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Graphical abstract | PMC10213810 |
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Keywords | MAY | Published: May 2, 2023 | PMC10213810 |
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Introduction | glioblastoma, GBM, cancer, tumor | GLIOBLASTOMA, TUMOR GROWTH, CANCER, TUMOR | The standard of care (SOC) for glioblastoma (GBM) is a combination of surgery, radiotherapy, and concomitant temozolomide followed by maintenance temozolomide (TMZ) as demonstrated by the EORTC-NCIC trial.Due to the unpredictable nature of cancer, responses to chemotherapy can vary from patient to patient, even when cancer cells are of the same histology. Several genome-based methodologies and immunotherapies are under clinical investigation. They have not demonstrated a survival advantage in GBM,A strategy to increase the survival of patients with GBM is to target the cancer stem cells (CSCs) that contribute to therapy resistance and cancer progressionThe “CSC concept” was proposed four decades ago and revised recently and posits that tumor growth is analogous to the renewal of healthy tissues and fueled by small numbers of dedicated stem cells capable of plasticity.For patients with rGBM, a viable treatment option is to select chemotherapies that will eliminate the CSCs, the main cause of treatment resistance, while reducing the bulk of tumor cells.Based on this proof of concept and on real-world data, a multi-institutional, randomized clinical trial (ClinicalTrials.gov: | PMC10213810 |
Results | deaths, glioma, physician-choice, tumor | TUMOR, RECURRENCE, MAY, BRAIN TUMORS, GLIOMA | Over a period of 3 years, 123 patients affected by rGBM or grade III glioma were screened and assessed for eligibility criteria to participate in a parallel-group-randomized controlled trial at 13 clinical sites across the US. The study protocol was approved by the Western Institutional Review Board (WIRB) and the independent ethics committee of each of the participating institutions. 78 patients with rGBM (diagnosed according to the 2016 WHO classification of brain tumors) were enrolled in the study (consort diagram: CONSORT diagram of ChemoID studyA total of 123 patients were screened between May 18, 2018, and May 30, 2021; 78 of these patients were randomized to either the ChemoID or physician-choice group. After 35 deaths were reported, the first prespecified interim efficacy analysis was performed.Study schema of the registered clinical trial A multi-institutional, randomized clinical trial of patients with rGBM was initiated to assess the efficacy of chemotherapy regimens selected by the ChemoID assay vs. best physician choice. The primary efficacy endpoint of this trial was median OS. Secondary endpoints were OS at 6, 9, and 12 months, median PFS at 4, 6, 9, and 12 months, objective tumor response, time to recurrence, and health-related quality of life.A predetermined interim survival efficacy analysis was conducted when 35 deaths were reported (August 20, 2021). Patient enrollment was stopped after the interim efficacy analysis because the study’s primary endpoint (overall survival [OS]) was met during the planned interim efficacy analysis. Intention-to-treat (ITT) analysis was conducted on all 78 randomized subjects.The median time of follow-up was 10.5 months for the ChemoID assay-guided group and 6.2 months for the physician-choice group at the time of the interim efficacy analysis data cutoff. The median time of follow-up at ITT analysis was 10.5 months for the ChemoID assay-guided group and 7.5 months for the physician-choice group.A post-randomization analysis of the demographics and baseline clinical characteristics of all randomized subjects demonstrated that subjects were balanced between the two study groups (Patient demographics and baseline characteristicsGlioblastomas were diagnosed following the 2016 WHO classification. | PMC10213810 |
ChemoID assay-guided therapy increased OS and progression-free survival (PFS) of patients with rGBM | death, physician-choice | EVENTS | A statistically significant difference was observed in the risk of death between groups (hazard ratio [HR] = 0.44; 95% confidence interval [CI], 0.24–0.81; p = 0.008) in the interim efficacy analysis. In the ChemoID assay-guided group, 67% of patients (18 of 27) died vs. 87% (20 of 23) in the physician-choice group. Furthermore, median overall survival (mOS) was 12.5 months (95% CI, 10.2–14.7) with ChemoID assay-guided therapy vs. 9 (95% CI, 4.2–13.8) with physician choice (log rank p = 0.010) (OS and PFS are significantly improved by ChemoID-guided therapy(A) Prespecified interim efficacy analysis of OS. The number of events; median OS; OS rates at 0, 6, 12, and 18 months; and the Kaplan-Meier curve for OS in all patients treated with ChemoID-guided (blue) vs. physician-choice (red) therapies. Symbols, censored observations.(B) Prespecified interim efficacy analysis of PFS. The number of events; median PFS; PFS rates at 0, 6, 12, and 18 months; and the Kaplan-Meier curve for PFS per investigator assessment in patients treated with ChemoID-guided (blue) vs. physician-choice (red) therapies. Symbols indicate censored observations.(C) Intention-to-treat analysis of OS. The number of events; median OS; OS rates at 0, 6, 12, and 18 months; and the Kaplan-Meier curve for OS in all patients treated with ChemoID-guided (blue) vs. physician-choice (red) therapies. Symbols, censored observations.(D) Intention-to-treat Analysis of PFS. The number of events; median PFS; PFS rates at 0, 6, 12, and 18 months; and the Kaplan-Meier curve for PFS per investigator assessment in patients treated with ChemoID-guided (blue) vs. physician-choice (red) therapies. Symbols indicate censored observations. A Cox proportional hazards model estimated hazard ratios (HRs) and CIs.Secondary endpoints: Interim efficacy analysis of OS and PFS probabilityNC, not calculable.The median progression-free survival (mPFS) was 10.1 months (95% CI, 4.8–15.4) for patients receiving ChemoID assay-guided therapy vs. 3.5 months (95% CI, 1.9–5.1) for physician-choice therapy (HR, 0.25; 95% CI, 0.14–0.44; p < 0.001) (ChemoID assay-guided therapy continued to demonstrate meaningful clinical benefit in mOS throughout follow-up. In ITT analysis, a statistically significant difference was also observed in the risk of death between groups (HR = 0.52; 95% CI, 0.24–0.81; p = 0.008). In the ChemoID assay-guided group, 70% of patients (30 of 43) died vs. 91% (32 of 35) in the physician-choice group. Furthermore, mOS was 12 months (95% CI, 10.8–13.2) with ChemoID assay-guided therapy vs. 7.5 (95% CI, 3.5–11.5) with physician choice (log rank p = 0.009) (Secondary endpoints: ITT analysis of OS and PFS probabilityThe mPFS was 6.5 months (95% CI, 3.3–9.7) for patients receiving ChemoID assay-guided therapy vs. 3.3 months (95% CI, 2.1–4.5) for physician-choice therapy (HR, 0.36; 95% CI, 0.23–0.57; p < 0.001) ( | PMC10213810 |
Exploratory analyses | PMC10213810 |
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ChemoID test results correlated with patients’ OS and PFS | tumor, death | TUMOR | Survival and PFS of each patient in the planned interim efficacy analysis were also analyzed as a function of the cell kill of the patient’s cultured tumor cells (both CSCs and bulk tumor cells) in response to the drug(s) used during treatment (Our analysis further revealed that for every 10% increase in CSC drug response, there was a significant increase (13%) in 6-month patient survival (HR, 0.87; p = 0.012), and for every 10% increase in bulk tumor cell response, the hazard of death decreased 13% (HR, 0.87; p = 0.024). We also found that for every 10% increase in cell kill, the hazard of progression at 6 months decreased by 14% for CSCs (HR, 0.86; p = 0.005) and 18% for bulk tumor cells (HR, 0.82; p = 0.001).For survival trials, HR is the standard reporting mechanism; however, restricted mean survival time (RMST) is also a robust method for assessing the treatment effect.In our exploratory studies, we also analyzed the cohort of patients with rGBM by removing subjects affected by The trial allowed the optional inclusion of BV during treatment because it has been shown in large trials and meta-analyses that BV treatment in combination with chemotherapy improves the management of symptoms and quality of life in patients with rGBM but not the OS. | PMC10213810 |
Correlation between chemotherapy treatments administered and the ChemoID test report predictions | tumor, physician-choice | TUMOR | The drug response to each chemotherapy and their combinations were analyzed to determine the proportion of patients who benefitted from a sensitive vs. non-sensitive chemotherapy chosen prospectively by the ChemoID assay. A pyramid diagram representation of the comparison in percent of cell kill of the most cytotoxic drugs found by the ChemoID assay compared with the actual cell kill percentages of the chemotherapy treatment used for both physician-choice and ChemoID-guided groups for each patient is shown in The distribution of cell kill predicted by the assay for the bulk of the tumor and the CSC assay of the drugs that were used to treat subjects in the physician-choice vs. the ChemoID-guided group is shown in | PMC10213810 |
Grade III/IV CRAEs association with chemotherapy in ITT analysis | deaths | ADVERSE EFFECTS | The relative percentage of grade III/IV chemotherapy-related adverse effects (CRAEs) in ITT analysis was lower in the ChemoID assay-guided group (51%) vs. the physician-choice group (79%), with no unexpected neurological CRAEs or deaths due to CRAEs in either arm ( | PMC10213810 |
Discussion | cancer, tumor, death, physician-choice | CANCER, TUMOR | To improve the outcome of rGBM, it is critical to use chemotherapies that are effective against the CSCs as they are proven to drive tumor development and relapse. We conducted a randomized clinical trial using the ChemoID CSC assay to guide chemotherapy for rGBM treatment. It is worth noting that patients in both arms were treated with a regimen chosen from the same panel of chemotherapy medications, with one group using the patient-specific ChemoID test report to guide chemotherapy selection and the other relying on the physicians’ best judgment.Planned interim efficacy analysis showed that the ChemoID-guided group’s mOS was 3.5 months longer than the physician-choice group’s (12.5 vs. 9 months) (In the ITT analysis, the study continued to meet its primary endpoint. The mOS was 4.5 months longer for the ChemoID-guided group compared with the physician-choice group (12 vs. 7.5 months) (To confirm the validity of the data analysis using the HR method to summarize the difference in survival curves between the two arms as described in the approved study protocol, we also analyzed the data using RMST. By analyzing the 1- or 1.5-year RMST and CIs for each of our primary results, we found that subjects who received ChemoID-guided therapy had a significant survival advantage, which proves that using other robust statistical analysis methods, the survival differences between the two groups were statistically significant. The data support the use of the ChemoID assay for guiding chemotherapy selection for rGBM. The OS and PFS advantages observed for the ChemoID-guided group are not due to differences in prognostic variables, such as age, sex, performance status, The current SOC treatment protocol for GBM is a combination of surgical resection, radiotherapy, and concomitant TMZ chemotherapy followed by maintenance TMZ as demonstrated in the EORTC-NCIC trial.Of note, the use of anti-CSC-guided therapy resulted in a 3.5-month mOS advantage when compared with the control group in the population evaluated at the interim efficacy analysis and a 4.5-month mOS advantage in the ITT population. A significant difference was observed in the risk of death between the two groups. More participants survived in the ChemoID assay-guided group compared with the non-guided group at 6, 9, and 12 months, demonstrating that patients with rGBM derive a survival benefit from treatment with CSC-directed therapy.In conclusion, the ChemoID assay was developed as an actionable tool for physicians to individualize cancer treatment by selecting the most effective therapies against CSCs from a panel of cytotoxic agents that are common and affordable for cancer patients. Treatments with more expensive targeted anti-cancer drugs and immunotherapies are not always feasible due to socioeconomic and health disparity issues in the US and around the world. Although there are newer targeted therapies, our clinical trial focused on screening SOC chemotherapies that are routinely covered and used by community oncologists globally. The results of our study highlight the clinical effectiveness of a personalized approach to treatment. The ability of the ChemoID assay to personalize chemotherapy selection is a promising way to provide more affordable treatment for patients with rGBM. The ChemoID assay is versatile, allowing it to be expanded to include other new agents. We anticipate personalized anti-cancer therapy targeting CSCs will be included sooner in the treatment plan, eliminating ineffective treatments and allowing patients to gain the greatest therapeutic benefit possible. | PMC10213810 |
