Single-arm phase 3 designs: An oxymoron?

BACKGROUND: Since the 1950s, randomized clinical trials (RCTs) have served as the gold standard for confirming the benefits of a new drug. Accordingly, phase 3 trials, the last steps in the evaluation process for a new drug, have been recommended to all be RCTs. Nevertheless, single-arm phase 3 trials still appear to be in use. METHODS: We performed a PubMed search to identify the use of a single-arm design in phase 3 trials, excluding only non-English articles. Three categories were distinguished: past use of an RCT, of any other trial design, or no previous trial; and according to diagnosis (oncology, infection, others). RESULTS: A total of 176 single-arm phase 3 trials (19 oncology, 43 infections and 114 others) were identified by the search, with exponential growth since 1994, in parallel with that of RCTs. Among them, 64 (36%) were preceded by an RCT, 58 (33%) by a non-randomized trial, and 54 (31%) had no previous trial, with no main influence of the diagnosis setting. Justification of the design was reported in 30 (18%) of those trials, with ethical concerns comprising one-third of those justifications. This was similar in the 14 single-arm phase 2-3 trials, with about one-third in each group, and 17% justification of a non-comparative design. CONCLUSION: The use of a single-arm phase 3 trial is heterogeneous, ranging from first trials up to confirmatory trials after a previously conducted RCT. Justification for these single-arm designs as confirmatory evidence should be more clearly reported, along with potential sources of bias.

Drug combinations screening using a Bayesian ranking approach based on dose-response models.

Drug combinations have been of increasing interest in recent years for the treatment of complex diseases such as cancer, as they could reduce the risk of drug resistance. Moreover, in oncology, combining drugs may allow tackling tumor heterogeneity. Identifying potent combinations can be an arduous task since exploring the full dose-response matrix of candidate combinations over a large number of drugs is costly and sometimes unfeasible, as the quantity of available biological material is limited and may vary across patients. Our objective was to develop a rank-based screening approach for drug combinations in the setting of limited biological resources. A hierarchical Bayesian 4-parameter log-logistic (4PLL) model was used to estimate dose-response curves of dose-candidate combinations based on a parsimonious experimental design. We computed various activity ranking metrics, such as the area under the dose-response curve and Bliss synergy score, and we used the posterior distributions of ranks and the surface under the cumulative ranking curve to obtain a comprehensive final ranking of combinations. Based on simulations, our proposed method achieved good operating characteristics to identifying the most promising treatments in various scenarios with limited sample sizes and interpatient variability. We illustrate the proposed approach on real data from a combination screening experiment in acute myeloid leukemia.

Identification of the Axis ß-Catenin-BTK in the Dynamic Adhesion of Chronic Lymphocytic Leukemia Cells to Their Microenvironment.

In the microenvironment, cell interactions are established between different cell types to regulate their migration, survival and activation. ß-Catenin is a multifunctional protein that stabilizes cell-cell interactions and regulates cell survival through its transcriptional activity. We used chronic lymphocytic leukemia (CLL) cells as a cellular model to study the role of ß-catenin in regulating the adhesion of tumor cells to their microenvironment, which is necessary for tumor cell survival and accumulation. When co-cultured with a stromal cell line (HS-5), a fraction of the CLL cells adhere to stromal cells in a dynamic fashion regulated by the different levels of ß-catenin expression. In non-adherent cells, ß-catenin is stabilized in the cytosol and translocates into the nucleus, increasing the expression of cyclin D1. In adherent cells, the level of cytosolic ß-catenin is low but membrane ß-catenin helps to stabilize the adhesion of CLL to stromal cells. Indeed, the overexpression of ß-catenin enhances the interaction of CLL with HS-5 cells, suggesting that this protein behaves as a regulator of cell adhesion to the stromal component and of the transcriptional regulation of cell survival. Inhibitors that block the stabilization of ß-catenin alter this equilibrium and effectively disrupt the support that CLL cells receive from the cross-talk with the stroma.

Fragility index of positive phase II and III randomised clinical trials of treatments for hepatocellular carcinoma (2002-2022).

