Trials Of Disease-modifying Therapies Research Articles

Patient-focused drug development in primary sclerosing cholangitis: Insights on patient priorities and involvement in clinical trials.

According to the new AASLD Practice Guidance, all patients with primary sclerosing cholangitis (PSC) should be considered for participation in clinical trials. However, PSC's rarity has posed challenges to characterizing patient interest in trial participation and identifying predictors of patient willingness to participate in drug trials. PSC Partners Seeking a Cure developed the "Our Voices" survey to inform the development of the Externally-Led Patient-Focused Drug Development Forum, an FDA initiative to capture patient experiences and perspectives on drug development. Of 797 survey respondents from over 30 countries, 536 (67%) identified slowing disease progression as the most important outcome. Eighty-nine percent identified their hepatologist/gastroenterologist as someone they would approach for advice about trials. Although 61% reported being willing to participate in drug trials, only 26% had ever been asked to participate. Notable barriers to trial involvement included unknown long-term risks (71%), long travel times to the study center (32%), and a liver biopsy requirement (27%). On multivariable logistic regression, pruritus (OR 1.62, 95% CI: 1.09-2.40, p = 0.017) was positively associated with willingness to participate in disease-modifying therapy trials, while jaundice (OR 0.34, 95% CI: 0.19-0.61, p < 0.001) and inflammatory bowel disease (OR 0.64, 95% CI: 0.42-0.98, p = 0.038) were negatively associated. Pruritus (OR 2.25, 95% CI: 1.50-3.39, p < 0.001) was also independently associated with willingness to participate in symptom treatment trials. Most patients with PSC report interest in participating in clinical trials, but few have been asked to participate. Referral of patients with PSC by their hepatologist/gastroenterologist to clinical trials and patient education on trial participation are vital to closing the gap between trial interest and participation. Pruritus may serve as a key indicator of patient interest in trial participation.

Simplifying Alzheimer’s Disease Monitoring: A Novel Machine-Learning Approach to Estimate the Clinical Dementia Rating Sum of Box Changes Using the Mini-Mental State Examination and Functional Activities Questionnaire

Simplifying Alzheimer’s Disease Monitoring: A Novel Machine-Learning Approach to Estimate the Clinical Dementia Rating Sum of Box Changes Using the Mini-Mental State Examination and Functional Activities Questionnaire

Poor reporting limited consideration of EDI in the Australian guidelines for the clinical care of people with COVID-19

ObjectivesActively addressing issues of equity, diversity, and inclusion (EDI) in healthcare guidelines provides an important avenue ensure that individuals and communities receive high-quality healthcare that meets their needs. In 2020, the National Clinical Evidence Taskforce was charged with developing Australian living guidelines for COVID-19 (the Guidelines). It was intended that the Guidelines would consider the biological and social determinants of health (BSDH) underpinning evidence-based recommendations for of the treatment of COVID-19. The objective of this paper is to describe the evidence available on BSDH that is reported in published trials of disease-modifying therapies for COVID-19. Study Design and SettingPublished papers of randomized controlled trials that informed clinical recommendations (for and against drug therapies for COVID-19) in the Guidelines were reviewed retrospectively using a case series design. We extracted reported characteristics relating to BSDH. These included age, sex, gender, geographical location, ethnicity (including indigenous), disability, migrant status, income, education, employment, and social support. A descriptive analysis was conducted to illustrate the characteristics available for use in guideline development. ResultsA total of 115 peer-reviewed papers describing randomized control trials of drug interventions for the treatment of COVID-19 were included. BSDH characteristics were poorly reported. Geographical location of the study was the only category reported in all papers. While age and sex were reported in most papers (n = 109 and 108, respectively), ethnicity was reported in only one-third of papers (n = 40), social support was reported in only three papers, and employment in one paper. No paper reported on gender, disability, migrant status, income, or education. ConclusionConsideration of EDI issues is a crucial component of guideline development. Although these issues were widely recognized to impact on health outcomes from COVID-19, reporting of these characteristics was poor in COVID trials. Urgent action is needed to improve reporting of EDI characteristics if they are to be meaningfully considered in guideline processes, and health inequity is overcome.

