Both efficacy and safety, suitable for the treatment of Chinese RA patients-the latest phase IV clinical research results announced!

*Only for medical professionals to read and refer to the "Lancet" sub-Journal published the results of phase IV clinical research on the treatment of RA with IGU.

Although the treatment methods for rheumatoid arthritis (RA) have been gradually enriched in the past ten years and new treatment drugs have been introduced, the disease remission rate of patients is still very low (<20% of patients reach the treatment goal) [1].

Moreover, affected by factors such as economics, the choice of medication for patients has great limitations.

In addition, the clinical manifestations and drug response heterogeneity of RA patients affect the formulation of treatment plans by clinicians, and the evaluation of many new treatment plans takes populations from different regions abroad as the research objects, and the extrapolation of their conclusions is open to question.

Therefore, we urgently need to combine China's actual conditions to explore and study treatment options suitable for the majority of domestic RA patients to achieve the treatment goals.

Iramod (IGU) is a new type of disease-improving anti-rheumatic drug (DMARD) with relatively low price and complete independent intellectual property rights in my country.

From 2011 to August 2012, IGU was successively marketed in China and Japan.
According to the results of pre-marketing Phase II and III studies and post-marketing clinical studies, IGU is considered to be a DMARD that can effectively treat active RA and is well tolerated At present, hundreds of thousands of patients nationwide have received IGU treatment.

In order to further verify the effectiveness and safety of IGU in the majority of patients, a total of 48 large and medium-sized hospitals and researchers across the country, led by Professor Li Zhanguo from Peking University People's Hospital, jointly carried out a phase IV clinical study of IGU for the treatment of active RA.

Recently, the results of the study were officially published in the journal "The Lancet-Regional Health" (Western Pacific) [2].

Figure 1: The results of IGU's IV clinical study were published in the journal "The Lancet-Regional Health".
A multi-center, large sample.
This phase IV clinical study is designed like this.
.
.
The study is open, single-arm, multi-center Clinical trials.

From March 2012 to August 2015, 48 domestic hospitals or clinical research centers recruited a total of 1759 patients with active RA as subjects for research.

This is a relatively rare large-sample study in the field of RA at home and abroad.

Table 1: The study’s inclusion criteria, exclusion criteria, and exclusion criteria.
The total study period is 24 weeks, divided into two research phases: The first phase (the first 12 weeks) is the IGU addition treatment period, and all RA patients enrolled in the group are in On the basis of the background treatment, IGU (25 mg bid) or IGU 25 mg bid is used as monotherapy; the second stage (the last 12 weeks) is the plan adjustment stage, and the clinician can adjust according to the patient’s disease activity except IGU Of other RA treatment drugs.

There were a total of 7 visits during the study period (Figure 2).

 Figure 2: Schematic diagram of the study design.
The study explored the clinical effects and safety of IGU in the treatment of RA.

In the clinical effect analysis, the primary endpoint is the ACR 20 response rate at week 24§, the secondary endpoint is the ACR 50, ACR 70 response rate at week 24, and the changes in DAS28* and HAQ# at week 24.

In the safety analysis, the primary endpoint was the incidence of adverse events (AE) throughout the study period, during which the incidence of serious adverse events (SAE) and adverse drug reactions (ADR) was also recorded.

§ACR 20/50/70: A series of efficacy observation indicators.
If the patient achieves 20%, 50% or 70% remission, it is ACR 20, ACR 50 or ACR 70 response; *DAS28: Evaluation of disease activity in RA patients; #HAQ : Health Assessment Questionnaire.

2 In a wider population, IGU still has good efficacy and safety for active RA.
So, what are the results of this phase IV clinical study? Below, we will introduce the clinical effects and safety analysis results and subgroup analysis data of IGU in the overall population in turn.

1 Clinical effect analysis In the study, as the treatment time passed, the ACR response rate gradually increased.

At the end of the 12th week, the response rates of ACR 20, ACR 50, and ACR 70 were 62.
2%, 29.
5%, and 11.
0%, respectively.

At the end of the 24th week, the response rates of ACR 20, ACR 50, and ACR 70 were 71.
9%, 47.
4%, and 24.
0%, respectively (Figure 3A).

After the enrolled patients received IGU treatment, the DAS28 and HAQ scores at each visit were significantly improved compared with baseline (P<0.
001).

At 12 weeks and 24 weeks of treatment, 11.
3% and 20.
0% of the cases achieved disease remission (DAS28<2.
6, Figure 3B).

 Figure 3: Evaluation of the efficacy of IGU at the 12th and 24th week (A) ACR response rate; (B) DAS28 disease activity patient distribution 2 Safety analysis The occurrence of AE, SAE and ADR during the entire study period The rates were 51.
7%, 3.
7%, and 38.
5%, respectively.
There were no new (that is, previously unreported) safety issues (Table 2).
The most common adverse events were gastrointestinal reactions, elevated transaminases, and neurological disorders.

