Power and sample sizes estimation in clinical trials with treatment switching in intention-to-treat analysis: a simulation study.

BACKGROUND: Treatment switching, also called crossover, is common in clinical trials because of ethical concerns or other reasons. When it occurs and the primary objective is to identify treatment effects, the most widely used intention-to-treat analysis may lead to underpowered trials. Here, we presented an approach to preview power reductions and to estimate sample sizes required to achieve the desired power when treatment switching occurs in the intention-to-treat analysis. METHODS: We proposed a simulation-based approach and developed an R package to perform power and sample sizes estimation in clinical trials with treatment switching. RESULTS: We simulated a number of randomized trials incorporating treatment switching and investigated the impact of the relative effectiveness of the experimental treatment to the control, the switching probability, the switching time, and the deviation between the assumed and the real distributions for the survival time on power reductions and sample sizes estimation. The switching probability and the switching time are key determinants for significant power decreasing and thus sample sizes surging to maintain the desired power. The sample sizes required in randomized trials absence of treatment switching vary from around four-fifths to one-seventh of the sample sizes required in randomized trials allowing treatment switching as the switching probability increases. The power reductions and sample sizes increase with the decrease of switching time. CONCLUSIONS: The simulation-based approach not only provides a preview for power declining but also calculates the required sample size to achieve an expected power in the intention-to-treat analysis when treatment switching occurs. It will provide researchers and clinicians with useful information before randomized controlled trials are conducted.

Long-term efficacy of meaning-centered group psychotherapy for cancer survivors: 2-Year follow-up results of a randomized controlled trial.

OBJECTIVE: Meaning-centered group psychotherapy for cancer survivors (MCGP-CS) is an effective intervention to improve personal meaning, psychological well-being, and depressive symptoms until 6 months after the intervention. In this study, the long-term effects of MCGP-CS (i.e., at 1- and 2-year follow-up) on meaning, psychological well-being and posttraumatic growth were assessed, in comparison to supportive group psychotherapy (SGP) and care as usual (CAU). METHODS: Cancer survivors (n = 170) were randomized into MCGP-CS, SGP, or CAU. Assessments were scheduled at baseline, 1 week, 3 months, 6 months, 1 year, and 2 years postintervention. Outcome measures were the Personal Meaning Profile, Ryff's Scales of Psychological Well-Being (SPWB), the Posttraumatic Growth Inventory, and their subscales. Linear mixed models (LMM) were used and results were both reported on an intention-to-treat (ITT) basis, as well as for intervention completers only. RESULTS: LMM and post hoc analyses with Bonferroni correction revealed that MCGP-CS participants reported more improvement on positive relations (subscale of SPWB) than CAU participants of 2-year postintervention (ITT analysis, Cohen's d = .82). Completers also reported more personal growth (subscale of SPWB) after MCGP-CS than after SGP 1-year postintervention (Cohen's d = .94). No long-term effects were found on the other outcome measures. CONCLUSIONS: In the 2 years after MCGP-CS, the short-term significant effects on personal meaning and most positive effects related to psychological well-being faded. However, MCGP-CS had a long-term positive effect on positive relations with others and on survivors' sense of personal growth. TRIAL REGISTRATION: Netherlands Trial Register: NTR3571.

Intention to treat and per protocol analysis in clinical trials.

In clinical epidemiology, experimental studies usually take the form of randomized controlled clinical trials (RCTs). The data analysis of an RCT can be performed by using two complementary strategies, that is according to the intention to treat (ITT) principle and the per protocol (PP) analysis. By using the ITT approach, investigators aim to assess the effect of assigning a drug whereas by adopting the PP analysis, researchers investigate the effect of receiving the assigned treatment, as specified in the protocol. Both ITT and PP analyses are essentially valid but they have different scopes and interpretations dependent on the context.

Tenecteplase Versus Alteplase Between 3 and 4.5 Hours in Low National Institutes of Health Stroke Scale.

