Adverse Events In Trials Research Articles

Adverse Events Reported in Trials Assessing Manual Therapy to the Extremities: A Systematic Review.

Objective: This review aimed to describe the quality and comprehensiveness of adverse event (AE) reporting in clinical trials incorporating manual therapy (MT) as an intervention for extremity conditions using the Consolidated Standards of Reporting Trials (CONSORT)-Harms extension as the benchmark. The secondary aim was to determine whether the quality of AE reporting improved after the availability of the CONSORT reporting checklist. Design: Systematic review. Methods: A literature search was conducted using multiple databases to identify trials where MT was used to treat extremity conditions. Studies that reported AEs were identified and evaluated using the CONSORT-Harms extension. The frequency of trials reporting study AEs before and after the publication of the updated 2010 CONSORT statement was calculated, along with the categorization of how study AEs were reported. Results: Of the 55,539 studies initially identified, 220 trials met all inclusion criteria. Eighty trials (36.4%) reported AE occurrence. None of the studies that reported AEs adhered to all 10 criteria proposed by the 2010 CONSORT-Harms extension. The most commonly reported criterion was number four, which clarified how AE-related information was collected (30% of trials). The least reported criterion was number six, which describes the participant withdrawals for each arm due to AEs and the experience with the allocated treatment (1.3% of trials). The nomenclature used to describe AEs varied substantially. Fifty-nine of 76 trials (33.3%) were published after the updated CONSORT Harms-checklist was available, compared to 21 of 44 trials (46.7%) published before it was available. Conclusion: Reporting of AEs in trials investigating MT for extremity conditions is poor. Every included trial lacked adherence to all 10 criteria proposed by the CONSORT-Harms Extension. The quality and comprehensiveness of AE reporting did not improve after the most recent CONSORT update recommending AE reporting. Clinicians must obtain informed consent before performing any intervention, including MT, which requires disclosing potential risks, which could be better known with improved tracking, analyzing, and reporting of AEs. The authors recommend improved adherence to best practices for adequately tracking and reporting AEs in future MT trials.

P974 Incidence of Perianal Complications in Clinical Trials for Therapies for Moderate to Severe Inflammatory Bowel Disease

Abstract Background Crohn’s disease (CD) and ulcerative colitis (UC) are chronic inflammatory bowel diseases (IBDs) with distinct clinical consequences. Distinct from patients with UC is that nearly 25% of patients with CD patients have or will develop perianal disease. Predictors for the development of new perianal disease or complications from existing perianal disease are not well described but such occurrences are included as adverse events (AEs) in clinical trials for IBD. We performed a systematic review and meta-analysis of perianal AEs in pivotal trials of therapies for IBD. Methods We conducted a search of PubMed, EMBASE, MEDLINE, Medline Plus, and CDSR library databases for registry and pivotal Phase II-III clinical trials of therapies for IBD. Safety data from clinicaltrials.gov was reviewed to identify incidence of perianal AEs using the terms "abscess" and "fistula." Reported perianal AEs included the following: anal abscess, fissure, fistula; perianal abscess, fistula; perineal abscess; perirectal and rectal abscess; subcutaneous (gluteal) abscess. Results Perianal AE incidence across all trials reviewed was 0.47% (91/19,327 patients). Perianal AEs were more likely to occur in patients with CD (0.77%, 70/9,046) than UC (0.20%, 21/10,281). Perianal AEs occurred more frequently in populations of drug-exposed patients than in patients exposed to placebo. In drug-exposed patients with UC, 0.22% (16/7,415) of patients experienced a perianal AE vs 0.17% (5/2,935) of patients exposed to placebo. In drug-exposed patients with CD, 0.76% (55/7,271) of patients experienced a perianal AE vs 0.61% (15/2,465) of patients exposed to placebo. The results are summarized in Table 1. Conclusion We found that perianal AEs occur in pivotal UC and CD clinical trials. Expectedly, the frequency of perianal AEs was higher in trials of CD than those for UC. However, the development of perianal AEs in trials of UC suggests that these patients may have been misclassified and have CD. Available data do not allow distinction between development of a perianal AE in a patient with known perianal disease or progression of undiagnosed clinical or subclinical perianal disease, nor does it allow for distinction in a patient not responding to the experimental agent. The finding that perianal AEs occurred more frequently with drug exposure than placebo may be due to fistula healing with consequential abscess formation or unique mechanistic effects that worsen perianal disease. These results highlight a probable rate of misclassification of patients with UC in pivotal trials, and suggest the possibility of subclinical perianal disease in some patients. Further clarification and study of these AEs and their implications are warranted.

