Over 200 publications, including the composite endpoints regulators now recognize. We publish our methodology in the open so reviewers meet it before your submission does.
Alzheimer's Association International Conference (AAIC) · 2024:Poster Tue-17 · Hendrix, Dickson et al.
Companies recently identified clinical study sites engaging in fraudulent practices, reducing success in Alzheimer's disease (AD) clinical trials. Successful trials are reliable…
When the sample size a conventional design demands is larger than the trial you can run, a Global Statistical Test lets the clinical-endpoint hypotheses be tested anyway. The paper sets out when GST applies, how it is pre-specified, and how it has been received in review.
Showing publications 51–100
Sorted newest first
2022 · Alzheimer's & Dementia
Hendrix, Suzanne · Nicodemus-Johnson, Jessie · Knowlton, Newman · Hennessey, Sean · Dickson, Samuel
2022 · Journal of Neurology, Neurosurgery & Psychiatry
2022 · The Journal of Prevention of Alzheimer's Disease
2022 · Journal of Alzheimer's Disease
2022 · Alzheimer's Disease Drug Development: Research and Development Ecosystem
Hendrix, Suzanne · Nicodemus-Johnson, Jessie · Knowlton, Newman · Hennessey, Sean · Dickson, Samuel
2021 · Alzheimer's & Dementia: Translational Research & Clinical Interventions
Dickson, Samuel · Hendrix, Suzanne · Brown, Bruce · Nicodemus-Johnson, Jessie
2021 · Alzheimer's & Dementia
Dickson, Samuel · Nicodemus-Johnson, Jessie · Knowlton, Newman · Syndergaard, Tess · Neff, Jacob · Hennessey, Sean · Hendrix, Suzanne
2021 · Movement Disorders
Hendrix, Suzanne · Hennessey, Sean · Dickson, Samuel
Objective: An exploratory analysis to examine the MDS-UPDRS 1-3 subitems of PD patients who underwent specialized light therapy (SLT) to assess the breadth of impact of SLT on motor and non-motor symptoms. Background: Several trials of light therapy have been conducted in PD patients using a variety of endpoints. These studies indicate benefit of PD on a variety of motor and non-motor symptoms; however, each study reports only one to a few endpoints. We previously reported the MDS-UPDRS 1-3 combined scores for a SLT PD study [1] and expand by reporting each of the subitems to better evaluate the impact of SLT. Method: A prospective, randomized, double-blind, multi-center, controlled study was conducted on PD subjects on dopaminergic therapy without significant motor complications. Participants were randomized 1:1 to narrow band blue/green light (active) or low intensity white light (control), thought to not provide clinical benefit for one hour in the evening for 6 months. The previously reported primary endpoint was change from baseline (BL) to 6 months (6M) in the MDS-UPDRS 1-3. Significance of the subitem analysis was considered at p<0.05, trending significance was p<0.10 and no corrections for multiple comparisons were done. Results: 92 subjects (45 active, 47 control) were enrolled at 3 centers. The primary endpoint MDS-UPDRS 1-3 improved by 17.7(2.8) for the active vs 9.7(3.4) for control. The difference of 8.0(4.4) trended towards significance P=0.074. The subitems for each of the part of the MDS-UPDRS are shown in [figure 1]. MDS-UPDRS 1 has 13 subparts, 3 subitems favored and another 3 trended for SLT. MDS-UPDRS 2 has 13 subparts, 2 favored and another 1 trended for SLT. MDS-UPDRS 3 has 33 subparts, 2 favored and another 2 trended for SLT. In total the MDS-UPDRS 1-3 has 59 subitems, 7 favored and 6 trended in favor of SLT. None of the 59 subitems favored or trended in favor for control. Conclusion: SLT had a broad impact across a broad range of subitems measured by MDS-UPDRS. Those that significantly favored SLT treatment include depressed mood, anxious mood, urinary problems, chewing and swallowing, eating tasks, rest tremor amplitude RUE, rest tremor amplitude RLE. Daytime sleepiness and fatigue which are typically worsened by dopaminergic treatments, trended in favor of SLT. If confirmed in larger SLT studies this would represent a broad ranging impact to the treatment of motor and non-motor symptoms in PD.
