Trial Design Phase Research Articles

Challenges of conducting a randomised placebo-controlled trial of spinal surgery: the SUcceSS trial of lumbar spine decompression

Although placebo-controlled trials are considered the gold standard for evaluating the efficacy of healthcare interventions, they can be perceived to be controversial and challenging to conduct for surgical treatments. The SUcceSS trial is the first placebo-controlled trial of lumbar decompression surgery for symptomatic lumbar canal stenosis. The SUcceSS trial has experienced common issues affecting the implementation of randomised placebo-controlled surgery trials, accentuated by the COVID-19 pandemic. Using the SUcceSS trial as an example, we discuss key challenges and mitigation strategies specific to the conduct of a randomised placebo-controlled surgical trial. Overall, the key lessons learned were (i) involving key stakeholders early and throughout the trial design phase may increase clinician and patient willingness to participate in a placebo-controlled trial of surgical interventions, (ii) additional resources (e.g. budget, staff time) are likely required to successfully operationalise trials of this nature, (iii) the level of placebo fidelity, timing of randomisation relative to intervention delivery, and nuances of the surgical procedure under investigation should be considered carefully. Findings are based on one example of a placebo-controlled surgical trial; however, researchers may benefit from employing or building from the strategies described and lessons learned when designing or implementing future trials of this nature.

Phase 3, randomized, open-label study of pembrolizumab plus lenvatinib versus chemotherapy for first-line treatment of advanced or recurrent endometrial cancer: ENGOT-en9/LEAP-001

BackgroundPembrolizumab plus lenvatinib is a novel combination with promising efficacy in patients with advanced and recurrent endometrial cancer. This combination demonstrated high objective response rates in a single-arm phase 1b/2...

Current COVID-19 vaccine trials in high-income countries: are placebo-controlled trials ethical?

Current COVID-19 vaccine trials in high-income countries: are placebo-controlled trials ethical?

Designing provider-focused implementation trials with purpose and intent: introducing the PRECIS-2-PS tool

BackgroundFirst articulated by Schwartz and Lellouch (1967), randomized controlled trials (RCTs) can be conceptualized along a continuum from more explanatory to more pragmatic. The purpose and intent of the former is to test interventions under ideal contexts, and the purpose and intent of the latter is to test interventions in real-world contexts. The PRagmatic Explanatory Continuum Indicator Summary-2 (PRECIS-2) is a validated tool that helps researchers make decisions about the elements of the trial to match the overall purpose and intent of the trial along the continuum. The PRECIS-2 tool has guided the design of hundreds of RCTs. However, a few aspects of the tool would benefit from greater clarity, including its application to provider-focused implementation trials rather than patient-focused intervention trials.Main textWe describe the newly developed PRECIS-2-Provider Strategies (PRECIS-2-PS) tool, an extension of the PRECIS-2 tool, which has been adapted for trials testing provider-focused strategies. We elaborate on nine domains that can make a provider-focused trial more explanatory or more pragmatic, including eligibility, recruitment, setting, implementation resources, flexibility of provider strategies, flexibility of intervention, data collection, primary outcome, and primary analysis. We detail the complementary roles that researchers and stakeholders play in the trial design phase, with implications for generalizability of trial results to the contexts in which they are intended to be applied.ConclusionsThe PRECIS-2-PS tool is designed to help research and practice teams plan for provider-focused trials that reflect the overall intent and purpose of the trial. The tool has potential to help advance the science of provider-focused strategies across a range of trials, with the ultimate goal of facilitating the adoption, integration, and sustainability of provider-focused strategies outside the context of trials.

The use of digitally collected patient-reported outcome measures for newly operated patients with total knee and hip replacements to improve post-treatment recovery: study protocol for a randomized controlled trial

