Cariprazin (1) – Reagila®

• Clinical trials
  • The studies RGH-MD-04 and RGH-MD-16 were identified in relation to the acute treatment of schizophrenia. These are randomised, multicentre, double-blind studies comparing cariprazine with aripiprazole and risperidone, respectively.
  • Study RGH-188-005 is a randomised, double-blind, registration trial conducted at 74 centres (in Bulgaria, France, Croatia, Poland, Romania, Russia, Serbia, Spain, the Czech Republic, Ukraine and Hungary) to compare cariprazine (N=230) with risperidone (N=231).

a) Adult patients with schizophrenia (acute treatment)

• No proof of additional benefit has been provided for adult patients requiring acute treatment for schizophrenia.
• The rigid dosing regimen used in these studies, without the possibility of individualised adjustment for each patient, does not meet the requirements of acute treatment. As it cannot be ruled out that a high proportion of patients in the studies were either over- or under-dosed with medicinal products, the studies are, on the whole, unsuitable for assessing the additional benefit compared with the appropriate comparator therapy. Consequently, no relevant data are available for patients with acute symptoms of schizophrenia; the additional benefit for these patients is not proven.

b1) Adult patients with schizophrenia (long-term treatment) – Adult patients with schizophrenia presenting predominantly with negative symptoms undergoing long-term treatment

• For adult patients in long-term treatment with predominantly negative symptoms, there is an indication of a minor additional benefit.
• On balance, the effects of cariprazine are assessed as a moderate – rather than merely minor – improvement in treatment-related benefit compared with the appropriate comparator therapy, as defined in Section 2(3) of the AMNutzenV, and the extent of the additional benefit is classified as minor.
• Due to the randomised and blinded design of the RGH-188-005 study, the potential for bias in the results is classified as minor, despite uncertainties regarding the scope for individual dose adjustment and the lack of data on accompanying measures. The certainty of the findings is therefore classified as an indication.
• mortality
  • By the end of the treatment phase, no deaths had been recorded in the cariprazine arm, whilst one death (0.4%) occurred in the risperidone arm. There is no statistically significant difference; no additional benefit can be inferred on the basis of mortality.
• Morbidity – Schizophrenia symptoms
  • Schizophrenia symptoms were assessed in the study using the PANSS (Positive and Negative Syndrome Scale) questionnaire.
  • The mean difference (MD) in the change from the start to the end of the study in the negative scale and in the factor score for negative symptoms differs statistically significantly between the treatment groups, with cariprazine showing an advantage (greater improvement) over risperidone in each case (MD for the negative scale: −1.48 [−2.38; −0.57], p = 0.001; MD for PANSS-FNS: −1.46 [−2.39; −0.53], p = 0.002).
  • For both scales, the 95% confidence interval does not lie entirely outside the non-significant range of –0.2 to 0.2; consequently, it cannot be concluded that the effect observed in the mean differences is clinically relevant.
• Morbidity – Depressive symptoms
  • Depressive symptoms were assessed using the total score on the Calgary Depression Scale for Schizophrenia (CDSS). No major difference was found between the study arms.
• Morbidity – Psychosocial functioning
  • Psychosocial functioning was assessed in the study using the Personal and Social Performance Scale (PSP).
  • No significant difference was found in the total score (MD: 4.63 [2.71; 6.56], p < 0.001), nor in the subscales ‘socially useful activities, including work and study’ (MD: −0.35 [−0.5; −0.20], p < 0.001), ‘personal and social relationships’ (MD: −0.24 [−0.37; −0.10], p < 0.001) and ‘self-care’ (MD: −0.20 [−0.34; −0.06], p = 0.004), a statistically significant difference in favour of cariprazine was observed.
  • The 95% confidence interval of the standardised mean difference (Hedges’ g) for the total score lies entirely outside the irrelevance range of –0.2 to 0.2. Overall, a clinically relevant effect can be inferred for the endpoint of psychosocial functioning.
  • Based on the statistically significant results and taking into account the extent of the effect, a moderate—rather than merely minor—improvement in the treatment-related benefit of cariprazine can be inferred.
• Morbidity – Clinical Global Impression
  • The overall impression of disease severity was assessed in the study using the Clinical Global Impression scale (CGI-I/-S).
  • Statistically significant advantages of cariprazine were observed on both the CGI-I (Improvement) and CGI-S (Severity) scales.
  • Although no additional benefit can be inferred on the basis of this endpoint alone, given the uncertainties mentioned, the direction of the effect confirms the positive result for the psychosocial functioning endpoint.
• Morbidity – Relapse
  • The pharmaceutical manufacturer operationalises relapse as a composite endpoint comprising various symptom severities (as measured by the PANSS and CGI-S) as well as events from the MedDRA-SMQs ‘Psychosis and Psychotic Disorders’, ‘Suicide/Self-harm’ and ‘Hostility/Aggression’. As this is a post-hoc definition and the composition is not sufficiently justified, the endpoint cannot be used for the benefit assessment.
• Health-related quality of life
  • Health-related quality of life was not assessed in the study. Consequently, no additional benefit can be inferred for this endpoint. The PSP score, initially identified by the pharmaceutical manufacturer as a quality-of-life endpoint, is considered under the category of morbidity.
• Side effects
  • There are no statistically significant differences between the treatment arms of the RGH-188-005 study in the analysis of serious AEs and therapy discontinuation due to AEs.
  • Similarly, in the additional endpoints assessed—suicidal behaviour using the Columbia Suicide Severity Rating Scale (C-SSRS), extrapyramidal motor disorders assessed using the Abnormal Involuntary Movement Scale (AIMS) to evaluate dyskinesia, and the Simpson-Angus Scale (SAS) to evaluate parkinsonism, no statistically significant differences were found.
  • The same applies to the analysis of the total score (items 1–3) and the individual items ‘objective restlessness’ (item 1), ‘awareness of restlessness’ (item 2) and ‘despair due to restlessness’ (item 3) of the Barnes Akathisia Rating Scale (BARS). Nor was there any statistically significant difference in the global clinical assessment of akathisia (item 4 of the BARS). Overall, it cannot be concluded that cariprazine offers any additional benefit or that it has less benefit due to side effects.
• Overall assessment
  • The results of the randomised, actively controlled and double-blind study RGH-188-005, which compared cariprazine with the appropriate comparator therapy risperidone, are available for the assessment of additional benefit. This study exclusively included patients on long-term treatment, the majority of whom presented with negative symptoms. An additional benefit can therefore only be inferred for this patient group within the target population.
  • No differences were observed in mortality or side effects, and no data on quality of life are available.
  • The statistically significant effects of cariprazine on the endpoint ‘psychosocial functioning’ are classified as minor in extent. The CGI results are used to support this conclusion. The PANSS Negative Scale and the PANSS-FNS show effects whose clinical relevance is questionable. No advantages or disadvantages were observed in the other endpoints.

b2) Adult patients with schizophrenia (long-term treatment) – Adult patients with schizophrenia without predominant negative symptoms undergoing long-term treatment

• As no relevant data have been presented for patients in long-term treatment without predominant negative symptoms, the additional benefit for this patient group is not proven.

Courtesy translation only, please refer to the German original.