2021 · Journal of Alzheimer's Disease Reports
2021 · Alzheimer's & Dementia
2020 · Alzheimer's & Dementia
Dickson, Samuel · Knowlton, Newman · Hendrix, Suzanne
Background: Alzheimer’s disease (AD) is a multi-symptom disease which has cognitive, behavioral, functional and global outcomes. These outcomes are all important measures of disease severity and are driven by the underlying disease process. These symptoms provide multiple, potentially conflicting, answers to the question, “Did the treatment work?” Method: Outcomes can be combined through standardization of outcomes using ranks or z-scores. Additionally, the standardization can be performed before calculating change from baseline or after. These four combinations are explored by simulations with no effect, corroborative effects across outcomes, and disparate effects across outcomes (a mix of positive and null effects) to demonstrate the type I error (no effect) and power under various secenarios along with other performance metrics. Result: All four methods of calculating a GST adequately control type I error. In the absence of ceiling and floor effects, the GST that calculates change from baseline first then combines evidence using z-scores has the highest power. In the presence of disparate effects, the GST can still be more powerful than any single outcome, though the effect is appropriately attenuated. The GSTs that use ranking outperform z-score methods in the presence of strong floor or ceiling effects. Conclusion: A clinical trial with a GST analyzed first can show success as a proof of concept even if the individual outcomes fail to achieve significance, signalling that a development can proceed to later phases. Change from baseline should be calculated first. If there are no ceiling or floor effects, standardization should be performed using z-scores, otherwise percentiles should be used. GSTs offer a good way to combine outcomes to demonstrate efficacy using fewer subjects.
2020 · Alzheimer's & Dementia
Knowlton, Newman · Hendrix, Suzanne
Background: The Sapphire II platform is a clinical diagnostic device intended for aiding clinical evaluation and measurement of beta-amyloid aggregation in anatomically defined regions of the anterior segment of the eye. It detects a specific fluorescent signature emission of ligand-marked beta amyloid complex in the supranuclear region of the human lens. The current study results are Sapphire II scan to be used to classify patients as normal, MCI and mild Alzheimer’s disease and the utility of Sapphire II screening compared to b-amyloid PET scans in MCI and Mild AD subjects. Method: A naïve Bayes classifier using a base model with the three most theoretically relevant parameters (τ1, τ2, φ). Sensitivity and specificity is assessed comparing the normal group to the collective MCI/Mild AD group. 48 participants; 28 MCI, 16 Mild AD patients and 4 Normal Control subjects were studied. Results: The Sapphire II naïve Bayes classifier with cross validation had sensitivity of 96%, specificity of 75%, and overall accuracy of 92%. Results based on 4 healthy controls only, with one of the control subjects tested positive in Sapphire II; additional testing on 10 healthy controls is in progress. Conclusion: Sapphire II offers a non-invasive, safe, easy to use, community based inexpensive method for accurately classifying individuals as normal, MCI or mild AD dementia on the basis of the beta amyloid in the lens of the eye. Sapphire II may offer a practical alternative to PET amyloid scans for biomarker confirmed AD diagnosis. Evaluation of individual PET scans and cognitive testing suggests that Sapphire II is more sensitive than PET.
2020 · Alzheimer's & Dementia
Background The AMBAR study enrolled 496 mild-to-moderate Alzheimer’s disease (AD) patients from Spain and US centers, 347 of which were randomized [1:1:1:1] to three treatment arms of plasma exchange (PE) with different doses of albumin with or without intravenous immunoglobulin (IVIG) or placebo (sham PE) arm. PE treatment showed slow cognitive and functional decline in AD patients, with variable significance in outcome (primary: ADCS-ADL, ADAS-Cog; secondary: CDR-Sb, ADCS-CGIC), baseline disease severity, and treatment arm (low-albumin; low-albumin+IVIG, high-albumin+IVIG, and all three combined). The percentage of patient dropouts ranged from 20% in the placebo to 34.9% in the low-albumin+IVIG group. In this analysis we investigated the effect of possible biases due to discontinuations and baseline imbalances, and assessed the consistency across outcomes. Method The impact of discontinuations was determined by least squares mean estimates from the Mixed Model for Repeated Measures (MMRM) analysis using the z-score carried forward analysis (zLOCF). The overall impact of the treatment on the disease was determined by a global statistical test which combined with equal weighting three outcomes (ADCS-ADL, ADAS-Cog, CDR-Sb) into a single outcome. An analysis of relevant outcomes was performed adjusting for key baseline characteristics. Result Analysis of discontinuations suggested that the treatment differences and effect sizes estimated using the primary model MMRM are likely to be conservative and that lowering dropouts is likely to increase effect sizes. Effect sizes were consistent across outcomes (between 51% and 76%). The GST score showed slowing of progression at month 14 with statistically significant differences between all active treatments and placebo from month 9 onward. When the model was adjusted for key baseline characteristics, the analysis showed statistically significant differences against placebo of all treatment groups in most of the relevant outcomes. Conclusion Results of this analysis disprove the possible bias of dropout effect in the AMBAR trial. Effect sizes were consistent across outcomes and the Global Statistical Test showed an overall impact of the treatment on the disease. The analysis corrected for baseline factors supports and reinforces the findings that the PE-treated arms were superior to the placebo group.
