Despite boosting engagement with preventive healthcare, an intensive food-as-medicine program did not improve glycemic control in patients with uncontrolled type 2 diabetes (T2D) and self-reported food insecurity any better than usual medical care.
METHODOLOGY:
A randomized clinical trial tested if an intensive food-as-medicine program improved glycemic control and affected healthcare use in patients with diabetes and food insecurity.
The trial included 500 patients (81% White, 55% women, mean age, 55 years) with T2D, glycated hemoglobin (A1c) levels of ≥ 8%, food insecurity, and residence within the service area of the participating clinics.
Patients were randomly assigned to either participate in the food-as-medicine program immediately (treatment group) or after 6 months (control group receiving usual care).
The food-as-medicine program provided healthy groceries for 10 meals/week for the entire household, along with dietitian consultations, nurse evaluations, health coaching, and diabetes education.
The primary outcome was participants’ A1c levels at 6 months, and secondary outcomes included healthcare use, self-reported diet, and healthy behaviors at both 6 months and 12 months.
TAKEAWAY:
After 6 months, both the treatment and control groups reported a substantial decline in A1c levels (1.5 and 1.3 percentage points, respectively), with a nonsignificant adjusted mean difference of −0.10 (P = .57).
Patients in the treatment group, as opposed to the control group, showed higher engagement with preventive healthcare at 6 months, making more visits to the program clinic (13.00 vs 0.72) and dietitians (2.7 vs 0.6).
The number of outpatient visits, reflecting healthcare usage, was also significantly higher in the treatment vs control group at 6 months (P = .007).
There was no detectable impact on total claims, with an insignificant reduction in inpatient or emergency department claims offset by an insignificant increase in outpatient claims.
IN PRACTICE:
“Programs targeted to individuals with elevated biomarkers require a control group to demonstrate effectiveness to account for improvements that occur without the intervention. Additional research is needed to design food-as-medicine programs that improve health,” the authors wrote.
A low-sodium diet was not associated with a reduction in future clinical events in a new study in ambulatory patients with heart failure. But there was a moderate benefit on quality of life and New York Heart Association (NYHA) functional class.
The study found that a strategy to reduce dietary sodium intake to less than 1500 mg daily was not more effective than usual care in reducing the primary endpoint of risk for hospitalization or emergency department visits due to cardiovascular causes or all-cause death at 12 months.
“This is the largest and longest trial to look at the question of reducing dietary sodium in heart failure patients,” lead author, Justin Ezekowitz, MBBCh, from the Canadian VIGOUR Center at the University of Alberta, Edmonton, Canada, told theheart.org |Medscape Cardiology.
But he pointed out that there were fewer events than expected in the study, which was stopped early because of a combination of futility and practical difficulties caused by the COVID pandemic, so it could have been underpowered. Ezekowitz also suggested that a greater reduction in sodium than achieved in this study or a longer follow-up may be required to show an effect on clinical events.
“We hope others will do additional studies of sodium as well as other dietary recommendations as part of a comprehensive diet for heart failure patients,” he commented.
Ezekowitz said that the study results did not allow blanket recommendations to be made on reducing sodium intake in heart failure.
But he added: “I don’t think we should write off sodium reduction in this population. I think we can tell patients that reducing dietary sodium may potentially improve symptoms and quality of life, and I will continue to recommend reducing sodium as part of an overall healthy diet. We don’t want to throw the baby out with the bathwater.”
Ezekowitz noted that heart failure is associated with neurohormonal activation and abnormalities in autonomic control that lead to sodium and water retention; thus, dietary restriction of sodium has been historically endorsed as a mechanism to prevent fluid overload and subsequent clinical outcomes; however, clinical trials so far have shown mixed results.
“The guidelines used to strongly recommend a reduction in sodium intake in heart failure patients, but this advice has backed off in recent years because of the lack of data. Most heart failure guidelines now do not make any recommendations on dietary sodium,” he said.