Background & Aims: The fragility index (FI), i.e., theminimum number of best survivors reassigned to the control group required to revert the statistically significant result of a clinical trial to non-significant, is a metric to evaluate the robustness of randomized controlled trials (RCTs). We aimed to assess the FI in the field of HCC. Methods: This is a retrospective analysis of phase 2 and 3 RCTs for the treatment of HCC published between 2002 and 2022. We included two-arm studies with 1:1 randomization and significant positive results for a primary time-to-event endpoint for the FI calculation, which involves the iterative addition of a best survivor from the experimental group to the control group, until positive significance (p <0,05, Log-rank test) is lost. Results: We identified 51 phase 2 and 3 positive RCTs, of which 29 (57%) were eligible for fragility index calculation. After reconstruction of the Kaplan-Meier curves, 25/29 studies remained significant, among which the analysis was performed. The median (interquartile range (IQR)) FI was 5 (2-10) and Fragility Quotient (FQ) was 3% (1%-6%). Ten trials (40%) had a FI of 2 or less. FI was positively correlated to the blind assessment of the primary endpoint (median FI 9 with blind assessment versus 2 without, p = 0.01), the number of reported events in the control arm (RS = 0.45, p = 0.02) and to impact factor (RS = 0.58, p = 0.003). Conclusions: Several phases 2 and 3 RCTs in HCC have a low fragility index, underlying the limited robustness on the conclusion of their superiority over control treatments. The fragility index might provide an additional tool to assess the robustness of clinical trial data in HCC. Impact and implications: The fragility index is a method to assess robustness of a clinical trial and is defined the minimum number of best survivors reassigned to the control group required to revert the statistically significant result of a clinical trial to non-significant. Among 25 randomised controlled trials in HCC, the median fragility index was 5, and 10 trials among 25 (40%) had a fragility index of 2 or less, indicating an important fragility.

A fixed-duration immunochemotherapy approach in CLL: 5.5-year results from the phase 2 ICLL-07 FILO trial.

In previously untreated, medically fit patients with chronic lymphocytic leukemia (CLL), research is focused on developing fixed-duration strategies to improve long-term outcomes while sparing patients from serious toxicities. The ICLL-07 trial evaluated a fixed-duration (15-month) immunochemotherapy approach in which after obinutuzumab-ibrutinib induction for 9 months, patients (n = 10) in complete remission (CR) with bone marrow (BM) measurable residual disease (MRD) <0.01% continued only ibrutinib 420 mg/day for 6 additional months (I arm), whereas the majority (n = 115) received up to 4 cycles of fludarabine/cyclophosphamide-obinutuzumab 1000 mg alongside the ibrutinib (I-FCG arm). Primary analysis at month 16 showed that 84 of 135 (62.2%) patients enrolled achieved CR with a BM MRD <0.01%. Here, we report follow-up at median 63 months. Peripheral blood (PB) MRD was assessed 6 monthly beyond the end of treatment using a highly sensitive (10-6) flow cytometry technique. In the I-FCG arm, the PB MRD <0.01% rate (low-level positive <0.01% or undetectable with limit of detection ≤10-4) in evaluable patients was still 92.5% (74/80) at month 40 and 80.6% (50/62) at month 64. No differences in the PB MRD status were apparent per to the IGHV mutational status. In the overall population, 4-year progression-free and overall survival rates were 95.5% and 96.2%, respectively. Twelve deaths occurred overall. Fourteen serious adverse events occurred beyond the end of treatment. Thus, our fixed-duration immunochemotherapy approach produced deep and sustained PB MRD responses, high survival rates, and low long-term toxicity. A randomized trial is needed to compare our immunochemotherapy approach with a chemotherapy-free strategy. This trial was registered at www.clinicaltrials.gov as #NCT02666898.

Immuno-regulatory malignant B cells contribute to Chronic Lymphocytic Leukemia progression.

Chronic Lymphocytic Leukemia (CLL) is a heterogeneous B cell neoplasm ranging from indolent to rapidly progressive disease. Leukemic cell subsets with regulatory properties evade immune clearance; however, the contribution of such subsets during CLL progression is not completely elucidated. Here, we report that CLL B cells crosstalk with their immune counterparts, notably by promoting the regulatory T (Treg) cell compartment and shaping several helper T (Th) subsets. Among various constitutively- and BCR/CD40-mediated factors secreted, tumour subsets co-express two important immunoregulatory cytokines, IL10 and TGFß1, both associated with a memory B cell phenotype. Neutralizing secreted IL10 or inhibiting the TGFß signalling pathway demonstrated that these cytokines are mainly involved in Th- and Treg differentiation/maintenance. In line with the regulatory subsets, we also demonstrated that a CLL B cell population expresses FOXP3, a marker of regulatory T cells. Analysis of IL10, TGFß1 and FOXP3 positive subpopulations frequencies in CLL samples discriminated 2 clusters of untreated CLL patients that were significantly different in Tregs frequency and time-to-treatment. Since this distinction was pertinent to disease progression, the regulatory profiling provides a new rationale for patient stratification and sheds light on immune dysfunction in CLL.