Identifying and Categorizing Adverse Events in Trials of Digital Mental Health Interventions: Narrative Scoping Review of Trials in the International Standard Randomized Controlled Trial Number Registry.

To contextualize the benefits of an intervention, it is important that adverse events (AEs) are reported. This is potentially difficult in trials of digital mental health interventions, where delivery may be remote and the mechanisms of actions less understood. We aimed to explore the reporting of AEs in randomized controlled trials of digital mental health interventions. The International Standard Randomized Controlled Trial Number database was searched for trials registered before May 2022. Using advanced search filters, we identified 2546 trials in the category of mental and behavioral disorders. These trials were independently reviewed by 2 researchers against the eligibility criteria. Trials were included where digital mental health interventions for participants with a mental health disorder were evaluated through a completed randomized controlled trial (protocol and primary results publication published). Published protocols and primary results publications were then retrieved. Data were extracted independently by 3 researchers, with discussion to reach consensus when required. Twenty-three trials met the eligibility criteria, of which 16 (69%) included a statement on AEs within a publication, but only 6 (26%) reported AEs within their primary results publication. Seriousness was referred to by 6 trials, relatedness by 4, and expectedness by 2. More interventions delivered with human support (9/11, 82%) than those with only remote or no support (6/12, 50%) included a statement on AEs, but they did not report more AEs. Several reasons for participant dropout were identified by trials that did not report AEs, of which some were identifiable or related to AEs, including serious AEs. There is significant variation in the reporting of AEs in trials of digital mental health interventions. This variation may reflect limited reporting processes and difficulty recognizing AEs related to digital mental health interventions. There is a need to develop guidelines specifically for these trials to improve future reporting.

Hopes for Antisense Oligonucleotides Remain Strong Despite Severe Adverse Events in Trials

Hopes for Antisense Oligonucleotides Remain Strong Despite Severe Adverse Events in Trials

Risk of Toxicity with Immunotherapy–Tyrosine Kinase Inhibitors for Metastatic Renal Cell Carcinoma: A Meta-Analysis of Randomized Controlled Trials

Aim: Few data are available regarding the safety profile of immunotherapy-tyrosine kinase inhibitor (IO-TKI) combinations in metastatic renal cell carcinoma. The authors investigated all-grade and grade 3-4 (G3-4) adverse events in trials comparing IO-TKI combinations with sunitinib monotherapy. Methods: The relative risks of several all-grade and G3-4 adverse events were analyzed. Results: Relative risks were similar between patients receiving IO-TKI combinations versus sunitinib monotherapy. However, the use of IO-TKI combinations was associated with a higher risk of all-grade and G3-4 diarrhea, all-grade hypothyroidism, G3-4 decreased appetite, all-grade and G3-4 aspartate transaminase increase and all-grade and G3-4 alanine transaminase increase. Conclusion: The results of the authors' meta-analysis suggest that risks of treatment-related adverse events should be carefully considered when choosing IO-TKI combinations in metastatic renal cell carcinoma patients.

Adverse events in trials of licensed drugs for irritable bowel syndrome with constipation or diarrhea: Systematic review and meta-analysis.

