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Pharmacokinetic assessment
BLOOD
Blood samples were collected for PK assessment before the first dose and at 1, 2, 3, 6, and 8 h after oral milademetan on days 1 and 14 of cycle 1, before the dose on days 2 and 8 of cycle 1, and before the dose and at 3 h after milademetan on day 1 of cycle 2. Milademetan concentrations were determined using a validated HPLC/MS method. The lower limit of quantification was 0.500 ng/mL. Noncompartmental analysis was used to calculate the PK parameters from milademetan plasma concentrations. In addition, the Phoenix WinNonlin 8.1 software (Certara, Princeton, NJ, USA) was used for PK analysis.
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Pharmacodynamic assessment
To investigate biomarkers that could be potentially linked to the milademetan mechanism of action, blood, bone marrow, and serum were collected.
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Efficacy assessment
extramedullary leukemia, AML, SD
DISEASE, REMISSION, AML
Bone marrow and peripheral blood results were used to assess the antitumor effect of milademetan. AML response criteria were defined as shown in Supplementary Table 1. A morphologic leukemia-free state (MLFS) was defined as bone marrow blasts < 5% in the absence of blasts with Auer rods and the absence of extramedullary leukemia. The presence/absence of hematological recovery or blood transfusion was not considered. Stable disease (SD) was defined as an absence of CR, CR with incomplete hematologic recovery (CRi) or partial hematologic recovery (CRh), partial remission (PR), or MLFS, provided that the criteria for the progressive disease were not met. SD had to last at least 3 months (assessed as SD more than thrice in a row) after initiating milademetan treatment. SD < 3 months was deemed not applicable. The best-measured response was defined as the best overall response (all time points after the start of study treatment until the end of treatment). The composite CR (CRc) duration was defined as the time between when the criteria for CRc (CR + CRi + CRh) were first met and when a relapse was first confirmed.
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Definitions and statistical analysis
DLTs, overdose
REGRESSION
All patients who received at least one milademetan dose were included in the safety analysis set. The MTD analysis set included patients who received at least one milademetan dose, had no missing data for examination or observation during the DLT evaluation period, and had a completed DLT evaluation. Without DLTs, the included patients received ≥ 75% milademetan of the specified days in cycle 1. Patients who experienced DLT during the DLT evaluation period and resumed the study treatment at a lower dose were included in the initial dose cohort. The efficacy analysis set included all patients who received at least one milademetan dose and underwent efficacy evaluation at least once after treatment initiation. The PK analysis set comprised patients who received at least one milademetan dose, for whom a PK sample was collected at least once after initiating treatment, and who had available PK measurement data. The biomarker analysis set included all patients who received at least one milademetan dose, whose specimens were collected for biomarker studies, and who had available measurement data. Following the first cycle, doses for subsequent cohorts were guided by an mCRM based on a Bayesian logistic regression model incorporating the escalation with the overdose control principle, clinical evaluation of the toxicological profile, and pharmacokinetics and pharmacodynamics information. Continuous variables were summarized with mean, standard deviation, and minimum, median, and maximum values, while categorical variables were summarized with a frequency table.In addition to descriptive statistics, the geometric mean and geometric coefficient of variation were used to describe the PK parameters. All analyses were conducted using SAS
PMC9813109
Results
AML
AML
This study protocol primarily evaluated the QD 14/28 milademetan schedule in AML patients. The QD 14/28 treatment schedule was required in this study to participate in another phase I study in combination with quizartinib (NCT03552029) [
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Safety
death, pneumonia, febrile neutropenia, TEAEs, SAEs, TEAE
PNEUMONIA, FEBRILE NEUTROPENIA, ADVERSE EVENTS, EVENT, DISEASE, ADVERSE EVENT, EVENTS
The median (minimum and maximum) total treatment duration of the 14 patients was 1.5 (1 and 8) cycles. The median (minimum and maximum) relative dose intensity was 100% (92.9% and 100%), 100% (7.1% and 100%), and 92.9% (70.7% and 100%) in the 90-, 120-, and 160 mg cohorts, respectively. A summary of TEAEs is provided in Table Summary of treatment-emergent adverse events (TEAEs)Treatment-emergent adverse event (TEAE) is an adverse event that occurs after the first administration or worsens relative to the pretreatment stateCoded with Medical Dictionary for Regulatory Activities (MedDRA) Version 21.1Most frequent treatment-emergent adverse events (TEAEs) [≥ 20% (all grades) or any (grade ≥ 3)]Treatment-emergent adverse event (TEAE) is an adverse event that occurs after the first administration or worsens relative to the pretreatment stateCoded with Medical Dictionary for Regulatory Activities (MedDRA) Version 21.1DLT assessment was completed by all 11 patients in the MTD analysis set, and no DLTs were reported in any of the three cohorts during the evaluation period (cycle 1). The MTD was not reached, thus, recommended dose was defined as 160 mg in the 14/28 treatment cycle. The five reported SAEs in four patients included febrile neutropenia (two events) and pneumonia (three events). Both febrile neutropenia events and one pneumonia event were drug-related. No death or AEs that caused treatment discontinuation were noted. All patients discontinued study treatment due to progressive disease (
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Pharmacodynamics (biomarker)
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TP53 genomic mutation status
A mutation in the
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MIC-1 status
MIC-1 is a secreted p53 downstream gene product used as a pharmacodynamic biomarker for p53 activation [Mean macrophage inhibitory cytokine-1 (MIC-1) serum level
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Discussion
nausea, DLTs, AML, vomiting, decreased appetite, heterogenous R/R
AML, DYSFUNCTION
This is the first report to evaluate the safety and tolerability of milademetan monotherapy administered in multiple doses for R/R AML patients. Of the 14 enrolled patients, 14, 12, and 11 were included in the safety, efficacy, and MTD analysis sets, respectively. The most common TEAEs were decreased appetite (64.3%) and nausea (42.9%). No dose-dependent increase was observed in the frequency of TEAEs that were grade ≥ 3, serious, or led to dose reduction/treatment interruption. No DLTs were noted during the DLT evaluation period (cycle 1), and the MTD could not be determined, thus, recommended dose was defined as 160 mg in this study (QD 14/28-day schedule).The safety results of this study demonstrated that milademetan was well tolerated up to 160 mg in the QD 14/28-day schedule without any new safety concerns. Gastrointestinal symptoms (e.g., decreased appetite, nausea, and vomiting) are common TEAEs with milademetan as well as other MDM2 inhibitors. In addition, the drug’s safety profile observed in this study is comparable with that of other MDM2 inhibitors [The None of the 12 patients in the efficacy analysis set had CR, CRh, CRi, or PR at 90, 120, or 160 mg doses of milademetan. MLFS and SD were observed in two (16.7%) and one (8.3%) patient, respectively, and their Other phase I studies of milademetan included combination therapies with azacytidine and quizartinib for R/R AML (NCT02319369) [Previous reports in AML patients revealed that p53 pathway dysfunction is common regardless of p53 mutation status. Therefore, MDM2 could be a therapeutic target [This study had some limitations. This is a small-scale (only three to six patients in each cohort), open-label phase I study with an ethnically homogeneous population, hence it is not possible to generalize the results to more large and heterogenous R/R AML groups. Insufficient follow-up period to assess long-term safety, response duration, or survival are other limitations. In addition, MDM2 status was not defined as an eligibility criterion in this study because no robust evidence was noted to indicate whether MDM2 status is a suitable predictive biomarker when this study began. Therefore, future clinical trials are needed to comprehensively investigate the efficacy and safety of milademetan.In conclusion, milademetan was generally safe and well tolerated up to 160 mg in the QD 14/28-day schedule in Japanese patients with R/R AML. MTD was not reached at up to 160 mg with the QD 14/28 schedule in this study. The PK parameters, including
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Acknowledgements
The authors thank the patients of this study and their families. All authors meet the International Committee of Medical Journal Editors criteria for authorship for this article and take responsibility for the integrity of the work, the data, and its accuracy. All authors had full access to the data in this study and take complete responsibility for the integrity of the data and the accuracy of the data analysis.All authors confirm that they contributed to the scientific content of this paper and meet the following four requirements: (a) significantly contributed to the conception and study design, data acquisition, or data analysis and interpretation; (b) drafted or revised the article for scientific content; (c) gave final approval for the published article; and (d) are accountable for all aspects of the work, ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. Medical writing assistance was provided by Ritu Guglani, MD, and Raghuraj Puthige, PhD of ENAGO Life Sciences, India, funded by Daiichi Sankyo Co., Ltd. This study was sponsored by Daiichi Sankyo Co., Ltd. The sponsor provided oversight of the clinical operations, data management, medical monitoring, drug supply, statistical analysis, drug safety process, medical writing, and journal article processing fees.