Patients' Perceived Importance of Medication and Adherence in Polypharmacy, a Quantitative, Cross-Sectional Study Using a Questionnaire Administered in Three Doctors' Private Practices in France.

BACKGROUND: Among the determinants of nonadherence, polypharmacy (common in people with multiple pathologies and especially in elderly patients), plays a major role. OBJECTIVE: In patients who are subject to polypharmacy involving different classes of medications, the first aim is to assess the impact of medication importance given by patients on (i) medication adherence and (ii) the respective effect of intentionality and habit in medication importance and medication adherence. The second objective is to compare the importance given to medication and adherence in the different therapeutic classes. PATIENTS AND METHODS: Patients taking 5-10 different medications for at least 1 month were included in a cross-sectional survey in three private practices in one region in France. RESULTS: This study included 130 patients (59.2 % female) with 851 medications in total. The mean ± standard deviation (SD) age was 70.5 ± 12.2 years. The mean ± SD of medications taken was 6.9 ± 1.7. Treatment adherence had a strong positive correlation with the patient-perceived medication importance (p < 0.001). Counter-intuitively, taking a large number of medications (≥7) was associated with being fully adherent (p = 0.02). A high intentional nonadherence score was negatively associated with high medication importance (p = 0.003). Furthermore, patient-perceived medication importance was positively associated with taking treatment by habit (p = 0.03). Overall nonadherence more strongly correlated with unintentional nonadherence (p < 0.001) than with intentional nonadherence (p = 0.02). Compared to the antihypertensive class, a decrease in adherence by medication was observed in psychoanaleptics (p < 0.0001) and drugs used in diabetes class (p = 0.002), and a decrease in importance in lipid-modifying agents class (p = 0.001) and psychoanaleptics (p < 0.0001). CONCLUSION: The perception of the importance of a medicine is associated with the place of intentionality and habit in patient adherence. Therefore, explaining the importance of a medicine should become an important part of patient education.

Nurselike cells sequester B cells in disorganized lymph nodes in chronic lymphocytic leukemia via alternative production of CCL21.

Tumor microenvironment exerts a critical role in sustaining homing, retention, and survival of chronic lymphocytic leukemia (CLL) cells in secondary lymphoid organs. Such conditions foster immune surveillance escape and resistance to therapies. The physiological microenvironment is rendered tumor permissive by an interplay of chemokines, chemokine receptors, and adhesion molecules as well as by direct interactions between malignant lymphocytes and stromal cells, T cells, and specialized macrophages referred to as nurselike cells (NLCs). To characterize this complex interplay, we investigated the altered architecture on CLL lymph nodes biopsies and observed a dramatic loss of tissue subcompartments and stromal cell networks as compared with nonmalignant lymph nodes. A supplemental high density of CD68+ cells expressing the homeostatic chemokine CCL21 was randomly distributed. Using an imaging flow cytometry approach, CCL21 mRNA and the corresponding protein were observed in single CD68+ NLCs differentiated in vitro from CLL peripheral blood mononuclear cells. The chemokine was sequestered at the NLC membrane, helping capture of CCR7-high-expressing CLL B cells. Inhibiting the CCL21/CCR7 interaction by blocking antibodies or using therapeutic ibrutinib altered the adhesion of leukemic cells. Our results indicate NLCs as providers of an alternative source of CCL21, taking over the physiological task of follicular reticular cells, whose network is deeply altered in CLL lymph nodes. By retaining malignant B cells, CCL21 provides a protective environment for their niching and survival, thus allowing tumor evasion and resistance to treatment. These findings argue for a specific targeting or reeducation of NLCs as a new immunotherapy strategy for this disease.

Humoral response to mRNA anti-COVID-19 vaccines BNT162b2 and mRNA-1273 in patients with chronic lymphocytic leukemia.