Background and Purpose- Thrombolysis with alteplase has beneficial effect on outcome and is safe within 4.5 hours. The present study compares the efficacy and safety of tenecteplase and alteplase in patients treated 3 to 4.5 hours after ischemic stroke. Methods- The data are from a prespecified substudy of patients included in The NOR-TEST (Norwegian Tenecteplase Stroke Trial), a randomized control trial comparing tenecteplase with alteplase. Results- The median admission National Institutes of Health Stroke Scale for this study population was 3 (interquartile range, 2-6). In the intention-to-treat analysis, 57% of patients that received tenecteplase and 53% of patients that received alteplase reached good functional outcome (modified Rankin Scale score of 0-1) at 3 months (odds ratio, 1.19; 95% CI, 0.68-2.10). The rates of intracranial hemorrhage in the first 48 hours were 5.7% in the tenecteplase group and 6.7% in the alteplase group (odds ratio, 0.84; 95% CI, 0.26-2.70). At 3 months, mortality was 5.7% and 4.5%, respectively. After excluding stroke mimics and patients with modified Rankin Scale score of >1 before stroke, the proportion of patients with good functional outcome was 61% in the tenecteplase group and 57% in the alteplase group (odds ratio, 1.24; 95% CI, 0.65-2.37). Conclusions- Tenecteplase is at least as effective as alteplase to achieve a good clinical outcome in patients with mild stroke treated between 3 and 4.5 hours after ischemic stroke. Clinical Trial Registration- URL: https://www.clinicaltrials.gov . Unique identifier: NCT01949948.

A systematic survey shows that reporting and handling of missing outcome data in networks of interventions is poor.

BACKGROUND: To provide empirical evidence about prevalence, reporting and handling of missing outcome data in systematic reviews with network meta-analysis and acknowledgement of their impact on the conclusions. METHODS: We conducted a systematic survey including all published systematic reviews of randomized controlled trials comparing at least three interventions from January 1, 2009 until March 31, 2017. RESULTS: We retrieved 387 systematic reviews with network meta-analysis. Description of missing outcome data was available in 63 reviews. Intention-to-treat analysis was the most prevalent method (71%), followed by missing outcome data investigated as secondary outcome (e.g., acceptability) (40%). Bias due to missing outcome data was evaluated in half the reviews with explicit judgments in 18 (10%) reviews. Only 88 reviews interpreted their results acknowledging the implications of missing outcome data and mostly using the network meta-analysis results on missing outcome data as secondary outcome. We were unable to judge the actual strategy applied to deal with missing outcome data in 65% of the reviews due to insufficient information. Six percent of network meta-analyses were re-analyzed in sensitivity analysis considering missing outcome data, while 4% explicitly justified the strategy for dealing with missing outcome data. CONCLUSIONS: The description and handling of missing outcome data as well as the acknowledgment of their implications for the conclusions from network meta-analysis are deemed underreported.

A mean score method for sensitivity analysis to departures from the missing at random assumption in randomised trials.

Most analyses of randomised trials with incomplete outcomes make untestable assumptions and should therefore be subjected to sensitivity analyses. However, methods for sensitivity analyses are not widely used. We propose a mean score approach for exploring global sensitivity to departures from missing at random or other assumptions about incomplete outcome data in a randomised trial. We assume a single outcome analysed under a generalised linear model. One or more sensitivity parameters, specified by the user, measure the degree of departure from missing at random in a pattern mixture model. Advantages of our method are that its sensitivity parameters are relatively easy to interpret and so can be elicited from subject matter experts; it is fast and non-stochastic; and its point estimate, standard error and confidence interval agree perfectly with standard methods when particular values of the sensitivity parameters make those standard methods appropriate. We illustrate the method using data from a mental health trial.

Nutrient intake and dietary changes during a 2-year multi-domain lifestyle intervention among older adults: secondary analysis of the Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) randomised controlled trial.