2020 · 2020 Alzheimer's Association International Conference
Background: Diet and nutrition are important modifiable risk factors for Alzheimer’s disease (AD). For the last two decades, the LipiDiDiet consortium has been investigating the role of nutrients and their synergistic action on key AD pathological features. Based on preclinical results, 11 nutrients were selected which, when applied in this specific combination, gave the best results in rodent AD models: i.e. the omega-3 fatty acids DHA and EPA, phospholipids, vitamins B6, B12, folic acid, C and E, choline, selenium, and UMP. The LipiDiDiet trial1 is a 6-year, double-blind, parallel-group, multi-centre, randomised controlled clinical trial, designed to investigate effects of the specific multinutrient combination Fortasyn Connect on cognition and related measures in prodromal AD. Initial 24 month results showed significant benefit on clinical dementia rating-sum of boxes (CDR-SB) and hippocampal and ventricular volumes in the modified intention-to-treat population. Here we report previously specified primary and secondary outcomes over 36 months of intervention. Method: Prodromal AD participants (n=311) were randomised to receive either active product (125 mL drink containing Fortasyn Connect) or a calorie-matched placebo control once daily. Result: 162 participants completed the 36-month period. With increasing treatment duration, the benefit of the active group over the control group exceeded what had been observed for the first 24 months (Soininen et al., Lancet Neurology 2017). For the 5-item neuropsychological test battery (NTB) on cognition, a significant between-group difference was observed in estimated mean change from baseline over 36 months favouring active intervention (0.212 [95% CI 0.044 to 0.380]; p=0.014; 60% reduction in decline). In addition, significant benefits were found on CDR-SB, NTB memory, and hippocampal, ventricular, and whole brain volumes on MRI. Self-reported compliance to the study product was high and there was no indication of safety concern. Conclusion: We observed significantly slower decline in cognition including memory, CDR-SB measuring cognition and function, and brain structural measures. Importantly, prolonged intervention with this specific combination of nutrients resulted in a broader range of endpoints showing statistically significant differences. Sustainable benefits lasting for 3 or more years have not been reported before in prodromal AD.
2020 · New England Journal of Medicine
2020 · International Journal of Geriatric Psychiatry
2019 · Journal of the American Medical Directors Association
Objective Benzodiazepines and related drugs (BDZRs) have been associated with an increased risk of Alzheimer's disease (AD) in later life. Despite this, it remains unclear whether ongoing BDZR use may further accelerate cognitive decline in those diagnosed with mild to moderate AD. Design This study was embedded within NILVAD, a randomized controlled trial of nilvadipine in mild to moderate AD. Cognition was measured at baseline and 18 months using the Alzheimer Disease Assessment Scale, Cognitive Subsection (ADAS-Cog). We assessed predictors of long-term BDZR use and analyzed the effect of ongoing BDZR use on ADAS-Cog scores at 18 months. Additionally, the impact of BDZR use on adverse events, incident delirium, and falls over 18-month follow-up was assessed adjusting for relevant covariates. Setting and Participants 448 participants with mild to moderate AD recruited from 23 academic centers in 9 European countries. Results Overall, 14% (62/448) were prescribed an ongoing BDZR for the study duration. Increasing total number of (non-BDZR) medications was associated with a greater likelihood of BDZR prescription (odds ratio 1.16, 95% confidence interval 1.05-1.29). At 18 months, BDZR use was not associated with greater cognitive decline on the ADAS-Cog controlling for baseline ADAS-Cog scores, age, gender, study arm, and other clinical covariates (β = 1.62, −1.34 to 4.56). However, ongoing BDZR use was associated with a greater likelihood of adverse events [incidence rate ratio (IRR) 1.19, 1.05-1.34], incident delirium (IRR 2.31, 1.45-3.68), and falls (IRR 1.66, 1.02-2.65) over 18 months that persisted after robust adjustment for covariates. Conclusions and Implications This study found no effect of ongoing BDZR use on ADAS-Cog scores in those with mild to moderate AD over 18 months. However, ongoing use of these medications was associated with an increased risk of adverse events, delirium, and falls. Thus, BDZR use should be avoided where possible and deprescribing interventions should be encouraged in older adults with AD.