Limitations of the study | tumor, tumors | TUMOR, TUMORS | Although this study provides good treatment options for patients with rGBM, some potential limitations should be noted. For example, ChemoID is a functional assay limited by the availability of viable tumor tissue samples. Our study only included rGBM subjects who underwent surgical resection or biopsy. Subjects with inoperable tumors or who were in poor health were not participants in our study. Future studies should incorporate patients with newly diagnosed | PMC10213810 |
STAR★Methods | PMC10213810 |
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Key resources table | PMC10213810 |
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Resource availability | PMC10213810 |
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Lead contact | Further information and requests for resources and reagents should be directed to and will be fulfilled by the lead contact, Pier Paolo Claudio ( | PMC10213810 |
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Materials availability | This study did not generate new unique reagents. | PMC10213810 |
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Experimental model and subject details | PMC10213810 |
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Patients | ICH, glioma, tumor | TUMOR, ADVERSE EVENTS, RECRUITMENT, MAY, GLIOMA, PATHOLOGY | 123 patients affected by recurrent GBM or grade III glioma were screened in this parallel-group randomized controlled clinical trial at 13 clinical sites across the US over a period of three years and assessed for inclusion and exclusion criteria to participate in the study (78 recurrent GBM patients were enrolled in the study (Consort Diagram – Subjects underwent surgical resection and biopsy. For histopathology confirmation and diagnosis of GBM, MGMT gene methylation status, and IDH-1/2 status, fresh tissue tumor biopsies from rGBM patients were sent to the sites’ hospital pathology lab for processing. The central ChemoID laboratory conducted the drug response assay using a second portion of the fresh biopsies. In accordance with CLIA and CAP requirements, samples were shipped to the ChemoID laboratory utilizing a secure FedEx overnight shipping container for clinical specimens. All recurrent GBM patients who registered for the trial underwent the ChemoID assay and were randomly assigned by the sites’ coordinators to a study group using a computer-generated algorithm (in REDCap).The patients were treated either with the standard of care chemotherapy chosen by the physician (ARM 1) or treatment directed by the ChemoID assay (ARM 2), depending on the randomly allocated study group. Data collection was performed by a REDCap electronic data capture application software.Chemotherapy medications were administered in accordance with the trial group to which each patient was assigned. Over the course of treatment, assessments of adverse events and drug compliance were made. Enrollment in the trial began in May 2018 after the lead institution completed the trial start-up procedures. Our trial was registered on The study protocol was approved by the Western Institutional Review Board (WIRB) and each of the independent ethics committees of the participating institution. This study was conducted in accordance with the Declaration of Helsinki and Good Clinical Practice (GCP) requirements described in the current revision of the International Conference on Harmonisation of Technical Requirements of Pharmaceuticals for Human Use (ICH) Guidelines and all applicable regulations, including current United States Code of Federal Regulations (CFR), Title 21, Parts 11, 50, 54, 56, and 312 and Title 45, Part 164. The IRB reviewed and approved the site’s informed consent form (ICF), and any other written information that was used for patient recruitment. All patients signed the informed consent before enrollment. | PMC10213810 |
Method details | PMC10213810 |
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Patient treatment | tumor, death, toxicity, cancer, intercurrent illness | CANCER, TUMOR, EVENT | Lead investigators agreed on the cytotoxic chemotherapies used in the trial, and the health insurance plans covered them, thus study participants incurred no additional medical bills. The regimens and doses tested by the ChemoID drug response assay were the same as the ones that could be chosen by the physicians for patients enrolled in the control arm (Patients received 1 of 14 cytotoxic chemotherapy regimens either chosen by the physician or guided by the ChemoID assay test report (The assay-guided group received the regimen that killed the most cancer stem cells and the bulk of the tumor. The treatment given to subjects in the control group was chosen from the same list of chemotherapies tested by the assay (For patients in the assay-guided group, in the event of unacceptable toxicity or progression, treatment was changed to the next best chemotherapeutic drug or combination based on the ChemoID assay report. In cases in which the assay predicted more than one high-cell kill drug, for patients randomized to the assay-guided arm, the protocol gave the physicians the ability to choose a treatment among the high-cell kill drugs based on the ChemoID assay report that would benefit the patient, considering the patient’s general health status.Bevacizumab is not expected to improve overall survivalIn the absence of treatment delays due to the presence of adverse event(s), treatment continued as specified in the above treatment modality sections or until one of the following criteria was applicable: hospice or patients’ death, intercurrent illness that prevents further administration of treatment, unacceptable adverse event(s), patient decides to withdraw consent for participation in the study, or general or specific changes in the patient’s condition render the patient unacceptable for further treatment in the judgment of the investigator. | PMC10213810 |
ARM 1 - Physician’s choice of chemotherapy regimens | physician-choice | Patients randomized to the physician-choice chemotherapy arm were treated with one of the regimens from the list of chemotherapies specified per the investigator’s discretion. Patients received treatment as per standard practice and continued on the treatment until hospice or as per investigator’s discretion if having continued response (SD, PR, or CR) and/or clinical benefit. The number of cycles of therapy administered as clinically appropriate was based on the health status, although it was recommended that patients should receive at least 4 cycles of therapy. | PMC10213810 |
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ARM 2 – ChemoID-guided drug response assay chemotherapy regimens | cancer, tumor | CANCER, TUMOR | The physician selected a treatment regimen based on ChemoID drug response assay results on cancer stem cells (CSC) and the bulk of tumor cells. Ideally, the regimen with the highest percentage cell-kill for cancer stem cells and the bulk of tumor combined was used; however, the physician had the flexibility to choose the best regimen according to anticipated patient tolerability. The regimens tested by the ChemoID drug response assay are the same as the ones that can be chosen by the Physician for patients enrolled in Arm 1. | PMC10213810 |
Patient follow-up | death, tumor, Tumor, seizures, ±, allergy, renal dysfunction, Cancer | ADVERSE EVENT, TUMOR, TUMOR, ADVERSE EVENTS, DISEASE, ALLERGY, ADVERSE EVENT, CANCER | Participants were followed for three years according to standard-of-care intervals by neurologic and neurosurgical clinical assessments or until death. At 6 and 12 months after planned Visit 24 there was a phone call to assess survival status.Participants were assessed at follow-up visits following standard-of-care treatments and chemotherapy drugs were dispensed according to groups and cohorts. Drug compliance and adverse event assessment were performed. Lab work and brain imaging were collected at visits as per standard-of-care.The outpatient visits window was ± 7–14 days from the intended date of the visit. Follow-up visits consisted of a clinical evaluation with particular attention to neurological function, seizures, and corticosteroid use as per standard-of-care management of the disease. Laboratory tests of blood counts, glucose levels, and blood count, liver function tests indicated if the participant was receiving chemotherapy, corticosteroids, and anti-epileptic drugs.CT scan or MRI was performed as standard of care for the entire time patients are in the trial, and at any other time if clinically indicated based on symptoms or physical signs suggestive of progressive disease. Imaging assessments were discontinued once a patient was off of the clinical trial, hospice, or death. Patients were followed for overall survival during the clinical trial.Participants were followed according to SOC intervals determined by neurologic and neurosurgical clinical assessments preferably with brain MRI scans pre- and post-intravenous gadolinium contrast unless the patient had a contraindication to gadolinium contrast then non-contrast brain MRI was obtained and or CT-scans of the brain pre and post intravenous contrast or without contrast, if the patient had a contraindication to CT intravenous contrast such as severe allergy and/or renal dysfunction.During treatment, adverse events were assessed according to National Cancer Institute Common Terminology Criteria for Adverse Events (version 5.0). Post-chemotherapy, patients had follow-up visits every 3 months, during which neurological function and corticosteroid levels were assessed and contrast-enhanced MRIs were performed (in addition to the post-surgery/baseline MRI).Response to chemotherapy was evaluated according to the 2D Response Assessment in Neuro-Oncology (RANO) criteria, in which in addition to contrast enhancement, tumor extension on T2-and fluid-attenuated inversion recovery (FLAIR)-weighted MRI are evaluated.Tumor assessments were performed by an independent neuro-radiology service composed of 2 readers and a third senior reader for adjudication of disagreements. All neuro-radiologists were blinded to groups and/or treatment assignments throughout the trial to determine the earliest time of progression independent of the impressions of the treating physicians to avoid bias.A record of all concomitant (OTC & prescription) taken 30 days prior to the screening visit through study termination was taken. | PMC10213810 |