Advancing age increases the risk for diseases and health concerns like cognitive decline, constituting a major public health challenge. Lifestyle, especially healthy diet, affects many risk factors related to chronic diseases, and thus lifestyle interventions among older adults may be beneficial in promoting successful ageing. We completed a randomised 2-year multi-domain lifestyle intervention trial aiming at prevention of cognitive decline among 631 participants in the intervention and 629 in the control group, aged 60-77 years at baseline. Dietary counselling was one of the intervention domains together with strength exercise, cognitive training and management of CVD risk factors. The aim of this paper was to describe success of the intervention - that is, how an intervention based on national dietary recommendations affected dietary habits as a part of multi-intervention. Composite dietary intervention adherence score comprising nine distinct goals (range 0-9 points from none to achieving all goals) was 5·0 at baseline, and increased in the intervention group after the 1st (P<0·001) and 2nd (P=0·005) year. The difference in change compared with the control group was significant at both years (P<0·001 and P=0·018). Intake of several vitamins and minerals decreased in the control group but remained unchanged or increased in the intervention group during the 2 years. Well-targeted dietary counselling may prevent age-related decline in diet quality and help in preventing cognitive decline.

Safety, Feasibility, and Efficacy of Vagus Nerve Stimulation Paired With Upper-Limb Rehabilitation After Ischemic Stroke.

BACKGROUND AND PURPOSE: Recent animal studies demonstrate that vagus nerve stimulation (VNS) paired with movement induces movement-specific plasticity in motor cortex and improves forelimb function after stroke. We conducted a randomized controlled clinical pilot study of VNS paired with rehabilitation on upper-limb function after ischemic stroke. METHODS: Twenty-one participants with ischemic stroke >6 months before and moderate to severe upper-limb impairment were randomized to VNS plus rehabilitation or rehabilitation alone. Rehabilitation consisted of three 2-hour sessions per week for 6 weeks, each involving >400 movement trials. In the VNS group, movements were paired with 0.5-second VNS. The primary objective was to assess safety and feasibility. Secondary end points included change in upper-limb measures (including the Fugl-Meyer Assessment-Upper Extremity). RESULTS: Nine participants were randomized to VNS plus rehabilitation and 11 to rehabilitation alone. There were no serious adverse device effects. One patient had transient vocal cord palsy and dysphagia after implantation. Five had minor adverse device effects including nausea and taste disturbance on the evening of therapy. In the intention-to-treat analysis, the change in Fugl-Meyer Assessment-Upper Extremity scores was not significantly different (between-group difference, 5.7 points; 95% confidence interval, -0.4 to 11.8). In the per-protocol analysis, there was a significant difference in change in Fugl-Meyer Assessment-Upper Extremity score (between-group difference, 6.5 points; 95% confidence interval, 0.4 to 12.6). CONCLUSIONS: This study suggests that VNS paired with rehabilitation is feasible and has not raised safety concerns. Additional studies of VNS in adults with chronic stroke will now be performed. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01669161.

Results of the ICTuS 2 Trial (Intravascular Cooling in the Treatment of Stroke 2).

BACKGROUND AND PURPOSE: Therapeutic hypothermia is a potent neuroprotectant approved for cerebral protection after neonatal hypoxia-ischemia and cardiac arrest. Therapeutic hypothermia for acute ischemic stroke is safe and feasible in pilot trials. We designed a study protocol to provide safer, faster therapeutic hypothermia in stroke patients. METHODS: Safety procedures and 4°C saline infusions for faster cooling were added to the ICTuS trial (Intravascular Cooling in the Treatment of Stroke) protocol. A femoral venous intravascular cooling catheter after intravenous recombinant tissue-type plasminogen activator in eligible patients provided 24 hours cooling followed by a 12-hour rewarm. Serial safety assessments and imaging were performed. The primary end point was 3-month modified Rankin score 0,1. RESULTS: Of the intended 1600 subjects, 120 were enrolled before the study was stopped. Randomly, 63 were to receive hypothermia plus antishivering treatment and 57 normothermia. Compared with previous studies, cooling rates were improved with a cold saline bolus, without fluid overload. The intention-to-treat primary outcome of 90-day modified Rankin Score 0,1 occurred in 33% hypothermia and 38% normothermia subjects, odds ratio (95% confidence interval) of 0.81 (0.36-1.85). Serious adverse events occurred equally. Mortality was 15.9% hypothermia and 8.8% normothermia subjects, odds ratio (95% confidence interval) of 1.95 (0.56-7.79). Pneumonia occurred in 19% hypothermia versus 10.5% in normothermia subjects, odds ratio (95% confidence interval) of 1.99 (0.63-6.98). CONCLUSIONS: Intravascular therapeutic hypothermia was confirmed to be safe and feasible in recombinant tissue-type plasminogen activator-treated acute ischemic stroke patients. Protocol changes designed to reduce pneumonia risk appeared to fail, although the sample is small. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01123161.