SODIUM-HF was a pragmatic, multinational, open-label, randomized trial conducted in six countries (Australia, Canada, Chile, Colombia, Mexico, and New Zealand), which included 809 patients (median age, 67 years) with chronic heart failure (NYHA functional class II–III) who were receiving optimally tolerated guideline-directed medical treatment. They were randomly assigned to usual care according to local guidelines or a low-sodium diet of less than 100 mmol (<1500 mg/day). Patients with a baseline sodium intake of less than 1500 mg/day were excluded.
In the intervention group, patients were asked to follow low-sodium menus developed by dietitians localized to each region. They also received behavioral counseling by trained dietitians or physicians or nurses.
Dietary sodium intake was assessed by using a 3-day food record (including 1 weekend day) at baseline, 6 months, and 12 months in both groups and, for the intervention group, also at 3 and 9 months to monitor and support dietary adherence.
Ezekowitz explained that although the best method for measuring sodium levels would normally be a 24-hour urine sodium, this would be impractical in a large clinical trial. In addition, he pointed out that urinary sodium is not an accurate measure of actual sodium levels in patients taking diuretics, so it is not a good measure to use in a heart failure population.
“The food record method of assessing sodium levels has been well validated; I think we measured it as accurately as we could have done,” he added.
Results showed that between baseline and 12 months, the median sodium intake decreased from 2286 mg/day to 1658 mg/day in the low-sodium group and from 2119 mg/day to 2073 mg/day in the usual care group. The median difference between groups was 415 mg/day at 12 months.
By 12 months, events comprising the primary outcome (hospitalization or emergency department visits due to cardiovascular causes or all-cause death) had occurred in 15% of patients in the low-sodium diet group and 17% of those in the usual care group (hazard ratio [HR], 0.89 [95% CI, 0.63 – 1.26]; P = .53).
All-cause death occurred in 6% of patients in the low-sodium diet group and 4% of those in the usual care group (HR, 1.38; P = .32). Cardiovascular-related hospitalization occurred in 10% of the low-sodium group and 12% of the usual care group (HR, 0.82; P = .36), and cardiovascular-related emergency department visits occurred in 4% of both groups (HR, 1.21; P = .60).
The absence of treatment effect for the primary outcome was consistent across most prespecified subgroups, including those with higher vs lower baseline sodium intake. But there was a suggestion of a greater reduction in the primary outcome in individuals younger than age 65 years than in those age 65 years and older.
Quality-of-life measures on the Kansas City Cardiomyopathy Questionnaire (KCCQ) suggested a benefit in the low-sodium group, with mean between-group differences in the change from baseline to 12 months of 3.38 points in the overall summary score, 3.29 points in the clinical summary score, and 3.77 points in the physical limitation score (all differences were statistically significant).
There was no significant difference in 6-minute-walk distance at 12 months between the low-sodium diet group and the usual care group.
NYHA functional class at 12 months differed significantly between groups; the low-sodium diet group had a greater likelihood of improving by one NYHA class than the usual care group (odds ratio, 0.59; P = .0061).
No safety events related to the study treatment were reported in either group.
Ezekowitz said that to investigate whether longer follow-up may show a difference in events, further analyses are planned at 2 years and 5 years.
Questions on Food Recall and Blinding
Commenting on the findings at the late-breaking clinical trials session at the ACC meeting, Biykem Bozkurt, MD, professor of medicine at Baylor College of Medicine, Houston, Texas, congratulated Ezekowitz on conducting this trial.
“We have been chasing the holy grail of sodium reduction in heart failure for a very long time, so I have to commend you and your team for taking on this challenge, especially during the pandemic,” she said.
But Bozkurt questioned whether the intervention group actually had a meaningful sodium reduction given that this was measured by food recall and this may have been accounted for by under-reporting of certain food intakes.
Ezekowitz responded that patients acted as their own controls in that calorie intake, fluid intake, and weight were also assessed and did not change. “So I think we did have a meaningful reduction in sodium,” he said.
Bozkurt also queried whether the improvements in quality of life and functional status were reliable given that this was an unblinded study.