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Data availability
Deidentified individual patient data and applicable supporting clinical trial documents may be available upon request at Vivli-Center for Global Clinical Research Data. Daiichi Sankyo will continue to protect the privacy of the clinical trial patients in cases where clinical trial data and supporting documents are provided according to company policies and procedures. Details on data sharing criteria and the procedure for requesting access can be found online (
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Declarations
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Conflicts of interest
Naohiro Sekiguchi received research funds from Ono, A2 Healthcare, Astellas, Janssen, MSD, Otsuka, Pfizer, PPD-SNBL, Sumimoto Dainippon, Daiichi Sankyo, and Bristol Myers Squibb. Senji Kasahara received research funds from Daiichi Sankyo. Toshihiro Miyamoto received research funds from Daiichi Sankyo and speaker fees from Bristol Myers Squibb, Otsuka, MSD, Astellas, Astellas Amgen, Celgene, AbbVie, and Takeda. Toru Kiguchi received speaker fees from Bristol Myers Squibb and Novartis, as well as research funds from Bristol Myers Squibb, Daiichi Sankyo, Otsuka, MSD, Takeda, Astella, Nippon Shinyaku, Novartis, Sumimoto Dainippon, Janssen, SymBio, Celgene, and Sanofi. Hitoshi Ohno received research funds from Daiichi Sankyo. Taiga Takagi, Masaya Tachibana, Hiroyuki Sumi, Yasuyuki Kakurai, and Tomonari Yamashita are employees of Daiichi Sankyo. Kensuke Usuki received speaker fees from Novartis as well as research funds from Astellas, Alexion, AbbVie, Gilead, SymBio, Daiichi Sankyo, Sumimoto Dainippon, Chugai, Otsuka, Novartis, Bristol Myers Squibb, Takeda, Astellas Amgen, Apellis, and Nippon Shinyaku.
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Ethical statement
This study was conducted and complied with all international and local laws, the principles of the Declaration of Helsinki, and the Good Clinical Practice Guidelines. All patients provided written voluntary informed consent to participate in this study. The study protocol and all its amendments were approved by the relevant institutional review boards or independent ethics committees.
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References
PMC9813109
1. Introduction
TB, sepsis, Sepsis, human immunodeficiency virus (HIV)
SEPSIS, SEPSIS, DISEASES, TUBERCULOSIS (TB)
Sepsis is a significant cause of mortality among people living with human immunodeficiency virus (HIV) in sub-Saharan Africa. In the planning period prior to the start of a large multi-country clinical trial studying the efficacy of the immediate empiric addition of anti-tuberculosis therapy to standard-of-care antibiotics for sepsis in people living with HIV, we used decision analysis to assess the costs and potential health outcome impacts of the clinical trial design based on preliminary data and epidemiological parameter estimates. The purpose of this analysis was to highlight this approach as a case example where decision analysis can estimate the cost effectiveness of a proposed clinical trial design. In this case, we estimated the impact of immediate empiric anti-tuberculosis (TB) therapy versus the diagnosis-dependent standard of care using three different TB diagnostics: urine TB-LAM, sputum Xpert-MTB/RIF, and the combination of LAM/Xpert. We constructed decision analytic models comparing the two treatment strategies for each of the three diagnostic approaches. Immediate empiric-therapy demonstrated favorable cost-effectiveness compared with all three diagnosis-dependent standard of care models. In our methodological case exemplar, the proposed randomized clinical trial intervention demonstrated the most favorable outcome within this decision simulation framework. Applying the principles of decision analysis and economic evaluation can have significant impacts on study design and clinical trial planning. Clinical tuberculosis (TB) caused by the pathogen Microbiological culture for the detection of TB is the gold standard, but it is expensive and has a long wait time [Randomized control trials have become increasingly innovative and complex as adaptive designs, multi-center, and multi-country trials become the standard for many diseases including TB and sepsis [Decision analytic modeling is an analytic and simulation approach that integrates and synthesizes sources of evidence in the form of parameter estimates to calculate the cost-effectiveness of applying an intervention. In turn, this estimate can be used to anticipate the impact of the approach on a health system, payer, or society at large, and can be an integral component of clinical trial planning [The purpose of this analysis was to highlight this approach as a case example where decision analysis can estimate the cost effectiveness of a proposed clinical trial design and allow investigators and stakeholders to visualize the potential costs and health impacts based on prior knowledge of expected utilities. In this case, we estimated the impact of immediate empiric anti-TB therapy versus the diagnosis-dependent standard of care using three different TB diagnostics, urine TB-LAM (Alere Determine TB-LAM Ag, Abbot, Chicago, IL, USA) [
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2. Methods
PMC10049353
Study Model and Parameters
TB, infection, sepsis
INFECTION, SEPSIS
We constructed three distinct decision-analysis models to assess the cost-effectiveness of immediate empiric anti-TB treatment versus diagnosis-dependent standard of care using the three different TB diagnostic approaches (urine TB-LAM, sputum Xpert MTB/RIF, and LAM/Xpert) (Underlying TB prevalence rates in persons with HIV, treatment success and failure rates, and the sensitivity/specificity of urine TB-LAM, Xpert MTB/RIF, and LAM/Xpert are found in Mortality and disability weights (quality adjusted life years, or QALYs) associated with TB/HIV infection, TB treatment, HIV without TB, and sepsis were obtained from the extant literature and applied to the decision tree (We performed a one-way sensitivity analysis on key parameters by varying each parameter over a range of possible values that were supported by the literature to estimate the effects of parameter uncertainly on the decision analytic cases. In one-way sensitivity analysis, variables were entered into the model with varying estimates based either on known parameter ranges or outcomes greater/less than 10% of the original parameter estimates when a range was not available. We calculated incremental cost effectiveness ratios (ICER) by calculating the differences in costs between early anti-TB treatment and standard care (C1-C0) divided by the differences in effectiveness between early anti-TB treatment and standard care (E1-E0). We conducted the cost effectiveness analysis using TreeAge Pro 2023 R1 software (Williamstown, MA, USA). Institutional review was not required because this is not deemed human subjects research due to the mathematical modeling with parameter estimates obtained from existing published literature.