Estimating efficacy in a randomized trial with product nonadherence: application of multiple methods to a trial of preexposure prophylaxis for HIV prevention.

Antiretroviral preexposure prophylaxis (PrEP) for persons at high risk of human immunodeficiency virus infection is a promising new prevention strategy. Six randomized trials of oral PrEP were recently conducted and demonstrated efficacy estimates ranging from 75% to no effect, with nonadherence likely resulting in attenuated estimates of the protective effect of PrEP. In 1 of these trials, the Partners PrEP Study (Kenya and Uganda, 2008-2011), participants (4,747 serodiscordant heterosexual couples) were randomized to receipt of tenofovir (TDF), coformulated TDF/emtricitabine (FTC), or placebo. Intention-to-treat analyses found efficacy estimates of 67% for TDF and 75% for TDF/FTC. We applied multiple methods to data from that trial to estimate the efficacy of PrEP with high adherence, including principal stratification and inverse-probability-of-censoring (IPC) weights. Results were further from the null when correcting for nonadherence: 1) among the strata with an estimated 100% probability of high adherence (TDF hazard ratio (HR) = 0.19, 95% confidence interval (CI): 0.07, 0.56; TDF/FTC HR = 0.12, 95% CI: 0.03, 0.52); 2) with IPC weights used to approximate a continuously adherent population (TDF HR = 0.18, 95% CI: 0.06, 0.53; TDF/FTC HR = 0.15, 95% CI: 0.04, 0.52); and 3) in per-protocol analysis (TDF HR = 0.18, 95% CI: 0.06, 0.53; TDF/FTC HR = 0.16, 95% CI: 0.05, 0.53). Our results suggest that the efficacy of PrEP with high adherence is over 80%.

Lag-censoring analysis: lights and shades.

'Intention-to-treat' (ITT) analysis is the recommended approach for the data analysis of randomized clinical trials (RCT). ITT analysis considers patients in the active or in the control arm as originally allocated by randomization, independently of their actual adherence to the assigned treatment. Lag-censoring analysis is a statistical method which takes into account the compliance of patients to the study protocol because the investigator censors a patient when or shortly after he/she stops the treatment being tested. Herein we describe the methodology underlying lag-censoring analysis in general terms and by considering the application of this technique in the analysis of a large RCT in haemodialysis patients, the Evaluation of Cinacalcet Hydrochloride Therapy to Lower Cardiovascular Events (EVOLVE) trial. Use and misuse of this technique are discussed.

Intention-to-treat analysis with treatment discontinuation and missing data in clinical trials.