Clinical trial monitoring evaluations and measurements | DISEASE, PATHOLOGY | From the medical chart (paper or electronic) this additional data was collected: age, gender, weight, pathology report, steroid and other medication doses over the course of treatment, ChemoID test results, MGMT gene methylation status, IDH-1 mutation status, chemotherapy regimens including doses, all brain imaging including but not limited to DICOM images of MRI and or CT scans, clinical assessment of disease at baseline and during the course of therapy from neuro-oncologic progress notes, Health-Related Quality of Life (HRQOL) questionnaires addressing physical, psychological, emotional, and social issues. | PMC10213810 |
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Risk assessment | gliomas | RECURRENT CANCER, GLIOMAS | The ChemoID assay was classified as a non-significant risk assay for patients by the ethics committees. The current study utilized only sample specimens obtained by established procedures that patients undergo routinely for the treatment of his/her recurrent cancer; there was no additional risk to the patient. Tissue for this study was obtained by patient consent and after it was assured that there was adequate tissue for routine histologic analysis. At no time tissue was obtained solely for carrying out the ChemoID assay. No investigational agents were included in the trial. There were no greater than minimal risks associated with this study since all chemotherapy drugs used were FDA-approved for the treatment of recurrent 2016-WHO grade III or IV gliomas. | PMC10213810 |
Patient tumor sample collection and processing | glioma | GLIOMA | Inclusion criteria included patients 18 and older with first-recurrence of grade III or grade IV glioma (according to the 2016-WHO guideline classification), | PMC10213810 |
Isolation of cancer cells from tumor biopsies | agitation, tumor | TUMOR, RESIDUAL TUMOR, BRAIN TUMOR, STERILE, PRIMARY TUMOR | To generate the primary tumor cell cultures, the fresh brain tumor tissue from surgical biopsies was minced using sterile scalpel blades and gently dissociated in a biosafety cabinet using 0.025% trypsin solution at 37°C for 10 min with gentle agitation and intermittent resuspension. Dissociated tumor cells were plated in RPMI with 20% FBS, 1% Penicillin/Streptomycin, Gentamycin Sulfate (complete media) in sterile plastic Petri dishes in the presence of residual tumor tissues and incubated at 37°C humid tissue culture incubator in the presence of 5% CO | PMC10213810 |
Enrichment of cancer stem cells (CSCs) | tumor, primary cancer | TUMOR, PRIMARY CANCER | Patient-derived CSC cultures were obtained as previously described in.CSCs from primary cancer cells (bulk of the tumor cells) were enriched by loading 2x10ˆ6 bulk of tumor cells into the bioreactor and culturing them for 7- days in RPMI media in the absence of growth factors. | PMC10213810 |
Assessment of CSCs' and bulk of the tumor chemotherapy response | tumor | TUMOR | Treatments with anti-cancer drugs and sensitivity tests were performed as described previously in.96-well plates are seeded in RPMI-1640 with 10% FBS, penicillin and streptomycin with a minimum of 20,000 individual tumor cells per regimen of bulk tumor cells or CSCs in 5 replicas and incubated at 37°C in a 5% COAfter the 1-h exposure, the treatment media containing the various chemotherapies were removed and replaced with fresh media. MTT assay was performed 24 h following chemotherapy treatment to assess cell survival as previously described.Inhibition of bulk tumor cells and CSCs survival was measured for each concentration (average counts in five replicates ±SE) of a given treatment (for a total of 15–18 different treatments per patient). Survival of tumor cells at each concentration was calculated as compared to control-2 and the overall percent of the bulk of tumor cells and CSCs killed was calculated for each treatment as the primary measures of potential therapy efficacy. | PMC10213810 |
Reporting of the assay | Percent survival (potential therapeutic efficacy) was calculated relative to appropriate negative and positive controls for each treatment. Efficacy and resistance of each drug and combinations were reported on the ChemoID assay results as a continuous number from <10% to 100% cell-kill as previously. | PMC10213810 |
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Quantification and statistical analysis | REGRESSION, SECONDARY | All statistical analyses followed the plan specified in the protocol with no deviations and were completed using Stata v17.1 (StataCorp) by independent biostatisticians. Two prespecified interim efficacy analyses were planned Baseline characteristics were compared using t-tests or Mann-Whitney U tests, as appropriate, for continuous and ordinal variables and Fisher’s exact tests for categorical variables. Kaplan-Meier curves were constructed using established methods, and median survival was calculated from these curves. Primary OS and secondary (PFS) HRs were constructed using Cox proportional hazard models with baseline HRs stratified by clinical site. Variance component estimation was performed via bootstrap resampling using 1000 bootstrapped replicates. Specific time-point survival probabilities (6, 9, and 12 months) were calculated using marginal probabilities obtained via logistic regression models, and associated odds ratios were reported. Additionally, an exploratory analysis was performed using a 1- or 1.5-year restricted mean survival time (RMST) to quantify the treatment effects. | PMC10213810 |
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Baseline data | As per protocol, initial analyses involved data cleaning, variable development, and exploratory data analyses. We used standard summaries to describe baseline characteristic distributions in terms of centrality, spread, shape, and possible outliers by arm, cohort, and treatment group. Graphical explorations emphasized the examination of the nature and extent of potential nonlinear relationships on the appropriate modeling scale (e.g. natural, log, logit, etc.) | PMC10213810 |
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Efficacy analysis | tumor | REGRESSION, TUMOR | The primary analysis was based on an intention-to-treat approach and included all subjects randomized at baseline. The primary efficacy outcome was overall survival (OS) in months. This outcome was compared between patients randomized to ChemoID-guided chemotherapy) versus standard of care. OS comparisons were examined using Cox Proportional Hazard Models for Overall Survival with baseline hazards stratified by site and medians were compared between treatment arms. Models examining adjustments for sex, race, age, and tumor stage were constructed, as well as for moderating effects of these variables (subpopulation investigations).Secondary analyses included logistic regression models for Overall and Progression-Free Survival at 4, 6, 9, and 12 months, Cox Proportional Hazard Models for Progression-Free Survival in months, Generalized Linear Models (GLMs) for analyses on objective tumor response (RANO), and Health-Related Quality of Life (HRQOL). Generalized Linear Mixed Models (GLMMs) were used for analyses of changes in any additional repeated outcome measures to incorporate within-person associations and examine distributions of participant-specific declines. Huber-White robust standard errors were used, and multiple variance structures were investigated to examine the sensitivity of primary analyses to the choice of association model. Shared Parameter Models (SPM) were used to examine any potential informative missing data effects. | PMC10213810 |
Interim analysis | We performed a predetermined interim analysis as per protocol. From the clinical trial protocol, two interim analyses based on the alpha spending approach of Lan and DeMets could be performed. One would be performed whenever 35 patients had passed away. If both the observed HR was less than or equal to 0.55 and its related p-value was less than 0.0167, the trial may be stopped for efficacy at this point. If the trial continued, the second interim analysis would take place after 70 people had expired. If the observed HR was less than or equal to 0.55 and its corresponding p-value was lower than or equal to 0.0218, the trial could be stopped for efficacy at this point. | PMC10213810 |
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References | PMC10213810 |
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Supplemental information | PMC10213810 |
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Document S1. Figures S1–S5 and Tables S1–S5 | PMC10213810 |
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Document S2. Article plus supplemental information | PMC10213810 |
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Acknowledgments | We thank all of the patients and their families who participated in this study. We are grateful to all coordinators and research staff at all study sites for their contributions. The authors gratefully acknowledge Logan Lawrence, Donna McIlvain, and Veronica Mayes for technical assistance with the assay. We thank Drs. Daniel Krummel and Josh Neman-Ebrahim for critically reviewing the manuscript. Cordgenics, LLC provided the funding support and resources for the ChemoID assay and had no role in the analysis and interpretation of the data. S.S. is supported by the | PMC10213810 |
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Author contributions | T.R., M.J.G., S.S., A.M.A., J.V., and P.P.C. designed the study. T.R., S.S., M.J.G., S.L.T., and C.M.H. drafted the manuscript. T.R., S.S., M.J.G., R.M.G., A.Y., D.A., R. Chaudhary, R. Chen, M.Z., C.L.-E., H.D.M., N.B., J.G., A.M., M.A., N.M., J.S., S.J., F.C., A.M.A., S.T.L., K.L.D., and C.M.H. carried out the investigation, had access to the data, interpreted the analyzed data, and had final responsibility for the decision to submit for publication. All authors critically reviewed the manuscript and approved the final version. An independent data manager and the senior authors had access to all of the data in the study and take responsibility for the integrity of the data. Two independent groups of statisticians had access to all of the data in the study and take responsibility for the accuracy of the data analysis. | PMC10213810 |
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Declaration of interests | P.P.C. and J.V. report ownership of intellectual property rights on the CSC platform technology licensed to Cordgenics, LLC. | PMC10213810 |
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Inclusion and diversity | One or more of the authors of this paper self-identifies as an underrepresented ethnic minority in their field of research or within their geographical location. While citing references scientifically relevant for this work, we also actively worked to promote gender balance in our reference list.Supplemental information can be found online at | PMC10213810 |
