To continue or not to continue? Antipsychotic medication maintenance versus dose-reduction/discontinuation in first episode psychosis: HAMLETT, a pragmatic multicenter single-blind randomized controlled trial

BACKGROUND: Antipsychotic medication is effective for symptomatic treatment in schizophrenia-spectrum disorders. After symptom remission, continuation of antipsychotic treatment is associated with lower relapse rates and lower symptom severity compared to dose reduction/discontinuation. Therefore, most guidelines recommend continuation of treatment with antipsychotic medication for at least 1 year. Recently, however, these guidelines have been questioned as one study has shown that more patients achieved long-term functional remission in an early discontinuation condition-a finding that was not replicated in another recently published long-term study. METHODS/DESIGN: The HAMLETT (Handling Antipsychotic Medication Long-term Evaluation of Targeted Treatment) study is a multicenter pragmatic single-blind randomized controlled trial in two parallel conditions (1:1) investigating the effects of continuation versus dose-reduction/discontinuation of antipsychotic medication after remission of a first episode of psychosis (FEP) on personal and social functioning, psychotic symptom severity, and health-related quality of life. In total 512 participants will be included, aged between 16 and 60 years, in symptomatic remission from a FEP for 3-6 months, and for whom psychosis was not associated with severe or life-threatening self-harm or violence. Recruitment will take place at 24 Dutch sites. Patients are randomized (1:1) to: continuation of antipsychotic medication until at least 1 year after remission (original dose allowing a maximum reduction of 25%, or another antipsychotic drug in similar dose range); or gradual dose reduction till eventual discontinuation of antipsychotics according to a tapering schedule. If signs of relapse occur in this arm, medication dose can be increased again. Measurements are conducted at baseline, at 3, and 6 months post-baseline, and yearly during a follow-up period of 4 years. DISCUSSION: The HAMLETT study will offer evidence to guide patients and clinicians regarding questions concerning optimal treatment duration and when to taper off medication after remission of a FEP. Moreover, it may provide patient characteristics associated with safe dose reduction with a minimal risk of relapse. TRIAL STATUS: Protocol version 1.3, October 2018. The study is active and currently recruiting patients (since September 2017), with the first 200 participants by the end of 2019. We anticipate completing recruitment in 2022 and final assessments (including follow-up 3.5 years after phase one) in 2026. TRIAL REGISTRATION: European Clinical Trials Database, EudraCT number 2017-002406-12. Registered 7 J

Computing Fairness: Ethics of Modeling and Simulation in Public Health

The field of public health increasingly utilizes computational models. In this context, computer scientists are confronted with moral dilemmas like those around modeling the distribution of scarce resources. However, there is a lack of research on the ethical implications of computer modeling and simulation (M&S). In this paper I aim to show that taking a transdisciplinary ethical perspective is useful when analyzing these implications. The practice of modeling geospatial distribution of automated external defibrillators for sudden cardiac arrest treatment is used as a case study. It is shown that there exists no consensus on what theory of justice should underlie choices in computer M&S of public health resources, and that professionals struggle with building equity considerations into their models. The example highlights new ethical consequences arising at the nexus of public health and M&S. Computer models and simulations are not morally neutral, but have the effect of making those involved in their creation more responsible for making just choices. For some moral dilemmas, such as those related to distributive justice, there may be no correct solution that can be readily modeled. Promoting professional responsibility through a code of ethics will not help prescribe a right course of action in these situations. I suggest therefore that procedural justice and deliberation with a range of stakeholders is needed to take ethical considerations into account “by design” when developing computer models and simulations for public health policy. Future research should reflect on the content and practical procedures for these deliberations

Awareness and Acceptability of Pre-Exposure Prophylaxis (PrEP) Among Men Who Have Sex with Men in Kazakhstan: A Mixed Methods Study

Objectives: Oral pre-exposure prophylaxis (PrEP) is an antiretroviral method of HIV prevention recommended to men who have sex with men (MSM) at high risk of infection. In Kazakhstan, which has one of the fastest growing HIV epidemics globally, PrEP is not currently available. The aim of this study is to explore the possibilities for PrEP initiatives in Kazakhstan by investigating awareness and acceptability of this prevention method among MSM. Methods: This mixed-methods study employs an online survey and qualitative interviews to describe PrEP awareness and acceptability. Results: Less than half (39.8%) of survey participants had heard of PrEP. However, a majority (85.2%) of MSM would possibly or defi nitely use PrEP if it was available. Awareness of PrEP was positively associated with willingness to use PrEP. The main reason to be interested in PrEP was an increased feeling of protection, whereas barriers were related to the idea of taking daily medication and the potential for side effects. Conclusion: PrEP is an essential component of HIV combination prevention. Our fi ndings suggest potential for PrEP programmes among MSM in Kazakhstan and possibly in other Central Asian nations, when taking into account burdens of taking PrEP as well as more structural health policy issues

Health data research on sudden cardiac arrest: perspectives of survivors and their next-of-kin