Motivated by a recent National Research Council study, we discuss three aspects of the analysis of clinical trials when participants prematurely discontinue treatments. First, we distinguish treatment discontinuation from missing outcome data. Data collection is often stopped after treatment discontinuation, but outcome data could be recorded on individuals after they discontinue treatment, as the National Research Council study recommends. Conversely, outcome data may be missing for individuals who do not discontinue treatment, as when there is loss to follow up or missed clinic visits. Missing outcome data is a standard missing data problem, but treatment discontinuation is better viewed as a form of noncompliance and treated using ideas from the causal literature on noncompliance. Second, the standard intention to treat estimand, the average effect of randomization to treatment, is compared with three alternative estimands for the intention to treat population: the average effect when individuals continue on the assigned treatment after discontinuation, the average effect when individuals take a control treatment after treatment discontinuation, and a summary measure of the effect of treatment prior to discontinuation. We argue that the latter choice of estimand has advantages and should receive more consideration. Third, we consider when follow-up measures after discontinuation are needed for valid measures of treatment effects. The answer depends on the choice of primary estimand and the plausibility of assumptions needed to address the missing data. Ideas are motivated and illustrated by a reanalysis of a past study of inhaled insulin treatments for diabetes, sponsored by Eli Lilly.

Estimation of treatment efficacy with complier average causal effects (CACE) in a randomized stepped wedge trial.

Complier average causal effects (CACE) estimate the impact of an intervention among treatment compliers in randomized trials. Methods used to estimate CACE have been outlined for parallel-arm trials (e.g., using an instrumental variables (IV) estimator) but not for other randomized study designs. Here, we propose a method for estimating CACE in randomized stepped wedge trials, where experimental units cross over from control conditions to intervention conditions in a randomized sequence. We illustrate the approach with a cluster-randomized drinking water trial conducted in rural Mexico from 2009 to 2011. Additionally, we evaluated the plausibility of assumptions required to estimate CACE using the IV approach, which are testable in stepped wedge trials but not in parallel-arm trials. We observed small increases in the magnitude of CACE risk differences compared with intention-to-treat estimates for drinking water contamination (risk difference (RD) = -22% (95% confidence interval (CI): -33, -11) vs. RD = -19% (95% CI: -26, -12)) and diarrhea (RD = -0.8% (95% CI: -2.1, 0.4) vs. RD = -0.1% (95% CI: -1.1, 0.9)). Assumptions required for IV analysis were probably violated. Stepped wedge trials allow investigators to estimate CACE with an approach that avoids the stronger assumptions required for CACE estimation in parallel-arm trials. Inclusion of CACE estimates in stepped wedge trials with imperfect compliance could enhance reporting and interpretation of the results of such trials.

Exercise for improving age-related hyperkyphotic posture: a systematic review.

OBJECTIVE: To evaluate previous research to determine if exercise can improve preexisting hyperkyphosis by decreasing the angle of thoracic kyphosis in adults aged ≥45 years. DATA SOURCES: PubMed, Embase, and the Cumulative Index to Nursing and Allied Health Literature databases were searched for studies related to posture, exercise, and age ≥45 years. Online conference proceedings of the American Society for Bone and Mineral Research, American Physical Therapy Association, and Gerontological Society of America were also searched. STUDY SELECTION: Two independent reviewers screened the titles and abstracts and selected studies that tested the effect of exercise on measures of kyphosis, or forward head posture, in individuals with hyperkyphosis at baseline (defined as angle of kyphosis ≥40°). Reviews, letters, notes, and non-English language studies were excluded. DATA EXTRACTION: A pilot-tested abstraction form was used by each reviewer to extract data from each study regarding details of exercise intervention, participant characteristics, safety, adherence, and results. The Cochrane Collaboration's tool for assessing risk of bias was used to assess methodologic quality. Discrepancies on the abstraction forms between the 2 reviewers were resolved by a third reviewer. A formal meta-analysis was not performed. DATA SYNTHESIS: Thirteen studies were abstracted and included in the review; of these, 8 studies saw improvements in ≥1 measure of posture. The main sources of bias were related to blinding participants and incomplete outcome data. The adherence reported across studies suggests that exercise is an acceptable intervention for individuals with age-related hyperkyphosis. CONCLUSIONS: The scarcity and quality of available data did not permit a pooled estimate of the effect of exercise on hyperkyphotic posture; however, the positive effects observed in high-quality studies suggest some benefit and support the need for an adequately designed randomized controlled trial examining the effect of exercise on hyperkyphosis.