Immunocompromised individuals such as patients with chronic lymphocytic leukemia (CLL) are at risk of impaired immune responses to vaccination. The objective of our study was to evaluate severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific antibody responses in patients with CLL after the first, second, and third doses of the BNT162b2 or mRNA-1273 vaccines and after a single dose for patients with confirmed previous COVID-19. In all, 530 patients were included in the study. Patients received 2 doses at a 4-week interval and a third dose if they were seronegative after the second dose. Response rate was 27% after dose 1 and 52% after dose 2. Post-dose 2 treatment-naïve patients had the highest response rate (72%) followed by patients previously treated by chemoimmunotherapy (60%). Among patients receiving therapy, those receiving Bruton tyrosine kinase inhibitor alone (22%) or in combination with anti-CD20 monoclonal antibodies or venetoclax (0%) had the poorer response rate whereas patients who received venetoclax monotherapy achieved a significantly higher response rate (52%). A multivariable analysis identified age older than 65 years, ongoing CLL treatment, and gamma globulin ≤6 g/L as independent predictors of the absence of seroconversion. Post-dose 2 seronegative patients had a global response rate of 35% after dose 3. This study provides an argument for the use of a third dose and for prophylactic SARS-CoV-2 neutralizing monoclonal antibodies.

Of some innovations in clinical trial design in hematology and oncology.

The design of clinical trials, formalized in the immediate post-war period, has undergone major changes due to therapeutic innovations, particularly the arrival of targeted therapies in onco-hematology. The traditional phase I-II-III regimen is regularly questioned and multiple adaptations are proposed. This article proposes to expose some of these modifications and the issues they lead to.

Diagnosis Yield and Safety of Surgical Biopsy in Interstitial Lung Diseases: A Prospective Study.

BACKGROUND: Surgical lung biopsy is essential in the diagnostic algorithm of interstitial lung disease (ILD) of unknown cause. Safety concerns have been recently reiterated. This study prospectively assessed the yield of diagnosis and safety of video-assisted thoracoscopic surgical lung biopsy (VATS-LB) for ILD diagnosis. METHODS: This prospective study, conducted in 6 ILD-referral Paris hospitals, included 103 patients with ILD. VATS-LB was proposed after initial multidisciplinary discussion. A final diagnosis was made after the procedure, during a second multidisciplinary discussion. The main outcome was to determine the final diagnoses and their proportion after VATS-LB. Other outcomes were the percentage of change in diagnosis and treatment propositions after VATS-LB and adverse events during 3 months after the operation, postoperative pulmonary function, quality of life, and pain. RESULTS: A definite diagnosis was reached in 87 patients (84.4%), and 16 remained unclassifiable (15.6%). After VATS-LB, the hypothesized diagnosis changed in 65 patients (63.1%) and treatment changed in 41 patients (39.8%). One patient died of acute exacerbation. In-hospital complications were predicted by a shorter preoperative 6-minute walking test distance and by forced vital capacity lower than 77%. Postoperative quality of life was not modified at 3 months, whereas forced vital capacity decreased slightly. Postoperative neuropathic pain was revealed in 5% of patients at 1 month and in 2% at 3 months. CONCLUSIONS: VATS-LB dramatically changed preoperative hypothetical diagnoses and treatment in ILD of unknown cause, with good patient survival in ILD referral centers.

Frontline treatment in CLL: the case for time-limited treatment.

Over the last decade, the advent of Bruton tyrosine kinase inhibitors (BTKi) has profoundly modified the therapeutic strategy in chronic lymphocytic leukemia (CLL), introducing the concept of treatment until progression. Initially, the bcl-2 inhibitor venetoclax (VEN) was used as a single agent and then was rapidly combined in VEN-based regimens associated with either anti-CD20 or with BTKi. These regimens yielded a high rate of complete remission, leading to their use as a fixed duration treatment. The decision between continuous treatment with BTKi and VEN-based combinations relies mostly on comorbidities, comedications, and patient/physician preferences. Notably, with BTKi, cardiovascular comorbidities, hypertension, and potential pharmacological interactions should be carefully evaluated. On the other hand, the risk of tumor lysis syndrome with VEN should be monitored at treatment initiation. TP53 alteration and IGHV mutational status should also be assessed, as they remain important for therapeutic decisions. Fit patients with a TP53 wild type and IGHV-mutated CLL may still benefit from fludarabine-cyclophosphamide-rituximab chemoimmunotherapy (CIT), as it may result in a very long remission duration. VEN-based treatments are well tolerated, and no additional toxicity has been observed when combined with anti-CD20 or BTKi. The 1-year fixed-duration association of VEN plus obinutuzumab was evaluated in frontline for older adult patients. Nonetheless, considering the favorable outcome, an extension of indication for fit younger patients is expected. The association of VEN and BTKi is promising, even if the follow-up is still short. It is currently being tested against CIT, BTKi continuous treatment, and VEN plus anti-CD20.