Development of a functional outcome measure for riboflavin transporter deficiency.

Riboflavin transporter deficiency (RTD) is a progressive inherited neuropathy of childhood onset, characterised clinically by pontobulbar palsy, sensory ataxia, sensorineural deafness, muscle weakness, optic atrophy and respiratory failure. A robust and responsive functional outcome measure is essential for future clinical trials of disease-modifying therapies including genetic therapies. The Charcot-Marie-Tooth disease Pediatric Scale (CMTPedS) is a well-validated outcome measure for CMT and related neuropathies, and might have utility for measuring disease progression in individuals with RTD. However, the CMTPedS requires modifications to account for phenotypic differences between children with CMT and RTD. The aim of this study was to develop a functional outcome measure based on the CMTPedS for specific use in individuals with RTD. The CMTPedS data collected over the last 10 years in individuals with RTD attending the Peripheral Neuropathy Management Clinic at the Children's Hospital at Westmead (Sydney, Australia) were reviewed to evaluate each item within the CMTPedS. A literature review of articles published until September 2021 for functional outcome measures generated an item pool for pilot testing. The results of this pilot testing, alongside analysis of existing CMTPedS item scores in the RTD cohort, informed the modification of the CMTPedS. CMTPedS data were reviewed for eight individuals over the past 10 years. Two items were identified as requiring modification or removal and additional items of proximal strength and function needed to be considered. Six studies were identified in the literature review, and five items were selected for pilot testing. 'Shoulder internal rotation' and the '30-s sit to stand test' were added as proximal measures of strength and function. The composite balance item comprising nine tasks in the CMTPedS showed a ceiling effect and was replaced with the single 'Feet apart on a line eyes open' balance item. 'Pinprick sensation' was removed due to a floor effect. This study provides preliminary evidence that the Riboflavin Transporter Deficiency Pediatric Scale (RTDPedS) is a functional outcome measure covering strength, upper and lower limb function, balance and mobility for individuals with RTD to assess disease severity and progression in clinical trials and cohort studies.

Psychometric Assessment of the Rett Syndrome Caregiver Assessment of Symptom Severity (RCASS).

Rett syndrome is a severe neurodevelopmental disorder that affects about 1 in 10,000 females. Clinical trials of disease modifying therapies are on the rise, but there are few psychometrically sound caregiver-reported outcome measures available to assess treatment benefit. We report on a new caregiver-reported outcome measure, the Rett Caregiver Assessment of Symptom Severity (RCASS). Using data from the Rett Natural History Study (n = 649), we examined the factor structure, using both exploratory and confirmatory factor analysis, and the reliability and validity of the RCASS. The four-factor model had the best overall fit, which covered movement, communication, behavior, and Rett-specific symptoms. The RCASS had moderate internal consistency. Strong face validity was found with age and mutation type, and convergent validity was established with other similar measures, including the Revised Motor-Behavior Assessment Scale, Clinical Severity Scale, Clinical Global Impression Scale, and the Child Health Questionnaire. These data provide initial evidence that the RCASS is a viable caregiver-outcome measure for use in clinical trials in Rett syndrome. Future work to assess sensitivity to change and other measures of reliability, such as test-retest and inter-rater agreement, are needed.

Biomarker-based staging of Alzheimer disease: rationale and clinical applications.