Clinical Study on the Eradication of Helicobacter pylori by Vonoprazan Combined with Amoxicillin for 10-Day Dual Therapy.

Vonoprazan holds significant research promise for Helicobacter pylori eradication, with the goal of determining the most effective drug regimen. In this study, H. pylori patients (426) were enrolled and randomized into 3 groups: an EA14 group (20 mg of esomeprazole qid and 1000 mg of amoxicillin tid for 14 days), a VA14 group (20 mg of vonoprazan bid and 750 mg of amoxicillin qid for 14 days), and a VA10 group (20 mg of vonoprazan bid and 1000 mg of amoxicillin tid for 10 days). Key outcomes encompassed the H. pylori eradication rate, patient adverse effects, and compliance. In the EA14, VA14, and VA10 groups, H. pylori eradication rates were 89.4%, 90.1%, and 88.7% in intention-to-treat analysis, and 94.2%, 94.4%, and 94.6% in per-protocol analysis, respectively. Adverse events incidences were 14.8%, 12.7%, and 5.6%, while compliance rates were 88.7%, 90.9%, and 95.8%, respectively. Notably, the VA10 regimen demonstrated comparable H. pylori eradication rates, adverse effect incidences, and compliance levels to the EA14 and VA14 regimens.

Effectiveness and Acceptability of Targeted Text Message Reminders in Colorectal Cancer Screening: Randomized Controlled Trial (M-TICS Study).

BACKGROUND: Mobile phone-based SMS text message reminders have the potential to improve colorectal cancer screening participation rates. OBJECTIVE: This study assessed the effectiveness and acceptability of adding targeted SMS text message reminders to the standard procedure for those who picked up but did not return their screening kit at the pharmacy within 14 days in a colorectal cancer screening program in Catalonia, Spain. METHODS: We performed a randomized control trial among individuals who picked up a fecal immunochemical test (FIT) kit for colorectal cancer screening at the pharmacy but did not return it within 14 days. The intervention group (n=4563) received an SMS text message reminder on the 14th day of kit pick up and the control group (n=4806) received no reminder. A 30-day reminder letter was sent to both groups if necessary. The main primary outcome was the FIT completion rate within 30, 60, and 126 days from FIT kit pick up (intention-to-treat analysis). A telephone survey assessed the acceptability and appropriateness of the intervention. The cost-effectiveness of adding an SMS text message reminder to FIT completion was also performed. RESULTS: The intervention group had higher FIT completion rates than the control group at 30 (64.2% vs 53.7%; P<.001), 60 (78.6% vs 72.0%; P<.001), and 126 (82.6% vs 77.7%; P<.001) days. Participation rates were higher in the intervention arm independent of sex, age, socioeconomic level, and previous screening behavior. A total of 339 (89.2%) interviewees considered it important and useful to receive SMS text message reminders for FIT completion and 355 (93.4%) preferred SMS text messages to postal letters. We observed a reduction of US $2.4 per participant gained in the intervention arm for invitation costs compared to the control arm. CONCLUSIONS: Adding an SMS text message reminder to the standard procedure significantly increased FIT kit return rates and was a cost-effective strategy. SMS text messages also proved to be an acceptable and appropriate communication channel for cancer screening programs. TRIAL REGISTRATION: ClinicalTrials.gov NCT04343950; https://www.clinicaltrials.gov/study/NCT04343950. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR2-10.1371/journal.pone.0245806.

Managed Care after Acute Myocardial Infarction (MC-AMI) - Poland's nationwide program of comprehensive post-MI care improves prognosis in 2-year follow-up. A single high-volume center intention-to-treat analysis.