2019 · The Journal of Prevention of Alzheimer's Disease
As research evolves in prodromal AD, the need to validate sufficiently sensitive outcome measures, e.g. the Alzheimer's Disease Composite Score (ADCOMS) is clear. In the LipiDiDiet randomized trial in prodromal AD, cognitive decline in the study population was much less than expected in the timeframe studied. While the primary composite endpoint was insufficiently sensitive to detect a difference in the modified intention to treat population, the per-protocol population showed less decline in the active than the control group, indicating better treatment effects with regular product intake. These results were further strengthened by significant benefits on secondary endpoints of cognition and function, and brain atrophy. The present post-hoc analysis investigated whether ADCOMS could detect a difference between groups in the LipiDiDiet population (138 active, 140 control). The estimated mean change in ADCOMS from baseline (standard error) was 0.085 (0.018) in the active and 0.133 (0.018) in the control group; estimated mean treatment difference −0.048 (95% confidence intervals −0.090, −0.007; p=0.023), or 36% less decline in the active group. This suggests ADCOMS identified the cognitive and functional benefits observed previously, confirming the sensitivity of this composite measure.
2019 · Alzheimer's & Dementia
Background: Amylyx has developed a novel therapeutic, AMX0035, for the treatment of neurodegenerative disease. AMX0035 is a proprietary combination of two small molecule compounds, Sodium Phenylbutyrate (PB) and Tauroursodeoxycholic Acid (TUDCA), de-signed to promote neuronal viability through simultaneous inhibition of ER stress and mitochondrial stress. PB and TUDCA have been evaluated separately in in vitro and in vivo models of Alzheimer’s disease (AD), and clinical trials in amyotrophic lateral sclerosis, Parkinson’s disease and Huntington’s disease. Amylyx discovered a synergy between these two compounds when administered together in a particular range of ratios across multiple preclinical models. Recruitment for the clinical trial began in late 2018. Methods: The study will evaluate safety, tolerability, and biomarkers of molecular target engagement, AD pathology, neurodegeneration and neurophysiology that indicate AMX0035 target engagement and neurobiological effects over 24 weeks. This will be a 6-month, parallel-group, randomized, double-blind, placebo-controlled study of people with late mild cognitive impairment (MCI) or early to moderate dementia due to AD. Participants in the active treatment arm will receive 3g of PB and 1g TUDCA administered orally twice daily. Results: Participants will be evaluated at Poster Presentations: Wednesday, July 17, 2019P1282baseline and at week 24 with multi-sequence structural and functional MRI to assess changes in regional brain volumes (T1), cerebral perfusion (ASL), functional connectivity (BOLD) and cerebrovascular pathology (FLAIR, SWI). Lumbar punctures will be performed at baseline and 24 weeks for selected CSF biomarkers including: amyloid-b1-42, tau, neurofilament light chain (NfL), and markers of mitochondrial redox, HDAC activity, neuronal injury, and neuroinflammation. Patients will be evaluated at weeks 1, 6,12, 18, and 24 for safety, tolerability, and changes in symptoms, as measured with the ADAS-Cog 13, ADCS-ADL, and NPI. Conclusions: This early phase trial is designed to evince target engagement, neurobiological effects, safety and tolerability of AMX0035with multiple objective endpoints including, standard clinical assessments and both established and novel biomarkers associated with neurocognitive impairment. Data will help determine whether to advance AMX0035 to a larger study to establish efficacy and safety and inform choices in study design, patient characteristics and outcome measures.
