Randomized control trial patients

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Bias is avoided not only by randomization but also by blinding. A study may be double blind, single blind, or open. In a double-blind study neither patient nor study physician knows to which treatment the patient has been assigned. Double-blind studies are advantageous if knowledge of the treatment might influence the course and therefore the results of the study.

Thus it is particularly important that the study physician is blinded to treatment if the endpoints are subjective. Blinding of patients to their treatment is important, for example, if their attitude could potentially affect their reliability in taking the test medication compliance or even their response to treatment. If only one party, either patient or study physician, is blinded to the treatment, the study is called single blind; a study with no blinding is described as open.

The highest possible degree of blinding should be chosen to minimize bias. The data subjected to statistical analysis in RCTs are those gathered from patient populations defined in the study protocol. The primary population for analysis is the so-called intention-to-treat ITT population, comprising all randomized patients. In analysis according to the ITT principle, patients are allocated to the group to which they were randomized, thus retaining the advantages of randomization such as structural equivalence.

Because the ITT population includes all patients who were randomized, the data for analysis include some patients whose treatment was interrupted, prematurely discontinued, or did not take place at all. The analysis strategy for ITT data is therefore conservative, i. Many studies define a modified ITT mITT population, which may for example comprise the patients who received at least a defined amount of study treatment.

An alternative strategy is to restrict analysis to the data from the per-protocol PP population. Patients in whom study conduct deviated from the protocol are excluded from analysis. These so-called protocol violations include, for example, failure concerning the application of inclusion or exclusion criteria and incorrect administration of the study treatment.

In analysis according to the PP principle, patients are allocated to the treatment groups depending on the treatment they actually received. Because the PP population includes only those patients who completed the study according to the protocol, the results may be distorted in favor of the investigational intervention To assess the robustness of the study findings, PP evaluation is carried out as a sensitivity analysis if the ITT population is the patient population for the primary efficacy analysis If the results of PP and ITT evaluation of the primary endpoint are very similar, they can be regarded as reliable.

Should this not be the case, the possible reasons for the discrepancy between the results of the ITT and PP analyses must be discussed in the results section of the publication.

The rates of live births in the three treatment groups did not differ significantly Table 1. Analysis according to the PP principle confirmed this finding. Neither aspirin and heparin combined nor aspirin alone were demonstrated to have a greater effect than placebo on the live birth rate. Relative risk and absolute difference were calculated for the comparisons between aspirin plus heparin and placebo and between aspirin alone and placebo. The p-value applies to all treatment group comparisons.

Clinical trials have to be performed according to national and international regulations. The Declaration of Helsinki, first formulated by the World Medical Association in and revised several times in the intervening years 20 , lays down fundamental ethical principles for research on human beings. The aim of GCP is to protect study participants and ensure high quality of study data.

In the International Committee of Medical Journal Editors made registration of a clinical trial in a public registry a precondition for its publication The professional code of conduct for physicians in Germany demands that every study in human subjects be submitted to the responsible ethics committee for approval.

The applications have to be accompanied by the study protocol, the information to be supplied to the patients, the consent form for participation, and confirmation that adequate insurance has been arranged. Trials of drugs and medical devices also have to be registered with state authorities. There are legally defined obligations to report suspected unexpected serious adverse reactions or early termination of a study, and the final study report must also be submitted.

In other words, information revealing the identity of a patient name or initials must be replaced by a code. Only patients who have agreed in advance to the recording, storage, processing and dissemination of their data may participate in a clinical study.

Any publication of an RCT must lucidly describe the planning, conduct, and analysis of the study. The most important aspects that have to be described in the publication are listed in Table 2. The progress of patients through an RCT and the numbers of patients whose data were analyzed can be depicted in a flow diagram Figure. Patient flow in a randomized controlled trial adapted from [ 23 ]. The study results and their interpretation must be discussed in detail in the study report and any subsequent publication, and the limitations of the methods used should be described, all with reference to the study design, the recent literature, and the current state of knowledge.