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Background | RECRUITMENT | The use of decentralised clinical trials (which bring trials to patients through remote processes and technology versus central on-site visits) has been thought to be a potential solution to common recruitment and retention barriers. However, there is a lack of evidence to understand the experiences, needs and preferences of the public to inform trial methodologies that appeal to different populations. We report participant experiences of SAFA, a partially decentralised randomised clinical trial, to inform the methodology used in future dermatology trials that aim to appeal to women aged 18 and over. | PMC10568833 |
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Methods | Acne | ACNE | Participants of the SAFA (Spironolactone for Adult Female Acne) trial were invited to take part in a qualitative semi-structured interview to explore their experience and perspectives of taking part in the trial. Questions focused on their experience of using decentralised methods to access and enrol in the trial (e.g. social media advertising), in addition to the decentralised trial visit and data collection methods used throughout. Interviews were conducted remotely, recorded, and transcribed. Data were analysed using reflexive thematic analysis. | PMC10568833 |
Results | Twelve SAFA participants (all women, age range 22–36 years) were interviewed. Initially, participants were influenced to enrol by trusted online information, the feeling of validation the trial provided, and the convenience and flexibility offered by the decentralised methods and research staff made participants feel valued and enabled them to engage in the trial with minimal interference to existing commitments. SAFA participants were generally accepting of trial demands, such as the text-heavy paperwork and on-site visits for blood collection and highlighted several areas relevant for trial conduct going forwards including where decentralised methods may (and may not) be accepted and how trial accessibility and understanding could be improved. | PMC10568833 |
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Conclusions | RECRUITMENT | The study has shown that decentralised methods used by responsive and approachable staff were widely accepted in the SAFA trial. Interviewees found the methods adopted in the SAFA trial helped the trial to fit with their needs and promoted a sense of feeling valued that encouraged ongoing trial engagement. Decentralised methods should be considered favourably when designing a dermatology trial as they can potentially enhance both recruitment and retention. | PMC10568833 |
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Trial registration number | ISRCTN 12892056. Registered on October 15, 2018. | PMC10568833 |
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Supplementary Information | The online version contains supplementary material available at 10.1186/s13063-023-07630-4. | PMC10568833 |
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Keywords | PMC10568833 |
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Background | Acne | ACNE, RECRUITMENT, RECRUITMENT | People’s willingness to volunteer their time to participate in clinical trials is crucial to the development of evidence that advances clinical treatment and healthcare practice. Recruitment and retention of participants have continued to be two of the largest challenges to date, with over half of the trials failing to meet recruitment targets, resulting in insufficient data, trial delays, increased costs and ethical concerns [Known barriers to participants enrolling on trials include fear of perceived risk, transport, time, distrust, and aversion to randomisation [Cochrane systematic reviews have shown there is a need to generate evidence-based solutions to these common barriers and to encourage participants to enrol and continue participation in research [The use of decentralised trials (which bring trials to patients through remote processes and technology versus requiring them to visit a central research site [COVID-19 has been the catalyst for a 93% increase in the use of digital technology to conduct decentralised trials as an alternative to in-person visits between 2020 and 2021 which is continuing to grow [Many dermatology trials are considered non-life threatening and rarely require complex examinations, leading some to believe that decentralised trials may be an attractive option for this type of research [This qualitative study aimed to explore the motivators and barriers to initial enrolment and ongoing participation in the partially decentralised dermatology trial called SAFA (Spironolactone for Adult Female Acne) and contribute to the following James Lind Alliance PRioRiTy questions on recruitment and retention, respectively [What are the key motivators influencing public decision to take part in an RCT?What motivates a participant to complete a clinical trial? | PMC10568833 |
Method | PMC10568833 |
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Setting | Acne, telephone/video, acne, acne vulgaris | RECRUITMENT, ACNE VULGARIS, SECONDARY, ACNE, ACNE | This was a qualitative sub-study conducted alongside a UK primary and secondary care phase III, double-blind, placebo-controlled trial of Spironolactone for persistent (at least 6 months) facial acne vulgaris for women aged 18 and over (Spironolactone for Adult Female Acne (SAFA) trial, Fig. SAFA trial schemaThe SAFA trial recruited participants from 05 Jun 2019 to 31 Aug 2022, with an enforced pause to recruitment from 23 Mar 2020 to 11 Jun 2020 due to the COVID-19 pandemic. Participants were recruited through primary care (search and mail-out or opportunistic recruitment), secondary care (opportunistic recruitment) and community and social media advertising.The SAFA trial was designed as a pragmatic trial with minimal burden (e.g. in-person visits, number of spironolactone retrievals from pharmacy) for participants, and required three in-person visits (baseline, 6 weeks and 12 weeks) with postal questionnaires at 24 weeks and up to 52 weeks. Due to the COVID-19 pandemic, the trial further decentralised to reduce in-person contact, specifically: all visits except the baseline visit could be replaced with telephone calls or video calls, acne assessment photos could be taken and sent to staff by participants, and trial medication that originally required on-site collection by participants was delivered to their home where necessary. Baseline visits required blood and pregnancy tests, so these remained in-person visits at research sites. These changes were sustained beyond government-enforced lockdown for the duration of the trial.This qualitative sub-study aimed to explore participants’ experiences of taking part in the SAFA trial, in particular their experience of recruitment to the trial, the experience of appointments during the trial and/or telephone/video appointments and any difficulties participating in the trial to inform dermatology trial methodology targeted towards women aged 18 and over. Standards for reporting qualitative research (SRQR) guidelines have been followed (Supplementary file | PMC10568833 |
Sampling strategy | RECRUITMENT | Participants enrolled in the SAFA trial were invited to take part in an optional qualitative interview with no monetary incentive. Participants were invited to take part opportunistically (based on their willingness and ability) by research staff at sites or by unblinding letters at 24 weeks. The total number of invited participants by research sites is unknown because they were not requested to keep a log, and 174 were invited through an unblinding letter sent 28 weeks after their baseline visit. Trial participants who were interested in being interviewed were asked to email the SAFA qualitative study mailbox accessed by the researchers conducting interviews (CB, AS, CC), who then responded to them via email to provide the Qualitative Research Information Sheet and Qualitative Interview Consent Form. There was no decline slip, therefore the reasons for not taking part are unknown. Once a hand or electronically signed consent was received, the interview time was confirmed and subsequently conducted by telephone or video call (participant preference). Participants were asked if they had questions during the recruitment process and again immediately before the interview.The qualitative sub-study was not funded as part of the trial and resources and ethical approval for this only later became available. Trial recruitment ran from June 2019 to August 2021, whilst invitations for qualitative interviews started in August 2021. | PMC10568833 |
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Interviews | To understand and interpret the subjective experiences and perspectives of the individuals being interviewed, and acknowledge the researcher’s role in shaping the meaning of the findings, the research questions were addressed with a constructivist approach [Three members of the research team (two students and one research fellow), independent from the SAFA trial, conducted the interviews (CB, AS, CC) from October 2021 to February 2022. All identifiable data were anonymised, and quotes were labelled with pseudonyms at the write-up. The duration of the interviews was on average 28 min (range 19–39). All interviews were transcribed verbatim, error-checked and data were handled using NVivo10. | PMC10568833 |
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Analysis | Reflexive thematic analysis [ | PMC10568833 |
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Ethics | Ethical approval for the trial was granted by Wales Research Ethics Committee 3 in January 2019 (reference number: 18/WA/0420). An amendment approving the qualitative sub-study was granted in August 2021. | PMC10568833 |
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Results | Twelve SAFA trial participants completed an interview (Table Characteristics of interview participants | PMC10568833 |