2019 · Neurology
Objective: To assess the effect of memantine (MEM) and a cholinesterase inhibitor (ChEI) vs ChEI alone on four syndrome domains of the Neuropsychiatric Inventory (NPI). Background: Neuropsychiatric symptoms negatively impact daily function and quality of life, hasten time to institutionalization, and increase overall healthcare costs. MEM significantly improved multiple domain scores of the NPI in patients with Alzheimer’s disease (AD) compared with placebo (PBO). Design/Methods: Data were pooled for participants with moderate to severe AD (baseline MMSE<20) from three, phase 3, randomized, double-blind, PBO-controlled 24-week trials (Tariot et al. JAMA, 2004; Porsteinsson et al. Alzheimer Research, 2008; Grossberg et al. CNS Drugs, 2013). The NPI has 12 items that were grouped into four syndrome domains: psychosis (agitation/aggression, hallucinations, delusions, irritability/lability), neurovegetative (aberrant motor behavior, nighttime behavior, appetite/eating change), frontal (disinhibition, euphoria/elation), and mood (anxiety, depression/dysphoria, apathy), based on previous analyses (Frisoni et al. Dement Geriatr Cogn Disord, 10:130–138, 1999). MEM/ChEI- and PBO/ChEI-treated participants were compared using an ANCOVA model estimating change from baseline at each time point. Results: Of 1262 patients, 637 were treated with MEM/ChEIs and 625 with PBO/ChEIs (age [mean±SD]: 75.7±8.3 years; baseline MMSE: 11.5±3.5; baseline NPI total score: 14.9±14.6). For all syndrome domains, mean treatment differences favored MEM/ChEIs over PBO/ChEIs. For psychosis symptoms, MEM/ChEI-treated patients improved significantly compared with PBO/ChEI-treated patients at 12 (LSMD −1.167, P<0.0001) and 24 (LSMD −1.238, P<0.0001) weeks. Similarly, neurovegetative scores were significantly improved for MEM/ChEI vs PBO/ChEI-treated patients at 12 (LSMD −0.621, P=0.0103) and 24 (LSMD −0.583, P=0.0441) weeks. For frontal and mood symptoms, no significant LSMDs were observed at 12 or 24 weeks. No analyses showed PBO/ChEI to be superior to MEM/ChEI. Conclusions: In patients with moderate to severe AD taking ChEIs, treatment with the combination of memantine and a ChEI was associated with significant benefit for psychosis and neurovegetative behavioral syndromes compared with ChEI alone.
2019 · Neurology
Objective: To assess maintenance of response on the Severe Impairment Battery (SIB) in participants treated with memantine (MEM) in combination with a cholinesterase inhibitor (ChEI) vs placebo (PBO) with ChEI. Background: Rigorous phase 3 studies have demonstrated the efficacy of memantine (MEM) on cognitive and behavioral symptoms of Alzheimer’s disease (AD) when added to ongoing ChEI treatment. Design/Methods: Data were pooled from two phase 3, randomized, double-blind, PBO-controlled 24-week trials (Tariot et al. JAMA, 2004; Grossberg et al. CNS Drugs, 2013) evaluating MEM for patients with moderate to severe AD (baseline MMSE score<20) receiving stable ongoing ChEI treatment. SIB scores were categorized by level of improvement (≥0-, ≥5-, ≥10-point improvement from baseline) at each timepoint (weeks 4, 8, 12, 18) and were considered maintained if the patient remained in the same improvement category at all following tests through endpoint (week 24). The percentages of patients who maintained response were compared between MEM/ChEI and PBO/ChEI. Results: A significantly greater proportion of MEM/ChEI-treated patients maintained ≥5-point improvements vs PBO/ChEI from weeks 4 to 24 (P=0.0182). From weeks 8 to 24 and 12 to 24, a significantly greater proportion of MEM/ChEItreated patients maintained ≥5- and ≥10-point improvements compared with PBO/ChEI-treated patients (Pvalues< 0.01). From week 18 to 24, a significantly higher proportion of patients treated with MEM/ChEI vs PBO/ChEI maintained score improvements of ≥0 (P=0.0478), ≥5 (P=0.0137), and ≥10 (P=0.0003) points. Conclusions: The combination of MEM with a ChEI resulted in greater percentages of patients who achieved and maintained cognitive improvements over 24 weeks vs PBO/ChEI. This treatment response was particularly pronounced among patients who experienced a 5-point or greater improvement on the SIB. Treatment effects continued to emerge at week 18 and were maintained through week 24, further demonstrating SIB sensitivity and the benefit of MEM when added to ongoing ChEI treatment.