Critical discussion plays a decisive part in clinical evaluation of the results. In the publication of the ALIFE study, the findings were compared with those of other RCTs investigating the effects of heparin on reduction of miscarriages and inconsistencies were discussed. Ultimately, the available study data did not justify the recommendation of anticoagulants for women with recurring miscarriages.

Although RCTs are the gold standard with regard to level of evidence, their generalizability, i. Moreover, the patients selected for a study are not necessarily representative, in that those seen in routine daily practice will often have numerous comorbidities and comedications. After marketing approval of a new treatment, phase-IV studies are carried out to establish its efficacy and safety in a larger and more heterogeneous population; as a rule these studies are RCTs.

Epidemiological studies, e. RCTs are the best type of study for determining whether there is a causal relationship between intervention and effect However, it seems clear that post-marketing studies comparing new and established treatments are still required. In clinical research, randomized controlled trials are the gold standard for demonstrating the efficacy and safety of a new treatment.

Randomized controlled trials cannot yield robust data unless they are planned, conducted, and analyzed in ways that are methodologically sound and appropriate to the question being asked. Methods to avoid bias, such as randomization and blinding, can help to prevent distortion of the study results.

The robustness of the results is tested by statistical analysis of the data from patient populations defined a priori. The quality of a randomized controlled trial depends crucially not only on adherence to methodological standards but also on strict compliance with the protocol regarding the clinical conduct of the study. Conflict of interest statement. National Center for Biotechnology Information , U.

Journal List Dtsch Arztebl Int v. Dtsch Arztebl Int. Published online Sep Also, persistent cough continued for 3. The mean lengths of hospital stay were 6.

Table II presents the durations of clinical recovery, symptoms, and hospital stay in the 2 groups in detail. Durations of hospital stay and symptoms with ivermectin versus standard of care control in patients with moderate to severe COVID Data are given in days.

Ten patients Three patients underwent invasive mechanical ventilation 2 in the ivermectin group and 1 in the control group. In the ivermectin group, a year-old woman with a history of diabetes mellitus and heart failure died. She was critically ill at the time of admission and died within the first 24 hours. Comparison of the needs for oxygen and medications, including antibiotics, with ivermectin versus standard of care control in patients with moderate to severe COVID The laboratory test results were not significantly different between the 2 groups on admission Table IV.

Although lymphopenia was detected in 7 Laboratory test results at baseline and admission day 2 in patients with moderate to severe COVID receiving treatment with ivermectin versus standard of care control. No potential adverse events, including wheezing, itching, skin rash, edema, hypotension or liver toxicity were observed in the patients of either group. With spread of the COVID pandemic, researchers have attempted to find drugs that can be potentially effective in treating this disease.

Most of the participants were middle-aged, and the male-to-female ratio was almost Given that this study was performed in hospitalized patients and the intervention included a single oral dose of ivermectin, the likelihood of missing participants was very low.

Based on the results of the current study, we found significant effects of ivermectin on parameters including hospital stay, dyspnea as an easily assessed symptom , cough, and lymphopenia.

Although in in vitro studies the dose of ivermectin needed for inducing antiviral effects was higher than the approved usual dose in humans, in animal models the concentration of ivermectin in the lung tissues was found to be 3-fold higher than the plasma concentration.

In the present study, shorter times to significant improvement in clinical symptoms and a shorter duration of hospital stay were detected in the ivermectin group. In a study by Gorial et al unpublished observations, , the mean length of hospital stay was significantly less in ivermectin group compared with that in the controls 7.

Rajter et al unpublished observations, did not observe a significant difference in lengths of hospital stay between the ivermectin and control groups, and patients received 1 dose of ivermectin at any time during the hospitalization. A possible explanation could have been a delay in prescribing ivermectin due to a lag in obtaining the required results from repeated COVID testing.