Disease staging, whereby the spatial extent and load of brain pathology are used to estimate the severity ofAlzheimer disease (AD), is pivotal to the gold-standard neuropathological diagnosis of AD. Current in vivo diagnostic frameworks for AD are based on abnormal concentrations of amyloid-β and tau in the cerebrospinal fluid or on PET scans, and breakthroughs in molecular imaging have opened up the possibility of in vivo staging of AD. Focusing on the key principles of disease staging shared across several areas of medicine, this Review highlights the potential for in vivo staging of AD to transform our understanding of preclinical AD, refine enrolment criteria for trials of disease-modifying therapies and aid clinical decision-making in the era of anti-amyloid therapeutics. We provide a state-of-the-art review of recent biomarker-based AD staging systems and highlight their contributions to the understanding of the natural history of AD. Furthermore, we outline hypothetical frameworks to stage AD severity using more accessible fluid biomarkers. In addition, by applying amyloid PET-based staging to recently published anti-amyloid therapeutic trials, we highlight how biomarker-based disease staging frameworks could illustrate the numerous pathological changes that have already taken place in individuals with mildly symptomatic AD. Finally, we discuss challenges related to the validation and standardization of disease staging and provide a forward-looking perspective on potential clinical applications.

Experimental Animal Models of Prodromal Parkinson's Disease.

There is an estimated 35-45% loss of striatal dopamine at the time of diagnosis of Parkinson's disease (PD), and cases clinically diagnosed in the early stages may already be pathologically in advanced stages. Recent large-scale clinical trials of disease-modifying therapies (DMT) also suggest the necessity of targeting patients at earlier stages of the disease. From this perspective, the prodromal phase of PD is currently the focus of attention, emphasizing the need for a prodromal mouse model that accurately reflects the pathophysiology, along with early biomarkers. To establish prodromal animal model of PD with high face validity that reflects the disease state, the model must possess high construct validity that accurately incorporates clinical and pathological features in the prodromal phase. Furthermore, as a preclinical model of DMT, the model must possess high predictive validity to accurately evaluate the response to intervention. This review provides an overview of animal models which reflect the characteristics of prodromal PD, including alpha-synuclein (aS) accumulation and associated early non-motor symptoms, with a focus on the aS propagation model and genetic model. In addition, we discuss the challenges associated with these models. The genetic model often fails to induce motor symptoms, while aS propagation models skip the crucial step of initial aS aggregate formation, thereby not fully replicating the entire natural course of the disease. Identifying factors that induce the transition from prodromal to symptomatic phase is important as a preclinical model for DMT to prevent or delay the onset of the disease.

Evidence for C-Peptide as a Validated Surrogate to Predict Clinical Benefits in Trials of Disease-Modifying Therapies for Type 1 Diabetes.

Type 1 diabetes is a chronic autoimmune disease in which destruction of pancreatic beta cells causes life-threatening metabolic dysregulation. Numerous approaches are envisioned for new therapies, but limitations of current clinical outcome measures are significant disincentives to development efforts. C-peptide, a direct byproduct of proinsulin processing, is a quantitative biomarker of beta cell function that is not cleared by the liver and can be measured in the peripheral blood. Studies of quantitative measures of beta cell function have established a predictive relationship between stimulated C-peptide as a measure of beta cell function and clinical benefits. C-peptide levels at diagnosis are often high enough to afford glycemic control benefits associated with protection from end-organ complications of diabetes, and even lower levels offer protection from severe hypoglycemia in type 1 diabetes, as observed in large prospective cohort studies and interventional trials of islet transplantation. These observations support consideration of C-peptide not just as a biomarker of beta cell function, but also as a specific, sensitive, feasible, and clinically meaningful outcome defining beta cell preservation or restoration for clinical trials of disease-modifying therapies. Regulatory acceptance of C-peptide as a validated surrogate for demonstration of efficacy would greatly facilitate development of disease-modifying therapies for type 1 diabetes.