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3. Results
TB, sepsis
SEPSIS
Immediate empiric-therapy demonstrated favorable cost-effectiveness compared with all three diagnosis-dependent standard of care models (urine TB-LAM, sputum Xpert MTB/RIF, and the combination LAM/Xpert). Of the three cost effectiveness models, the sputum Xpert diagnostic strategy presented the most favorable incremental effectiveness of early empiric treatment compared with the standard approach (0.08) and ICER (USD 2021.26); followed by urine LAM incremental effectiveness (0.05) and ICER (USD 2683.19); and combined LAM/Xpert incremental effectiveness (0.03) and ICER (USD 4269.73). In sensitivity analysis, the parameter that contributed the most to increased effectiveness of the immediate empiric anti-TB treatment strategy was the proportion of those persons treated with immediate anti-TB treatment who had rifampin susceptible TB, followed by the proportion alive at day seven among those who presented with symptoms of sepsis but who were not found to have diagnostic confirmation of TB, and lastly the proportion of those with rifampin resistance (
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4. Discussion
TB
Here, we demonstrated an analytic approach that can provide early proof of concept of the potential costs and health utilities of a proposed randomized control trial demonstrating a mortality benefit to the hypothetical early empiric anti-TB therapy arm regardless of the diagnostic strategy used (urine LAM, sputum Xpert MTB/RIF, or LAM+Xpert). This approach also provided costs estimates and ICER for the time horizon of the clinical trial, which may allow for more precise clinical trial budget estimates [Decision analysis models can help support or refute the underlying hypothesis or treatment modality in question, further refine the budget impact of the trial itself, and differentiate the incremental cost and effect using various diagnostic approaches. Finally, this type of model gave further weight to determining which variables contribute to the overall effectiveness of the intervention, in this case drawing attention to the importance of optimally treating rifampin-susceptible TB. Thus, future strategies should be considered that tailor the composition of the immediate empiric regimen that optimizes rifampin-susceptible TB treatment, such as higher doses of isoniazid and rifampin to overcome potentially suboptimal pharmacokinetics [
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Limitations
DISEASE, LENS
We caution that these results and the limited model horizon should not be extrapolated beyond the lens of the clinical trial period, as they only provide early estimates using the preliminary data to support the underlying clinical trial hypothesis, and the demonstrated need of the clinical trial to provide true efficacy and mortality estimates. By incorporating this decision analytic structure prior to enrollment, the same approach can be updated during any pause for interim analysis to update prior parameter estimates. The final decision analytic model can be updated following the completion of the clinical trial using data from the trial itself. Specifically, follow-up decision analysis can then be based on both clinical trial data and real-world epidemiological estimates with a lengthened time horizon (a lifetime horizon with long-term follow up data that includes QALY utility adjustments over a longer period of time) that truly captures the disease burden and trajectory, at the societal- or country-level perspectives. These estimates can also provide the basis for finalized cost estimates, such as those discounted at a 3% annual rate per the guidelines of the Public Health Service Panel on Cost Effectiveness in Health and Medicine or other projections of market pressure and resource allocation constraints [
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Author Contributions
J.K.-M., S.K.H., T.A.T. and C.C.M. conceptualized the study. J.K.-M. and J.M.L. conducted the data analysis. S.K.H., T.A.T., C.C.M., S.G.M. and C.M. provided clinical domain knowledge and finalized model parameter estimates. J.K.-M. drafted the first draft of the manuscript. All authors have read and agreed to the published version of the manuscript.
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Institutional Review Board Statement
Not applicable, not research on human subjects.
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Informed Consent Statement
Not applicable.
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Data Availability Statement
Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study. Additional model findings are available upon request.
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Conflicts of Interest
The authors declare that they have no competing interest.
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References
HIV and sepsis
Decision model of combined urine LAM+Xpert. In this model, we compare the two future arms of a randomized control trial. ‘Treat all’ means deliver early antimicrobial therapy in the context of suspected TB-sepsis and ‘selective treatment’ indicates standard of care (wait and treat once a diagnosis is confirmed. This example is a visual representation of the decision tree associated with the combined TB-LAM/Xpert diagnostic testing.A tornado diagram indicating the sensitivity analysis of input parameters for combined LAM+Xpert. Each line is a variable that is a part of the mathematical model and the blue bar represents their contribution to the difference in QALYs from the base case.Decision analytic model inputs based on data from patients with HIV and sepsis in Uganda.
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Subject terms
NBIs
Adolescence is a time of multiple transitions and a vulnerability period for mental health difficulties. There are many barriers to the treatment of mental health conditions which is one reason for developing alternatives to help improve efficacy in treatment and prevention. One approach is to use nature-based interventions (NBIs) to improve mental wellbeing. In this experimental proof-of-principle intervention study, we randomly allocated a sample of adolescents to brief exposure (6 min) to either a virtual woodland nature video or a busy train journey and tested the effect on mental wellbeing. Results showed beneficial effects in the nature condition on several self-reported outcomes including stress, relaxation, affect, mood, attention, nature connection and nature spirituality. The intervention was mainly acceptable and feasible to do suggesting that overall brief virtual nature interventions may have utility in a range of mental health contexts for adolescents including as self-help universal or targeted prevention strategies, adjunct to psychological therapy and as preparation for more intensive NBIs. Additionally, brief virtual nature interventions support accessibility for those who may be limited on time, unable to access real-life nature or who may be more
PMC10584913
Introduction
disability
Mental health difficulties are associated with high levels of disability globallyTraditionally, mental healthcare has been driven by our collective ‘rule of rescue’, focusing primarily on treatmentFor these reasons more focus on prevention interventions has been called for in many quartersNature-based interventions (NBI) have the potential to alleviate mental health difficulties in young people via both treatment and prevention approachesNBIs are wide-ranging in scope and may involve full contact with wild natural environments such as in the Japanese art of Shinrin Yoku (forest bathing) It is also important to recognise that access to natural environment spaces is not equally distributed across the population. First, more deprived areas tend to have less green space access than affluent areasIn the present, proof-of-principle study we tested the effect of a brief nature walk video versus an urban control on several mental wellbeing indices including stress, relaxation, negative and positive affect, mood, rumination and self-reported attention. We also set out to test the effect on nature connection and nature spirituality. The study was designed to test the following specific hypotheses: a brief immersive video of a woodland walk (nature condition) relative to a comparison video of a busy underground train journey (urban condition) will improve (i) mental wellbeing and (ii) a sense of connection to nature. We also tested (iii) whether nature spirituality would increase in the virtual nature condition. We note here that we follow the conceptualisation of non-religious spirituality put forward elsewhere, where spirituality may be seen in connection to oneself, others, nature, as well as to transcendence but may not involve religiosity per seThis study was reviewed and approved by the Psychology Ethics Committee at the University of Exeter (reference number: 530476) and the experiment was carried out in accordance with the principles outlined in the Helsinki Declaration.