Despite ivermectin having several advantageous characteristics, including single-dose administration, oral formulation, and associations with a shorter recovery time and no adverse events in hospitalized adults with COVID, it needs further investigations to be considered for approval as a COVID—specific treatment. In the current study, 2 days after the intervention, ivermectin was associated with a significantly decreased frequency of lymphopenia.

The potential mechanisms of lymphopenia in patients with COVID include lymphocyte apoptosis; destruction of lymphatic organs, such as thymus and spleen, directly by the virus; lymphocyte apoptosis by disturbed inflammatory cytokines; and inhibition of lymphocytes following metabolic disorders, such as hyperlactic acidemia. The risks for adverse events with such combinations are very low, 30 and no adverse events were associated ivermectin use in the present study.

No adverse events associated with ivermectin use were reported in other similar studies unpublished observations, Rajter et al, ; unpublished observations, Gorial et al, Although several doses and treatment durations of ivermectin are recommended, this study used a single dose of 0. Ahmed et al 14 studied the effects of ivermectin alone 12 mg once daily for 5 days or in combination with doxycycline 12 mg ivermectin single dose and mg stat doxycycline on day 1, followed by doxycycline mg q12h for 4 days compared with placebo; time to virologic clearance was less in the 5-day ivermectin treatment arm versus the placebo group.

Therefore, a treatment regimen with ivermectin can be considered due to its lower cost, availability, oral route of administration, and fewer associated adverse events in comparison with other available drugs.

There are some concerns regarding the neurotoxicity of ivermectin, as the drug targets glutamate-gated chlorine channels in invertebrates and may cross-react with GABA-gated chlorine channels in mammalians. For this reason, in the present study, a single dose of the drug was used on the first admission day, before progression of the disease to CNS involvement.

This study had a number of limitations. First, the sample size was small, and the effects of the drug on mortality could not be evaluated. Therefore, further studies with larger sample sizes are warranted. A further limitation of this study was the assessment of patients with moderate to severe disease who required hospitalization. Regarding the mechanism of action of this drug, its application during the first days of symptom onset may be associated with higher clinical response.

Although benefits of ivermectin were apparent in this study, due to the small sample size, further studies with larger sample sizes; different drug dosages, dosing intervals, and treatment durations; and especially in patients with different severity of disease are needed for generalization of the findings on effects and optimization.

Based on the findings from the present study, a single weight-based dose 0. This drug was well tolerated, with a good tolerability profile and few adverse events with oral administration.

The authors have indicated that they have no conflicts of interest with regard to the content of this article. All of the authors read and approved the submitted manuscript. Written informed consent was obtained from the patients or their parents prior to manuscript submission for their personal or clinical details in addition to any identifying images to be published in this study.

The data from the patients of this study have not been reported in any other submission. National Center for Biotechnology Information , U. Clin Ther. Published online May 6. John S.

Author information Article notes Copyright and License information Disclaimer. Postal code: Accepted Apr Elsevier hereby grants permission to make all its COVIDrelated research that is available on the COVID resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source.

This article has been cited by other articles in PMC. Associated Data Data Availability Statement All data generated or analyzed during this study were included in this published article. Abstract Purpose Given the coronavirus disease COVID pandemic, there is a global urgency to discover an effective treatment for patients withthis disease.

Methods In this randomized, double-blind clinical trial, patients with COVID admitted to 2 referral tertiary hospitals in Mazandaran, Iran, were randomly divided into 2 groups: intervention and control. Findings Sixty-nine patients were enrolled mean [SD] ages: ivermectin, Implications A single dose of ivermectin was well-tolerated in symptomatic patients with COVID, and important clinical features of COVID were improved with ivermectin use, including dyspnea, cough, and lymphopenia.

Randomization and Masking The patients were randomly divided into 2 groups ivermectin and control by a simple randomization method using a table of random numbers. Measures Demographic, clinical, laboratory, and imaging data from all participants were recorded at baseline on the first day of admission. Ethical Considerations The ethics committee of Mazandaran University of Medical Sciences approved the study protocol protocol no.