Comorbidities in multiple sclerosis and their influence on the choice of treatment

Clinical trials of disease-modifying therapies (DMTs) for people with multiple sclerosis (pMS) are conducted in selected populations, excluding patients with comorbidities or concomitant medications. However, a large percentage of pMS have some additional disease, which could affect the response and choice of the DMT. The objective of this review is to assess how concurrent pathologies can impact the choice of DMTs. Relevant articles were selected through a systematic search in PubMed. Comorbidities were grouped for better classification into autoimmune, chronic infections, cardiovascular and metabolic, oncological and neuropsychiatric. In autoimmune pathologies, it is key to take into account the effects of TME on them and the possibility of interaction with their specific treatments. Immunomodulatory therapies are safe for people with chronic infections. Immunosuppressive treatments are generally contraindicated in people with active infections. In cardiovascular and metabolic comorbidities, infusion reactions associated with monoclonal antibodies, and the phenomena of starting treatment with S1P modulators, must be taken into account. DMTs with an immunosuppressive effect are contraindicated in people with active malignancies. Although psychiatric pathology per se does not preclude the use of DMTs, caution should be exercised when new psychiatric symptoms appear. For these reasons, among the multiple factors that must be considered when starting or changing a DMT in pMS, comorbidities constitute a decisive element.

Embedding Patient Input in Outcome Measures for Long-Term Disease-Modifying Parkinson Disease Trials.

Clinical trials of disease-modifying therapies in PD require valid and responsive primary outcome measures that are relevant to patients. The objective is to select a patient-centered primary outcome measure for disease-modification trials over three or more years. Experts in Parkinson's disease (PD), statistics, and health economics and patient and public involvement and engagement (PPIE) representatives reviewed and discussed potential outcome measures. A larger PPIE group provided input on their key considerations for such an endpoint. Feasibility, clinimetric properties, and relevance to patients were assessed and synthesized. Although initial considerations favored the Movement Disorder Society-sponsored revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Part III in Off, feasibility, PPIE input, and clinimetric properties supported the MDS-UPDRS Part II. However, PPIE input also highlighted the importance of nonmotor symptoms, especially in the longer term, leading to the selection of the MDS-UPDRS Parts I + II sum score. The MDS-UPDRS Parts I + II sum score was chosen as the primary outcome for large 3-year disease-modification trials. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Investigating trial design variability in trials of disease-modifying therapies in Parkinson’s disease: a scoping review protocol

IntroductionParkinson’s disease (PD) is a debilitating neurological disorder for which the identification of disease-modifying interventions represents a major unmet need. Diverse trial designs have attempted to mitigate challenges of population...

C-peptide and metabolic outcomes in trials of disease modifying therapy in new-onset type 1 diabetes: an individual participant meta-analysis

Metabolic outcomes in type 1 diabetes remain suboptimal. Disease modifying therapy to prevent β-cell loss presents an alternative treatment framework but the effect on metabolic outcomes is unclear. We, therefore, aimed to define the relationship between insulin C-peptide as a marker of β-cell function and metabolic outcomes in new-onset type 1 diabetes. 21 trials of disease-modifying interventions within 100 days of type 1 diabetes diagnosis comprising 1315 adults (ie, those 18 years and older) and 1396 children (ie, those younger than 18 years) were combined. Endpoints assessed were stimulated area under the curve C-peptide, HbA1c, insulin use, hypoglycaemic events, and composite scores (such as insulin dose adjusted A1c, total daily insulin, U/kg per day, and BETA-2 score). Positive studies were defined as those meeting their primary endpoint. Differences in outcomes between active and control groups were assessed using the Wilcoxon rank test. 6 months after treatment, a 24·8% greater C-peptide preservation in positive studies was associated with a 0·55% lower HbA1c (p<0·0001), with differences being detectable as early as 3 months. Cross-sectional analysis, combining positive and negative studies, was consistent with this proportionality: a 55% improvement in C-peptide preservation was associated with 0·64% lower HbA1c (p<0·0001). Higher initial C-peptide levels and greater preservation were associated with greater improvement in HbA1c. For HbA1c, IDAAC, and BETA-2 score, sample size predictions indicated that 2-3 times as many participants per group would be required to show a difference at 6 months as compared with C-peptide. Detecting a reduction in hypoglycaemia was affected by reporting methods. Interventions that preserve β-cell function are effective at improving metabolic outcomes in new-onset type 1 diabetes, confirming their potential as adjuncts to insulin. We have shown that improvements in HbA1c are directly proportional to the degree of C-peptide preservation, quantifying this relationship, and supporting the use of C-peptides as a surrogate endpoint in clinical trials. JDRF and Diabetes UK.

