Introduction to Pivotal Randomized

Patients enrolled into pivotal randomized controlled trials (RCTs) may differ substantially from those treated in a real-world (RW) setting, which may result in a different benefit–risk profile.

Furthermore, these patients were not adequately represented in the pivotal randomized trials for non-vitamin K antagonist oral anticoagulants (NOACs).

Clinical outcome data were extracted from pre-specified cohorts of HF-naïve patients in the pivotal randomized controlled trials (RCTs).

The association between HIV infection and increased risk of these non-AIDS related comorbidities is strongest for viraemic individuals as highlighted by two pivotal randomized trials, the Strategies for Management of Antiretroviral Therapy (SMART) study and Strategic Timing of Antiretroviral Treatment START study [3,4].

CONCLUSIONS our results suggest that initial or early monotherapy with ESL is effective and well-tolerated for the management of adult patients with focal epilepsy in clinical practice, with results that are at least similar to those reported in the pivotal randomized clinical trial of ESL monotherapy.

A patient-reported outcome (PRO) is a measurement of the patient’s condition, reported directly by the patient, without the interpretation by a clinician or anyone else [1] Recently, there has been a growing interest in the integration of PROs as part of data collection about toxicity and symptoms experienced by patients with cancer This integration could have relevant implications not only for a more accurate reporting of adverse events and definition of quality of life (QoL) within clinical trials [2], but also for a better patients’ management in routine clinical practice [3] Many tools and questionnaires have been validated to properly measure QoL and symptoms in patients with lung cancer The inclusion of these measures in clinical trials has several important advantages It allows providing a patient-focused assessment of the burden and the impact of disease Moreover, it allows completely assessing the clinical benefit of a therapy, by complementing the information provided by commonly used efficacy endpoints, including overall survival, and the traditional description of safety based on physicians’ assessment Furthermore, the availability of QoL data from trials could allow a more accurate patient-physician communication about the treatment strategies offered in clinical practice However, a systematic review that we performed in order to evaluate the adoption of QoL among endpoints in randomized phase III trials conducted in lung cancer, published between 2012 and 2018 in 11 major journals, showed quite disappointing findings [4] Beyond the importance in clinical trials, PROs can play an important role in clinical practice Several studies have demonstrated a clear benefit in terms of patients’ QoL [5,6] Our experience, focused on the adoption of PROs in patients receiving active anticancer treatment at Mauriziano Hospital in Turin, showed that the introduction of PROs, thanks to an active role of nurses, was feasible, produced high patients’ satisfaction and a significant QoL improvement compared to the traditional modality of visit [6] In details, we compared 2 groups: patients in the control group underwent “usual” visits, while patients in the “PRO” group received a paper questionnaire by a dedicated nurse before each visit, in order to provide information about symptoms and toxicities After 1 month, mean change from baseline of global QoL was significantly better in the PRO group, and significantly higher proportion of patients obtained a clinically significant improvement in global QoL score In addition to QoL benefit, several studies have shown a significant improvement in overall survival with the adoption of electronic PROs in patients with lung cancer [7-9] In a pivotal randomized trial involving US patients with different solid tumors (including lung cancer) undergoing chemotherapy, patients assigned to the control arm received usual care, while subjects assigned to experimental arm could report their symptoms remotely from home, using tablet computers or computer kiosks [5,7] Doctors received a report of symptoms referred by patients during visits, and nurses received email alerts when patients reported severe or worsening symptoms Beyond the QoL improvement (the primary endpoint of the trial), a significantly longer life expectancy in the experimental arm (median 31 2 months) compared to the usual care arm (26 0 months) was reported [7] A French randomized trial, conducted in lung cancer patients without evidence of disease progression after or during initial treatment, compared a web-mediated follow-up algorithm (experimental arm), based on weekly self-scored patient symptoms, with routine follow-up with CT scans scheduled every 3-6 months according to the disease stage (control arm) [8] In the experimental arm, the oncologist received automatically an alert email when self-scored symptoms matched predefined criteria Notably, a significant improvement in overall survival was found in patients assigned to experimental arm [9] The adoption of electronic PROs in clinical practice could have many advantages [10] Regular discussion of PROs questionnaires, filled out electronically by patients and received by nurses or doctors, could allow a systematic check of the clinical trend of symptoms and side-effects The early, proactive identification of worsening symptoms and toxicities could help prevent the occurrence of severe adverse events needing ER access and hospitalization Adoption and discussion of PROs would reasonably have a positive psychological impact on patients, increasing their satisfaction with healthcare services While the adoption of electronic PROs could initially appear as a challenging organizational effort, we believe that their benefits will definitely be evident in the long-term The use of PROs may allow a significant benefit in terms of patients’ QoL, and this should be more than enough to consider its adoption in clinical practice, which - overall survival benefit or not – is worth the trouble References: 1 Di Maio M, et al Patient-reported outcomes in the evaluation of toxicity of anticancer treatments Nat Rev Clin Oncol 2016;13(5):319-25 2 Marandino L, et al Deficiencies in health-related quality-of-life assessment and reporting: a systematic review of oncology randomized phase III trials published between 2012 and 2016 Ann Oncol 2018;29:2288-2295 3 Sperti E, Di Maio M Outcomes research: Integrating PROs into the clinic - overall survival benefit or not, it's worth the trouble Nat Rev Clin Oncol 2017;14(9):529-530 4 Reale ML, et al Quality of life analysis in lung cancer: A systematic review of phase III trials published between 2012 and 2018 Lung Cancer 2020 Jan;139:47-54 5 Basch E, et al Symptom Monitoring With Patient-Reported Outcomes During Routine Cancer Treatment: A Randomized Controlled Trial J Clin Oncol 2016;34(6):557-65 6 Baratelli C, et al The role of patient-reported outcomes in outpatients receiving active anti-cancer treatment: impact on patients' quality of life Support Care Cancer 2019;27(12):4697-4704 7 Basch E, et al Overall Survival Results of a Trial Assessing Patient-Reported Outcomes for Symptom Monitoring During Routine Cancer Treatment JAMA 2017;318(2):197-198 8 Denis F, et al Randomized Trial Comparing a Web-Mediated Follow-up With Routine Surveillance in Lung Cancer Patients J Natl Cancer Inst 2017 Sep 1;109(9) 9 Denis F, et al Two-Year Survival Comparing Web-Based Symptom Monitoring vs Routine Surveillance Following Treatment for Lung Cancer JAMA 2019;321(3):306-307 10 Marandino L, et al COVID-19 Emergency and the Need to Speed Up the Adoption of Electronic Patient-Reported Outcomes in Cancer Clinical Practice JCO Oncol Pract 2020;16(6):295-298 Keywords: patient-reported outcomes, health-related quality of life, ePROs.