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Theme 1: the influence of trust when deciding to enrol | ’d, I’d been reading, acne | ACNE | This first theme describes participants’ motivators for enrolling on the trial and factors that they described as important in this. Many participants had tried and tested new treatments for acne off the shelf or through their doctor, but due to a lack of effective results continued to read about possible treatment options on websites and online acne communities.Many participants belonged to Facebook groups, Reddit forums and reported using the internet to contribute and read about acne treatments, which led some to be aware that Spironolactone is used as a treatment in America.I found out about it [Spironolactone] on Reddit..it’s sort of like a forum/social media site. The way it works is there’s different communities on there, where people can put up posts and share things. There’s one dedicated to skincare and I’m part of a worldwide skincare one. Katy, age 27Due to the trusted information received from this source, several participants were already aware of the use of Spironolactone for acne and unsuccessfully sought it from their GP. It is possible that when they became aware of the SAFA trial, they saw an access point to a new but familiar treatment. This familiarity may have contributed to their low level of safety concern.I’d been reading about spironolactone and hearing about it, because it’s used widely in America. I’d actually tried to acquire some off licence, through my GP, years ago. I actually thought it was a very good thing, because I’d already known about it - then the success they’ve had in America, where it is used widely. Natalie, age 27Had the drug been an unknown one, I would have not been so keen to take part. Helen, age 30Participants felt that advertisements for the trial were produced to a high standard of quality and not something easily produced by the layperson, which in combination with the affiliated University and NHS logos, were a strong sign of legitimacy.It was at the University of [University Name], or [Hospital Name] Hospital, so yes, went and just applied. Sam, age 25Participants that enrolled through social media felt that it provided a safe, low-effort and direct access point to research from home and a seamless transition into the trial.I was worried there might be loads of hoops to jump through and it would end up dragging on for so long that I’d give up! But actually it was really quick and easy to get involved. Laura, age 36One concern reported by participants was the self-taken digital photo used to assess the severity of their facial acne and eligibility for the trial. Many worried the photos would not provide an accurate representation of their skin due to the lighting or picture clarity, with concerns that the severity of the acne might not be recognised.I had to take my own photos of my skin and send them in for the doctor to review, and then you’ve got, obviously, the deep concerns for my end, as did I get the right photos? Are they clear enough?..it’s very different sending in a photo than someone actually physically looking at your skin face-to-face. Linda, age 32Concerns of inaccurate representation raise issues around participants’ trust in the digital assessment process and subsequent validation of the severity of their acne. | PMC10568833 |
Theme 2: the feeling of validation | ’d, acne | SAID, ACNE | This second theme describes how participants felt a sense of validation from the opportunity to take part in the SAFA trial. Many participants reported that previous treatment had been ineffective and felt that the burden of acne was not considered as serious by their GP. Access to the SAFA trial appeared to counter these feelings and made patients believe their acne was being ‘taken seriously’.Some women, before becoming aware of the SAFA trial, had approached their GPs and, unsuccessfully, requested Spironolactone as a treatment option. Once enrolled participants said they felt grateful that they could try a new treatment and receive access to specialist support that they otherwise may not have had.My GP had never put me forward to go to the hospital. She’d always just said try different things. Seeing a nurse who is like a dermatologist specialist, and like the doctor, was really useful. Jasmine, age 22Participants described how, from initial contact, site research staff delivering the trial had a significant impact on their experience. Participants discussed how they felt valued when they received a quick response to their online expression of interest, which included being talked through the trial remotely or in person by a member of the research team and the opportunity to ask questions.I found that the team at the Hospital were really friendly and welcoming.. I was also kept informed by the team at the hospital about next steps, and that was explained really well to me. I felt like they were really welcoming for me to ask questions as well. I had a really positive experience. Katy, age 27The importance of making time to talk to participants was highlighted when one woman shared her experience of feeling bombarded with medical jargon, questions, and a lot of information during her in-person visits. She justified the experience by believing it was the nature of the job and the strain COVID had put on the staff.The lady who ran those [in-person visits], she sometimes was practically running in front of me from room to room and it was just all very like [makes sound], it’s quite hectic.. I just needed a bit of time to go through it a bit slower with me and help me understand what they were saying. Emily, age 26Participants appreciated being provided with the choice of how to complete their follow-up trial visit (e.g. in-person or remotely). Providing the option allowed many to overcome work, care and travel barriers in a time-efficient manner and because the trial and research teams worked around them, it made them feel as though their input was valued...I was getting all the kids in the car ready for the school run and she was like, ‘Are you sure you can talk now?.. She was always happy to call back or call around what I was doing. So that was really good; very flexible. Kat, age 30 | PMC10568833 |
Theme 3: offsetting participant burden with the understanding of trial needs | dyslexia, pain, acne, ’ | MINOR, ACNE | Study participants reported an’ overwhelmingly positive experience and trust in the research staff, which often led them to overlook minor inconveniences. However, when asked directly about certain aspects of the trial, and more broadly, what could be done to improve their experience there were several suggestions. This third theme explores how trials may be improved from participants' experiences.Some participants described the ‘massive booklet about the study’ (the participant information sheet) they received as part of the introduction to the trial as ‘intense’ and ‘complicated’ which caused them to delay reading it. However, all appeared to understand the purpose of the information sheet. One participant with dyslexia showed consideration for those who may have additional learning needs or were slightly less confident when accessing and understanding the information in the written information sheets.The information sheet..was quite wordy! For people that maybe have additional learning needs, they may have benefitted from maybe bigger text, or different colour text on different coloured background, but that's just me putting a dyslexic mind to it. Emily, age 26It was the combination of the written information and clear explanation with research staff that enabled participants to understand different components of the trial, including randomisation, trial tasks and the possibility of receiving a placebo.When asked about their feelings regarding the possibility of being randomised to placebo, most hoped they were on the active drug but also that they ‘knew exactly what they were signing up for’. Despite the potential disappointment of receiving the placebo, participants felt it was important that they were contributing to finding better treatments for women with acne.I was on the placebo then I still would have taken part in something that ultimately will help people with acne, so yes, I wasn’t upset about being on the placebo either because it’s gone a long way, I hope, to help the medication being more available for other women with acne. Emily, age 26One participant, who believed she was receiving the placebo because the drug she received did not match descriptions of Spironolactone on the internet, committed to the trial for 6 weeks before leaving because she felt it was not a good use of personal time. This individual was subsequently prescribed Spironolactone and found the treatment effective by 3 months.I’ve been dealing with this for the past two to three years now; you get to a point where unfortunately I just didn’t feel that I had that time to spare. As much as I’d like to help medical research, it had gone on long enough for me and I needed a solution by that time. Liz, age 36When asked about the questionnaires, the belief in the research team led many to feel that the volume of data being collected and the questions themselves, although an inconvenience, must be needed and generally accepted as being ‘part and parcel’ of the study.I mean one thing that was a bit of a pain with it, but, again, it’s one of those things where like it’s part of the process and it has to be done, was that one of the questions felt quite redundant and repetitive. Natalie, age 27On reflection, participants felt they could have provided more accurate questionnaire answers to reflect any change if they were able to keep their completed questionnaires.It was quite difficult when I didn’t have my previous set of answers to actually even remember where, on this arbitrary scale, I had placed myself. I was giving a number, but I was like, ‘Is that higher or lower than the number I gave last time?’ because I want it to be lower or I want it to be higher. Shok, age 24Last, although accepted as a consequence of participating in the trial, on-site visits to provide blood samples and collect research drugs from the pharmacy brought up frustrations around hospital parking and the long period such appointments took.to have my bloods taken at phlebotomy took 40 minutes extra out of the appointment time. Linda, age 32The parking at the hospital’s not easy! It’s quite expensive. It was a little bit challenging getting an appointment around work. Kat, age 30 | PMC10568833 |
Discussion | acne | ACNE | This paper described the experiences of participants taking part in a partially decentralised dermatology trial [For many interview participants, their first interaction with the SAFA trial was through the social media advert. Findings from this study show that trusted affiliations and the perceived quality of the social media advert increased initial trust, which is a particularly important motivator that should be focused on during social media advertising campaigns [In a broader context, the themes of trust and validation align with a recent overview of systematic reviews focused on psychosocial barriers and facilitators [Commonly reported barriers to trial participation include fear, perceived risk and practical difficulties [Building upon the significance of trust and validation it’s important to discuss the comprehension of the different components of the trial and its role in participation and engagement. A recent meta-analysis revealed that the proportion of participants in clinical trials who understood different components encountered during informed consent (e.g. placebo, randomisation, study purpose) ranged from 52 to 76% [Also, interview data from this study suggest that participants believed they may be able to provide more accurate data in follow-up questionnaires if they had access to previously completed versions. The impact on questionnaire validity should be carefully considered alongside existing guidelines on optimal questionnaire design and administration to enhance completeness in a clinical trial [A primary concern raised by participants was around the photographic acne assessment. A recent meta-analysis suggested that ‘teledermatology’ diagnoses are less reliable than those made in person [Future trials may consider the use of image validation software that can provide instant feedback to participants, and participants should be assured that where there is doubt, they will be invited to attend a face-to-face appointment. | PMC10568833 |