The effect of disease modifying therapies on fatigue in multiple sclerosis.

Fatigue is one of the most common and debilitating symptoms in people with multiple sclerosis (PwMS). Disease-modifying therapies (DMTs) are currently the gold standard in the treatment of MS and their effectiveness has been assessed through randomized clinical trials (RCTs). However, there is limited evidence on the impact of DMTs on fatigue in (PwMS). We conducted a systematic review to 1) understand whether fatigue is included as an outcome in MS trials of DMTs; 2) determine the effects on fatigue of treating MS with DMTs and 3) assess the quality of MS trials including fatigue as an outcome. Two independent researchers systematically searched MEDLINE, EMBASE and ClinicalTrials.gov from 1993 to January 2023 for RCTs that measured fatigue as an outcome. Adherence to reporting standards was assessed with the Consolidated Standards of Reporting Trials (CONSORT)-Patient-Reported Outcomes (PRO), while the risk of bias (RoB) was assessed with the RoB 2 tool by the Cochrane Handbook for Systematic Reviews of Interventions. The systematic review protocol was registered in PROSPERO (CRD42022383321). The search strategy identified 130 RCTs of DMTs of which 7 (5%) assessed fatigue as an outcome. Of the 7 trials, only two presented statistically significant results. In addition, the reporting of fatigue among RCTs was suboptimal with a mean adherence to the CONSORT-PRO Statement of 36% across all trials. Of the 7 trials included, four were assessed as 'high' RoB.. Fatigue has a major impact on PwMS yet there is limited trial-based evidence on the impact of DMTs on fatigue. Assessment of fatigue as an outcome is underrepresented in trials of DMTs and the reporting of PRO trial data is suboptimal. Thus, it is imperative that MS researchers conduct RCTs that include fatigue as an outcome, to support clinicians and people with MS (PwMS) to consider the impact of the different DMTs on fatigue.

Quality of life should be the primary outcome for disease-modifying therapy trials in MS: Commentary

Quality of life should be the primary outcome for disease-modifying therapy trials in MS: Commentary

Quality of life should be the primary outcome for disease-modifying therapy trials in MS—Yes

Quality of life should be the primary outcome for disease-modifying therapy trials in MS—Yes

Does the Multiple Sclerosis Impact Scale-29 (MSIS-29) have the range to capture the experience of fully ambulatory multiple sclerosis patients? Learnings from the ASCLEPIOS studies.

Trials of disease-modifying therapies (DMTs) for multiple sclerosis (MS) often include patients with minimal disability. Patient-reported outcome instruments used in these trials have often not captured physical and psychological treatment effects concomitant with observed clinical benefits. To examine whether the Multiple Sclerosis Impact Scale-29 (MSIS-29) captures changes in the impact of MS in a sample of patients enrolled in the Phase 3 ASCLEPIOS studies (ofatumumab vs. teriflunomide). Measurement properties (i.e. item fit, reliability, and targeting) of the MSIS-29 were analyzed using Rasch measurement theory (RMT) in data from two phase 3 ofatumumab clinical trials including patients with relapsing-remitting or secondary progressive MS (N = 1882). Targeting of the MSIS-29 items to the patient population was explored within groups categorized by Expanded Disability Status Scale (EDSS) scores. Under RMT analyses, both the Physical and Psychological Impact scales of the MSIS-29 were not appropriately targeted to the overall sample of patients. In particular, 49% and 30% of patients with an EDSS score ≤ 2.5 had fewer physical and psychological impacts, respectively, than would typically be captured by these MSIS-29 items compared to patients with EDSS scores of ≥ 3. The MSIS-29 is commonly used to evaluate the patient-reported physical and psychological impact of MS. However, it may be limited in evaluating changes associated with DMTs in patients with minimal disability.

