• Darren Wogman

Clinical Trial Dataset Analysis - A phase 2a efficacy, safety and tolerability study

Write up the analysis of your syndicate clinical trial data as part of a scientific paper. A phase2a, six week, randomised, double-blind, parallel group, placebo control, multicentre study to evaluate the efficacy, safety and tolerability of Franklin wilkinsatide on treating patients with schizophrenia.


An assignment by: Darren Wogman MSc. Completed as part of Pharmaceutical Medicine MSc at King's College London


Methods

Subjects

The Franklin Wilkinsatide (FWA) versus placebo, phase IIA, randomized, double-blind, parallel group, 6-week, multicenter trial, compared the efficacy and tolerability of Franklin Wilkinsatide (taken orally once daily) with that of placebo in adult patients with schizophrenia.

Patients were between the ages of 18-65 and had been diagnosed with schizophrenia as per DSM-V criteria, established through clinical interview. Eligible patients agreed to stop taking any prescribed anti-schizophrenia medication for the entirety of the trial and did have any confounding abnormalities, disease nor any active substance abuse problem. Additionally, any patients who were determined to be at a high risk of self-harming were excluded from the study. Patients were randomly assigned to one of four double-blind treatment groups.

Study Design

Over 6 weeks, 107 patients were randomised into 4 study arms (27 patients in each). The multicenter study was double-blind, placebo-controlled and has a parallel-group design. Patients were randomly assigned to one of four dosage groups that would receive a 6-week administration of placebo or Franklin Wilkinsatide (50, 100 or 200 mg/day). The trial was conducted in accordance with the Good Clinical Practice guidelines and the Declaration of Helsinki. The Medicine and Healthcare Regulatory Agency (MHRA) gave approval of the clinical protocol before the start of the trial study. Patients or legal guardians provided informed consent.

Psychiatric histories were provided before any drug administration in addition, medical examinations were performed in order to determine patient suitability for the study. Baseline Positive and Negative Syndrome Scale (PANSS) and Clinical Global Impression - Severity (CGI-S) scores were taken for all patients who were then given their doses and followed up after 6 weeks. For secondary end-point analysis, the BNSS collection was seen as redundant and unnecessarily onerous on the patients by the Ethics Committee as PANNS negative symptom scores were already being collected as part of the primary end-point analysis. Any adverse events reported were noted into the case report form, where possible, a link to study drug was determined and acted on, where necessary.

End Points

The primary end-point was an improvement in the total PANSS score after the 6-week study period. As prespecified, subjects who left the study or were lost prior to the end of the trial were considered to have made no improvement. The secondary end-points were change in CGI-S scores from baseline, change in scores from baseline in PANSS subgroups and change from baseline in the BNSS score. However, as previously stated BNSS scores were not taken. Recorded adverse effects were used as a measure of for the tolerability and safety secondary end-point measure.

Statistical Methods and Power

Two-tailed t-tests were carried out. Sample sizes were calculated to 80% power, with 20% consideration for drop-outs.

Analyses of efficacy were completed under the intent-to-treat (ITT) principle, which includes every participant that received even a single drug or placebo administration after baseline PANSS and CGI-S assessments were carried out.

Based on data from previous studies, 26 individuals in each study arm would provide 80% power for the primary end-point analysis. We planned to assess the improvement in scores at 50mg/day, 100mg/day and 200mg/day of FWA. Figure 1 – Flow of participants through the study. This figure is reproduced in the appendix in a larger format

Results

Patient Characteristics

This was a multi-centre study. 107 individuals with a schizophrenia diagnosis were randomly assigned to one of the four treatment groups, as such, 107 patients were included in the ITT statistical analysis.

There were no apparent differences in demographics of the treatment groups or in their clinical status as seen in table 1.

The patients’ mean age was 42 years (range= 18–65); 64% (N=69) were male. The overall study dropout rate was 7% (N=8), however, there were 5 times as many in 200mg treatment group compared to the other groups treatment groups (N= 5, 1, 1, 1 respectively). Study dropouts mainly withdrew without providing a reason or were lost (N= 4) however, some individuals may have withdrawn for treatment-related effects (N=3), on a worst-case assumption. Where drop outs occurred, no change from baseline was assumed for the purposes of statistical analysis. Table 1 – Baseline demographics of participants*. This table is reproduced in the appendix in a larger format.

Efficacy

As improvements in symptoms show a reduction in both the PANSS and CGI-S scores, all values have been inverted in order to make data analysis clearer. To this end, positive changes show a positive result and vice-versa.

Primary End Point

In all dose ranges of FWA showed efficacy when compared to placebo in their treatment of schizophrenia as measured by improvements to total PANSS scores (figure 2). This was reached by a total of 69 patients in the active groups (N= 82). Made up from 23 of 28 subjects at 50mg/day, 22 of 26 subjects at 100mg/day and 25 of 28 subjects at 200mg/day (50mg/day 0.002<P<0.01, 100mg/day P<0.001) as seen in table 3.