Bayesian survival analysis for early detection of treatment effects in phase 3 clinical trials.

Despite appealing characteristics for the clinical trials setting, Bayesian inference methods remain scarcely used, especially in randomized controlled clinical trials (RCT). This is particularly true when dealing with a survival endpoint, likely due to the additional complexities to model specifications. We propose to use Bayesian inference to estimate the treatment effect in this setting, using a proportional hazards (PH) model for right-censored data. Implementation of such an estimation process is illustrated on two working examples from cancer RCTs, the ALLOZITHRO and the CLL7-SA trials, both originally analyzed using a frequentist approach. In these two different settings, we show that Bayesian sequential analyses can provide early insight on treatment effect in RCTs. Relying on posterior distributions and predictive posterior probabilities, we find that Bayesian sequential analyses of the ALLOZITHRO trial, which was terminated early due to an unanticipated deleterious effect of the intervention on survival, allow quantifying early that the treatment effect was opposite to what was expected. Then, incorporating historical data in the sequential analyses of the CLL7-SA trial would have allowed the treatment effect to be closer to the protocol hypothesis. These post-hoc results give grounds to advocate for a wider use of Bayesian approaches in RCTs, including those with right-censored endpoints, as informative decision tools.

Treating secondary antibody deficiency in patients with haematological malignancy: European expert consensus.

OBJECTIVES: Secondary antibody deficiency (SAD), associated with severe, recurrent or persistent infections, is common in patients with haematological malignancies (HM), but unifying guidance on immunoglobulin replacement therapy (IgRT) in these patients is lacking. We aimed to develop consensus statements for the use of IgRT in patients with HM. METHODS: A Delphi exercise was employed to test the level of agreement on statements developed by a Task Force based on available data and their clinical experience. In Round 1, an Expert Panel, comprising specialist EU physicians caring for patients with HM, helped to refine the statements. In Round 2, experts rated their agreement with the statements. In Round 3, experts who had scored their agreement as ≤4 were invited to review their agreement based on the overall feedback. RESULTS: Three definitions and 20 statements were formulated and tested for consensus, covering measurement of IgG levels, initiation and discontinuation of IgRT, dosing, and the use of subcutaneous IgG. Consensus (agreement ≥70% on Likert-type scale) was reached for all three definitions and 18 statements. CONCLUSIONS: Recommendations have been developed with the aim of providing guidance for the use of IgRT to prevent severe, recurrent or persistent infections in patients with HM and SAD.

Prognostic value of high-sensitivity measurable residual disease assessment after front-line chemoimmunotherapy in chronic lymphocytic leukemia.

Measurable residual disease (MRD) status is widely adopted in clinical trials in patients with chronic lymphocytic leukemia (CLL). Findings from FILO group trials (CLL2007FMP, CLL2007SA, CLL2010FMP) enabled investigation of the prognostic value of high-sensitivity (0.7 × 10-5) MRD assessment using flow cytometry, in blood (N = 401) and bone marrow (N = 339), after fludarabine, cyclophosphamide, and rituximab (FCR)-based chemoimmunotherapy in a homogeneous population with long follow-up (median 49.5 months). Addition of low-level positive MRD < 0.01% to MRD ≥ 0.01% increased the proportion of cases with positive MRD in blood by 39% and in bone marrow by 27%. Compared to low-level positive MRD < 0.01%, undetectable MRD was associated with significantly longer progression-free survival (PFS) when using blood (72.2 versus 42.7 months; hazard ratio 0.40, p = 0.0003), but not when using bone marrow. Upon further stratification, positive blood MRD at any level, compared to undetectable blood MRD, was associated with shorter PFS irrespective of clinical complete or partial remission, and a lower 5-year PFS rate irrespective of IGHV-mutated or -unmutated status (all p < 0.05). In conclusion, high-sensitivity (0.0007%) MRD assessment in blood yielded additional prognostic information beyond the current standard sensitivity (0.01%). Our approach provides a model for future determination of the optimal MRD investigative strategy for any regimen.