Background: Consent for data research in acute and critical care is complex as patients become at least temporarily incapacitated or die. Existing guidelines and regulations in the European Union are of limited help and there is a lack of literature about the use of data from this vulnerable group. To aid the creation of a patient-centred framework for responsible data research in the acute setting, we explored views of patients and next-of-kin about the collection, storage, sharing and use of genetic and health-related data for observational research. Methods: We conducted qualitative interviews (n = 19) with Dutch sudden cardiac arrest survivors who donated clinical and socio-economic data and genetic samples to research. We also interviewed their next-of-kin. Topics were informed by ethics literature and we used scenario-sketches to aid discussion of complex issues. Results: Sudden cardiac arrest survivors displayed limited awareness of their involvement in health data research and of the content of their given consent. We found that preferences regarding disclosure of clinically actionable genetic findings could change over time. When data collection and use were limited to the medical realm, patients trusted researchers to handle data responsibly without concern for privacy or other risks. There was no consensus as to whether deferred consent should be explicitly asked from survivors. If consent is asked, this would ideally be done a few months after the event when cognitive capacities have been regained. Views were divided about the need to obtain proxy consent for research with deceased patients’ data. However, there was general support for the disclosure of potentially relevant post-mortem genetic findings to relatives. Conclusions: Sudden cardiac arrest patients’ donation of data for research was grounded in trust in medicine overall, blurring the boundary between research and care. Our findings also highlight questions about the acceptability of a one-time consent and about responsibilities of patients, researchers and ethics committees. Finally, further normative investigation is needed regarding the (continued) use of participants’ data after death, which is of particular importance in this setting. Our findings are thought to be of relevance for other acute and life-threatening illnesses as well

Towards trust-based governance of health data research

Developments in medical big data analytics may bring societal benefits but are also challenging privacy and other ethical values. At the same time, an overly restrictive data protection regime can form a serious threat to valuable observational studies. Discussions about whether data privacy or data solidarity should be the foundational value of research policies, have remained unresolved. We add to this debate with an empirically informed ethical analysis. First, experiences with the implementation of the General Data Protection Regulation (GDPR) within a European research consortium demonstrate a gap between the aims of the regulation and its effects in practice. Namely, strictly formalised data protection requirements may cause routinisation among researchers instead of substantive ethical reflection, and may crowd out trust between actors in the health data research ecosystem; while harmonisation across Europe and data sharing between countries is hampered by different interpretations of the law, which partly stem from different views about ethical values. Then, building on these observations, we use theory to argue that the concept of trust provides an escape from the privacy-solidarity debate. Lastly, the paper details three aspects of trust that can help to create a responsible research environment and to mitigate the encountered challenges: trust as multi-agent concept; trust as a rational and democratic value; and trust as method for priority setting. Mutual cooperation in research—among researchers and with data subjects—is grounded in trust, which should be more explicitly recognised in the governance of health data research

Towards trust-based governance of health data research

Developments in medical big data analytics may bring societal benefits but are also challenging privacy and other ethical values. At the same time, an overly restrictive data protection regime can form a serious threat to valuable observational studies. Discussions about whether data privacy or data solidarity should be the foundational value of research policies, have remained unresolved. We add to this debate with an empirically informed ethical analysis. First, experiences with the implementation of the General Data Protection Regulation (GDPR) within a European research consortium demonstrate a gap between the aims of the regulation and its effects in practice. Namely, strictly formalised data protection requirements may cause routinisation among researchers instead of substantive ethical reflection, and may crowd out trust between actors in the health data research ecosystem; while harmonisation across Europe and data sharing between countries is hampered by different interpretations of the law, which partly stem from different views about ethical values. Then, building on these observations, we use theory to argue that the concept of trust provides an escape from the privacy-solidarity debate. Lastly, the paper details three aspects of trust that can help to create a responsible research environment and to mitigate the encountered challenges: trust as multi-agent concept; trust as a rational and democratic value; and trust as method for priority setting. Mutual cooperation in research-among researchers and with data subjects-is grounded in trust, which should be more explicitly recognised in the governance of health data research

To continue or not to continue? Antipsychotic medication maintenance versus dose-reduction/discontinuation in first episode psychosis:HAMLETT, a pragmatic multicenter single-blind randomized controlled trial

Background: Antipsychotic medication is effective for symptomatic treatment in schizophrenia-spectrum disorders. After symptom remission, continuation of antipsychotic treatment is associated with lower relapse rates and lower symptom severity compared to dose reduction/discontinuation. Therefore, most guidelines recommend continuation of treatment with antipsychotic medication for at least 1 year. Recently, however, these guidelines have been questioned as one study has shown that more patients achieved long-term functional remission in an early discontinuation condition - a finding that was not replicated in another recently published long-term study. Methods/design: The HAMLETT (Handling Antipsychotic Medication Long-term Evaluation of Targeted Treatment) study is a multicenter pragmatic single-blind randomized controlled trial in two parallel conditions (1:1) investigating the effects of continuation versus dose-reduction/discontinuation of antipsychotic medication after remission of a first episode of psychosis (FEP) on personal and social functioning, psychotic symptom severity, and health-related quality of life. In total 512 participants will be included, aged between 16 and 60 years, in symptomatic remission from a FEP for 3-6 months, and for whom psychosis was not associated with severe or life-threatening self-harm or violence. Recruitment will take place at 24 Dutch sites. Patients are randomized (1:1) to: continuation of antipsychotic medication until at least 1 year after remission (original dose allowing a maximum reduction of 25%, or another antipsychotic drug in similar dose range); or gradual dose reduction till eventual discontinuation of antipsychotics according to a tapering schedule. If signs of relapse occur in this arm, medication dose can be increased again. Measurements are conducted at baseline, at 3, and 6 months post-baseline, and yearly during a follow-up period of 4 years. Discussion: The HAMLETT study will offer evidence to guide patients and clinicians regarding questions concerning optimal treatment duration and when to taper off medication after remission of a FEP. Moreover, it may provide patient characteristics associated with safe dose reduction with a minimal risk of relapse. Trial status: Protocol version 1.3, October 2018. The study is active and currently recruiting patients (since September 2017), with the first 200 participants by the end of 2019. We anticipate completing recruitment in 2022 and final assessments (including follow-up 3.5 years after phase one) in 2026. Trial registration: European Clinical Trials Database, EudraCT number 2017-002406-12. Registered 7 June 2017