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Results
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Randomisation
We first checked whether there were differences between randomisation conditions on demographic information and the baseline measures. No differences were observed suggesting that the randomisation procedure was successful (see Table Means, standard deviations and proportions of baseline characteristics and study measures. P-values refer to differences between conditions. Tests used were ANOVA for continuous data and χ
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The effect of nature exposure
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Stress & relaxation
There was a significant effect of Condition on the stress VAS over time (F(1,73) = 4.81, Change in stress over time by nature and urban conditions.
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Affect and mood
There was a significant effect of Condition on the PANAS NEG scale (F(1,73) = 11.28, Change in nature positive and negative affect over time by nature and urban conditions.
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Nature connection & nature spirituality
There was a significant effect of condition on the NCI (F(1,73) = 5.37, Change in nature connection and nature spirituality over time by Nature and Urban conditions.
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Affect regulation
There was no significant difference between the conditions on change in rumination as measured by the BSRI (F(1,73) = 1.96,
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Attention
In the nature condition, participants reported being more focussed and alert immediately after the experiment relative to the Urban condition (F(1,74) = 7.03,
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Post experiment questions
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Attention check
The majority of participants in the nature condition (33, 89.19% correct) and Urban condition (33, 84.62% correct) successfully completed the attention check at the end of the video. There was no difference between the two conditions (χ
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Acceptability and feasibility
Twenty-four participants in the Nature condition (64.86%) and 33 in the Urban condition (84.62%) reported that the video felt either ‘slightly realistic’ or ‘very realistic’ when watching it, which was a significant difference (χ
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Discussion
phobic, agoraphobic, depressive, depression-related low
BLIND
Our findings support both of the general hypotheses that brief exposure to an immersive nature video, relative to an urban comparison condition would (i) reduce stress and improve indices of mental wellbeing in adolescents and (ii) increase nature connection. Our novel hypothesis on increasing nature spirituality (iii) was also supported. The positive findings are consistent with previous research where virtual nature interventions often, but not always, show benefitIn the present study, we first showed that the randomisation to the Nature and Urban conditions was successful, with no significant baseline differences found on any measure. This is an important step, and broader methodological issue, as previous work in this area has shown that both lack of randomisation and lack of the use of a control group can inflate the positive finding rateTo encourage adherence to task in this online remote context, we asked participants a factual checking question specific to each condition. This proved to be helpful given that the majority in each condition answered their respective questions correctly and we suggest continuing to use measures to increase adherence to online interventions in future research.There was a difference between conditions on positive affect which decreased significantly in the urban condition but not in the nature condition, suggesting that rather than improving positive affect, the nature condition was able to buffer it, relative to the deleterious effects in the urban condition. This may be very important when considering future early intervention and prevention strategies for adolescent mental health, especially for those for whom accessing nature is challenging. Buoying mental wellbeing for those at-risk adolescents may mean the difference between sustaining wellness and facing the unfolding of clinical mental health difficulties.An increase in nature spirituality in the virtual nature condition is a novel finding that may also be important for future research directions. As has been pointed out by RyffThe paucity of spirituality considerations in clinical and counselling training programmes is slowly being addressedWe recognise that virtual exposure to natural environments may have value in improving mental wellbeing and even preventing mental illness, and may be appropriate for those struggling to get outside or who are agoraphobic, socially phobic or have depression-related low motivation. However, consistent with other viewsAlthough just a single subjective item explored the effect of nature on attention, participants self-reported feeling more alert and attentive after watching the video. It should be noted that in both virtual experimentsThe majority of the sample reported that the video was too long although we consider it brief, under the average time for virtual exposure (8 min) in a recent review The strengths of this study include remote blind randomisation of participants to experimental or comparison condition, the use of a number of well-validated psychometric instruments and the novel finding of an increase in nature spirituality following brief virtual nature exposure. We acknowledge, however, several limitations. First, in this proof-of-principle study we are unable to determine the precise features of environment that are likely to be beneficial to mental wellbeing. As discussed elsewhere this is an important frontier in the research We were unable to use objective measures of stress (e.g. salivary cortisol) or indices such as heart rate variability collected via wearables, or objective measures of attention or other executive functions. We were also unable to include any follow up measurement time points to test, for example, the potential mid-term effect on reducing depressive symptoms over weeks and months. Clearly in this proof-of-principle, experimental design of a brief intervention we were unable to test effects of prevention of mental health conditions in adolescents but this should be a focus of future research. The sample of adolescents in this study was also overwhelmingly female and ethnically white and so it will be important for future studies to test for effects in males and other ethnic groups.We suggest that future research priorities should focus on augmenting virtual nature interventions to increase their effectiveness and this could be achieved in several ways. First, the intervention could be repeated multiple times over a number of days or weeks and dose-response relationships assessed. Second, more active components could be added, for example, mindful awareness
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Methods
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Procedure
RECRUITMENT
The study used an experimental design and recruited participants through opportunity sampling. Recruitment methods included social media (e.g. Facebook, Instagram, LinkedIn), posters placed around the University campus and through word of mouth. Digital and paper advertisements contained a QR code for participants to access study information and a consent form. Once participants had provided informed consent, they completed baseline measures housed in the Gorilla Experiment Builder. Participants were then randomly assigned 1:1 to either the nature or urban condition using the Gorilla randomizer node. This process is automatic and not influenced by the researchers. Participants were shown a brief, 6-min video of either a nature or urban setting and were presented with an attention check question to measure adherence. Participants were then asked to complete the post-experiment self-report battery. At the end of the study, participants were given a full debrief of the study aims and were invited to be kept updated with the study results. Signposting to mental health services was also provided. Lastly, participants were automatically entered into a prize draw for the chance to win one of three possible cash voucher prizes (1 × £30, 2 × £10).
PMC10584913
Participants
The sample consisted of 76 adolescents (mean age = 20.42, SD = 1.15, range = 18–25) and included 61 females (85.53%), 11 males (14.47%). The majority, 65, was white (85.53%) with 11 (14.47%) participants reporting other ethnicities (3 ‘Asian’, 1 ‘Black’, 3 ‘Mixed’ and 4 ‘Other’).