Strengths and limitations | RECRUITMENT | The strengths of this study include its novelty and potential application and impact in practice. To our knowledge, this is one of the first trials exploring the impact of decentralised methods on participant enrolment and ongoing engagement in a dermatology trial.Some limitations of this study should be considered. We captured the experiences of SAFA participants who volunteered, without incentive, to take part in this qualitative sub-study and for this reason, there may be some inherent selection bias in the attitudes of those who took part. We did not interview eligible participants who chose not to enrol, who may have had different views from those who chose to participate in the qualitative interview. Non-recruited potential participants may have been able to provide insight into deterrents of participation to understand what may be adapted to make the trial more attractive to take part in. In addition, some interviews were carried out up to 8 months after a participant had completed the trial, which made some details of the trial hard to recall for some participants (e.g. details of the questionnaire). A larger sample size may have raised previously uncovered topics of interest. For this reason, future evaluations should be included, where possible, from the trial start with participants and non-participants. Participants should also be allowed the opportunity to share why they have declined the interview, which could inform recruitment strategies. | PMC10568833 |
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Future research | RECRUITMENT | Continued efforts should be made to understand what and how different trial conduct methods can improve accessibility and understanding to enhance trust and influence enrolment and ongoing engagement in trials.The role of infographics and videos during recruitment to improve viewer understanding is a growing area of research [Also, with consideration for ethical issues [Some participants in this study expressed frustrations when they did need to attend the hospital site for trial urine and blood tests, which highlights a relevant consideration for trial methodology going forwards. Home-based blood sample collection and drug delivery to home have recently increased in popularity [ | PMC10568833 |
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Conclusions | RECRUITMENT | If applied appropriately, the use of decentralised methods has the potential to influence the enrolment and ongoing participation of dermatology trial participants and help address well-known recruitment and retention issues amongst research communities [This study was aimed at women aged 18 and over, the key practical findings will therefore be of interest to trialists and healthcare professionals wishing to target this population for future interventions. | PMC10568833 |
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Acknowledgements | We would like to thank the participants for sharing their experiences and express our sincere gratitude to the staff who carried out the SAFA trial at recruiting centres including; hospital dermatology centres recruiting for the study: Queen Elizabeth Hospital, Birmingham; Bristol Royal Infirmary Dermatology Centre, Bristol; University Hospital of Wales, Cardiff; General Hospital, Epsom; District Hospital, Harrogate; St Mary’s Hospital (Imperial College NHS Healthcare Trust), London; Queen’s Medical Centre, Nottingham; General Hospital, Poole; St Mary’s General Hospital Dermatology Centre, Portsmouth; Swansea Bay University Health Board, Swansea; participant identification centres (PICs) for searching their patient lists and mail outs and clinical research networks for helping to identify potential PICs. | PMC10568833 |
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Authors’ contributions | SR, ZE, JN, AL, CW, IS and MS all contributed to the study design. IS, IM and MS were involved in the development of the topic guides. CB, AS and CC were responsible for data collection. CB, AS, CC, IM and MS conducted data analysis and interpretation of the results. All authors were involved in the preparation of the manuscript and approved the final version to be published. | PMC10568833 |
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Funding | This project is funded by the National Institute for Health Research (NIHR) Health Technology Assessment (HTA) programme (Grant Reference Number: 16/13/02) and supported by NIHR CTU support funding at Southampton CTU. The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care. The NIHR HTA funder will play no role in the execution, analysis, interpretation of data, or study publication. The study is registered on the UK NIHR study portfolio meaning there are research nurses based at UK hospitals who help in screening potential patients to identify those eligible for the study.Southampton CTU, an NIHR CTU support-funded UK Clinical Research Collaboration registered CTU, is coordinating the study. The University of Southampton is the sponsor for the study. | PMC10568833 |
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Availability of data and materials | The datasets generated and/or analysed during the current study are not publicly available to protect the identity of the participants but are available from the corresponding author on reasonable request.The standards for reporting qualitative research and topic guides used to inform the interviews are available as supplementary material.Please direct all data enquiries to the corresponding author. | PMC10568833 |
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Declarations | PMC10568833 |
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Ethics approval and consent to participate | The SAFA trial and qualitative sub-study received a favourable ethical opinion from the Wales Research Ethics Committee (18/WA/0420) and has Health Research Authority approval (IRAS 246637).All participants provided informed consent to participate in the qualitative interview. | PMC10568833 |
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Consent for publication | Not applicable. | PMC10568833 |
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Competing interests | The authors declare that they have no competing interests. | PMC10568833 |
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References | PMC10568833 |
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1. Introduction | URTIs, infections, upper respiratory tract infections | UPPER RESPIRATORY TRACT INFECTIONS, INFECTIONS | Bovine colostrum is considered to provide anti-infective protection. Here, we present the first randomized controlled trial (RCT) aimed at assessing the preventive use of colostrum against upper respiratory tract infections (URTIs) in healthy pre-school children. We analyzed 57 children—35 in the colostrum (COL—dried bovine colostrum) and 22 in the placebo (PBO—dried whey) group, who received these substances as follows: first 15 days 2 × 500 mg and then 30 days 1 × 500 mg. The reporting on the children’s health status, specifically on the frequency and gravity of URTI symptoms and abdominal side effects, was performed via an online survey. The influence of colostrum on the frequency of days with URTI symptoms remained significant until the 20th week of observation and reached 31% of median reduction. The median reduction reached 37% when the gravity of symptoms was analyzed. When we grouped symptomatic days into episodes of second gravity level, the reduction in their frequency was even larger (50%) and lasted until the end of the trial (21 weeks). No significant side effects, especially abdominal, were reported during the trial. Colostrum supplementation in pre-school children is well tolerated, safe and provides protection from frequency of URTIs and their gravity.Of all childhood health issues, upper respiratory tract infections (URTIs) seem to be the most common problems, according to various authors, as they typically occur 3–8 times a year [Limiting the number and gravity of URTIs with the use of various approaches has been a goal of medicine throughout its entire history, usually with a limited degree of success. Traditionally, the preventive attempts included the use of several natural products derived from plants or animals, including probiotic supplementation [Bovine colostrum has long been claimed to have the potential to modulate and boost human immunity to infections. However, valid clinical tests have only proven this for selected groups of subjects, such as those represented by either extreme physically active or heavily stressed out and overworked adult individuals [Considering the above and recognizing the great importance of conclusively establishing whether the bovine colostrum is capable of preventing URTIs in healthy children, we decided to perform a triple-blind placebo-controlled trial in an attempt to resolve this issue. The trial was performed concomitantly with a group of pre-school children attending one of the only two kindergarten facilities participating in the study. This was aimed to reduce the bias resulting from participants being exposed to unpredictable pathogens’ variety related to seasonal shift and to various environmental factors. Our team recently conducted a survey-based study on the effectiveness of colostrum in prevention of URTIs among medical university students [ | PMC10459079 |
2. Materials and Methods | PMC10459079 |
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2.1. Recruitment, Blinding and Randomization | allergy | RECRUITMENT, ALLERGY, POLAND | All trial subjects were pre-school children (3–7 years of age; mean, 4.3 ± 1.21 years; male to female ratio—1:0.8) attending one of the two large (over 300 pupils) public kindergartens facilities in Szczecin, Poland. Trial participants were invited through the advertisements posted in these facilities. The only exclusion criterion was an allergy to cow’s milk. The general health status of all participants was considered to be good, suitable for participating in kindergarten activities.Trial administration, which included the enrolment process, collection of formal consent forms, blinding and randomization of participants and database maintenance, was performed by a dedicated person—the administrator. He was also the only person who contacted participants via email and provided them with links to the online survey forms (both the initial and daily/weekly surveys). The polls the participants responded to were based on the EU Survey system, an official online survey management tool provided for free by the European Commission [After receiving the approval by the Ethical Committee of the Pomeranian Medical University in Szczecin, the study also obtained the acceptance from the managements of both facilities where the children were enrolled. The recruitment of participants began with a series of meetings where parents and guardians were provided with a comprehensive explanation of the study principles in both verbal and written form. They were given the opportunity to ask any questions regarding their child’s participation in the trial.We obtained formal consent forms from the parents and guardians of 89 participants. Upon recruitment, the administrator immediately assigned a trial ID number to each participant, by which they were referred to for the rest of the trial. This way, the identity of all children remained anonymous to all investigators (including cooperating kindergartens managements), as well as other participants (parents and guardians), until the completion of data analysis. Upon blinding, the random assignment to tested groups was performed with the MS Excel Random Sort tool. Out of 89 participants recruited, we were able to form the colostrum (COL) group consisting of 45 children and the placebo (PBO) group consisting of 44 children. | PMC10459079 |
