Cannabidiol (Epidyolex®) for severe behavioral manifestations in patients with tuberous sclerosis complex, mucopolysaccharidosis type III and fragile X syndrome: protocol for a series of randomized, placebo-controlled N-of-1 trials.

BACKGROUND: Many rare genetic neurodevelopmental disorders (RGNDs) are characterized by intellectual disability (ID), severe cognitive and behavioral impairments, potentially diagnosed as a comorbid autism spectrum disorder or attention-deficit hyperactivity disorder. Quality of life is often impaired due to irritability, aggression and self-injurious behavior, generally refractory to standard therapies. There are indications from previous (case) studies and patient reporting that cannabidiol (CBD) may be an effective treatment for severe behavioral manifestations in RGNDs. However, clear evidence is lacking and interventional research is challenging due to the rarity as well as the heterogeneity within and between disease groups and interindividual differences in treatment response. Our objective is to examine the effectiveness of CBD on severe behavioral manifestations in three RGNDs, including Tuberous Sclerosis Complex (TSC), mucopolysaccharidosis type III (MPS III), and Fragile X syndrome (FXS), using an innovative trial design. METHODS: We aim to conduct placebo-controlled, double-blind, block-randomized, multiple crossover N-of-1 studies with oral CBD (twice daily) in 30 patients (aged ≥ 6 years) with confirmed TSC, MPS III or FXS and severe behavioral manifestations. The treatment is oral CBD up to a maximum of 25 mg/kg/day, twice daily. The primary outcome measure is the subscale irritability of the Aberrant Behavior Checklist. Secondary outcome measures include (personalized) patient-reported outcome measures with regard to behavioral and psychiatric outcomes, disease-specific outcome measures, parental stress, seizure frequency, and adverse effects of CBD. Questionnaires will be completed and study medication will be taken at the participants' natural setting. Individual treatment effects will be determined based on summary statistics. A mixed model analysis will be applied for analyzing the effectiveness of the intervention per disorder and across disorders combining data from the individual N-of-1 trials. DISCUSSION: These N-of-1 trials address an unmet medical need and will provide information on the effectiveness of CBD for severe behavioral manifestations in RGNDs, potentially generating generalizable knowledge at an individual-, disorder- and RGND population level. TRIAL REGISTRATION: EudraCT: 2021-003250-23, registered 25 August 2022, https://www.clinicaltrialsregister.eu/ctr-search/trial/2021-003250-23/NL .

The SNAP Trial: 2-Year Results of a Double-Blind Multicenter Randomized Controlled Trial of a Silicon Nitride Versus a PEEK Cage in Patients After Lumbar Fusion Surgery.

STUDY DESIGN: Randomized controlled trial. OBJECTIVES: Lumbar interbody fusion with cages is performed to provide vertebral stability, restore alignment, and maintain disc and foraminal height. Polyetheretherketone (PEEK) is commonly used. Silicon nitride (Si3N4) is an alternative material with good osteointegrative properties. This study was designed to assess if Si3N4 cages perform similar to PEEK. METHODS: A non-inferiority double-blind multicenter RCT was designed. Patients presenting with chronic low-back pain with or without leg pain were included. Single- or double-level instrumented transforaminal lumbar interbody fusion (TLIF) using an oblique PEEK or Si3N4 cage was performed. The primary outcome was the Roland-Morris Disability Questionnaire (RMDQ). The non-inferiority margin for the RMDQ was 2.6 points on a scale of 24. Secondary outcomes included the Oswestry Disability Questionnaire (ODI), Visual Analogue Scales (VAS), SF-36 Physical Function, patient and surgeon Likert scores, radiographic evaluations for subsidence, segmental motion, and fusion. Follow-up was planned at 3, 6, 12, and 24-months. RESULTS: Ninety-two patients were randomized (i.e. 48 to PEEK and 44 to Si3N4). Both groups showed good clinical improvements on the RMDQ scores of up to 5-8 points during follow-up. No statistically significant differences were observed in clinical and radiographic outcomes. Mean operative time and blood loss were statistically significantly higher for the Si3N4 cohort. Although not statistically significant, there was a higher incidence of complications and revisions associated with the Si3N4 cage. CONCLUSIONS: There was insufficient evidence to conclude that Si3N4 was non-inferior to PEEK.

Methylphenidate for attention-deficit/hyperactivity disorder in patients with Smith-Magenis syndrome: protocol for a series of N-of-1 trials.