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Conditions
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The virtual nature condition
visual and auditory
This condition contained a short virtual nature video (6 min) combining immersive visual and auditory aspects of both green and blue space. The recording is a point-of-view walk that begins along a woodland pathway surrounded by tall trees, followed by a section of riverside walking in the woodland, ending with a further pathway walk. Various natural sounds, such as birdsong, the rustling of leaves and water trickling in the river, can be clearly heard in the video. The reasoning for selecting this nature video was to combine both green and blue space and to provide a short but immersive, holistic virtual nature experience that analogous to natural green/blue spaces used in previous real-world research
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Urban comparison condition
This comparison condition included a recording of equivalent duration to the virtual nature condition (6:00 min) that attempted to emulate a real-world urban environment. The video is taken inside a London underground train during a busy rush hour period. The video features a virtual passenger waiting at a busy and congested platform for a London Underground train to arrive. The train arriving is full of commuters and features lots of people trying to board the train. Upon entering the train, the commuter stands for the rest of the duration of the video, at close proximity to the ceiling. Noisy urban sounds can be heard throughout the video such as loud engine sounds of the trains travelling, arriving and departing from various stations, commuters talking and public service announcements being made. The experience in this recording involves exposure to multiple potential urban environmental stressors through virtual immersion in a noisy, crowded setting which in the real-world may increase aversive emotional responses Stills from the videos in the Nature and Urban conditions.
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Measures
PMC10584913
Short Warwickshire Edinburgh Mental Wellbeing Scale (SWEMWBS)
The SWEMWBS is a seven-item unidimensional measure of wellbeing
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International Positive and Negative Affect Schedule Short Form (I-PANAS-SF)
The I-PANAS-SF is a 10-item scale measuring state positive affect (PA) and negative affect (NA) using a five-point Likert scale (1 = “not at all/ very slightly to 5 = “extremely”)
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Brief State Rumination Index (BSRI)
The BSRI is an eight-item scale measuring state rumination using a visual analogue scale (VAS; 0 = “completely disagree” to 100 = “completely agree”)
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Stress
State stress levels were measured using a VAS (0 = “completely disagree” to 100 = “completely agree”), asking participants to rate how strongly they agree with the statement “I am stressed right now”. VAS stress scales have been shown to be equal to questionnaire methods of assessing stress
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Perceived Stress Scale (PSS-4)
The PSS-4
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Nature connection
The Nature Connection Index
PMC10584913
Nature spirituality
For the present study, a small set of items was needed to test our exploratory hypothesis on nature spirituality in adolescents whilst not overburdening participants. To ensure that items were likely to be tapping into state spirituality and therefore sensitive to change after a short duration, we used the stem of “Right now,…” for each item. We selected items we believed would be most appropriate for this sample of adolescents experiencing a virtual nature scene. We selected four items from the 20-item Ecospirituality Scale
PMC10584913
Bespoke items
Three additional items were included following the experiment. These were “Right now, I feel relaxed/composed”. “Right now, I feel that my mood is positive”. “Right now, I can focus clearly and I feel alert”. Each item used a VAS (0–100).
PMC10584913
Feasibility and acceptability
anxiety, depressive symptoms
We asked three questions at the end of the experiment to assess feasibility and acceptability of the intervention, including, “Overall, how realistic did watching the video feel?”, “How did you find the overall length of the video? And “Would you recommend this to a friend or family member who is experiencing anxiety or depressive symptoms?
PMC10584913
Sample size calculation
We based our sample size calculation on detecting a difference in short-term psychological change following a nature-based intervention
PMC10584913
Acknowledgements
RECRUITMENT
Thanks to Emily Kekwick for assisting with the recruitment and delivery of the study.
PMC10584913
Author contributions
M.O and H.B. conceived and deigned the online experiment and M.O. analysed the results. Both authors wrote and reviewed the manuscript.
PMC10584913
Competing interests
FOUNDERS
The authors declare no competing interests. Both M.O and H.B. are founders of the ROWAN group which is a non-political, non-advocacy collaboration between clinicians, academics, students and members of the public set up to investigate the connection between nature and wellbeing.
PMC10584913
References
PMC10584913
Purpose
To assess study design and a range of anatomical and functional changes after internal limiting membrane (ILM) peeling using forceps developed for atraumatic ILM pick-up compared to standard forceps.
PMC10198899
Methods
FTMH, idiopathic full-thickness macular hole
We conducted a masked proof-of concept randomised controlled trial (RCT) on 65 patients who underwent ILM peeling for idiopathic full-thickness macular hole (FTMH) using etched-tip forceps (etched-tip group, 33 eyes) compared to standard ILM forceps (smooth-tip group, 32 eyes). Patients were assessed preoperatively, 3 weeks, 3 and 6 months postoperatively.
PMC10198899
Results
The primary closure rate was 95.4%. There was no statistically significant difference between the groups in terms of final visual acuity (66.9 vs 70.9 ETDRS letters,
PMC10198899
Conclusions
The study was successfully completed with masking maintained and a low risk of bias. Multiple endpoints relating to ILM peeling were assessed, and estimates were provided that can be used for future studies. Although the study was not powered to assess any specific endpoint, the anatomical and functional outcomes assessed did not significantly differ.
PMC10198899
Supplementary Information
The online version contains supplementary material available at 10.1007/s00417-022-05932-y.
PMC10198899
Keywords
PMC10198899
Introduction
trauma
Internal limiting membrane (ILM) peeling has become an integral part of the surgical repair of primary idiopathic full-thickness macular holes (iFTMH) and is a common step in a variety of different vitreoretinal procedures, offering several advantages [Etched-tip forceps have been developed to facilitate picking up the ILM atraumatically, by the creation of a laser-ablated micro-pattern on the end of the forceps (Fig. Schematic diagram of etched-tip and standard ILM forceps. The forceps differ only for the tip that in etched-tip model has a specific pattern of 10 × 10 × 5 micron teeth (created on the forceps surface by laser ablation) pointed towards the grasping edge at 30 degreesMultiple parameters need to be considered to evaluate potential forceps-related iatrogenic trauma, with their extent, methodology of assessment and variability ill-defined and no clear parameters to guide sample size calculation. In this regard, feasibility and proof-of-concept studies play a crucial role in investigating this area, representing a key first step in assessing specific study designs and endpoints with the intent to use them in subsequent larger-scale trials [We therefore conducted a proof-of-concept randomised controlled trial (RCT) of patients undergoing conventional ILM peeling for primary iFTMH using standard smooth-tip ILM peeling forceps (Alcon Grieshaber REVOLUTION DSP ILM forceps, Alcon, Fort Worth, TX, US) as compared to etched-tip ILM forceps (Alcon Grieshaber FINESSE SHARKSKIN ILM forceps). We assessed the appropriateness of the trial design including masking and multiple exploratory functional and anatomic outcomes.