Nocebo effects occurring in patients receiving placebo frequently impact on adverse events reported in randomized controlled trials (RCTs) in irritable bowel syndrome (IBS). Therefore, we conducted a systematic review and meta-analysis to assess the proportion of patients randomized to placebo or active drug experiencing any adverse event in trials of licensed drugs for IBS with constipation (IBS-C) or diarrhea (IBS-D), and to estimate the risk of developing adverse events among patients randomized to placebo. We searched MEDLINE, EMBASE CLASSIC and EMBASE, and the Cochrane central register of controlled trials (through June 2021) to identify RCTs comparing licensed drugs with placebo in adults with IBS-C or IBS-D. We generated Forest plots of pooled adverse event rates in both active drug and placebo arms and pooled risk differences (RDs) with 95% confidence intervals (CIs). There were 21 RCTs of licensed drugs versus placebo in IBS-C (5953 patients placebo) and 17 in IBS-D (3854 patients placebo). Overall, 34.9% and 46.9% of placebo patients in IBS-C and IBS-D trials, respectively, developed at least one adverse event, with a statistically significantly higher risk of any adverse event and withdrawal due to an adverse event with active drug. In IBS-C and IBS-D trials, rates of each individual adverse event were generally higher with active drug. However, in IBS-C trials, only diarrhea or headache was significantly more common with active drug (RD 0.066 (95% CI 0.043-0.088) and RD 0.011 (95% CI 0.002-0.021), respectively), and in IBS-D trials only constipation, nausea, or abdominal pain (RD 0.096 (95% CI 0.054-0.138), 0.014 (95% CI 0.002-0.027), and 0.018 (95% CI 0.002-0.034), respectively). Patients with IBS randomized to placebo have a high risk of reporting adverse events, which might relate to both nocebo and non-nocebo factors. Although patients' expectations and psychosocial factors may be involved, further understanding of the mechanisms are important to control or optimize these effects in RCTs, as well as in clinical practice.

Regular treatment with formoterol and an inhaled corticosteroid versus regular treatment with salmeterol and an inhaled corticosteroid for chronic asthma: serious adverse events.

Regular treatment with formoterol and an inhaled corticosteroid versus regular treatment with salmeterol and an inhaled corticosteroid for chronic asthma: serious adverse events.

Synopses of Cochrane Reviews from Cochrane Library Issue 12 2020 Through Issue 3 2021.

Synopses of Cochrane Reviews from Cochrane Library Issue 12 2020 Through Issue 3 2021.

Serious adverse events in trials evaluating biologics in psoriasis

Serious adverse events in trials evaluating biologics in psoriasis

Online monitoring of patient self-reported adverse events in early phase clinical trials: Views from patients, clinicians, and trial staff.

Background/aimsNew classes of cancer drugs bring a range of unknown and undesirable adverse events. Adverse event monitoring is essential in phase I trials to assess toxicity and safety. In phase II, the focus is also on efficacy but robust data on adverse events continue to inform the safety and the adverse event profile. Standard, clinician-led monitoring has been shown to underestimate patients’ symptoms. Hence, patient-reported adverse event monitoring has been argued to complement and improve the information on adverse events in early phase clinical trials. With advances in information technology, real-time patient self-reported adverse events in trials are feasible. This study explored the experiences and procedures for reporting adverse events in early phase trials among patients, clinical staff, and trial staff, and their views on using an electronic patient-reported outcome adverse event system in this setting.MethodsQualitative interviews were conducted with patients, purposively sampled across ages, gender, and different phases of trials, and with clinical and trial-related staff involved in early phase trials (e.g. consultants, research nurses, hospital-based trial assistants/data managers, trial unit management staff). Interviews explored patient experiences and views on current adverse event reporting processes and electronic patient-reported outcome adverse event reporting. Framework analysis techniques were used to analyse the data.ResultsInterviewees were from two hospital trusts with early phase portfolios in England and a trial unit, and included sixteen patients, five consultants, four research nurses, five hospital-based trial staff, and two trial unit staff. Interviews identified three key themes (patient experiences, data flow, and views on electronic patient-reported outcome adverse event reporting). Stakeholders emphasised the intensity of trials for patients and the importance of extensive information provision within the uncertainty of early phase trial drugs. Regular face-to-face appointments for patients supplemented by telephone contact aimed to capture any adverse events. Delayed or under-reporting of mild- or low-severity symptoms was evident among patients. Hospital-based staff highlighted the challenges of current data collection including intense timescales, monitoring by trial sponsors, and high workload. Positive views on electronic patient-reported outcome adverse events highlighted that this could provide a more comprehensive and accurate view on the side effects of new drugs. Clinical staff emphasised patient safety and the need for clear responsibilities for monitoring. The need for careful decision-making about data flow and symptom attribution was highlighted; with trial unit staff emphasising the need for clinician review.ConclusionTechnology advances mean it is timely to explore the benefits and challenges of electronic patient-reported outcome adverse event reporting. This is a complex area warranting further consideration within the trial community. We have developed an online patient self-reporting tool and a small pilot with early phase trial patients is underway.