BackgroundThe number of total knee replacements (TKRs) and total hip replacements (THRs) has been increasing noticeably in high-income countries, such as Germany. In particular, the number of revisions is expected to rise because of higher life expectancy and procedures performed on younger patients, impacting the budgets of health-care systems. Quality transparency is the basis of holistic patient pathway optimization. Nevertheless, a nation-wide cross-sectoral assessment of quality from a patient perspective does not yet exist. Several studies have shown that the use of patient-reported outcome measures (PROMs) is effective for measuring quality and monitoring post-treatment recovery. For the first time in Germany, we test whether early detection of critical recovery paths using PROMs after TKR/THR improves the quality of care in a cost-effective way and can be recommended for implementation into standard care.Methods/designThe study is a two-arm multi-center patient-level randomized controlled trial. Patients from nine hospitals are included in the study. Patient-centered questionnaires are employed to regularly measure digitized PROMs of TKR/THR patients from the time of hospital admission until 12 months post-discharge. An expert consortium has defined PROM alert thresholds at 1, 3, and 6 months to signal critical recovery paths after TKR/THR. An algorithm alerts study assistants if patients are not recovering in line with expected recovery paths. The study assistants contact patients and their physicians to investigate and, if needed, adjust the post-treatment protocol. When sickness funds’ claims data are added, the cost-effectiveness of the intervention can be analyzed.DiscussionThe study is expected to deliver an important contribution to test PROMs as an intervention tool and examine the determinants of high-quality endoprosthetic care. Depending on a positive and cost-effective impact, the goal is to transfer the study design into standard care. During the trial design phase, several insights have been discovered, and there were opportunities for efficient digital monitoring limited by existing legacy care models. Digitalization in hospital processes and the implementation of digital tools still represent challenges for hospital personnel and patients. Furthermore, data privacy regulations and the separation between the in- and outpatient sector are roadblocks to effectively monitor and assess quality along the full patient pathway.Trial registrationGerman Clinical Trials Register: DRKS00019916. Registered November 26, 2019 – retrospectively registered.

PEMBELAJARAN IPA SMP BERBASIS KETERAMPILAN PROSES SAINS DENGAN MODEL DISCOVERY LEARNING UNTUK MENINGKATKAN PEMAHAMAN KONSEP SISWA

This study aims to improve students' understanding of the concept by applying Science Process Skill Based Learning (PBKPS) with the Discovery Learning model. The method used in this research is Research and Development using 3D models, namely Define, Design, and Develop. Define is the activity of gathering various information needed (need assessment). Design is the activity of designing an initial product or learning draft. Develop is a product developing activity. At the trial design phase that is used is One Group Pretest-Posttest Design. The population used in this study was Jayapura VII Class VIII SMP Negeri 2 totaling 280 people. The sampling technique is done by using purposive technique and cluster sampling. The number of samples in this study were 30 people. The results showed that: 1) Science Process Skills-based learning (KPS) can be implemented well by the teacher, and 2) the acquisition of N-gain understanding of the concept of the limited trial results is classified as moderate.

P.149The MYODA operational seamless clinical trial design phase I to III: a new approach for rare diseases to evaluate the safety, efficacy, pharmacokinetics, and pharmacodynamics of BIO101 (MAS activator) in paediatric patients with a genetically confirmed diagnosis of Duchenne muscular dystrophy

Clinical development of new medications is traditionally broken down into 3 phases. This prevents patients from participating in more than one of the development phases and comes with a burden on site staff (with repeated site initiation and training) leading to prolonged development timelines (up to 10 years) and difficulties in patient recruitment, especially in rare diseases such as DMD. There is a significant need, therefore, for utilization of novel designs, which will make clinical development more amenable for patients and more efficient for study site staff. Biophytis is developing BIO101 (20-hydroxyecdysone, MAS activator) for DMD. The pre-clinical proof-of-concept (PoC) for BIO101 demonstrates combined beneficial effects on skeletal muscle and respiratory functions in DMD animal models, suggesting a range of benefit in a broad DMD population. To ensure an optimal and patient-centered clinical development of BIO101, a seamless methodology is intended to be utilized. The trial design should take into consideration the needs and struggle of the patients who participate in the study. An operational seamless design is one that can cover the requirements, in terms of needed evidence, to support a new medicine (i.e. from phase I to phase III), while offering participants an access to the trial medication and reduce the need for repeated screening procedures. Biophytis proposes a 3-part study that combines Phase I to III of the clinical development in one operational seamless study with adaptive elements. Patients with DMD with various degrees of loss of ambulation will be recruited in one of the four-ascending multiple-dose cohorts of 1 week-duration (Part1), they will continue at the same dose for 24 weeks (Part2=phase II) in order to support dose(s) that will be tested for the pivotal Part 3. Continuing patients from Part 1 and 2 with additional patients will enter a 48 week-period (Part 3) to establish longer term safety and efficacy of BIO101.