BACKGROUND: Smith-Magenis syndrome (SMS) is a rare genetic neurodevelopmental disorder characterized by intellectual disability and severe behavioural and sleep disturbances. Often, patients with SMS are diagnosed with attention-deficit/hyperactivity disorder (ADHD). However, the effectiveness of methylphenidate (MPH), the first-line pharmacological treatment for ADHD, in patients with SMS is unclear. Our objective is to examine the effectiveness of MPH for ADHD symptoms in individuals with SMS, proposing an alternative trial design as traditional randomized controlled trials are complex in these rare and heterogeneous patient populations. METHODS AND ANALYSIS: We will initiate an N-of-1 series of double-blind randomized and placebo-controlled multiple crossover trials in six patients aged ≥ 6 years with a genetically confirmed SMS diagnosis and a multidisciplinary established ADHD diagnosis, according to a power analysis based on a summary measures analysis of the treatment effect. Each N-of-1 trial consists of a baseline period, dose titration phase, three cycles each including randomized intervention, placebo and washout periods, and follow-up. The intervention includes twice daily MPH (doses based on age and body weight). The primary outcome measure will be the subscale hyperactivity/inattention of the Strengths and Difficulties Questionnaire (SDQ), rated daily. Secondary outcome measures are the shortened version of the Emotion Dysregulation Inventory (EDI) reactivity index, Goal Attainment Scaling (GAS), and the personal questionnaire (PQ). Statistical analysis will include a mixed model analysis. All subjects will receive an assessment of their individual treatment effect and data will be aggregated to investigate the effectiveness of MPH for ADHD in SMS at a population level. CONCLUSIONS: This study will provide information on the effectiveness of MPH for ADHD in SMS, incorporating personalized outcome measures. This protocol presents the first properly powered N-of-1 study in a rare genetic neurodevelopmental disorder, providing a much-needed bridge between science and practice to optimize evidence-based and personalized care. TRIAL REGISTRATION: This study is registered in the Netherlands Trial Register (NTR9125).

A narrative review of estimands in drug development and regulatory evaluation: old wine in new barrels?

BACKGROUND: An estimand defines the target of estimation for a clinical trial through specification of the treatment, target population, variable, population-level summary and of the strategies for intercurrent events. A carefully defined estimand aligns the clinical trial design and analysis with the scientific question of interest and adequately accounts for so-called intercurrent events. The ICH E9(R1) addendum suggests five estimand strategies. We evaluated to what extent current practice in drug development and regulatory assessment fits in the estimand framework. METHODS: We systematically evaluated what estimands, especially what strategies for intercurrent events are advised in European Medicines Agency disease guidelines, used in sponsors' trials and additionally requested by the European Medicines Agency in assessment dossiers. We selected four therapeutic areas: nervous system, oncology, cardiovascular diseases and respiratory diseases. For each, we evaluated all disease guidelines with approved drugs, the dossiers of the most recently approved drugs matching the guidelines and corresponding regulatory questions. RESULTS: Strategies for intercurrent events were present in 18 (53%) of 34 guidelines, in all 34 sponsor documentations and in 15 (44%) of 34 sets of regulatory questions. Treatment policy was advised in 13 (38%) guidelines and was applied in 9 corresponding sponsor documentations. Of these 9, it was the sole strategy in 4 cases and accompanied by another strategy in 5 cases. Hypothetical strategy was not advised in guidelines. However, it was the leading strategy applied in 25 (74%) sponsor documentations. Composite strategy was advised in 3 (9%) guidelines and applied accompanied by another strategy in 2 corresponding sponsor documentations. While on treatment strategy was not advised in guidelines, but was applied in 2 sponsor documentations. Principal stratum strategy was advised in 2 guidelines but not applied in corresponding sponsor documentations. Of the regulatory questions, treatment policy was present in 2 cases (6%), hypothetical in 6 cases (18%), composite in 6 cases (18%) and while on treatment in 1 case (3%). CONCLUSIONS: Estimand attributes are present in guidelines, sponsor documentations and regulatory questions, but not described as estimands. Treatment policy was most often advised in guidelines, but hypothetical was the leading strategy applied in sponsor documentations. Thus, results indicate not a full concordance between the regulatory target of estimation and what is actually estimated. The lack of concordance was mostly due to limitations in collection of intercurrent events data to enable a treatment policy strategy. There is, therefore, a need to better define estimands at the design stage and throughout the applications dossiers and assessment reports.

Goal attainment scaling as an outcome measure in rare disease trials: a conceptual proposal for validation.

BACKGROUND: Goal Attainment Scaling (GAS) is an instrument that is intended to evaluate the effect of an intervention by assessing change in daily life activities on an individual basis. However, GAS has not been validated adequately in an RCT setting. In this paper we propose a conceptual validation plan of GAS in the setting of rare disease drug trials, and describe a hypothetical trial where GAS could be validated. METHODS: We have used the COnsensus-based Standards for the selection of health Measurement INstruments (COSMIN) taxonomy to deduce which measurement properties of GAS can be evaluated, and how. As individual GAS scores cannot be interpreted outside the context of a RCT, the validation of GAS needs to be done on trial as well as on individual level. RESULTS: The procedure of GAS consists of three steps. For the step of goal selection (step 1) and definition of levels of attainment (step 2), face validity may be assessed by clinical experts. For the evaluation of the goal attainment (step 3), the inter and intra rater reliability can be evaluated on an individual level. Construct validity may be evaluated by comparison with change scores on other instruments measuring in the same domain as particular goals, if available, and by testing hypotheses about differences between groups. A difference in mean GAS scores between a group who received an efficacious intervention and a control group is an indication of well-chosen goals, and corroborates construct validity of GAS on trial level. Responsiveness of GAS cannot be evaluated due to the nature of the construct being assessed. CONCLUSION: GAS may be useful as an instrument to assess functional change as an outcome measure in heterogeneous chronic rare diseases, but it can only be interpreted and validated when used in RCTs with blinded outcome assessment. This proposed theoretical validation plan can be used as a starting point to validate GAS in specific conditions.