Progressive resistance training for adolescents with cerebral palsy: the STAR randomized controlled trial.

To evaluate the effect of progressive resistance training of the ankle plantarflexors on gait efficiency, activity, and participation in adolescents with cerebral palsy (CP). Sixty-four adolescents (10-19y; 27 females, 37 males; Gross Motor Function Classification System [GMFCS] levels I-III) were randomized to 30 sessions of resistance training (10 supervised and 20 unsupervised home sessions) over 10 weeks or usual care. The primary outcome was gait efficiency indicated by net nondimensional oxygen cost (NNcost). Secondary outcomes included physical activity, gross motor function, participation, muscle strength, muscle and tendon size, and muscle and tendon stiffness. Analysis was intention-to-treat. Median attendance at the 10 supervised sessions was 80% (range 40-100%). There was no between-group difference in NNcost at 10 (mean difference: 0.02, 95% confidence interval [CI] -0.07 to 0.11, p=0.696) or 22 weeks (mean difference: -0.08, 95% CI -0.18 to 0.03, p=0.158). There was also no evidence of between-group differences in secondary outcomes at 10 or 22 weeks. There were 123 adverse events reported by 27 participants in the resistance training group. We found that 10 supervised sessions and 20 home sessions of progressive resistance training of the ankle plantarflexors did not improve gait efficiency, muscle strength, activity, participation, or any biomechanical outcome among adolescents with CP. Thirty sessions of progressive resistance training of the ankle plantarflexors over 10 weeks did not improve gait efficiency among ambulatory adolescents with cerebral palsy. Resistance training did not improve muscle strength, activity, or participation. Ninety percent of participants experienced an adverse event. Most adverse events were expected and no serious adverse events were reported.

Systematic Review of adverse events reporting in clinical trials leading to approval of targeted therapy and immunotherapy.

Aim: Reporting toxicities of targeted therapies(TTs) and immunotherapy in oncology requires special attention. Materials & methods: We identified TTs and immunotherapies approved by the US FDA for solid malignancies in the adult population. Publications were reviewed according to a 24-point score based on the Consolidated Standards of Reporting Trials guidance. Results: We identified 81 trials (>45,000 patients). The experimental drug was studied as single agent in 51% of the cases; setting of disease was mainly (95%) advanced/metastatic. Lowest scores in adverse event (AE) description regarded: reporting recurrent/late toxicities and duration of the AEs (>90%), time of occurrence and indication of all-grade AEs (>75%). Conclusion: Suboptimal reporting of AEs in trials leading to approval of TTs and immunotherapy was shown. Improving AE descriptions should be a priority in ongoing trials.

Novel Antiatherosclerotic Therapies.