To this point, Ezekowitz pointed out that the KCCQ quality-of-life measure was a highly validated instrument and that improvements were seen in these measures at 3, 6, and 12 months. “It is not like these were spurious findings, so I think we have to look at this as a real result,” he argued.
Commenting on the study at an ACC press conference, Mary Norine Walsh, MD, director of the heart failure and cardiac transplantation programs at St Vincent Heart Center in Indianapolis, Indiana, said the trial had answered two important questions: that sodium reduction in heart failure may not reduce heart failure hospitalization/death but that patients feel better.
“I think we can safety tell patients that if they slip up a bit they may not end up in hospital,” she added.
Objective To evaluate the efficacy of covid-19 convalescent plasma to treat patients admitted to hospital for moderate covid-19 disease with or without underlying immunodeficiency (CORIPLASM trial).
Design Open label, randomised clinical trial.
Setting CORIMUNO-19 cohort (publicly supported platform of open label, randomised controlled trials of immune modulatory drugs in patients admitted to hospital with moderate or severe covid-19 disease) based on 19 university and general hospitals across France, from 16 April 2020 to 21 April 2021.
Participants 120 adults (n=60 in the covid-19 convalescent plasma group, n=60 in the usual care group) admitted to hospital with a positive SARS-CoV2 test result, duration of symptoms <9 days, and World Health Organization score of 4 or 5. 49 patients (n=22, n=27) had underlying immunosuppression.
Interventions Open label randomisation to usual care or four units (200-220 mL/unit, 2 units/day over two consecutive days) of covid-19 convalescent plasma with a seroneutralisation titre >40.
Main outcome measures Primary outcomes were proportion of patients with a WHO Clinical Progression Scale score of ≥6 on the 10 point scale on day 4 (higher values indicate a worse outcome), and survival without assisted ventilation or additional immunomodulatory treatment by day 14. Secondary outcomes were changes in WHO Clinical Progression Scale scores, overall survival, time to discharge, and time to end of dependence on oxygen supply. Predefined subgroups analyses included immunosuppression status, duration of symptoms before randomisation, and use of steroids.
Results 120 patients were recruited and assigned to covid-19 convalescent plasma (n=60) or usual care (n=60), including 22 (covid-19 convalescent plasma) and 27 (usual care) patients who were immunocompromised. 13 (22%) patients who received convalescent plasma had a WHO Clinical Progression Scale score of ≥6 at day 4 versus eight (13%) patients who received usual care (adjusted odds ratio 1.88, 95% credible interval 0.71 to 5.24). By day 14, 19 (31.6%) patients in the convalescent plasma group and 20 (33.3%) patients in the usual care group needed ventilation, additional immunomodulatory treatment, or had died. For cumulative incidence of death, three (5%) patients in the convalescent plasma group and eight (13%) in the usual care group died by day 14 (adjusted hazard ratio 0.40, 95% confidence interval 0.10 to 1.53), and seven (12%) patients in the convalescent plasma group and 12 (20%) in the usual care group by day 28 (adjusted hazard ratio 0.51, 0.20 to 1.32). In a subgroup analysis performed in patients who were immunocompromised, transfusion of covid-19 convalescent plasma was associated with mortality (hazard ratio 0.39, 95% confidence interval 0.14 to 1.10).
Conclusions In this study, covid-19 convalescent plasma did not improve early outcomes in patients with moderate covid-19 disease. The efficacy of convalescent plasma in patients who are immunocompromised should be investigated further.
Data are available upon reasonable request. The data for this article will be made available after publication on request from any qualified researchers or academics. The data include: analysed deidentified participant data, data dictionary, study protocol, statistical analysis plan, and informed consent form, among other data. The data will be shared for two years after publication on receipt of a request sent to raphael.porcher@aphp.fr.