PMC10198899
Methods
This masked randomised controlled feasibility trial was registered on the ISRCTN registry (reference 70,557,873), and the protocol is available at
PMC10198899
Sample size
As a proof-of-concept study, the sample size was set as 60, based on the methodology of Viechtbauer et al. [
PMC10198899
Recruitment criteria
diabetic retinopathy, VFs, FTMH, amblyopia, glaucoma
DIABETIC RETINOPATHY, BACKGROUND RETINOPATHY, AMBLYOPIA, SECONDARY, HIGH MYOPIA, MACULAR DISEASE, GLAUCOMA, INTRAOCULAR INFLAMMATION, OPTIC NERVE DISEASE
We included patients over 50 years affected by iFTMH of any size and less than 12-month duration. We excluded patients in whom ILM peeling was not planned, secondary FTMH, previously vitrectomized eyes, pre-existing significant macular disease (early/intermediate AMD allowed), glaucoma, optic nerve disease, diabetic retinopathy worse than background retinopathy, uncontrolled intraocular inflammation, high myopia, amblyopia and conditions hindering visual fields (VFs) or imaging.
PMC10198899
Participants, randomisation and masking
Patients were randomised into two groups based on the forceps used for the ILM peeling: etched-tip ILM forceps in group ‘etched-tip’ and in group ‘smooth-tip’. Randomisation to study intervention was carried out by research staff using online randomisation, with a block size of 2 (REDCap,
PMC10198899
Surgical procedure
cataract, tamponade
CATARACT, SEPARATION
Surgery was standardised with 23- or 25-gauge transconjunctival pars plana vitrectomy with posterior hyaloid face separation, if not pre-existing. All phakic patients underwent combined cataract surgery. After core and peripheral vitrectomy, ILM staining was performed with heavy brilliant blue G (BBG) 0.025% for 30-s contact time. All surgeons used pinch peeling as their preferred ILM peeling initiation technique. After the air-fluid exchange, 16% C2F6 was used as tamponade, and patients were instructed to position face-down for 3 days then non supine for 7 days. All surgeries were recorded.
PMC10198899
Surgery evaluation
retinal trauma
SECONDARY, RETINAL HAEMORRHAGE
Immediately following surgery, surgeons were asked to guess the type of forceps allocated, disclose any unmasking, grade the ease of ILM peel initiation, the downward force required and the ability to release the ILM from the forceps, using a 5-point scale ranging from 1 (very difficult) to 5 (very easy).Surgical videos were graded by two independent observers (MF and AR) masked to the forceps and surgeon, with arbitration by a third (RJH) in cases of disagreement. Position and number of ILM primary and secondary pick-up points or attempts, any retinal haemorrhage, retinal trauma and ILM peeling duration were registered.
PMC10198899
Ophthalmic examination
A complete ophthalmic examination, including visual acuity (VA), slit-lamp biomicroscopy and dilated fundoscopy, was carried out preoperatively (within 14 days of surgery) and at 3 weeks, 3 and 6 months postoperatively. Visual acuity using a protocol refraction and ETDRS vision testing at 4 m was measured by masked research staff preoperatively and at 3 and 6 months postoperatively.
PMC10198899
Visual field protocol
Central VFs (Humphrey Field Analyzer Central 10–2 Swedish Interactive Threshold Algorithm-Standard test, Carl Zeiss Meditec, San Leandro, CA) were performed preoperatively and 6 months postoperatively. The test was performed in both eyes with the fellow eye first and repeated if they failed to achieve a pre-defined reliability criterion of < 15% false positives. Only VFs meeting these criteria were analysed. Technicians and assessors were masked to the forceps used.
PMC10198899
Imaging protocol and analysis
streaks inferior, swelling, haemorrhages
POSTERIOR, OPTIC NERVE, HAEMORRHAGES
The Heidelberg Spectralis spectral-domain OCT device (Heidelberg Engineering, Heidelberg, Germany) was used by masked technicians. Posterior Pole scan, 30° × 25°, 240 Sects. (30 μm), high speed, ART 20 and a Peri-papillary Pre-set RNFL scan ART 100 were acquired preoperatively and at each FU. In addition, a 5° × 15°, 49 Sects. (30 μm), high speed, ART 20 was performed preoperatively and a separate high-definition infrared (IR) image with high ART (25) preoperatively and the 3-week visit. Images were exported anonymised for masked grading at a certified image grading centre (NetwORC UK, Central Angiographic Resource Facility, Queen’s University, Belfast, Northern Ireland).The 3-week IR images were graded for the number of haemorrhages and dark RNFL lesions with corresponding RNFL thickening on SD-OCT representing SANFL lesions (Fig. Three weeks postoperative infrared image illustrating a closed hole with 3 areas of subacute nerve fibre layer swelling shown as dark streaks inferior to the fovea (marked with white arrows)Using the Heidelberg auto-segmentation algorithm the inner retinal thickness (IRT), as a combined value of the RNFL, ganglion cell layer and inner plexiform layer thicknesses, was evaluated using the 1, 3, 6 mm ETDRS grid as well as the custom 8 × 8 grid centred on the fovea. The RNFL thickness was measured using the automated Heidelberg RNFL thickness algorithm in 6 peripapillary zones. All automatic segmentations were manually checked and adjusted in case of gross segmentation errors by masked graders.Finally, various parameters describing a dissociated optic nerve fibre layer (DONFL) appearance were calculated using the en-face OCT from the 6-month scans. An axial slab encompassing the inner surface of the ILM to the outer border of the RNFL using the automated segmentation algorithm was selected (Fig. Composite diagram showing methodology for DONFL quantification.
PMC10198899
Statistical analysis
retinal defects, VF
RETINA
Due to randomisation, demographic and baseline characteristics were similar in the two groups, and thus, no formal statistical comparisons were made.The remaining analyses compared 3-week and 6-month outcomes between the two study groups. Due to pandemic COVID restrictions, the 3-month imaging data was only available on 46/65 participants and hence was not analysed. Continuous variables normally and non-normally distributed were analysed using the unpaired For VF data, only the index eyes’ data was used. The difference between the baseline and 6-month FU was used to compare the change in mean deviation (MD) between the two groups.For the IRT data from the 8 × 8 grid data, the central 4 squares encompassing the foveal area and the peripheral squares (as variably outside the peel area) were excluded, meaning that only 32 pre-defined grid positions were included in the analysis. Inner retinal defects in these 32 grid positions were calculated and defined as follows. The baseline inner retina (IR) measurements were normalised in each square as follows:A ‘defect’ was defined as a value below 1.96 standard deviations below the mean using this normalised IR variable. Once the threshold was identified, for each patient, the number of defect areas was calculated.
