Bath Ankylosing Spondylitis Disease Activity Index response
We previously highlighted that NICE guidance determines that BASDAI 50 at 12 weeks defines treatment continuation with anti-TNFs in clinical practice. Given much of the evidence on prognosis, costs and utility scores links to the absolute values of BASDAI and BASFI scores, it is important to consider absolute
changes in BASDAI and BASFI separately for responders and non-responders, that is the conditional scores. However, the published clinical effectiveness evidence does not report the conditional scores. In this section we use the results from the extended synthesis model to evaluate the conditional scores by simulating BASDAI and BASFI scores for two equivalent cohorts of patients, one treated with an anti-TNF and the other with conventional therapy.
Brief description of methods
From the inferences obtained using the synthesis model above, it is possible to derive the conditional change score in responders and non-responders using simulation. While the synthesis focuses on the pooling of mean estimates of change scores and proportion of responders to BASDAI 50, to derive conditional mean scores there is the need to consider the distributions at the individual patient level. Hence, conditional scores could not directly be derived from the synthesis, but through a simulation procedure based on the assumptions and results of the synthesis model. The simulation procedure is described in detail inAppendix 5. Briefly, we used a simulation sample size of 10,000 patients. Given results depend on the baseline distributions of BASDAI and BASFI scores and on the change scores from baseline for placebo, we used the averages across trials (weighted by the number of patients in each trial) in AS. Baseline BASDAI scores were thus assumed normally distributed with mean 6.11 and SD 1.56; the change from baseline for placebo was simulated from a normal distribution with mean–0.61 and SD 1.44. For BASFI, the baseline was assumed to have a mean of 5.27 and a SD 1.79 and the change from baseline for placebo a mean of–0.19 and a SD 0.22. The correlation between baseline BASFI and BASDAI scores was valued at (AiC information has been removed). This value was based on the sample correlation on BASDAI and BASFI at baseline from etanercept studies [the individual patient data were available in the Microsoft Excel®(Microsoft Corporation, Redmond, WA, USA) file for the etanercept submission]; the Spearman’s rank correlation coefficient was (AiC information has been removed) in 314-EU study167in AS and (AiC information has been removed) in 1031 study166in nr-AxSpA.
Results for ankylosing spondylitis
The conditional change scores derived from the synthesis model (and underlying assumptions) are reported inTable 77. While it is natural to consider that conditional change in BASDAI scores differ between respondents and non-respondents, differences in the baseline of respondents and non-respondents may be less intuitive. These are, however, natural. If we consider two patients that obtained the same change score in BASDAI from anti-TNF treatment, for example–2 units, but one started with a baseline of 4 and another with a baseline of 5, the first would be considered a responder and the second would not. For this reason, respondents are expected to have a lower BASDAI than non-responders. Results of the prediction of conditional scores using the synthesis model are presented inTable 77.
Results show, as expected, that the change in BASDAI score for respondents is more negative than the mean change score (–3.86 for the 42% predicted anti-TNF responders vs.–2.63 for all anti-TNF users; in the control arm, responders were predicted to have a change score of–2.70 vs.–0.66 for all participants). Non-respondents were still expected to have a negative change score in both arms revealing some level of symptom control but this was lower than the mean (–1.73 vs.–2.63 for anti-TNF users and–0.45 vs.–0.66 in control arm). The baseline BASDAI and BASFI were predicted to be lower for respondents than
non-respondents (e.g. the BASDAI baseline for responders to treatment was 4.76 in respondents when the group baseline was 6.08).
We requested the conditional data from the pivotal trials in AS from each manufacturer. These data were subsequently provided by all manufacturers for their pivotal trials. Conditional scores observed in the trials are summarised inTable 78. The results show that there are some differences between the conditional results predicted using the synthesis and the ones observed in trials. Differences are especially relevant for the conditional baseline scores; although the synthesis model predicts, for example, that treated patients that respond have a baseline BASDAI score of 4.76 and those that do not respond have a baseline score of 7.03, the trials show much smaller differences. Despite incorporating all evidence available at the aggregate level, the predictive ability of the conditional baseline score from the synthesis could only be improved if we had access to the individual patient data, as this methodology is strongly dependent on assumptions over the distribution of scores across patients.