A fixed-duration, measurable residual disease-guided approach in CLL: follow-up data from the phase 2 ICLL-07 FILO trial.

Trials assessing first-line, fixed-duration approaches in chronic lymphocytic leukemia (CLL) are yielding promising activity, but few long-term data are available. We report follow-up data from a phase 2 trial (ICLL07 FILO) in previously untreated, medically fit patients (N = 135). Patients underwent obinutuzumab-ibrutinib induction for 9 months; then, following evaluation (N = 130 evaluable), those in complete remission and with bone marrow measurable residual disease (BM MRD) <0.01% (n = 10) received ibrutinib for 6 additional months; those in partial remission and/or with BM MRD ≥0.01%, the majority (n = 120), also received 4 cycles of immunochemotherapy (fludarabine/cyclophosphamide-obinutuzumab). Beyond end of treatment, responses were assessed every 3 month and peripheral blood MRD every 6 months. At median follow-up 36.7 months from treatment start, progression-free and overall survival rates (95% confidence interval) at 3 years were 95.7% (92.0% to 99.5%) and 98% (95.1% to 100%), respectively. Peripheral blood MRD <0.01% rates were 97%, 96%, 90%, 84%, and 89% at months 16, 22, 28, 34, and 40, respectively. No new treatment-related or serious adverse event occurred beyond end of treatment. Thus, in previously untreated, medically fit patients with CLL, a fixed-duration (15 months), MRD-guided approach achieved high survival rates, a persistent MRD benefit beyond the end of treatment, and low long-term toxicity. This trial was registered at www.clinicaltrials.gov as #NCT02666898.

Diagnosis and Treatment of Chronic Lymphocytic Leukemia: Recommendations of the French CLL Study Group (FILO).

As a result of significant recent developments, the management of patients with chronic lymphocytic leukemia (CLL) is changing, and new therapeutic options will continue to emerge in the near future. The recommendations of the French Innovative Leukemia Organization (FILO-CLL) group presented here are intended to provide practical recommendations for physicians taking care of CLL patients, taking into account the availability of both biological tests and therapies in daily practice in France at the time of publication. This text details the documented information and guidelines on diagnosis, indications for treatment, infectious complications and therapeutic strategies in frontline and relapsed CLL as well as in particular conditions such as autoimmune cytopenia or Richter syndrome.

Effect of chemoprevention by low-dose aspirin of new or recurrent colorectal adenomas in patients with Lynch syndrome (AAS-Lynch): study protocol for a multicenter, double-blind, placebo-controlled randomized controlled trial.

Lynch syndrome (LS) is the most common cause of inherited colorectal cancer (CRC) and confers a high lifetime risk of CRC estimated to be up to 60%. Colonoscopy is recommended every 2 years in LS patients above the 20-25-year-old age bracket, and every year when colonic neoplasia has been detected. Efficient chemoprevention has the potential to represent a cost-effective intervention in these high-risk patients and could allow a delay in colonoscopy surveillance. Several epidemiological studies have shown that regular use of low dose aspirin is associated with a 20 to 30% reduction in the risk of sporadic colonic adenomas and colorectal cancer regardless of family risk. However, in recent large randomized trials in specific populations, aspirin use showed no protection for colorectal cancer. A prospective randomized CAPP-2 trial evaluated the effect of aspirin use in LS patients. The primary analysis of this trial showed no significant decrease in CRC in LS patients under daily aspirin. However, a preplanned secondary analysis after an extended follow-up showed a significant reduced risk of CRC in the aspirin group in the per-protocol analysis. The real effect and clinical benefit of aspirin are still to be consolidated in this population. The AAS-Lynch trial-a prospective, multicentric, double-blind, placebo-controlled, randomized clinical trial-was designed to investigate if daily aspirin therapy, at a dose of 100 or 300 mg, would decrease the occurrence or recurrence of colorectal adenomas in patients under 75 years of age, compared with placebo. TRIAL REGISTRATION: ClinicalTrials.gov NCT02813824 . Registered on 27 June 2016. The trial was prospectively registered.