PMC10198899
Discussion
retinal rigidity, Müller cell foot plate avulsion, paracentral scotomata, temporal VF defects, retinal injury, trauma
RETINA
This is the first proof-of-concept RCT assessing a newly developed types of ILM peeling forceps as compared with a standard one with a wide range of anatomical and functional endpoints. As a proof-of-concept study, it was successful, and the outcomes’ validity was strengthened by the trial design with robust randomisation and masking processes. Our trial provides a blue-print for future studies with outcome methodology and estimates that can be used to assess sample size to detect specific differences with appropriate sample sizes. Importantly, although RCT is a well-known tool for comparison, no previous study compared different types of ILM forceps, and no study design or set of outcomes has been previously validated to this aim.We particularly focused on various endpoints to assess IR changes which occur consequently to ILM peeling and could be exacerbated by surgical trauma. The ILM is a < 10-μm thick, transparent membrane, forming the inner boundary of the retina. Although thin, its mechanical strength is in the megapascal range similar to articular cartilage and about 1000-fold stronger than the cellular layers, forming at least 50% of the retinal rigidity [Inner retinal layer changes occurring after ILM peeling can be focal related to direct instrument trauma or in a regular characteristic pattern as a consequence of Müller cell foot plate avulsion, termed DONFL [It has been suggested that alternative ILM peeling techniques may be associated with varying degrees of retinal injury and recovery [The functional consequences of the iatrogenic IR trauma and post-ILM peeling anatomical changes are uncertain. Some authors described paracentral scotomata, temporal VF defects and reduced retinal sensitivity after ILM peeling whilst others have not, and a DONFL appearance is not thought to have any functional consequences [We attempted to control for several other factors potentially related to IR changes. Vital dyes may influence the iatrogenic stress exerted on the retinal tissue [There are several limitations to our study. Importantly, it was designed as a proof-of-concept study and therefore not powered to detect a specific level of difference between the two groups. Inter-surgeon variability could have masked clearer differences. Finally, we did not perform microperimetry and analysed the VFs via MD score; therefore, focal defects may have been missed. Assessing microperimetry at the grasp sites themselves could be analysed in future studies.In conclusion, we successfully conducted a first-in-class masked randomised proof-of-concept study of two different forceps types used for ILM peeling. The findings do not support any clear benefit of etched-tip forceps over standard forceps during ILM peeling, but it is important to note that being a proof-of-concept study, the sample size was not chosen to assess any one endpoint. The trial design and data produced can serve as a model for future trials with appropriate sample sizes.
PMC10198899
Funding
The study was funded as an IIS (IIT#38075469) by Alcon, with payment to Newcastle University. D Steel discloses that his institution has received research grants from Alcon, DORC, Bayer, and Boehringer-Ingleheim, and he has acted as a consultant to Alcon, Novo Nordisk, BVI, Roche, Apellis and Gyroscope for projects unrelated the subject matter in this manuscript. M Habib discloses that his institution has received research grants from Bayer, Alimera and Boehringer-Ingelheim, and he has received honoraria from Novartis, Bayer, Alimera and Roche for projects unrelated the subject matter in this manuscript. R Hillier has acted as a consultant to Roche for projects unrelated the subject matter in this manuscript.
PMC10198899
Declarations
PMC10198899
Ethical approval and informed consent
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutions where the study was carried out and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. UK multicentre ethical approval (North of Scotland Research Ethics Committee reference: 19/NS/0124). Informed consent was obtained from all individual participants included in the study.
PMC10198899
Conflict of interest
The authors declare no competing interests.
PMC10198899
References
PMC10198899
Background
Diabetes
TYPE 2 DIABETES, DIABETES
Edited by: Pranav Kumar Prabhakar, Lovely Professional University, IndiaReviewed by: Gopal L. Khatik, National Institute of Pharmaceutical Education and Research, India; Ewan Pearson, University of Dundee, United KingdomThis article was submitted to Clinical Diabetes, a section of the journal Frontiers in EndocrinologyUnderstanding which group of patients with type 2 diabetes will have the most glucose lowering response to certain medications (which target different aspects of glucose metabolism) is the first step in precision medicine.
PMC9869378
Aims
obesity, hypertriglyceridemia
INSULIN RESISTANCE, OBESITY, TYPE 2 DIABETES, HYPERTRIGLYCERIDEMIA
We hypothesized that people with type 2 diabetes who generally have high insulin resistance, such as people of Māori/Pacific ethnicity, and those with obesity and/or hypertriglyceridemia (OHTG), would have greater glucose-lowering by pioglitazone (an insulin sensitizer) versus vildagliptin (an insulin secretagogue).
PMC9869378
Methods
weight, blood pressure, diabetes
TYPE 2 DIABETES, DIABETES
A randomised, open-label, two-period crossover trial was conducted in New Zealand. Adults with type 2 diabetes, HbA1c>58mmol/mol (>7.5%), received 16 weeks of either pioglitazone (30mg) or vildagliptin (50mg) daily, then switched to the other medication over for another 16 weeks of treatment. Differences in HbA1c were tested for interaction with ethnicity or OHTG, controlling for baseline HbA1c using linear mixed models. Secondary outcomes included weight, blood pressure, side-effects and diabetes treatment satisfaction.
PMC9869378
Results
weight gain
346 participants were randomised (55% Māori/Pacific) between February 2019 to March 2020. HbA1c after pioglitazone was lower than after vildagliptin (mean difference -4.9mmol/mol [0.5%]; 95% CI -6.3, -3.5; p<0.0001). Primary intention-to-treat analysis showed no significant interaction effect by Māori/Pacific vs other ethnicity (1.5mmol/mol [0.1%], 95% CI -0.8, 3.7), and per-protocol analysis (-1.2mmol/mol [0.1%], 95% CI -4.1, 1.7). An interaction effect (-4.7mmol/mol [0.5%], 95% CI -8.1, -1.4) was found by OHTG status. Both treatments generated similar treatment satisfaction scores, although there was greater weight gain and greater improvement in lipids and liver enzymes after pioglitazone than vildagliptin.
PMC9869378
Conclusions
Comparative glucose-lowering by pioglitazone and vildagliptin is not different between Māori/Pacific people compared with other New Zealand ethnic groups. Presence of OHTG predicts greater glucose lowering by pioglitazone than vildagliptin.