2.2. Outline of the Trial and Participation Issues | URTIs | To ensure a more coherent population, particularly in terms of exposure to infectious agents responsible for the URTIs, we included children from just two kindergartens in the trial. This helped to minimize potential variations in exposure and create a more homogenous study population. To increase the consistency of trial conditions further, we conducted the study in exactly the same timeframe between the end of September and mid-February, when the risk of contracting the URTIs is highest in our geographic zone. The rationale behind such a design was fully explained in the report from our previous study with medical university students [After blinding and randomization processes were completed by 29 September 2022, the parents and guardians were invited to collect the supplemented material sufficient for the entire period of the trial. The appropriate packages identifiable only by the trial ID numbers were distributed by the management of the kindergartens in which the trial was conducted. At this stage, 14 participants (2 from the COL group and 12 from the PBO group) were excluded because of not collecting the supplement despite the repeated summons. We found no rational explanation for such a disparity in the collection of supplements between the COL and the PBO group participants.Immediately after the beginning of supplementation, 3 additional participants resigned (1 from the COL group and 2 from the PBO group) without specifying any reason. After 4 months of the trial, 2 additional participants resigned (1 from the COL and 1 from the PBO groups), again without providing the reason for withdrawal. Out of the 70 participants who remained in the trial until its completion, we made the decision to exclude an additional 13 participants (5 from the COL group and 8 from the PBO group) from the final analysis, due to their poor consistency in responding to daily surveys. The minimal response rate was established at 80% of daily surveys.The trial started on 1 November 2022, upon the signal given by the administrator to all participating children. Over the first 15 days, the participants were taking 2 of the 500 mg sachets of supplementation material per day. They were supposed to take one sachet in the morning and one in the evening on an empty stomach, with water or with a teaspoon of natural yogurt. Then, for the following 30 days, the administration schedule consisted of just one sachet in the morning, and after 45 days, the supplementation period terminated.In addition to that, the parents and guardians were instructed to give 8 consecutive doses of the supplementation material (twice daily for 4 days) to their children whenever symptoms of newly developing URTI occurred until the end of the trial. The trial lasted for 147 days until 24 February 2023, when daily surveys were terminated. | PMC10459079 |
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2.3. Supplementation Material | POLAND | The tested materials’ packages, consisting of 100 unlabeled pouches containing either COL or PBO, were provided free of charge by Genactiv Trade Sp. z o. o., Poznań, Poland. The COL sachets contained a mixture of 500 mg of freeze-dried bovine colostrum obtained within 2 h after calf delivery, mixed with 500 mg of dried banana powder. The PBO doses consisted of 500 mg of spray-dried whey mixed with 500 mg of dried-out banana. These were the typical supplementation materials’ doses that were efficiently used in our previous experiments, causing measurable biological effects [ | PMC10459079 |
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2.4. Surveys | The online surveys allowed us to gather all the information on the health status and other important health-related parameters from trial participants. These surveys were provided to their parents and guardians through direct links sent via email, using the EU Survey tool [Three types of surveys were used in this trial were (1) initial, (2) daily and (3) weekly. Through the initial survey, we obtained the data needed for descriptive statistics and an overview of the characteristics of the trial participants. The daily surveys were the most important source of data for our experiment. Their questionnaire consisted of 6 questions, with the most important of them focusing on the participants’ health status, particularly inquiring about the severity of the URTI symptoms. Our weekly surveys served to enumerate days with any potential gastrointestinal side effects.The inquiry about the gravity of the URTIs symptoms was based on the following original scale, effectively introduced in our previous study, [ | PMC10459079 |
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2.5. Outcomes | SECONDARY | Our first primary outcome was the frequency of days with any URTI symptoms (FSD—frequency of symptomatic days). This was the ratio calculated based on enumerating days with presence of any degree of URTI symptoms (1–3 URTI score) and dividing this by the number of days within the period of interest (Our second primary outcome was the average gravity score (AGS) of URTI symptoms. This was a ratio calculated after summarizing the URTI scores (0–3) and dividing them by the number of days within the period of interest.Both of the primary outcomes were analyzed over the entire 21-week (147 days) period of the experiment, as well as within several periods, namely 4, 8, 12, 14, 16, 18 and 20 weeks counted from the beginning of supplementation.Our secondary outcome was the number of URTI episodes (NUE) over the entire trial period. This required finding a subjective definition of an episode, which would fit the most accurate medical description of URTI and allow for a credible enumeration of such episodes in our trial. We decided to define an URTI episode as at least 3 days of symptoms at the 2nd severity level, being separated by at least 3 asymptomatic days. | PMC10459079 |
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2.6. Statistical Analysis | Statistical analyses were performed with the use of Med Calc statistical software version 22.110 (Ostend, Belgium). Two-sided | PMC10459079 |
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2.7. Bioethical Approval | MAY | The trial was performed in accordance with the protocol approved by the Pomeranian Medical University Bioethics Committee (KB-006/24/2022) on 18 May 2022. | PMC10459079 |
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3. Results | PMC10459079 |
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3.1. Study Group Characteristics | We analyzed data from 57 children—35 in the COL group and 22 in the PBO group. There were no significant differences regarding gender distribution between groups ( | PMC10459079 |
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3.2. Colostrum Decreases Frequency of Days with URTI Symptoms | URTIs’ | The main measure of URTIs’ occurrence used in our experiment was the frequency of days with URTI symptoms (FSD) over various periods of the trial. When analyzing all days with any severity level of URTI symptoms over a period of 21 weeks from the beginning of the trial supplementation, which was the entire period of daily survey collection, the results were found to be at the border of statistical significance (Testing the same at weeks 8, 12, 16 and 18 of the trial produced statistically significant differences between the COL and the PBO groups, with the reduction in FSD medians ranging between 30% and 37% ( | PMC10459079 |
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3.3. Colostrum Reduces Average Gravity Scores of URTI Symptoms | AGS | Our second primary outcome, the average gravity score of URTI symptoms (AGS), was assessed based on reporting to daily surveys on the intensity of symptoms according to the grading scale described in the Material and Method section. Parallel to the result obtained with FSD, when this parameter was analyzed over 21 weeks, the results reached a near-significant level (At weeks 4, 8, 12, 14, 16 and 18 of the trial, testing the same parameter showed that colostrum provided variable but consistently statistically significant protection from the gravity of URTIs, as assessed by the reduction in AGS medians in the COL group compared to the PBO group. This reduction ranged between 33% and 45% ( | PMC10459079 |
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3.4. Colostrum Reduces Number of URTI Episodes | EVENTS, SECONDARY | Due to the difficulty in defining URTI events, especially based on the self-reported URTI symptom days, we decided to use the number of URTI episodes (NUE) over the entire duration of the trial as a secondary outcome. At week 21 of the trial, there was a statistically important difference between the result obtained in the COL group versus the PBO group ( | PMC10459079 |
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3.5. Colostrum Produced No Gastrointestinal Side Effects | bloating, diarrhea, abdominal pain | Over the entire course of the trial (21 weeks), we observed no serious side effects that would lead to a discontinuation of supplementation. The reports on the symptoms (bloating, abdominal pain and diarrhea) involving the gastrointestinal tract showed no difference between the COL and the PBO groups ( | PMC10459079 |
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4. Discussion | URTIs, first-ever | GASTROINTESTINAL INFECTIONS | The evidence leading to a justified conclusion that bovine colostrum provides effective prevention against the URTIs is building up. Our results demonstrating this effect in terms of frequency and severity of URTIs in pre-school children come from the first-ever reported randomized, triple-blind, placebo-controlled trial performed with a general, presumably healthy population. Previous reports from the pediatric field, predominantly presenting very promising data on the effectiveness of colostrum in the prevention of respiratory, as well as gastrointestinal infections, were based on observational cohort studies [ | PMC10459079 |
4.1. Colostrum Reduces URTI Frequency and Severity | AGS, ’ reduction, URTIs, ’ | Our two main measures of colostrum effectiveness in the prevention of URTIs were the frequency of symptomatic days (FSDs) and the URTI symptoms’ average gravity score (AGS). The information on URTI symptoms’ appearance was self-reported by parents and guardians based on a gravity scale named the URTI score (grades 0–3; see Materials and Methods).For the first primary outcome, the FSD, we summed up all days reported with any symptoms (no matter the gravity level) and used the sum to calculate the frequency of days with URTIs within particular periods of the experiment. By the 20th week of the trial, we observed a statistically significant reduction in the FSD median by a third in the COL as compared to the PBO group. The analyses of the periods between the beginning of supplementation and weeks 4, 8, 12, 14, 16, 18, 20 and 21 revealed that the colostrum supplementation started to exert its significant protective impact on the appearance of days with URTI symptoms no earlier than by the week 8. This protective effect was then observed at week 12, as well as weeks 16, 18 and 20, while at weeks 14 and 21, the results were borderline significant (Our second primary outcome was the AGS of URTI symptoms. The statistically significant reduction in AGS medians was observed in the COL vs. the PBO group when the period from beginning of supplementation until week 20 was assessed. The repeated measures of periods ending at weeks 4, 8, 12, 14, 16 and 18 also consistently showed a significant result in this regard, while the borderline significance was found at week 21 (When AGS medians’ reduction induced by colostrum supplementation is confronted with FSD results, a more consistent statistically significant difference in favor of the COL group over all analyzed periods is observed. Especially striking is the difference observed in AGS in the period ending at week 4, while there is no such difference for FSD, thus suggesting the earlier development of a protective effect against the gravity versus frequency of URTIs. The outcome medians’ reduction rate also favors the gravity reduction, ranging between 33% and 45% for AGS, while for FSD, this range is just from 30% to 37%. While it has not been confirmed by any test, the above-presented reasoning allows us to assume that even if URTIs develop in colostrum-protected children, they seem to have a milder course. However, more studies are needed to verify this notion. | PMC10459079 |
