1.1.Study Design, Patient Population, and Methodology

1.Overview of Efficacy

1.1.Study Design, Patient Population, and Methodology

Study XXXXXXX was a double-blind, randomised, placebo-controlled, multicentre phase 3 study to evaluate the efficacy and safety of a 50 mg TestDrug qw dosage regimen compared to placebo and to the regimen currently recommended in the SPC (25 mg biw). This study was conducted in accordance with good clinical practices. The planned enrollment was 400patients to be randomised based on a 1:4:3 allocation to receive either placebo, TestDrug 50 mg qw, or TestDrug 25 mg biw, respectively. Adults with active RA were eligible for participation. Prior receipt of DMARDs was permissible; however, all DMARDs except methotrexate (MTX) were to be discontinued a minimum of 28 days prior to the first dose of study drug. At the time of enrollment, receipt of concomitant MTX at a dose of up to 25 mg a week was permitted; however, the dose of MTX was to be stable for at least 1 month prior to the first dose of study drug and remain stable during the study. Study drug was administered for 16 weeks in a blinded fashion. Patients who met the eligibility criteria received TestDrug (TestDrug 50 mg qw or TestDrug 25 mg biw) for 16weeks or placebo for 8weeks followed by TestDrug 25 mg biw for the remaining 8weeks of the treatment period.

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Efficacy analyses included all patients who received at least 1 dose of study drug. All statistical tests were 2-sided except where noted for non-inferiority evaluations, and p-values of less than 0.05 were considered to denote significant differences in efficacy.

ACR 20 responses were compared between the TestDrug 50 mg qw and placebo groups at 8 weeks using the Cochran-Mantel-Haenszel test stratified by presence or absence of concomitant MTX at baseline. Patients who discontinued prior to the week 8 evaluation were considered nonresponders. The Breslow-Day test was used to assess homogeneity of odds ratios across the MTX strata.

Similarly, the ACR 20 responses were compared between the TestDrug 25 mg biw and placebo groups and between the 2 TestDrug groups at 8 weeks, using the Cochran-Mantel-Haenszel test stratified by presence or absence of concomitant MTX at baseline. Pair-wise comparisons were performed. Corresponding pair-wise analyses were conducted for the ACR 20 responses at week 16 and for the ACR 50 and ACR 70 responses at weeks 8 and 16. Patients who discontinued prior to a time point of interest were considered nonresponders for analyses of ACR 20, ACR 50, and ACR 70.

The non-inferiority analysis compared the TestDrug 50 mg qw and TestDrug 25 mg biw groups with respect to the proportion of patients achieving an ACR 20 response at week 8. Non-inferiority could be claimed if at least 50% of the benefit of TestDrug 25 mg biw compared to placebo was preserved by TestDrug 50 mg qw.

The basis for the noninferiority assessment was the lower 1-sided 95% confidence limit for the difference between TestDrug 50 mg qw and TestDrug 25 mg biw, which represents a lower bound for the difference. Non-inferiority endpoints require an estimate of the advantage of active treatment over placebo, i.e., the treatment effect. Studies with a non-inferiority component often rely on historical information to estimate the size of the treatment effect in the comparator group. However, study XXXXXXX had a sufficient number of patients exposed to placebo for a period of 8 weeks to allow estimation of the treatment effect within the study, rather than relying on historical estimates. For the active treatment arms, additional information on the relative efficacy was captured after 16 weeks of exposure. The number of patients in each group was adequate to show the superiority of the active groups to placebo and the noninferiority of the 50 mg qw dosage regiment to the 25 mg biw dosage regimen.

Individual components of the ACR response and the duration of morning stiffness were analysed as percent improvement from baseline, with a last observation carried forward (LOCF) approach used to handle missing post-baseline data. Patients with a missing baseline or a score of zero at baseline were excluded from the analysis of percent improvement. Pairwise comparisons between treatment groups were performed under an analysis of variance model that considered treatment group, baseline MTX usage, and the interaction of the 2 as predictors. An analysis of the ranked percent improvement from baseline values was used for the duration of morning stiffness, which had a decidedly nonnormal statistical distribution.

The ordinal ACR response (ACR-N) was calculated for each patient at weeks 8 and 16 using LOCF to handle missing post-baseline data. ACR-N was calculated as the minimum percent improvement from baseline in any one of the following disease activity measures: 1) tender joint count, 2) swollen joint count, and 3) median of the physician and patient global assessments, pain assessment, HAQ disability index, and CRP.¡Error! Marcador no definido. If the minimum was less than 0, the ACR-N was set to 0. ACR-N and the individual components of the ACR response were analysed in a similar manner.