BACKGROUND: Managed Care in Acute Myocardial Infarction (MC-AMI) is a program introduced in Poland aimed at comprehensive, scheduled, and supervised care for AMI patients to improve longterm prognosis. AIMS: Our study aimed to compare 24-month mortality and the incidence of major cardiovascular events (MACE: a composite of death, recurrent MI, and hospitalization for heart failure) in a cohort of AMI patients treated in the MC-AMI era (intention-to-treat analysis) vs. similar population treated before the MC-AMI era. METHODS: We analyzed 2323 consecutive patients with AMI: 1261 patients enrolled in the MC-AMI era (study group) and 1062 patients treated 12 months before the MC-AMI era (control group). In the study group, 57% of patients participated in MC-AMI while 43% of patients remained under standard care. The patients were followed up for 24 months. Mortality and MACE were recorded. RESULTS: Treatment in the MC-AMI era was related to a 30% reduction in all-cause mortality and a 14% reduction of MACE although it was not related to the reduction of hospitalization for heart failure (HF) or AMI in 24 months. The 24-month survival rate was the highest in MC-AMI enrolled patients while patients treated in the MC-AMI era but not enrolled had a similar prognosis to those treated before the MC-AMI era. Multivariable Cox regression analysis revealed the MC-AMI era to be inversely associated with mortality in 24-month follow-up (hazard ratio [HR], 0.49; 95% confidence interval [Cl], 0.38-0.65; P <0.001). CONCLUSIONS: AMI treatment in the MC-AMI era reduces 24-month mortality and MACE. Moreover, AMI treatment in MC-AMI is inversely related to mortality, MACE, and hospitalization for HF. The effect is pronounced in patients enrolled in MC-AMI.

Common misunderstandings of evidence-based medicine.

Currently, most evidence assessments in guidelines or health technology assessments (HTAs) rely on the assumption that a randomized controlled trial (RCT) is always the best source of evidence. However, if the outcome in a control group is certain, e.g. death within a short time with an almost 100% chance, or if an event can only occur in the treatment group, there is no need for a randomized control group; the evidence cannot be improved by a control group, nor by an RCT design. If a cause-effect relationship is certain ("primary or direct evidence"), a therapeutic effect can be diluted in the population of an RCT by cross-over, etc. This can lead to serious misinterpretations of the effect. While experts such as the GRADE group or Cochrane institutes recommend using all available evidence, the leading approach in many guidelines and HTAs is assessing "the best available trials", i.e. RCTs. But since RCTs only deliver probabilities of cause-effect relationships, it is not appropriate to demand RCTs for certain effects. A control group can only diminish the net value of a treatment since the outcome in the control group is subtracted from the outcome in the treatment group. Therefore, under identical circumstances, an RCT will always show lower effect rates compared to a single arm study of the same quality, for desired as well as for adverse effects. Considering these inconsistencies in evidence-based medicine interpretation, the evidence pyramid with RCTs at the top is not always a reliable indicator for the best quality of evidence.

Intention-to-treat versus as-treated versus per-protocol approaches to analysis.

Randomized controlled trials (RCTs) are considered the most rigorous study design for testing hypotheses and the gold standard for evaluating intervention effectiveness. However, RCTs are often conducted under the assumption of ideal conditions that may differ from real-world scenarios in which various issues, such as loss to follow-up, mistakes in participant enrollment or intervention, and low subject compliance or adherence, may occur. There are various group-defining strategies for analyzing RCT data, including the intention-to-treat (ITT), as-treated, and per-protocol (PP) approaches. The ITT principle involves analyzing all participants according to their initial group assignments, regardless of study completion and compliance or adherence to treatment protocols. This approach aims to replicate real-world clinical settings in which several anticipated or unexpected conditions may occur with regard to the study protocol. For the PP approach, only participants who meet the inclusion criteria, complete the interventions according to the study protocols, and have primary outcome data available are included. This approach aims to confirm treatment effects under optimal conditions. In general, the ITT principle is preferred for superiority and inequality trials, whereas the PP approach is preferred for equivalence and non-inferiority trials. However, both analytical approaches should be conducted and their results compared to determine whether significant differences exist. Overall, using both the ITT and PP approaches can provide a more complete picture of the treatment effects and ensure the reliability of the trial results.