TABLE 77 Conditional scores predicted for the AS population using the synthesis model
BASDAI BASFI
Control Treatment Control Treatment
Base case % responders to BASDAI 50 0.09 0.42 Change in score Responders –2.89 –3.86 –1.72 –3.08 Non-responders –0.36 –1.64 –0.04 –0.44 All –0.59 –2.57 –0.19 –1.55 Baseline Responders 4.01 4.80 3.52 4.20 Non-responders 6.33 7.08 5.46 6.07 All 6.12 6.12 5.28 5.28
TABLE 78 Conditional scores observed in trials in AS
BASDAI BASFI
Control Treatment Control Treatment
ATLAS61trial (adalimumab, studies=4)
% responders to BASDAI 50 0.16 0.46 Change in score Conditional on response –4.5 –4.64 –2.74 –2.92 Conditional on non-response –0.2 –0.82 –0.17 –0.72 Total –0.90 –2.58 –0.59 –1.73 Baseline Conditional on response 6.31 6.14 4.50 4.53 Conditional on non-response 6.37 6.35 5.91 5.78 Total 6.36 6.25 5.68 5.21
GO-RAISE90(golimumab, studies=12)
% responders to BASDAI 50 0.15 0.46 Change in score Conditional on response –4.25 –4.74 –1.80 –3.03 Conditional on non-response –0.18 –1.22 0.38 –0.53 Total –0.81 –2.84 0.05 –1.68 Baseline Conditional on response 6.52 6.25 3.56 4.45 Conditional on non-response 6.63 6.69 5.39 5.48 Total 6.61 6.49 5.11 5.01
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Results for non-radiographic axial spondyloarthritis
The conditional results were also predicted for the nr-AxSpA population using both scenarios implemented of the synthesis model.
For this population, conditional data were provided by only two manufacturers (Pfizer and AbbVie). Conditional scores observed are summarised inTables 79and80.
Prediction results are consistent with those in AS, and the differences between the conditional results predicted using the synthesis and the ones observed in trials are also present in this analysis.
Interpretation/discussion
Conditional scores predicted using synthesis model C differ from those seen in the trials. Differences are probably because of distributional assumptions over the baseline and change scores. Only with access to the individual patient data could such predictions be improved. Note that the synthesis model itself does not rely as heavily on such assumptions, and thus any concerns should not be transposed to the results obtained inAnkylosing spondylitis populationandNon-radiographic axial spondyloarthritis population.
TABLE 78 Conditional scores observed in trials in AS (continued)
BASDAI BASFI
Control Treatment Control Treatment
314-EU study167(etanercept, studies=11)a
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a Pooled results for etanercept arms (etanercept 25 mg twice weekly and etanercept 50 mg once weekly).
For the trials of adalimumab and etanercept were week 12 responders, for golimumab they were week 14 responders (week-12 data for week-14 responders is available but not reported in the table).
TABLE 79 Conditional scores predicted for the nr-AxSpA population using results and assumptions of the synthesis modela
BASDAI BASFI
Control Treatment Control Treatment
Scenario 1
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a Based on a BASDAI baseline score of (AiC information has been removed) a placebo change in BASDAI score of (AiC information has been removed), a BASFI baseline score of (AiC information has been removed) and a placebo change in BASFI score of (AiC information has been removed), which represent the results seen in the certolizumab trial
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TABLE 80 Conditional scores observed in trials in nr-AxSpA
BASDAI BASFI
Control Treatment Control Treatment
ABILITY-158
trial (adalimumab, studies=18)
% responders to BASDAI 50 0.14 0.40 Change in score Conditional on response –3.9 –4.79 –2.78 –2.75 Conditional on non-response –0.69 –0.55 –0.40 –0.32 Total –1.16 –2.23 –0.75 –1.29 Baseline Conditional on response 5.64 6.21 4.37 3.60 Conditional on non-response 6.46 6.53 4.91 4.97 Total 6.34 6.40 4.83 4.43 RAPID-axSpA64 (certolizumab, study=19)
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