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Treatment with convalescent plasma (ie, passive polyclonal antibody administration to provide immediate immunity) has been used to improve the survival rate of patients with severe acute respiratory syndromes of viral causes in emergency settings and when no specific antiviral treatment is available
At the early stages of the covid-19 pandemic, using high titre covid-19 convalescent plasma seemed to be an immediate therapeutic option, but many randomised clinical trials and observational studies have reported conflicting results on the efficacy of convalescent plasma
Evaluation of the efficacy of covid-19 convalescent plasma in patients with underlying immunosuppression has been limited and the emergence of variants resistant to other passive immunotherapies (ie, monoclonal antibodies) has restricted the treatment options for these patients
WHAT THIS STUDY ADDS
This multicentre, randomised clinical trial indicates that transfusion of high titre covid-19 convalescent plasma to patients admitted to hospital with mild-to-moderate covid-19 within nine days of the onset of symptoms might not improve early outcomes
In the subgroup of patients with immunosuppression, the evidence indicated a lower odds of death at 14 and 28 days after transfusion of covid-19 convalescent plasma, but this finding was not significant
HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE, OR POLICY
This study, and other trials and cohort studies, support further evaluation of transfusion of covid-19 convalescent plasma in patients with underlying immunosuppression
Treatment options for patients who are immunocompromised are scarce if non-existent because of the changing genetic variability of the SARS-CoV2 virus
Introduction
Early in the covid-19 pandemic, transfusion of covid-19 convalescent plasma was identified as a potential treatment that needed evaluation.1 The overall efficacy of covid-19 convalescent plasma in patients admitted to hospital for covid-19 has not been established.2 High titre convalescent plasma might be beneficial, however, particularly if used early before seroconversion3 4 or in patients who lack an effective humoral response.5 6 Treatment with monoclonal antibodies has been shown to be effective as an early intervention7 or later in seronegative patients admitted to hospital.8 Major limitations exist for monoclonal antibodies, however, including accessibility and cost,9 as well as loss of efficacy, as recently shown with the emergence of the immune evading omicron subvariants of the SARS-CoV-2 virus.10
By contrast with monoclonal antibodies, covid-19 convalescent plasma, from convalescent donors who have been vaccinated, is cheaper, readily available, and adaptable to a changing viral landscape, and potentially less prone to immune resistance. Although the recent omicron variant dominant periods have been associated with a decrease in the efficacy of almost all available monoclonal antibodies,11 high titre convalescent plasma (before the omicron dominant period) from convalescent donors who were vaccinated might retain anti-omicron neutralisation activity.12 This anti-omicron neutralisation capacity is further increased in plasma from donors convalescing after the omicron variant of the virus who were vaccinated.13
As well as immunomodulating drugs that specifically target the inflammatory phase of the disease, oral direct antiviral agents, such as molnupiravir14 or nirmatrelvir with ritonavir,15 are another therapeutic option. These drugs have drawbacks, however, such as the need to start treatment within five days of the onset of symptoms and drug interactions for nirmatrelvir-ritonavir, particularly in patients who are immunosuppressed. The intravenous antiviral agent, remdesivir, has shown only limited efficacy against the SARS-CoV-2 virus in patients admitted to hospital with covid-19.16 Careful assessment of the efficacy and safety of covid-19 convalescent plasma therefore is an important aspect of public health, particularly in patients who are immunosuppressed and do not have a vaccine mediated immune response. These patients are at risk of severe disease and have limited treatment options. We report the results of a randomised controlled trial that assessed the efficacy of covid-19 convalescent plasma (four units, about 840 mL) in patients with and without immunosuppression, who were admitted to hospital with moderate SARS-CoV-2 infection associated with pneumonia but who did not require assisted ventilation at the time of inclusion.
Methods
Trial design
CORIMUNO-19 is a publicly supported platform, established by Assistance Publique-Hôpitaux de Paris, France, at the beginning of the covid-19 pandemic, dedicated to performing cohort, open label, randomised controlled trials of immune modulatory drugs in patients admitted to hospital with moderate or severe covid-19 disease.17 CORIPLASM (Efficacy of Convalescent Plasma to Treat Covid-19 Patients, a Nested Trial in the CORIMUNO-19 Cohort) was an embedded multicentre, open label, randomised controlled trial in patients with moderate covid-19 pneumonia conducted in French hospitals. Online supplemental appendix II and III have the full trial protocol and statistical analysis plan.