INTRODUCTION Pivotal Randomized Controlled Trials (RCTs) constitute scientific evidence in support of therapeutic choices when a drug is authorized in the market.

The pivotal randomized studies have demonstrated that the risk of PPM is higher with self-expanding valves compared with balloon-expandable valves.

Because routine monitoring of anticoagulant effects of NOACs is not necessary, appropriate dosing following the criteria of each NOACs defined in pivotal randomized trials is important.

CONCLUSION Data on apixaban concentrations and anti-Factor Xa activity from a pivotal randomized double-blind study of apixaban for the prevention of stroke in NVAF patients have confirmed that the chromogenic anti-factor Xa assay can accurately assess apixaban concentrations in patients regardless of age.

OBJECTIVES Whether elderly patients with adverse comorbidities or strong vascular meandering benefit from mechanical thrombectomy to the same degree as patients who participated in the pivotal randomized controlled trials on this procedure (MR CLEAN, ESCAPE, EXTEND-IA, SWIFT PRIME, REVASCAT, DAWN, and DEFUSE 3) remains unknown.

Direct oral anticoagulants (DOACs) have shown equal or greater efficacy in stroke/systemic embolism prevention, and a better safety profile than VKA in post-hoc analysis of the pivotal randomized controlled trials in patients with non-valvular AF and stage 3 CKD, yet evidence of its risk-benefit profile in more advanced stages of CKD is scarce.

The study enrolled adults with morphologically confirmed higher-risk MDS, non-proliferative CMML, or LB-AML (20–30% myeloblasts in bone marrow); these patients were eligible for enrollment because the diseases are part of the higher-risk MDS spectrum, and were included in the pivotal randomized study that demonstrated significant improvement in overall survival (OS) with azacitidine versus conventional care regimens [3, 8, 9].

For patients with progressive radioactive iodine-refractory differentiated thyroid cancer (RR-DTC), multi-kinase inhibitors (MKIs) including sorafenib and lenvatinib prolonged progression-free survival compared with placebo in pivotal randomized phase 3 trials, although the benefit in overall survival has not been clearly confirmed, possibly because the patients who received placebo were permitted to cross-over to lenvatinib upon disease progression.

METHODS This post hoc analysis of two pivotal randomized, placebo-controlled studies in patients with episodic migraine and chronic migraine examined the effect of erenumab 70 and 140 mg on migraine pain.