Both AE and ADR occurred 4 weeks before the administration and gradually decreased afterwards (Figure 4).

Table 2: Incidence rates of AE, SAE and ADR Figure 4: Changes in the incidence of AE and ADR over time 3 subgroup analysis studies In addition to analyzing the overall population, it is also based on the patient’s course of disease, gender, age, and treatment The scheme has been analyzed in layers.

The results showed that the course of the disease: the response rates of ACR 20, ACR 50 and ACR 70 at week 24 for patients with a course of less than 2 years and ≥ 2 years were 76.
3% vs.
70.
6% (P=0.
033), 55.
1% vs.
45.
1 % (P=0.
001) and 30.
0% vs.
22.
3% (P=0.
003), that is, RA patients with a shorter course of disease respond better to IGU treatment; Figure 5: Grouped by course of disease (<2 years or ≥2 years), each Comparison of ACR 20, ACR 50, and ACR 70 response rates in subgroups by gender: The ACR 20, ACR 50, and ACR 70 response rates of male and female patients at the 24th week of treatment were 78.
5% vs.
70.
5%, 54.
8% vs.
45.
9%, respectively , 30.
7% vs.
22.
7% (P<0.
05), that is, the response of male patients to IGU treatment is slightly better than that of female patients; Figure 6: Grouped by gender, the response rates of ACR 20, ACR 50 and ACR 70 in each subgroup are compared by age: At the 12th and 24th week, there was no significant difference in the response rates of ACR 20, ACR 50 and ACR 70 between patients aged <65 and ≥65 years (P>0.
05), indicating that the elderly RA patients can also Significant benefit in the treatment of IGU, the efficacy of IGU is not affected by age; Figure 7: Grouped by age (<65 years or ≥65 years), the ACR20/50/70 response rate comparison of each subgroup The treatment plan: whether it is single Drug treatment was still combined treatment, and there was no significant difference in IGU efficacy.

In addition, from the perspective of safety, the gender and course of RA patients have nothing to do with the occurrence of AE, SAE, and ADR; the incidence of AE and ADR in the subgroup aged ≥65 years is slightly higher than that in the subgroup aged <65 years.
However, the difference between the groups was not statistically significant (P>0.
05); the incidence of AE, SAE, and ADR in the IGU monotherapy group was significantly lower than that in the combination therapy group (P<0.
05).

What new information does the results of phase 3IV clinical studies bring to us? IGU is an anti-rheumatic drug with independent intellectual property rights in my country, which can exert anti-inflammatory and immune regulation effects.

In many previous clinical studies, IGU has fully demonstrated its remarkable efficacy and good safety.

This phase IV clinical study is a national and prospective real-world clinical study.
Not only is the sample size large, but the overall design of the trial is flexible and rigorous.
It is effective and safe for the treatment of RA with IGU in a complex clinical environment.
A more comprehensive and in-depth exploration and analysis have been carried out on the performance, and the conclusions can fully reflect the true clinical situation, have a certain representativeness and universality, and lay a solid evidence basis for the clinical application of IGU.

For the first time, the study carried out a stratified analysis of different IGU treatment options, patients’ course of disease, gender and age, and confirmed that IGU has a better treatment response to male RA patients with a shorter course, and the efficacy is not affected by age and treatment options.
The safety and tolerability are also within the acceptable range.

These results not only strongly supplement the previous evidence on IGU, but also answer the doubts of clinicians when applying IGU (such as the choice of medication in early treatment strategies, the safety of medication in elderly patients, the feasibility of combining multiple DMARDs, etc.
Question), it also helps to determine the target patient group of IGU in a real environment.

The further digestion and understanding of the results will help doctors to apply IGU more scientifically and rationally for treatment, and will also benefit patients more.

In this phase IV clinical study of expanded population and combined drugs, IGU can effectively treat active RA with good safety and no new adverse reactions.

This further confirms that the wide application of IGU in developing countries will help to improve the current situation of low remission rate of RA treatment, and it is a more cost-effective therapeutic drug.

References: [1]H Zhu, R Li, Z Da, et al.
Remission assessment of rheumatoid arthritis in daily practice in China: a cross-sectional observational study[J].
Clin Rheumatol, 2018, 37(3):597 -605.
[2]R Mu, C Li, X Li, et al.
Effectiveness and safety of iguratimod treatment in patients with active rheumatoid arthritis in Chinese: A nationwide, prospective real-world study[J].
The Lancet Regional Health- Western Pacific, 2021, 10.
Doi: 10.
1016/j.
lanwpc.
2021.
100128.