Many measures can control lipid risk factors for atherosclerosis. Yet, even with excellent control of dyslipidemia, other sources of risk remain. Hence, we must look beyond lipids to address residual risk. Lifestyle measures should form the foundation of cardiovascular risk control. Many pharmacological interventions targeting oxidation have proven disappointing. A large program tested inhibition of a LpPLA2 (lipoprotein-associated phospholipase A2), culminating in 2 large-scale clinical trials that did not meet their primary end points. A variety of antioxidants have not shown benefit in clinical trials. Numerous laboratory and clinical studies have inculpated inflammatory pathways in the pathogenesis of atherosclerotic events. The p38 MAPK (mitogen-activated protein kinase) inhibitor losmapimod and an inhibitor of a leukocyte adhesion molecule, P-selectin, did not alter adverse events in trials. Low-dose methotrexate, despite the promising observational studies, did not lower biomarkers of inflammation or alter cardiovascular outcomes in the CIRT (cardiovascular inflammation reduction trial). Four large-scale investigations underway will determine colchicine's ability to reduce recurrent events in secondary prevention. The CANTOS (Canakinumab Anti-inflammatory Thrombosis Outcomes Study) showed that an antibody that neutralizes IL (interleukin)-1β can reduce recurrent cardiovascular events in secondary prevention. The success of CANTOS points to the pathway that leads from the NLRP3 (NOD-like receptor family, pyrin domain-containing protein 3) inflammasome through IL-1β to IL-6 as an attractive target for further study and clinical development beyond lipid therapies to address the unacceptable burden of risk that remains despite our best current care in secondary prevention.

Comparison of effect sizes between enriched and nonenriched trials of analgesics for chronic musculoskeletal pain: a systematic review.

To investigate the use of an enriched study design on the estimates of treatment effect in analgesic trials for chronic musculoskeletal pain. Database searches were conducted from 2004 to 2014. We included randomized placebo-controlled trials evaluating pain medications for chronic musculoskeletal pain. Methodological quality was assessed using the PEDro scale. The estimates of treatment effect on pain and adverse events were compared between enriched and nonenriched designs. Metaregression was used to assess the association between the effect size estimate and the study design controlling for analgesic dose and methodological quality. We included 108 trials, of which 99 were included in the meta-analysis (n=44 171). There were no overall differences in effect sizes between enriched and nonenriched designs for pain intensity. There was a significant difference for a reduction in any adverse events favouring enriched designs for opioids, but not for other analgesics or the outcome serious adverse events. There was an association between effect size and methodological quality, with failure to blind the outcome assessor and failure to use intention-to-treat analysis being associated with larger effect sizes. There is no evidence that the use of an enriched study design changes the treatment effect size estimate for pain. There is some evidence that clinical trials that employ enriched designs report a reduced risk of adverse events in trials for chronic musculoskeletal pain, but it is unclear whether enriched designs influence estimates of serious adverse events. Features of trial design and study quality were associated with treatment effect estimates.

Completeness of reporting of adverse events in trials of maintenance immunosuppression in kidney transplantation: a systematic review

Decision-making regarding immunosuppression after transplantation relies on robust evidence on the benefits and harms of available drugs. We aimed to evaluate the reporting of adverse events (AEs) in trials of maintenance immunosuppression in kidney transplantation. We conducted a systematic review of published randomized controlled trials of maintenance immunosuppression following kidney transplantation in the Cochrane Kidney and Transplant Register (January 2003-December 2015). Appraisal against the 23-item harms extension of the Consolidated Standards of Reporting Trials statement was conducted. Of 233 trials, 163 (69%) reported at least one AE. Only 17 (10%) provided definitions or justified the AEs, 13 (8%) described methods and 27 (17%) measured severity. Forty AE types were reported, with gastrointestinal being the most common [116 (71%)]. The frequency of reporting did not reflect known drug side-effect profiles. For example, of 90 calcineurin inhibitor trials, only 22% reported tremors, 3% paresthesia and none anxiety, aggression or mood swings. Trials that reported at least one adverse effect were more likely to be industry funded {adjusted odds ratio [OR] 7.6 [95% confidence interval (CI) 3.4-17.1]}, multicenter [OR 5.9 (95% CI 1.7-18.7)] and with follow-up time <24 months [OR 3.7 (95% CI 1.4-10.2)]. AEs in kidney transplant immunosuppression trials appear to be selectively reported and may be unreliable for clinical decisions. Adherence to the Consolidated Standards of Reporting Trials harms extension should be mandatory to ensure transparent reporting of AEs that are important to patients and clinicians.