At hospital admission, patients were evaluated for eligibility criteria: adults aged ≥18 years admitted to hospital, positive test result for the SARS-CoV-2 virus by nasopharyngeal polymerase chain reaction or computed tomography scan, or both, before randomisation, onset of symptoms <9 days, illness of mild or moderate severity according to the WHO Clinical Progression Scale (admitted to hospital, mild disease, no oxygen needed; admitted to hospital, moderate disease, oxygen <3 litres needed, online supplemental appendix I), not pregnant, no previous severe grade 3 allergic reaction to plasma transfusion, and no current bacterial infection reported.
ABO compatibility with available covid-19 convalescent plasma was verified before inclusion of patients. Written informed consent was obtained from all patients or their legal representatives at inclusion in CORIMUNO-19. Specific written informed consent was sought from eligible patients before inclusion in the CORIPLASM trial. The independent clinical research organisation compiled the computerised randomisation list, and the patient’s randomisation number was accessed through a secure site by a site study team member. Randomisation was performed within two hours of enrolment. Eligible patients were randomised 1:1 to receive convalescent plasma or usual care. Usual care could include the use of dexamethasone, tocilizumab, supportive care, including supplemental oxygen, antiviral agents, and antibiotics. A data and safety monitoring board provided guidance on the trial after inclusion of every 60 patients.
Study product
Convalescent donors were eligible for plasma donation 15 days after the end of symptoms related to covid-19 disease. Apheresis plasma was collected by Etablissement Français du Sang and underwent pathogen reduction (Intercept Blood System, Cerus, Concord, CA) and standard testing according to current regulations in France. Anti-SARS-CoV-2 potency was assessed in each donation, with a requirement for a SARS-CoV-2 seroneutralisation titre ≥40, as described by Gallian et al.18 Antibody content was determined by immunoglobulin G enzyme linked immunosorbent assay (Euroimmun, Bussy-Saint-Martin, France). Covid-19 convalescent plasma with a seroneutralisation titre ≥40, made available for the trial and collected between April and June 2020, gave a mean enzyme linked immunosorbent assay ratio of 6.1 (standard deviation 2.9, range 0.4-13.0). After the first three patients received two units of ABO compatible covid-19 convalescent plasma according to the protocol, all subsequent patients randomised to the convalescent plasma group received four units of convalescent plasma (200-220 mL/unit, 2 units/day over two consecutive days) provided by different donors.
Study endpoints
As in all of the CORIMUNO-19 nested trials, an early primary endpoint was defined as a WHO Clinical Progression Scale score of ≥6 (online supplemental appendix I) on day 4 of randomisation. Higher values on the WHO Clinical Progression Scale indicate a worse outcome. The primary endpoint specific to the CORIPLASM trial was survival without the need for assisted ventilation (including non-invasive ventilation or high flow oxygen) at day 14 of randomisation (WHO Clinical Progression Scale score <6) or additional immunomodulatory treatment, with the exception of corticosteroids included within the standard of care (changes to the protocol, online supplemental file 1). Secondary endpoints were WHO Clinical Progression Scale score on days 4, 7, and 14 after randomisation, overall survival on days 14 and 28 after randomisation (ie, for the periods days 1-14 and days 1-28, respectively), time to discharge, time to end of dependence on oxygen supply, and changes to a series of biological parameters at days 4, 7, and 14 after randomisation.
Predefined subgroup analyses included immunosuppression status (underlying immunodeficiency: yes/no), duration of symptoms before randomisation (≤5 days, >5 days), and use of steroids. Safety data included all clinical and biological adverse events observed during the study follow-up. Immunodeficiency was defined as the presence of at least one of these medical conditions: active malignant neoplasm, lymphoid or myeloid neoplasms, haematopoietic stem cell or solid organ transplantation, or HIV/AIDS and not receiving highly active antiretroviral treatment.