With 200 patients in the TestDrug 50 mg qw group and 50 in the placebo group, the study had approximately 98% power to declare TestDrug 50 mg qw superior to placebo, assuming ACR 20 responses at 8 weeks of 25% and 55% for the placebo and TestDrug 50mg qw groups, respectively. Assuming ACR 20 responses at 8 weeks of 25%, 55%, and 55% for the placebo, TestDrug 50 mg qw, and TestDrug 25 mg biw groups, respectively, the design provided approximately 87% power to demonstrate the non-inferiority of TestDrug 50 mg qw.

1.2.Efficacy Endpoints

The primary endpoint was to determine whether there is a statistically significant difference in the proportions of patients achieving an ACR 20 response between 50 mg TestDrug administered SC once weekly and placebo after 8 weeks of study drug treatment. The ACR20 Response Criteria for improvement were defined by Felson et al.[i]

The secondary endpoint was to compare the effectiveness of 50 mg TestDrug given once weekly and 25 mg TestDrug given twice weekly with respect to the ACR 20 improvement criteria after 8 weeks of treatment, using a non-inferiority analysis. The endpoint was achievement of the ACR 20 response criteria for improvement.

The following outcome measures were also evaluated:

ACR 20 response after 16 weeks was compared between the TestDrug treatment groups.
ACR 50 and ACR 70 responses after 8 and 16 weeks was compared among treatment groups.
Percent improvement from baseline in individual ACR criteria after 8 and 16 weeks was compared among treatment groups.
ACR-N after 8 weeks of treatment was compared among treatment groups.

1.3.Efficacy Results and Discussion

1.3.1.ACR 20 Response at Week 8 (50 mg qw vs Placebo)

TABLE 2.5.1.3.1A PRIMARY ENDPOINT: NUMBER (%) OF PATIENTS ACHIEVING ACR 20 RESPONSE AT WEEK 8
Study Population / Placebo
n = 53 / TestDrug
50 mg qw
n = 214 / p-Valuea
All patients / 10 (19) / 107 (50) / <0.0001
a: p-values determined by Cochran-Mantel-Haenszel row means test.

1.3.2.ACR 20, ACR 50, and ACR 70 Responses at Weeks 8 and 16

The 2 TestDrug regimens had comparable ACR 20 responses at 8 weeks (Table2.5.1.3.2A). TestDrug 50 mg qw met the predefined criterion of preserving at least 50% of the observed benefit of TestDrug 25 mg biw compared to placebo. The observed benefit of TestDrug 25 mg biw compared to placebo was 30% (49% minus 19%), and 50% of this benefit was 15%. The lower limit of the 1-sided 95% CI for the difference in treatment effect between the two TestDrug groups was -7.7%, well within the -15% limit that established that the 2dosing regimens are comparable.

In addition to evaluation using the 1-sided 95% lower confidence limit specified in the protocol, a more stringent 1-sided 97.5% lower confidence limit for the difference between the 2 TestDrug groups was also used. With the 1-sided 95% confidence limit (lower limit 7.7%), TestDrug 50 mg qw preserved at least 74% of the benefit of TestDrug 25 mg biw. Using the more stringent 1-sided 97.5% confidence limit (lower limit –9.4%), noninferiority was still achieved, with at least 69% of the benefit preserved.

Furthermore, 55% of patients in the TestDrug 50 mg qw group and 63% in the TestDrug 25 mg biw group achieved an ACR 20 response at week 16 (Table 2.5.1.3.2A). Although the protocol did not include a placebo group at week 16, calculations showed that noninferiority of TestDrug 50 mg qw at week 16 could have been claimed if ACR 20 responses in a placebo control group had been as high as 30%, based on a 1-sided 95% confidence limit. If a week 16 placebo response of 17% is assumed, then TestDrug 50 mg qw would have preserved at least 64% of the benefit based on a 1-sided 95% confidence limit. Therefore, if there had been a placebo group at week 16 in the current study, TestDrug 50 mg qw would almost certainly have been shown to preserve at least 50% of the benefit of TestDrug 25 mg biw over placebo.

The proportions of patients achieving ACR 50 and ACR 70 responses were also similar in the 2 TestDrug groups (Table 2.5.1.3.2A). Although it appears that there is a somewhat higher response at week 16 for TestDrug 25 mg biw than for 50 mg qw, the responses are within the variability that one would expect. For example, in study 16.0009 (an earlier phase 3 trial of TestDrug in RA patients), the ACR 20 and ACR 50 responses at week 16 were 55% and 31%, respectively, for the TestDrug 25 mg biw group.