Secondary End point

CGI-S scores showed improvement with FWA treatment compared to placebo and was seen in 64 of the active patients (N=82), compared to 12 of the placebo group (N=25). Made up from 23 of 28 subjects at 50mg/day, 21 of 26 subjects at 100mg/day and 20 of 28 subjects at 200mg/day When looking at PANSS subgroup scores, there is a clear improvement across all areas when compared to placebo and there does appear to be a treatment effect wherein larger doses provide a greater change in all subgroup scores as can be seen in table 2. Table 2 – Primary and Secondary end-points after 6 weeks*. This table is reproduced in the appendix in a larger format

Adverse Events and Safety Data

FWA did not generate significant tolerability problems. Only 7% of patients dropped-out of the study as a result of adverse events and 63% of these (N=5) occurred in the 200mg treatment group. Compared to 1% drop-out in the placebo arm.

Adverse effects were seen in a total of 15 patients however, only 8 of these were serious enough to result in drop-out.

Table 4 lists all adverse events in treatment groups

Discussion

This study is the first multicenter, placebo-controlled assessment of the efficacy and tolerability of Franklin Wilkinsatide. Enrolled individuals had a mean age of 42 (±14), mostly male. It is unclear what phase of illness patients were in. Iit is not known whether the patient population have previously responded to drugs or other treatments therefore the magnitude of the drug effect in devoid of any context. Nonetheless, these patients were highly symptomatic, shown from the mean baseline PANSS score of 120 (± 10.66). The literature describes a characterisation of “severely ill” to a PANSS of 116 (Leucht et al., 2005a). The PANSS scale is the gold-standard measure of schizophrenia (Van den Oord et al., 2006). Trial participants do not appear to be particularly in-line with patient populations seen in other studies of this type, as the baseline severity is considerably higher, average total PANSS score of 66 is more in line with the current literature (Santor et al., 2007, Leucht et al., 2005a). Given the severity of illness, it is possible that the magnitude of improvements observed will be less pronounced in a more representative patients population.

CGI-S scale is a 7-point measure of the severity of the mental illness seen in patients and can be related to PANSS scores (Rabinowitz, Mehnert and Eerdekens, 2006). Using CGI-S scales, the patient population would be described as being ‘markedly ill’ with a mean baseline score of 5 (Leucht et al., 2005b). This would indicate less severity of illness that was seen with the PANNS score but, CGI-S is a much more limited assessment.

A reduction of 1 point in the CGI-S is clinically significant (Rabinowitz, Mehnert and Eerdekens, 2006). A 20% reduction of PANSS scores has been used as the clinically significant change in clinical trials (Kane et al., 2009) although, other studies suggest a clinically significant decrease at being 14.7 score reduction on the PANSS scale and not necessarily a proportional decrease (Hermes et al., 2012). In fact, in Hermes et al (2012) the mean baseline PANNS scores for their patient population were much lower at 75.6 (±17.6) compared to the 120 (± 10.66) seen in this trial. It is reasonable to suggest that the changes observed in the 100mg/day and 200mg/day groups is clinically significant. While standard deviation ranges are very wide, the result for 100mg/day has high statistical significance (p = <0.001) and as this meets both 20% reduction and 14.7 point reduction in PANNS criteria for clinical significance. When we consider the 95% confidence intervals for the calculated means, we can see that there are improvements in the active groups, although these may not necessary be at clinically significant levels. The range of the intervals is wide for both 50mg/day and 100mg/day but the lower bounds of both these ranges are positive (5.78 and 15.99 respectively) indicating that the null hypothesis can be rejected.

This view is supported by secondary end-point outcomes (figure 3 and figure 4) whereby CGI-S score reductions of 1.58 (±1.3) reach the threshold of clinical significance described previously. While the standard deviation is again quite high, it would be good to be able to consider the statistical significance of the change through p value analysis which has not been carried out by the independent statisticians. When we consider the outcome of tolerability, the view to continue development with 100mg/day is strengthened; 1 drop-out and 3 suspected adverse events, the same frequency as seen with the placebo, compared with 5 drop-outs for the 200mg/day dosage. Figure 2 – Mean total PANSS score changes by dosage after 6 weeks. This figure is reproduced in the appendix in a larger format. Table 3 – Improvement in PANSS subgroups after 6 weeks. This table is reproduced in the appendix in a larger format. Figure 3 – Mean changes in CGI-S scores at 6 weeks. This figure is reproduced in the appendix in a larger format Figure 4 – Mean changes in PANSS subgroup scores at 6 weeks. This figure is reproduced in the appendix in a larger format.

All doses of FWA showed greater efficacy than placebo in the treatment of schizophrenia. A positive dose-response relationship appeared to emerge in efficacy analysis. The highest doses provided greater efficacy (compared to placebo) of all PANSS criteria subgroups with statistically significant changes for the 100mg/day dosages (200mg/day significance was not calculated as it was excluded from analysis on safety and tolerability grounds). The 100mg/day and 200mg/day dose levels provided a significant improvement of schizophrenia measures. While 50mg/day showed statistically significant results in reduction of total PANSS score, it did not reach a clinically significant level.