A dynamic application of PRECIS-2 to evaluate implementation in a pragmatic, cluster randomized clinical trial in two nursing home systems

BackgroundPRECIS-2 (PRagmatic Explanatory Continuum Indicator Summary-2) can assess how clinical trial design decisions (along the explanatory-pragmatic continuum) influence the applicability of trial results to intended stakeholders. The tool has been used to assess features of trials during the trial design phase and also upon completion. The ongoing PRagmatic trial Of Video Education in Nursing homes (PROVEN), which is evaluating the effectiveness of a suite of videos to improve advance care planning, is one of the first large pragmatic, cluster randomized trials within nursing home health care systems. While certain features of pragmatic trials remain static once designed (e.g., recruitment, outcomes), successful implementation of a system-wide program requires on-going evaluation and adaptation. This report’s objectives were to apply PRECIS-2 in a novel manner during the actual conduct of the PROVEN trial to assess how dynamic adaptations shifted implementation to either a more explanatory or a more pragmatic approach.MethodsWe assessed PROVEN’s protocol as initially designed according to the three PRECIS-2 domains pertinent to implementation: (1) Organization, (2) Flexibility-Delivery, and (3) Flexibility-Adherence. We then applied this framework to conduct a formative evaluation of decisions made while the trial was ongoing to adapt the implementation approach along the pragmatic versus the explanatory continuum in response to emergent challenges.ResultsBased on the PRECIS-2 rubric, the initial design of the PROVEN implementation approach reflected a hybrid of pragmatic and explanatory features. Most notably, within the Flexibility-Delivery, the trial had a relatively pragmatic approach to protocol delivery by front-line nursing home providers, balanced with a more explanatory approach to protocol monitoring enabled by the analytic capabilities of the research team. This more intensive monitoring proved critical in revealing implementation problems once the study began. Dynamic adaptations made in response to these challenges generally reflected shifts to more explanatory approaches within the Flexibility-Delivery and Flexibility-Adherence domains including ever more intensive compliance monitoring, as well as detailed coaching of front-line providers delivering the intervention by the research team.ConclusionsPragmatic trials conducted in the nursing home setting may benefit from a more dynamic approach to implementation. Allowing fluidity between pragmatic and explanatory features may still preserve the trial's applicability to intended stakeholders’ needs. PRECIS-2 provides a useful formative evaluation tool to assess these adaptations in “real-time.”Trial registrationUS National Library of Medicine, ClinicalTrials.gov, ID: NCT02612688. Registered on 19 November 2015

A randomized phase II trial of fulvestrant with or without ribociclib after progression on aromatase inhibition plus cyclin-dependent kinase 4/6 inhibition in patients with unresectable or metastatic hormone receptor positive, HER2 negative breast cancer.

TPS1112 Background: CDK4/6i, including palbociclib and ribociclib (R), have demonstrated remarkable benefit in progression free survival (PFS) in patients (pts) with HR+, HER2- MBC with anti-estrogen therapy. Switching between anti-estrogen therapies at disease progression is standard of care in the treatment of HR+ MBC. We evaluate the strategy of switching anti-estrogen therapy to fulvestrant (F) and maintaining CDK4/6 inhibition with R in pts with HR+, HER2- MBC who have progressed on an AI + CDK4/6i. Methods: Trial Design Phase II, multi-center, randomized, double-blind, placebo-controlled trial to evaluate F +/- R in pts with HR+, HER2- MBC who have previously progressed on any AI + CDK4/6i: Screened at 2 different scenarios: Scenario 1: Before receiving any CDK4/6i Scenario 2: Time of progression of disease (POD) while being treated with an AI + CDK4/6i Intervention At randomization, pts assigned 1:1 to either a) F + R or b) F + placebo, with treatment given in 4-week cycles. Major Eligibility Criteria 1, Metastatic BC, 2. HR+ HER2-, 3. Measurable or unmeasurable disease Specific Aims Primary: PFS. Secondary: Objective response rate, clinical benefit rate, overall survival, and duration of response. Biomarker assessment: amplification of cyclin D1 and cyclin E, phosphoRb and TK1 expression, Rb1 and p16 loss, and ctDNA for ESR1 and PIK3CA mutations. Statistical Methods Assuming a median PFS of 3.8 months with F alone, we predict that F + R will lead to a median PFS of at least 6.5 months. A one-sided log-rank test with a sample size of N = 120 and alpha = 0.025, achieves 80% power to detect a difference in PFS of 2.7. With a 10% dropout, n = 132. Clinical trial registry number NCT02632045.