S11 - Systematic review of adverse events reporting in clinical trials leading to approval of targeted therapy and immunotherapy

Background: Reporting toxicities of targeted therapies(TTs) and immunotherapy in oncology requires care in respect to way of measurement, duration of adverse events (AEs) and impact on treatment dose intensity. New drugs are approved by regulatory agencies on the basis of the safety and efficacy results deriving frompivotal trials, but the impact on broader use is often misunderstood. Methods: We identified the TTs and immunotherapies approved by FDA for solid malignancies in adult patients from 2000 to Oct 2015. The trials which led to this indication were retrieved from the FDA website. Publications were reviewed according to a 24-point score based on the Consolidated Standards of Reporting Trials (CONSORT) guidance. Results: We identified 81 trials, mainly performed in colorectal, lung, breast cancer and melanoma, globally involving more than 45.000 patients. The experimental drug was studied as single agent in 51% of the cases and associated with chemotherapy in 32%; setting of trials was mainly thetreatment of advanced disease (95% of the trials). When specified, the median rate of elderly population (> 65 years) who were treated was 37%. The items that reported the higher proportion of trials with a low score in AEs description are the following: reporting recurrent and late toxicities and duration of the AEs (in more than 90% of the trials); description of time of occurrence (86% of the trials) and indication of all AEs, instead of only those occurred with a frequency above a fixed threshold (75% of the trials). Limitations in methods for presenting AEs, in description of the toxicities leading to therapy withdrawal and in follow up interval assessment were present in more than 50% of the analysed papers. Dose reductions due to AEs were not reported in 1 out of 3 trials. Conclusions: Suboptimal reporting of AEs in trials leading to approval of TTs and immunotherapy was shown. Improving AEs caption and description should be a priority in ongoing trials as well as post-marketing safety analysis. This is particularly true for AEs of new drugs, frequently mild or moderate in severity but potentially longer in duration and recurrent, with a clear impact on patients'quality of life.

Changes in Neuropsychiatric Inventory Associated with Semagacestat Treatment ofAlzheimer's Disease.

In a recent report, 76 weeks' treatment with a gamma-secretase inhibitor (semagacestat) was associated with poorer cognitive outcomes in Alzheimer's disease (AD). We sought to examine the effect of semagacestat treatment on neuropsychiatric symptoms (NPS). 1,537 participants with mild to moderate AD were randomized to 76 weeks' treatment with placebo versus two doses of semagacestat. NPS were assessed with the Neuropsychiatric Inventory (NPI-Total and subdomains). Cognition was assessed with the Alzheimer's Disease Assessment Scale-Cognitive (first 11 items, ADAS11). Mixed-Model Repeated Measures was used to compare the effects of treatment assignment on change in NPI-total and subdomains over time. Survival analysis was used to assess the treatment effect on time to first worsening of NPS (NPI-Total ≥10 or NPI subdomain ≥4) for subjects with no or minor NPS at baseline. Participants on high dose semagecestat (140 mg) had greater increase in NPI-Total and greater risk of incident first worsening in NPI-Total and in subdomains of aberrant motor behavior, appetite, depression/dysphoria, and sleep. ADAS11 increased more in participants whose NPI-Total increased. In participants with mild to moderate AD, high dose semagacestat treatment was associated with greater severity and faster worsening of NPS in a pattern resembling an agitated depression. Increased NPS was associated with cognitive decline regardless of treatment assignment. These findings suggest that greater NPS may be the result of gamma-secretase treatment and emphasize the importance of monitoring NPS as potential adverse events in trials of novel treatments for AD.