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4.2. URTI Episodes | common-cold | SEPARATION, EVENT | We also made an attempt to assess the number of URTI episodes over the entire trial period. However, this parameter was found to be of limited value, mainly due to the necessity of manipulating the raw data in order to manually enumerate the episodes, as well as the challenge of accurately defining URTI episodes. For the purpose of this analysis, we defined the most probable episodes as being those of the second severity level (mediocre symptoms) and lasting for at least 3 days, with 3 days of separation from another event. The difficulty with this approach was that many symptomatic days could not be included in the identifiable episodes. In some instances, they were not part of a ≥3-day-long sequence or, in other cases, the separation of such sequences was not long enough (<3 days). The latter case was the main problem when we initially attempted to count episodes of all severity levels, including those with the mildest symptoms. The symptoms of the first gravity level were sometimes reported over long periods without a 3-day separation between them, thus making it impossible to accurately calculate the individual URTI episodes of all severity levels.Another problem with enumerating the URTI episodes is that the old definition of the common-cold event seems to be currently less practical. The classical description of such an event was that it typically lasted for about 7 days and appeared with mild-to-moderate symptoms [ | PMC10459079 |
4.3. How Colostrum Use May Prevent the URTIs | infection, viral infection, URTIs, infections | VIRUS, DISEASE, VIRAL INFECTION, INFECTIONS, INFECTION, SECONDARY, CYTOTOXICITY | Many experiments, of both in vitro and in vivo types, have demonstrated various influences of colostrum or its components on individual immune system elements, which may translate into a boosting of the anti-infectious resistance [The absolute majority of URTIs, even exceeding 90% of all cases, is of viral origin [There are two types of adaptive immune responses involved in antiviral reactions: the usually initiating antiviral adaptive response is cellular cytotoxicity based on the action of CD8+ T cells, and the humoral response depends on the cooperation of CD4+ T-cells and B cells. The antibodies produced by plasma cells (the most mature form of B cells) against viral antigens are the most abundant and are therefore a highly effective tool for neutralizing viruses in both antiviral prevention and terminating the active viral infections. Regarding the above, it can be assumed that the effective prevention of URTIs due to colostrum supplementation should be attributed to adaptive immunity, which has been partly confirmed by the literature reporting on the effectiveness of colostrum and its individual components on the modulation of the adaptive immune system [The antiviral action of adaptive immunity requires prior immunization against antigens of the particular pathogen. Such a process can happen via several modes of action: (1) immune reaction during active infection with some novel virus, (2) natural contact with viral antigens available in the environment in non-infectious form and (3) medicinal vaccination with viral antigens. The effective protection by the immune system (especially antibodies) can be obtained usually between 5 and 7 days from the first immunogenic contact with the virus. This time is required to develop the primary immune response, and before the process is complete, the infection develops with little obstacles, and its course depends mostly on the general fitness of the patient and relatively limited actions of natural immunity. What can potentially be improved by colostrum supplementation in such a case is the ability of the immune system to produce a primary immune response as quickly as possible. Various components of colostrum have been found to positively modify the development and efficiency of adaptive immunity [The time required for the immune-response development can be largely decreased when the patient has immunogenic contact with a particular viral antigen prior to contracting it in infectious form. In such a case, the effective response may develop even within 2–3 days and is called a secondary immune response. This is obtained either over the course of a previous infection with a particular virus or alternatively due to natural, as well as medicinal, vaccination, and it may lead to a shorter and milder course of disease. Natural vaccination is most commonly a case of ingesting the inactivated viral antigens, followed by an immunization process happening within the intestinal immune system, which is based mostly on Peyer’s patches [The highest level of protection from adaptive immunity, which practically eliminates the possibility of developing the disease, is achieved when the concentration of specific antiviral immunoglobulins in the blood serum and other body fluids is high enough. Such a protection from viral infection usually lasts for several months to a year from the last effective immunization. This implies that in order to remain free of the broad range of infections, regular contact with stimulating antigens of a wide variety needs to be maintained continuously. Because this contact occurs mostly with ingested antigens, it is necessary to constantly maintain intestinal homeostasis, in addition to ensuring the overall efficiency of the immune system in general terms.Colostrum has been repeatedly proven to be among the most efficient products capable of restoring and maintaining intestinal homeostasis [Supplementation with colostrum may have one more beneficial effect, which is a positive influence on the general fitness. This is obtained partly through improving the function of the digestive tract, which allows for better nutritional status. Furthermore, although colostrum itself is of limited nutritional value, especially in small supplementation doses, it contains all extrinsic amino acids, as well as a relatively high concentration of several vitamins, minerals and other microelements. This may help to replenish the body’s resources. Several of those supplementary elements are also known to help improve the immune system’s status [ | PMC10459079 |
4.4. There Were No Side Effects from Colostrum Use | bloating, gastrointestinal symptoms, diarrhea, abdominal pain | EVENTS | One of the most important concerns of investigators when introducing a novel medical procedure in children is the potential of triggering unexpected results. In the past, the use of colostrum has been blamed for causing side effects such as gastrointestinal symptoms, including abdominal pain, bloating and diarrhea. The symptoms usually last for the first few days of supplementation and are most probably related to the repair processes in the gut, as such processes naturally involves some acute inflammatory events. Therefore, we urged parents and guardians to pay special attention to any unusual symptoms appearing in their children. Over the entire trial period, none of such effects was reported. In addition, all parents and guardians responded to the question pointing specifically to abdominal symptoms. There was no statistically significant difference between the COL group and the PBO group in this regard ( | PMC10459079 |
4.5. Strengths and Limitations | The strengths of our study include the following: (1) RCT design with triple blinding, (2) short duration of supplementation period critical to boost immunity and (3) continuous outcome reporting. The limitation is a relatively limited sample size. | PMC10459079 |
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5. Conclusions | ’ reduction, gastrointestinal symptoms, URTIs | Our study provides the first solid RCT-based evidence that bovine colostrum can be effectively used to prevent and decrease the gravity of URTIs in pre-school children. The results we obtained allow us to conclude the following:Kindergarten children 4–7 years of age receiving the pre-season colostrum supplementation may have up to 31% less days with URTI self-reported symptoms over 20 weeks from beginning of supplementation than children receiving a placebo.These children tested within the same period (20 weeks) presented an even bigger median reduction in their URTI gravity score (−37%) in the COL vs. the PBO groups, which supposedly results not exclusively from sick days’ reduction but also from milder course of the URTIs.The number of episodes, defined as 3 consecutive days of second degree of URTI gravity separated from other episodes by at least 3 days, was reduced in the COL group by 50% as compared to the PBO group over the entire period of the trial (21 weeks).The observed effects of our study were obtained with main supplementation lasting for less than just 1/3 of the trial period.There were no significant side effects observed during the trial, neither in the COL nor in the PBO groups. Moreover, there was no statistically significant difference between these groups in regard to gastrointestinal symptoms.Overall, it can be concluded that our typical mild (15 days 2 × 500 mg + 30 days 1 × 500 mg) pre-seasonal supplementation with bovine colostrum provides significant protection to pre-school children from both frequency and gravity of URTIs over 140 days (20 weeks) of the fall/winter infectious season. The outcome of our study also indicates that the use of bovine colostrum in order to protect pre-school children from URTIs may have very important socioeconomic influence on the lives of their relatives and caregivers. | PMC10459079 |
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Author Contributions | Conceptualization, M.H. and M.B.-H.; data curation, M.H. and K.S.-Ż.; formal analysis, M.H. and K.S.-Ż.; funding acquisition, B.M.; investigation, M.H.; methodology, M.H.; project administration, M.H.; resources, B.M.; software, M.H.; supervision, M.H. and M.B.-H.; validation, M.H. and K.S.-Ż.; visualization, M.H. and K.S.-Ż.; writing—original draft, M.H.; writing—review and editing, K.S.-Ż., L.B. and M.B.-H. All authors have read and agreed to the published version of the manuscript. | PMC10459079 |
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Institutional Review Board Statement | MAY | The trial was performed in accordance with the protocol approved by the Pomeranian Medical University Bioethics Committee (KB-006/24/2022) on 18 May 2022. | PMC10459079 |
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Informed Consent Statement | Written informed consent was obtained from the patient(s) caregivers to publish this paper. | PMC10459079 |
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Data Availability Statement | Data are available upon request. | PMC10459079 |
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Conflicts of Interest | POLAND | The authors declare the following financial interest/personal relationship which may be considered a potential competing interest: Maciej Hałasa receives renumeration from Genactiv Trade, Poznań, Poland—the manufacturer of COL. | PMC10459079 |
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