Risk of new disease activity in patients with multiple sclerosis who continue or discontinue disease-modifying therapies (DISCOMS): a multicentre, randomised, single-blind, phase 4, non-inferiority trial

Multiple sclerosis typically has onset in young adults and new disease activity diminishes with age. Most clinical trials of disease-modifying therapies for multiple sclerosis have not enrolled individuals older than 55 years. Observational studies suggest that risk of return of disease activity after discontinuation of a disease-modifying therapies is greatest in younger patients with recent relapses or MRI activity. We aimed to determine whether risk of disease recurrence in older patients with no recent disease activity who discontinue disease-modifying therapy is increased compared to those who remain on disease-modifying therapy. DISCOMS was a multicentre, randomised, controlled, rater-blinded, phase 4, non-inferiority trial. Individuals with multiple sclerosis of any subtype, 55 years or older, with no relapse within the past 5 years or new MRI lesion in the past 3 years while continuously taking an approved disease-modifying therapy were enrolled at 19 multiple sclerosis centres in the USA. Participants were randomly assigned (1:1 by site) with an interactive response technology system to either continue or discontinue disease-modifying therapy. Relapse assessors and MRI readers were masked to patient assignment; patients and treating investigators were not masked. The primary outcome was percentage of individuals with a new disease event, defined as a multiple sclerosis relapse or a new or expanding T2 brain MRI lesion, over 2 years. We assessed whether discontinuation of disease-modifying therapy was non-inferior to continuation using a non-inferiority, intention-to-treat analysis of all randomly assigned patients, with a predefined non-inferiority margin of 8%. This trial is registered at ClinicalTrials.gov, NCT03073603, and is completed. 259 participants were enrolled between May 22, 2017, and Feb 3, 2020; 128 (49%) were assigned to the continue group and 131 (51%) to the discontinue group. Five participants were lost to follow-up (continue n=1, discontinue n=4). Six (4·7%) of 128 participants in the continue group and 16 (12·2%) of 131 in the discontinue group had a relapse or a new or expanding brain MRI lesion within 2 years. The difference in event rates was 7·5 percentage points (95% CI 0·6-15·0). Similar numbers of participants had adverse events (109 [85%] of 128 vs 104 [79%] of 131) and serious adverse events (20 [16%] vs 18 [14%]), but more adverse events (422 vs 347) and serious adverse events (40 vs 30) occurred in the discontinue group. The most common adverse events were upper respiratory infections (20 events in 19 [15%] participants in the continue group and 37 events in 30 [23%] participants in the discontinue group). Three participants in the continue group and four in the discontinue group had treatment-related adverse events, of which one in each group was a serious adverse event (multiple sclerosis relapse requiring admission to hospital). One participant in the continue group and two in the discontinue group died; no deaths were deemed to be related to treatment. We were unable to reject the null hypothesis and could not conclude whether disease-modifying therapy discontinuation is non-inferior to continuation in patients older than 55 years with multiple sclerosis and no recent relapse or new MRI activity. Discontinuation of disease-modifying therapy might be a reasonable option in patients older than 55 years who have stable multiple sclerosis, but might be associated with a small increased risk of new MRI activity. Patient-Centered Outcomes Research Institute and the National Multiple Sclerosis Society.

β-Amyloid Load on PET Along the Continuum of Dementia With Lewy Bodies.