TABLE 2.5.1.3.2A. NUMBER (%) OF PATIENTS ACHIEVING ACR 20,
ACR 50, AND ACR 70 RESPONSES
Parameter / Placeboa
(n = 53) / TestDrug
50 mg qw
(n = 214) / TestDrug
25 mg biw
(n = 153)
ACR 20
Week 8 / 10 (19) / 107 (50)b / 75 (49)b
Week 16 / --- / 117 (55) / 96 (63)
ACR 50
Week 8 / 3 (6) / 38 (18)c / 28 (18)c
Week 16 / --- / 63 (29) / 50 (33)
ACR 70
Week 8 / 1 (2) / 5 (2) / 7 (5)
Week 16 / --- / 17 (8) / 12 (8)
a: Patients received blinded placebo for 8 weeks followed by blinded TestDrug 25mg biw for the remaining 8 weeks of the treatment period.
b: CMH Row Means p-value  0.001 for comparison with placebo.
c: CMH Row Means p-value  0.05 for comparison with placebo.

1.3.3.ACR-N

The mean ACR-N score at week 8 in the TestDrug 50 mg qw group (24.2) was significantly better than the mean score in the placebo group (10.4; p < 0.0001). Similarly, the mean ACR-N score in the TestDrug 25 mg biw group (22.9) was significantly better than placebo (p < 0.0001).

1.3.4.Examination of Subgroup Populations

Subgroup analyses for various demographic factors were conducted to assess whether there was a treatment-by-subgroup interaction for the primary endpoint. Subgroups included gender, race (categorised as caucasian or non-caucasian), body weight, age (categorised as median age or > median age), and components of the ACR response criteria at baseline (categorised as  median score or > median score). The subgroup analyses revealed no significant treatment-by-subgroup interactions for any subgroup variable (p > 0.10).

1.3.5.LOCF Sensitivity Analysis

An LOCF analysis of the ACR 20 response at week 8 was conducted to assess the impact of missing data. For the primary analysis, patients with missing data in the week8 visit window were considered to be non-responders. An LOCF analysis was conducted in which missing data was imputed on a component-by-component basis using an LOCF approach, after which the ACR 20 response was computed. The proportions of ACR20 responders in the LOCF analysis were 21% in the placebo group, and 51% and 49% in the TestDrug 50mg qw and TestDrug 25 mg biw treatment groups, respectively. Thus, the results of the LOCF analysis were nearly identical to the results of the primary analysis.

1.4.Efficacy Conclusions

The primary efficacy endpoint of the study was achieved: 50% of patients in the TestDrug 50 mg qw group demonstrated at least a 20% improvement from baseline in the ACR criteria at 8 weeks, compared to 19% of patients in the placebo group (p<0.0001). Results were comparable in the TestDrug 25 mg biw group, with 49% of patients achieving an ACR 20 response at week 8 (p = 0.0001 compared to placebo).

In addition to the primary efficacy comparison of TestDrug 50 mg qw versus placebo, a noninferiority analysis was done to compare TestDrug 50 mg qw to TestDrug 25 mg biw. The non-inferiority endpoint was met using the prospectively defined 1-sided 95% confidence limit, as well as a more stringent 1-sided 97.5% confidence limit. In fact, the endpoint would have been achieved had the protocol prospectively defined preservation of 74%, rather than 50%, of the treatment benefit of the currently recommended 25 mg biw dosage regimen.

The proportions of patients achieving ACR 20, ACR 50, and ACR 70 responses were similar in the 2 TestDrug groups, and patients in both TestDrug groups achieved statistically significant improvements in ACR 20 and ACR 50 scores at week 8 compared with the placebo group. Likewise, patients in both TestDrug groups showed significantly greater improvements from baseline than patients in the placebo group in all individual components of the ACR criteria except swollen joint counts. The mean ACR-N score for each TestDrug group was also significantly different from that of the placebo group. Comparability of the 2 TestDrug groups was not affected by concomitant MTX usage.

Therefore, the data presented support the administration of TestDrug 50 mg administered once weekly as 2 simultaneous 25-mg injections.

[i]Felson DT, Anderson JJ, Boers M, et al. American College of Rheumatology preliminary definition of improvement in rheumatoid arthritis. Arthritis Rheum. 1995;6:727-735.