It would be ideal to discern if differences observed across the PANSS subgroups scores were a result of drug action on changes to; primary, negative and general symptoms or is due to an improvement in related symptoms that impact the scale criteria such as, dysphoria (Zimbroff et al., 1997). Table 4 – Summary of adverse events. This table is reproduced in the appendix in a larger format.

The most frequent adverse events (table 4) associated with FWA was nausea, although the number of adverse events was small it is difficult to determine if this was a true treatment-related effect. The working assumption that the single case of chronic diarrhoea seen at the 200mg/day may be linked to this nausea effect but, further investigation should be done to determine if this is idiosyncratic or as a result of the drug.

This study was testing the hypothesis that “There will be a difference in the reduction of symptoms according to the PANSS scale between FWD and placebo in the treatment of schizophrenia.” And in this regard, it would be reasonable to reject the null hypothesis and accept this experimental hypothesis.

In conclusion, the results of this Phase IIA study demonstrated a strong potential for FWA in the use as a treatment for schizophrenia and shows good clinical efficacy and tolerability which represents a useful therapeutic advance. Although it was not possible to follow-up on all enrolled patients to determine reasons for drop-outs, it was assumed that dosing frequency would have increased dosing adherence, maximising study outcomes and improving relapse potential when compared to other treatment available. Further studies should be carried out on patient populations that are more representative of trials that have already taken place in order to better compare the effects of FWA with other treatments available.

It is the recommendation of this study to repeat this study as a Phase IIB trial, with a larger trial population in order to confirm the observed results before moving into a Phase III study. The standard deviation ranges mean that it would be inappropriate to suggest moving into phase III before this confirmatory work can be carried out. If the proposed Phase IIB study can confirm these results, we would suggest moving into Phase II trials with the dose that has the greatest risk:benefit and perhaps, a suggestion to complete a further Phase II trial looking at an interim dose of 150mg/day as this is likely to be efficacious and should have a reduced adverse effect profile compared to the 200mg/day.

We feel given the positive results when looking at mean changes, alongside the positive changes seen in 95% confidence intervals that it is likely for a larger Phase IIB trial to provide confirmatory data to support an application for a Phase III trial, despite clear inadequacies in the standard deviation ranges. With a larger sample size, the level of uncertainty should be satisfactorily addressed.


References


Hermes, E., Sokoloff, D., Stroup, T. and Rosenheck, R. (2012). Minimum Clinically Important Difference in the Positive and Negative Syndrome Scale With Data From the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE). The Journal of Clinical Psychiatry, 73(04), pp.526-532.


Kane, J., Correll, C., Goff, D., Kirkpatrick, B., Marder, S., Vester-Blokland, E., Sun, W., Carson, W., Pikalov, A. and Assunção-Talbott, S. (2009). A Multicenter, Randomized, Double-Blind, Placebo-Controlled, 16-Week Study of Adjunctive Aripiprazole for Schizophrenia or Schizoaffective Disorder Inadequately Treated With Quetiapine or Risperidone Monotherapy. The Journal of Clinical Psychiatry, 70(10), pp.1348-1357.


Leucht, S., Kane, J., Kissling, W., Hamann, J., Etschel, E. and Engel, R. (2005a). What does the PANSS mean?. Schizophrenia Research, 79(2-3), pp.231-238.


Leucht, S., Kane, J., Kissling, W., Hamann, J., Etschel, E. and Engel, R. (2005b). Clinical implications of Brief Psychiatric Rating Scale scores. British Journal of Psychiatry, 187(4), pp.366-371.


Pinna, F., Deriu, L., Diana, E., Perra, V., Randaccio, R., Sanna, L., Tusconi, M. and Carpiniello, B. (2015). Clinical Global Impression-severity score as a reliable measure for routine evaluation of remission in schizophrenia and schizoaffective disorders. Annals of General Psychiatry, 14(1), p.6.


Rabinowitz, J., Mehnert, A. and Eerdekens, M. (2006). To What Extent Do the PANSS and CGI-S Overlap?. Journal of Clinical Psychopharmacology, 26(3), pp.303-307.


Santor, D., Ascher-Svanum, H., Lindenmayer, J. and Obenchain, R. (2007). Item response analysis of the Positive and Negative Syndrome Scale. BMC Psychiatry, 7(1).


Van den Oord, E., Rujescu, D., Robles, J., Giegling, I., Birrell, C., Bukszár, J., Murrelle, L., Möller, H., Middleton, L. and Muglia, P. (2006). Factor structure and external validity of the PANSS revisited. Schizophrenia Research, 82(2-3), pp.213-223.


Zimbroff, D., Kane, J., Tamminga, C., Daniel, D., Mack, R., Wozniak, P., Sebree, T., Wallin, B., Kashkin, K. and Setindole Study Group (1997). Controlled, dose-response study of sertindole and haloperidol in the treatment of schizophrenia. Sertindole Study Group. American Journal of Psychiatry, 154(6), pp.782-791.


Appendix, Figures and Tables



Table 1

Table 2

Table 3

Table 4

Parallel Study Design

Subgroup Change

CGI-S Change

Total Change

Flow of Participants

An assignment by: Darren Wogman MSc. Completed as part of Pharmaceutical Medicine MSc at King's College London

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