β-Amyloid (Aβ) plaques can co-occur with Lewy-related pathology in patients with dementia with Lewy bodies (DLB), but Aβ load at prodromal stages of DLB still needs to be elucidated. We investigated Aβ load on PET throughout the DLB continuum, from an early prodromal stage of isolated REM sleep behavior disorder (iRBD) to a stage of mild cognitive impairment with Lewy bodies (MCI-LB), and finally DLB. We performed a cross-sectional study in patients with a diagnosis of iRBD, MCI-LB, or DLB from the Mayo Clinic Alzheimer Disease Research Center. Aβ levels were measured by Pittsburgh compound B (PiB) PET, and global cortical standardized uptake value ratio (SUVR) was calculated. Global cortical PiB SUVR values from each clinical group were compared with each other and with those of cognitively unimpaired (CU) individuals (n = 100) balanced on age and sex using analysis of covariance. We used multiple linear regression testing for interaction to study the influences of sex and APOE ε4 status on PiB SUVR along the DLB continuum. Of the 162 patients, 16 had iRBD, 64 had MCI-LB, and 82 had DLB. Compared with CU individuals, global cortical PiB SUVR was higher in those with DLB (p < 0.001) and MCI-LB (p = 0.012). The DLB group included the highest proportion of Aβ-positive patients (60%), followed by MCI-LB (41%), iRBD (25%), and finally CU (19%). Global cortical PiB SUVR was higher in APOE ε4 carriers compared with that in APOE ε4 noncarriers in MCI-LB (p < 0.001) and DLB groups (p = 0.049). Women had higher PiB SUVR with older age compared with men across the DLB continuum (β estimate = 0.014, p = 0.02). In this cross-sectional study, levels of Aβ load was higher further along the DLB continuum. Whereas Aβ levels were comparable with those in CU individuals in iRBD, a significant elevation in Aβ levels was observed in the predementia stage of MCI-LB and in DLB. Specifically, APOE ε4 carriers had higher Aβ levels than APOE ε4 noncarriers, and women tended to have higher Aβ levels than men as they got older. These findings have important implications in targeting patients within the DLB continuum for clinical trials of disease-modifying therapies.

How should future clinical trials be designed in the search for disease-modifying therapies for Parkinson’s disease?

ABSTRACT Introduction Although there has been substantial progress in research and innovations in symptomatic treatments, similar success has not been achieved in disease-modifying therapy (DMT) for Parkinson’s disease (PD). Considering the enormous motor, psychosocial and financial burden associated with PD, safe and effective DMT is of paramount importance. Areas covered One of the reasons for the lack of progress in DMT for PD is poor or inappropriate design of clinical trials. In the first part of the article, the authors focus on the plausible reasons why the previous trials have failed and in the latter part, they provide their perspectives on future DMT trials. Expert opinion There are several potential reasons why previous trials have failed, including broad clinical and etiopathogenic heterogeneity of PD, poor definition and documentation of target engagement, lack of appropriate biomarkers and outcome measures, and short duration of follow-up. To address these deficiencies, future trials may consider- (i) a more customized approach to select the most suitable participants and therapeutic approaches, (ii) explore combination therapies that would target multiple pathogenetic mechanisms, and (iii) moving beyond targeting only motor symptoms to also assessing non-motor features of PD in well-designed longitudinal studies.

Disclosure of Genetic Risk Factors for Alzheimer's Disease to Cognitively Healthy Individuals-From Current Practice towards a Personalised Medicine Scenario.

Alzheimer's disease (AD) is a genetically complex disorder. In addition to the relatively small number of pathogenic variants causing autosomal dominant AD, many others have been associated with the much more common sporadic form. The E4 allele of the Apolipoprotein E (APOE) is the first discovered genetic risk factor for AD. In addition, more than 70 genetic risk loci contributing to AD have been identified. Current guidelines do not recommend AD susceptibility genetic testing in cognitively healthy adults because the implications for clinical care are limited. However, secondary prevention clinical trials of disease-modifying therapies enrol individuals based on genetic criteria, and participants are often informed of APOE testing results. Moreover, the availability of direct-to-consumer genetic testing allows individuals to learn their own AD genetic risk profile without medical supervision. A number of research protocols for AD susceptibility genetic testing have been proposed. In Italy, disclosure processes and protocols beyond those developed for inherited dementia have not been established yet. We reviewed the literature on the current practice and clinical issues related to disclosing AD genetic risk to cognitively healthy individuals and provide suggestions that may help to develop specific guidelines at the national level.