Abstract OT2-01-19: A randomized phase II trial of fulvestrant with or without ribociclib after progression on aromatase inhibition plus cyclin-dependent kinase 4/6 inhibition in patients with unresectable or metastatic hormone receptor positive, HER2 negative breast cancer

Abstract Background Cyclin dependent kinase 4 and 6 inhibitors (CDK4/6i), including palbociclib and ribociclib (R), have demonstrated remarkable benefit in progression free survival (PFS) in patients (pts) with hormone receptor positive (HR+), HER2- metastatic breast cancer (MBC) when combined with anti-estrogen therapy. Switching between anti-estrogen therapies at disease progression is standard of care in the treatment of HR+ MBC. We evaluate the strategy of switching anti-estrogen therapy to fulvestrant (F) and maintaining CDK4/6 inhibition with R in pts with HR+, HER2- MBC who have progressed on an aromatase inhibitor (AI) + CDK4/6i. Trial Design Phase II, multi-center, randomized, double-blind, placebo-controlled trial to evaluate F +/- R in pts with HR+, HER2- MBC who have previously progressed on any AI + CDK4/6i. Pts can be screened and registered at two different time points: Scenario 1: Before receiving any CDK4/6i Scenario 2: At the time of progression of disease (POD) while being treated with an AI + CDK4/6i In scenario 1, the study will provide pts with letrozole + R, but pts will not be randomized until they demonstrate POD. At randomization, pts will be assigned 1:1 to either a) F + R or b) F + placebo, with treatment given in 4-week cycles. F will be given as a 500 mg dose intramuscularly every 2 weeks for 3 times and then every 4 weeks, as per standard of care. R or placebo will be given orally at 600 mg daily, 3 weeks on/1 week off. CT scans and bone scan are to be performed prior to every third cycle. Serum and whole blood samples and optional tissue biopsies for biomarker assessment will be performed prior to study treatment (scenario 1), prior to randomization to R +/- F, and when the patient goes off study. Main Eligibility Criteria: 1. Age ≥ 18 years with unresectable or metastatic BC 2. Estrogen and/or progesterone receptor positive, HER2 negative, as per ASCO-CAP 3. Postmenopausal status or receiving ovarian suppression 4. Measurable or unmeasurable disease; stable CNS disease allowed 5. No clinically significant cardiac disease 6. No concomitant CYP3A4/5 inducer or inhibitor Specific Aims Primary: Progression free survival (PFS), defined as the time from randomization to POD or death. Secondary: Objective response rate (ORR), clinical benefit rate (CBR = ORR + stable disease rate), overall survival (OS), and duration of response. Pts in scenario 1 will also be assessed for PFS, OS, CBR, and safety while receiving AI + R (pre-randomization). Biomarker assessment will include amplification of cyclin D1 and cyclin E, phosphoRb and TK1 expression, Rb1 and p16 loss, and ctDNA for ESR1 and PIK3CA mutations. Target Accrual 132 pts accrued from 11 academic medical centers in the U.S, with a goal of completing accrual in two years (∼60 to 72 pts in each scenario). Statistical Methods Assuming a median PFS of 3.8 months with F alone, we predict that F + R will lead to a median PFS of at least 6.5 months. A one-sided log-rank test with a sample size of N=120 and alpha=0.025, achieves 80% power to detect a difference in PFS of 2.7 months. N=132 pts allows for a 10% drop-out rate. Citation Format: Mundi PS, Codruta C, Accordino MK, Sparano J, Andreopoulou E, Vadhat LT, Tiersten A, Esteva F, O'Regan R, Jain S, Mayer I, Forero A, Crew KD, Hershman DL, Kalinsky KM. A randomized phase II trial of fulvestrant with or without ribociclib after progression on aromatase inhibition plus cyclin-dependent kinase 4/6 inhibition in patients with unresectable or metastatic hormone receptor positive, HER2 negative breast cancer [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr OT2-01-19.

Analysis of the costs of a large prevention trial

Total direct costs of the Women's Health Trial (WHT), a large multicenter prevention trial, were reduced by more than 50% by means of research cost analysis conducted during the trial design phase. The unit costs of specific trial activities were estimated so that total direct costs of the trial could be predicted from design parameters. The relative costs of screening, treatment, and follow-up, and the fixed costs associated with each clinical center in a multicenter prevention trial were taken into account. Direct costs of the WHT were reduced from $195 million to $95 million by refinement of the trial protocol, selection of an efficient design, and consideration of trial logistics. The analyses suggest several ways to reduce costs in a prevention trial. Use of the case-cohort approach can reduce costs substantially when the protocol includes collection of specimens or data that are costly to process. When establishing and maintaining a clinical center represents a significant proportion of a clinical center's costs, use of a smaller number of larger clinical centers offers important cost savings. Because restrictive eligibility requirements reduce the recruitment potential of each clinical center, use of high-risk participants may not improve the efficiency of a prevention trial; its favorable impact on sample size may fail to compensate for its cost in terms of additional clinical centers and higher recruitment costs.