Falls as Adverse Events in Psychosocial Treatment of Depression: Findings from a Clinical Trial in Nursing Homes.

Falls pose a significant health risk for nursing home residents and are associated with depression and medical treatments for depression. Data on falls as an adverse event to psychosocial treatments are lacking. We examined risk of falls as an adverse event in a clinical trial of a behavioral treatment for depression. Participants were 82 depressed nursing home residents. Adverse events were recorded at each research contact. We used the rate ratio based on the respective incidence densities in the treatment and control groups to measure association between fall rate and treatment. The treatment group had almost six times higher risk of falls than the control group, a statistically significant association. Findings suggest that it may be of value to include statistical analysis of falls as adverse events in trials of behavioral interventions for depression.

Statin tolerability: In defence of placebo-controlled trials.

BackgroundStatin intolerance is a barrier to effective lipid-lowering treatment. A significant number of patients stop prescribed statins, or can take only a reduced dose, because of adverse events attributed to the statin, and are then considered statin-intolerant.MethodsExamination of differences between statin and placebo in withdrawal rates due to adverse events – a good measure of tolerability – in statin cardiovascular outcome trials in patients with advanced disease and complex medical histories, who may be more vulnerable to adverse effects. The arguments commonly used to dismiss safety and tolerability data in statin clinical trials are examined.ResultsRates of withdrawal due to adverse events in trials in patients with advanced disease and complex medical histories are consistently similar in the statin and placebo groups. We find no support for arguments that statin cardiovascular outcome trials do not translate to clinical practice.ConclusionsGiven the absence of any signal of intolerance in clinical trials, it appears that statin intolerance in the clinic is commonly due to the nocebo effect causing patients to attribute background symptoms to the statin. Consistent with this, over 90% of patients who have stopped treatment because of an adverse event can tolerate a statin if re-challenged. Consequently, new agents, including monoclonal antibodies to proprotein convertase subtilisin/kexin type 9, will be useful when added to statin therapy but should rarely be used as a statin substitute.

Safety Profile of Subjects Treated to Very Low Low-Density Lipoprotein Cholesterol Levels (

Recent US guidelines expand the indications for high-intensity statin therapy, yet data on the safety of attaining very low-density lipoprotein cholesterol (LDL-C) levels are scarce. Among 16,304 participants in the Justification for the Use of Statins in Prevention: An Intervention Trial Evaluating Rosuvastatin (JUPITER) with on-treatment LDL-C levels, we identified 767 who did and 7,387 who did not achieve LDL-C <30 mg/dl on rosuvastatin 20 mg daily and 718 participants who did and 7,436 who did not achieve LDL-C reductions of ≥70% on rosuvastatin, and 8,150 allocated to placebo. In participants with an LDL-C <30 mg/dl, we observed an increase in the risk of physician-reported type 2 diabetes with an adjusted hazard ratio (95% confidence interval) of 1.56 (1.09 to 2.23, p = 0.01) and physician-reported hematuria (hazard ratio 2.10 [1.39 to 3.19], p <0.001) compared with rosuvastatin-treated participants with LDL-C ≥30 mg/dl. There was also an increased risk of certain musculoskeletal, hepatobiliary, and psychiatric disorders. No difference in renal failure, cancer, memory impairment, or hemorrhagic stroke was observed, although there were few events in these categories. In rosuvastatin-treated participants, achieving LDL-C reduction ≥70% versus <70% did not appear to be associated with increased risk of hepatobiliary, renal, or urinary disorders. In conclusion, in this post hoc analysis in the JUPITER, achieving LDL-C levels <30 mg/dl with high-intensity statin therapy appeared to be generally well tolerated but associated with certain adverse events, including more physician-reported diabetes, hematuria, hepatobiliary disorders, and insomnia. These data may guide the monitoring of patients on intensive statin therapy and adverse events in trials of therapies that lead to very low LDL-C levels.