Ethics in musculoskeletal regenerative medicine; guidance in choosing the appropriate comparator in clinical trials.

BACKGROUND: Regenerative Medicine (RM) techniques aimed at the musculoskeletal system are increasingly translated to clinical trials and patient care. This revolutionary era in science raises novel ethical challenges. One of these challenges concerns the appropriate choice of the comparator in (randomized controlled) trials, including the ethically contentious use of sham procedures. To date, only general guidelines regarding the choice of the comparator exist. OBJECTIVE: To provide specific guidelines for clinical trial comparator choice in musculoskeletal RM. METHODS: In this manuscript, we discuss the ethics of comparator selection in RM trials. First, we make a classification of RM interventions according to different health states from disease prevention, return to normal health, postponing RM treatment, supplementing RM treatment, substituting RM treatment, improving RM outcome, and slowing progression. Subsequently, per objective, the accompanying ethical points to consider are evaluated with support from the available literature. RESULTS: a sham procedure is demonstrated to be an ethically acceptable comparator in RM trials with certain objectives, but less appropriate for musculoskeletal RM interventions that aim at preventing disease or substituting a surgical treatment. The latter may be compared to 'standard of care'. CONCLUSION: From a scientific perspective, choosing the correct comparator based on ethical guidelines is a step forward in the success of musculoskeletal RM.

The POWER-tool: Recommendations for involving patient representatives in choosing relevant outcome measures during rare disease clinical trial design.

In clinical trials, it is relevant to ask patients and/or their caregivers which aspects concerning their disease they consider important to measure when a new intervention is being investigated. Those aspects, useful as outcome measures in a trial, are of pivotal importance for the result of the trial and the subsequent decision-making. In rare diseases the choice of outcome measures may be even more important, due to the small numbers and heterogeneity of the patients that are included. We have developed a tool to involve patients in the determination of outcome measures and the choice of measurement instruments. This tool was developed together with a patient think tank, consisting of a group of rare disease patient representatives, and by interviewing end users. We have road-tested our tool in an ongoing trial, and evaluated it during a focus group meeting. The tool consists of three steps: 1) Preparation, 2) Consultation of patients, 3) Follow-up during which the consultation results are implemented in the trial design. The tool provides guidelines for researchers to include the patient's opinion in the choice of outcome measures in the trial design stage. We describe the development of the POWER-tool (Patient participation in Outcome measure WEighing for Rare diseases), and first experiences of the tool in an ongoing trial.

MEDUCATE trial: effectiveness of an intensive EDUCATional intervention for IT-mediated MEDication management in the outpatient clinic - study protocol for a cluster randomized controlled trial.

BACKGROUND: Using information technology for medication management is an opportunity to help physicians to improve the quality of their documentation and communication and ultimately to improve patient care and patient safety. Physician education is necessary to take full advantage of information technology systems. In this trial, we seek to determine the effectiveness of an intensive educational intervention compared with the standard approach in improving information technology-mediated medication management and in reducing potential adverse drug events in the outpatient clinic. METHODS/DESIGN: We are conducting a multicenter, cluster randomized controlled trial. The participants are specialists and residents working in the outpatient clinic of internal medicine, cardiology, pulmonology, geriatrics, gastroenterology and rheumatology. The intensive educational intervention is composed of a small-group session and e-learning. The primary outcome is discrepancies between registered medication (by physicians) and actually used medication (by patients). The key secondary outcomes are potential adverse events caused by missed drug-drug interactions. The primary and key secondary endpoints are being assessed shortly after the educational intervention is completed. Sample size will be calculated to ensure sufficient power. A sample size of 40 physicians per group and 20 patients per physician will ensure a power of >90 %, which means we will need a total of 80 physicians and 1,600 patients. DISCUSSION: We performed an exploratory trial wherein we tested the recruitment process, e-learning, time schedule, and methods for data collection, data management and data analysis. Accordingly, we refined the processes and content: the recruitment strategy was intensified, extra measures were taken to facilitate smooth conductance of the e-learning and parts were made optional. First versions of the procedures for data collection were determined. Data entry and analysis was further standardized by using the G-standard database in the telephone questionnaire. TRIAL REGISTRATION: ISRCTN registry: ISRCTN50890124 . Registered 10 June 2013.

Interpretation and inference in noninferiority randomized controlled trials in drug research.

Noninferiority (NI) trials in drug research are used for the purpose of demonstrating that a new treatment is not worse than a proven active comparator, thereby indirectly showing that the treatment is effective. This article explains and addresses the complications in the interpretation of NI trials that arise from the indirect comparison. On the basis of our review of 232 trials, we conclude that the interpretation and inference of NI trials are complicated, partly because of the incompleteness of the information.