2019 · Alzheimer's & Dementia
2019 · Handbook of Behavioral Neuroscience
A challenge to the endeavor of assessing cognition in patients with Alzheimer's disease (AD) is the lack of reliability, validity, and responsiveness of the tests that have been traditionally employed. A further consideration is the lack of continuity between tests preferred for use in memory clinics and other specialist centers as compared with those selected for use in clinical drug trials of putative new therapies for AD. In contrast to the lack of continuity in AD, in other indications, such as major depressive disorder (MDD), similar paradigms, though different tests, have been employed to detect cognitive deficits, to measure cognitive change and, more recently, to identify cognitive markers that might indicate risk factors for disease onset. In this chapter, we contrast the assessment of cognition in AD and MDD, especially in the context of identifying cognitive deficits and the measurement of efficacy.
2019 · Alzheimer's & Dementia: Translational Research & Clinical Interventions
2019 · Journal of the American Heart Association
2019 · The Journal of Prevention of Alzheimer's Disease
There is an urgent need to develop reliable and sensitive blood-based biomarkers of Alzheimer's disease (AD) that can be used for screening and to increase the efficiency of clinical trials. The European Union-North American Clinical Trials in Alzheimer's Disease Task Force (EU/US CTAD Task Force) discussed the current status of blood-based AD biomarker development at its 2018 annual meeting in Barcelona, Spain. Recent improvements in technologies to assess plasma levels of amyloid beta indicate that a single sample of blood could provide an accurate estimate of brain amyloid positivity. Plasma neurofilament light protein appears to provide a good marker of neurodegeneration, although not specific for AD. Plasma tau shows some promising results but weak or no correlation with CSF tau levels, which may reflect rapid clearance of tau in the bloodstream. Blood samples analyzed using -omics and other approaches are also in development and may provide important insight into disease mechanisms as well as biomarker profiles for disease prediction. To advance these technologies, international multidisciplinary, multi-stakeholder collaboration is essential.
2019 · Neurology
Objective: To evaluate the effect of the combination of memantine (MEM) with a cholinesterase inhibitor (ChEI) vs placebo (PBO) with ChEI on total Severe Impairment Battery (SIB) and three higher-order cognitive domains (memory, language, and praxis). Background: The SIB is used to assess cognitive changes in patients with Alzheimer’s disease (AD), allowing for reliable, valid, and sensitive detection of treatment effects when floor effects may be present on other cognitive tests. MEM results in significant improvements on the SIB compared with PBO in moderate to severe AD patients treated concurrently with a ChEI. Design/Methods: Data were pooled from two phase 3, randomized, double-blind, PBO-controlled 24-week trials (Tariot et al. JAMA, 2004; Grossberg et al. CNS Drugs, 2013) in patients with moderate to severe AD (baseline MMSE score<20). The SIB was administered at baseline and weeks 4, 8, 12, 18, and 24. Based on Schmitt et al. Alzheimer Dis Assoc Disord, 2006, SIB domains were aggregated to create higher-order subscales of memory (memory, attention, orientation, orienting to name), language (language, social interaction), and praxis (praxis, visuospatial ability, construction). Results: Compared with PBO/ChEI, MEM/ChEI significantly improved total SIB scores at weeks 8, 12, 18, and 24 (all, P<0.05). An analysis of higher-order domains demonstrated that MEM/ChEI treatment conferred significant effects on memory and language vs PBO/ChEI at weeks 12, 18, and 24 (all, P<0.05). On the higher-order domain of praxis, MEM/ChEI showed significant effects vs PBO/ChEI at all timepoints (weeks 4, 8, 12, 18, and 24, all P<0.05). Conclusions: The combination of MEM with a ChEI produced early and consistent improvements in cognition for patients with moderate to severe AD. Analysis of higher-order domains on the SIB further supported the efficacy of MEM in maintaining key cognitive functions (memory, language, and praxis), even when these patients are receiving the standard of ongoing ChEI treatment.
Loading more publications…
Looking for older work, or a specific methodology paper? Our research team can point you to the right reference.
Ask our team
