthcare system. In hospitals with increasingly constrained budgets, especially those in developing countries, the present study delivered a helpful message concerning selecting a cost-effective diacerein for knee OA treatment. Additionally, the availability of a cost-effective generic option can enhance patient access to essential medication, potentially improving adherence and overall health outcomes.

The present study’s limitations include short-term FU. However, with a 24-week monitoring period, similar improved pain and functional performances could be detected in both groups. A long-term study should expand both agents’ efficacy and safety profiles. Lastly, although the present study had a small sample size, with a minimum number of sample sizes required for normal data distribution and no lost FU patients, the results were considered reliable.

5. Conclusion

The generic diacerein (Diaceric®) had similar efficacy as the original diacerein (Artordar®) after a 24-week FU regarding significantly improved VAS and PBMs: 5-time sit to stand test and 3MWT. However, the original had a faster statistically improved VAS than the other.

Acknowledgments

We thank Waraya Mingsiritham, BA, who prepared appointments for all patient visits and stations related to patient performance evaluation.

Author contributions

Conceptualization: Aree Tanavalee, Srihatach Ngarmukos.

Data curation: Nonn Jaruthien, Chotetawan Tanavalee, Pakpoom Somrak.

Formal analysis: Nonn Jaruthien, Chotetawan Tanavalee, Chavarin Amarase.

Funding acquisition: Chavarin Amarase.

Investigation: Nonn Jaruthien, Chotetawan Tanavalee, Pakpoom Somrak.

Methodology: Nonn Jaruthien, Chotetawan Tanavalee, Chavarin Amarase, Pakpoom Somrak.

Resources: Chavarin Amarase.

Software: Chotetawan Tanavalee, Chavarin Amarase, Pakpoom Somrak.

Supervision: Aree Tanavalee, Srihatach Ngarmukos.

Validation: Aree Tanavalee, Srihatach Ngarmukos, Chotetawan Tanavalee.

Visualization: Aree Tanavalee, Srihatach Ngarmukos, Chavarin Amarase.

Writing – original draft: Nonn Jaruthien, Srihatach Ngarmukos.

Writing – review & editing: Nonn Jaruthien, Aree Tanavalee.