Another recent pivotal randomized trial found that LuPSMA was superior to cabazitaxel in patients with advanced castration-resistant prostate cancer (11).

Primary prevention implantable cardioverter-defibrillators (ICDs) in patients with recent myocardial infarction or coronary revascularization and those with newly diagnosed or severe heart failure (HF) are considered non-evidence-based, as defined by pivotal randomized clinical trials.

1048Background: Addition of P to T+chemo for MBC pts has been shown to improve overall survival (OS) in a pivotal randomized trial (hazard ratio [HR] = 0.

Indeed, apart from edoxaban, which at the lower dose was showing further excess safety compared with warfarin [3], no significant interaction as regard both efficacy and safety was observed in the three pivotal randomized clinical trials between higher and lower doses of factor-Xa inhibitors [3].

Conclusions In this real-world study, the observed effectiveness of COVID-19 vaccines in HCWs was in line with the efficacy reported in pivotal randomized trials.

” In their article, the authors performed a descriptive overview of existing metaanalyses that included published pivotal randomized controlled trials (RCTs) of direct oral anticoagulants versus lowmolecularweight heparins in cancer patients with venous thromboembolism.

8% was spent on drugs that were approved based on a pivotal randomized clinical trial.

Methodology: TRIDENT (NCT04471844) is an international, pivotal randomized trial comparing standard RT with concomitant TMZ vs the triple combination of RT with concomitant TMZ and TTFields.

Pivotal randomized trials conducted to obtain US Food and Drug Administration approval excluded bicuspid anatomy.

Pivotal randomized clinical studies demonstrated that afatinib significantly prolonged progression-free survival compared with platinum-based chemotherapy (LUX-Lung 3, LUX-Lung 6), and with gefitinib (LUX-Lung 7), with manageable side effects.

Endpoints utilized in left heart disease trials have been applied with success to TR trials, and innovative trial designs will allow the initiation of pivotal randomized trials.

The historical grid laser photocoagulation is no longer recommended as first-line treatment of diabetic macular edema owing to the findings of the pivotal randomized controlled trials, and anti-vascular endothelial growth factor therapy has emerged as first-line therapy.

While results from pivotal randomized trials are available, French-specific, “real-life” data pertaining to the four OAC treatments available are awaited.

Recent findings Data on early-to-moderate stage CKD derived from pivotal randomized controlled trials in broader atrial fibrillation and VTE populations support the favorable risk–benefit ratio of DOACs compared with VKAs in patients in these groups.

We illustrate how this approach was used to design a pivotal randomized trial in acute myeloid leukemia and discuss historical data that informed the simulation model and operational challenges when implementing it.

We conducted a Medline search using various combinations of "smart watch" "atrial fibrillation" "wearables", and "Kardia" to identify pivotal randomized trials published before June 1, 2019, for inclusion in this review.

This approach is supported by 2 pivotal randomized clinical trials showing that the early introduction of peanut and other food allergens significantly reduces the risk of food allergy.

Apremilast has demonstrated a favourable safety profile for the treatment of psoriasis based on its pivotal randomized controlled trials (RCTs), ESTEEM 1 and 2.

These approvals were based on two pivotal randomized controlled trials (RCTs), OPERA I and OPERA II, comparing ocrelizumab 600 mg with an active comparator, interferon β-1a 44 μg (Rebif), and the first trial with positive results in patients with PPMS, which compared ocrelizumab with placebo.

Because of the clinical safety of this chemically inert monatomic gas, the lack of an alternative for neuroprotection, and encouraging phase 2 trial data, a multinational pivotal randomized clinical trial (XePOHCAS) has been launched to assess the utility of xenon for patients that have been successfully resuscitated following an out of hospital cardiac arrest but still remain comatose, indicating ongoing neurological ischemic-perfusion injury.

DESIGN Pivotal randomized controlled trials (RCTs) in oncology were identified from the pan-Canadian Oncology Drug Review (pCODR) database (primary analysis) and the Food and Drug Administration's (FDA) drug approvals page (secondary analysis) between January 2012 and May 2016.

The strict eligibility criteria of pivotal randomized clinical trials can limit the generalizability of their results (3).

For two stimulation targets, pivotal randomized trials have been conducted; both failed a futility analysis.

LAY SUMMARY There is currently no prognostic model specifically developed for recommended or ideal transarterial chemoembolization (TACE) candidates with hepatocellular carcinoma, despite these patients being frequently identified as the best target population in pivotal randomized controlled trials.

There are multiple available treatments to enhance stroke rehabilitation, although few interventions have confirmed significant clinical improvements on motor function in pivotal Randomized Clinical Trials.