PMC9869378
Clinical trial registration
PMC9869378
Introduction
obesity, Obesity, T2D, hyperglycaemia, heart failure, diabetes
OBESITY, OBESITY, RENAL DISEASE, HIGH TRIGLYCERIDES, INSULIN RESISTANCE, ELEVATED TRIGLYCERIDES, HYPERGLYCAEMIA, HEART FAILURE, TYPE 2 DIABETES, DIABETES
The epidemic of type 2 diabetes (T2D) is of significant concern due to increased morbidity, mortality, and health care costs. Current treatment guidelines recommend early use of sodium glucose transport protein 2 inhibitors (SGLT2i) and glucagon like peptide 1 receptor agonists (GLP1RA) for those with high cardiovascular risk, heart failure or renal disease (The glucose lowering response to non-insulin therapies that target discrete aspects of glucose metabolism is, extremely variable between individuals with T2D. Knowledge of which medications are likely to be most effective for individuals with T2D is important to minimise cost, side effects and periods of hyperglycaemia associated with initiating an ineffective medication. In the absence of knowledge about which subgroups of people with T2D respond better to a particular medication, relatively low glucose lowering response to certain treatments may be inappropriately attributed to non-adherence. There is emerging evidence for stratification of glucose lowering response to certain medications for T2D by baseline characteristics, such as ethnicity, obesity and triglyceride levels.Ethnicity as a marker for differential medication responsiveness has been investigated as a simple tool for therapeutic stratification of T2D medications. Both SGLT2i and dipeptidyl peptidase 4 inhibitor (DPP4i) have been reported to be more effective in lowering HbA1c in people of Asian compared with European ethnicity (It is unclear whether differences in treatment response by ethnicity are due to biological differences in underlying T2D aetiology, or whether ethnicity serves as a proxy for residual confounders such as level of glycaemia, concomitant diabetes therapies, dietary factors, medication adherence or other health inequities. Biological differences in underlying T2D aetiology using routinely assessed clinical markers of insulin resistance, such as obesity and/or high triglycerides (OHTG), have been shown to predict less glucose-lowering to DPP4i (Māori are the indigenous people of Aotearoa, New Zealand and share common Polynesian ancestry with Pacific peoples. Obesity and elevated triglyceride levels are prevalent in people of Māori and Pacific ethnicities (
PMC9869378
Materials and methods
PMC9869378
Participant eligibility
infection, T2D
INFECTION, RECRUITMENT
Patients with T2D for >1 year, who had been on stable doses of metformin and/or sulfonylurea for >3 months were eligible to participate if they were aged 18–80 years inclusive, had HbA1c > 58 mmol/mol [> 7.5%] and < 111 mmol/mol [<12.3%], had never been on DPP4i or thiazolidinedione, had no insulin use, had no active infection requiring antibiotics, had no contraindication to either trial medication, and were able to give written informed consent. These eligibility criteria were modified to enable those on stable doses of two other types of oral glucose-lowering medications to participate in this trial (acarbose or dapagliflozin) as dual therapy with either metformin or sulfonylurea. Recruitment targeted 40% of participants being of Māori and/or Pacific ethnicity.
PMC9869378
Settings and location
The trial participants were recruited at nine sites across urban (Auckland and Waikato) and rural settings (Te Tai Tokerau (Northland) and Te Tairāwhiti (East Coast of the North Island) in NZ.
PMC9869378
Trial design
We conducted an investigator-initiated, multi-centre, open-label, two-treatment (pioglitazone 30mg once daily [P], vildagliptin 50mg once daily [V]), two-period (16-weeks each), randomised, crossover trial. There was no washout period between medications because medication withdrawal could have caused detrimental rebound hyperglycaemia and this was deemed unnecessary due to neither of the two medications having a continuing glucose lowering effect beyond 4 weeks. The primary outcome of HbA1c measurement, which reflects glycaemia over the preceding 8-12 weeks, would therefore reflect results only from the last medication during the 16-week treatment period, without any carry over effect from the first medication. The strength of the PV/VP crossover design is that both interventions were evaluated for each participant, which allows comparison at the individual rather than group level alone (
PMC9869378
Outcome and baseline measures
diabetes, co-morbidities, Diabetes
DIABETES, SECONDARY, DIABETES
The primary outcome measure was HbA1c after each 16-week treatment period. The primary analysis was to test stratification in HbA1c response by Māori or Pacific ethnicity and the pre-specific secondary analysis was to test stratification in HbA1c response by OHTG status. To minimise confounding by adherence or treatment change, protocol adherence was considered to be those who on assessment had >75% adherence to the trial medication based on pill counts, had not commenced any additional glucose-lowering therapies since the baseline eligibility visit, and had not stopped any baseline glucose-lowering medication. HbA1c data were considered invalid if they were obtained more than 7 days after completing the study medication phase. Secondary outcome measures included body weight, blood pressure (BP), frequency of side effects, and Diabetes Treatment Satisfaction Questionnaire (DTSQ) (Self-reported ethnicity was recorded at the baseline visit. Participants were asked to tick all of the following categories that applied: Māori, Pacific, NZ European, Other European, Indian, Other Asian, Other (asked to specify). Prioritised ethnicity classification as Māori or Pacific was defined if either of these ethnicities were ticked or specified in “Other”. Diabetes diagnosis date, current and past diabetes medications, co-morbidities and other medications were verified by medical records. Fasting blood tests were performed to assess HbA1c, glucose, lipids, renal, liver function at baseline and were repeated at the end of each treatment period. OHTG was defined by the presence of BMI ≥30kg/m
PMC9869378
Randomisation
Eligible participants were randomised 1:1 to one of the two sequences (VP or PV) by a central trial pharmacist using a secure trial database. The randomised study medication was couriered to the participant’s nominated address by the central trial pharmacy. Randomisation lists were prepared by the trial statistician, using permuted block randomisation with variable block sizes (2 or 4) and stratified by recruiting region and self-reported ethnicity (Māori and Pacific vs non-Māori/non-Pacific, including New Zealand European, other European, Indian, Asian, and other groups). This was an open-label trial, where both participants and research staff were aware of the treatment sequences [VP/PV] after randomisation.
PMC9869378
Statistical analysis
REGRESSION, SECONDARY
We aimed to recruit a total of 300 participants, with a target sample size of 40% Māori and Pacific people. This sample size would provide 80% power at 5% significance level to detect a minimal effect size of 0.35 standard deviation (SD) between Māori and Pacific vs non-Māori/non-Pacific groups on the difference in HbA1c between two test medications, allowing for 10% loss to follow up. Full details were reported in the published trial protocol (All randomised participants were included in the primary outcome analysis, following the intention to treat (ITT) principle. Missing HbA1c data after each treatment were imputed using the baseline value or any lab data collected post-baseline before the scheduled assessment window. Per protocol (PP), analysis was also performed on the primary outcome, including only those participants who provided complete outcome data with no major protocol violations. All outcomes were assessed using valid visit data collected within the scheduled assessment window. No imputation was considered on secondary outcomes. Statistical analyses were performed using SAS version 9.4 (SAS Institute Inc., Cary, NC, USA).Baseline demographic and clinical characteristics of all randomised participants were summarised overall and by ethnicity. Continuous variables were presented as mean and SD. Categorical variables were presented in frequencies and percentages. Whether the difference in achieved HbA1c for the two medications was different between Māori and Pacific vs non-Māori/non-Pacific participants was tested using a linear mixed model with both fixed and random effects. The fixed effects included the baseline outcome value, period, medication class, patient group and its interaction with the medication. The random effect included patients as the cluster. The model-adjusted mean difference between two medications was estimated for each patient group, and the interaction effect between medications and patient groups was estimated with a 95% confidence interval (CI). Similar regression analyses were conducted to test the medication response with other patient groups of interest, including OHTG status (high BMI ≥30kg/m
PMC9869378