Statistical analysis
The sample size was set at 120 participants (60 per group), with a bayesian interim analysis after 60 participants were randomised. We computed that the trial would have a frequentist power of 97.2% to detect a decrease in event proportions from 0.50 to 0.20, and 73.9% to detect a decrease in event proportions from 0.50 to 0.30. The study statisticians, who were masked to the group assignments, oversaw the interim and final analyses. Interim analysis reports were shared only with members of the data and safety monitoring board and not with the trial investigators. The trial investigators were blinded to all results during the trial.
The treatment effect was mainly expressed as an absolute risk difference for the early primary endpoint, and a hazard ratio for the longer term primary endpoint. Both were analysed in a bayesian framework. A posterior probability of absolute risk difference <0 or hazard ratio <1 but >0.99 at the interim analysis or >0.95 at the final analysis, indicated efficacy. We also computed posterior probabilities of absolute risk difference <−5.5% and hazard ratio <0.85, denoting a moderate or greater effect. At the interim analysis, a posterior probability of moderate or greater impact <0.20 defined a futility boundary. The treatment effect was summarised by the posterior median and equal tail credible intervals.
Because decision rules are one sided, consistent credible intervals would theoretically be one sided 95% credible intervals, but we chose to report two sided 90% credible intervals with the same upper boundary. For the early primary endpoint, the posterior distribution of absolute risk difference was computed analytically, with a beta prior distribution, with parameters one and one for the proportion in each group. An odds ratio adjusted for age and centre (centre being treated as a random effect) was also estimated with a bayesian logistic regression model. For the longer term primary endpoint, the posterior hazard ratio distribution adjusted for age and centre was computed with Markov chain Monte Carlo with normal prior distributions, with mean 0 and variance 106 for the log hazard ratio. Different prior distributions were used as sensitivity analyses.
Secondary outcomes were analysed in a frequentist framework, except for WHO Clinical Progression Scale scores, analysed as an ordinal variable with a bayesian proportional odds model. Analyses of secondary outcomes were also adjusted for age and centre. For time to discharge and time to end of dependence on oxygen supply, we estimated adjusted subdistribution hazard ratios with Fine-Grey models, death being the competing event. Estimating subdistribution hazard ratios was preferred over cause specific hazard ratios because subdistribution hazard ratios have a one-to-one relation with the cumulative incidence (ie, the proportion) of events, and we considered that subdistribution hazard ratios would therefore be more relevant than the ratio of rates at which these events occur in time. We used interaction tests between the treatment group and subgroups to test for treatment effect heterogeneity between the subgroups, with similar regression models as the main adjusted analyses. The statistical analysis plan has full details of the statistical analyses (online supplemental appendix III).
Analyses were done on an intention-to-treat basis. The original protocol specified a modified intention-to-treat analysis excluding patients declining the intervention and those who could not receive the planned plasma treatment because ABO compatible covid-19 convalescent plasma was not available. Because those situations did not occur, no modified intention-to-treat analysis was performed. No correction for multiplicity was done for secondary outcomes, and corresponding results should be regarded as exploratory. Two interim analyses were conducted (online supplemental table S1). Statistical analyses were done with SAS (version 9.4, SAS Institute) and R (version 4.0.5, R Foundation) statistical software.
Patient and public involvement
Patients or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research, because the trial has been designed in an emergency setting. However, according to the French law, the results have been sent to all participants or to their families.
Results
Between 16 April 2020 and 21 April 2021, 120 patients (60 in the covid-19 convalescent plasma group and 60 in the usual care group) were enrolled (online supplemental figure S1). Table 1 shows the characteristics of the study participants, which were well balanced between the two groups.
Characteristics of participants at baseline in the two groups. Total group numbers that are not n=60 are indicated
Median time from onset of symptoms to randomisation (transfusion of covid-19 convalescent plasma or usual care) was seven days in both groups. We saw a positive anti-S and anti-N SARS-CoV-2 serology in 10/23 (44%) evaluable patients receiving convalescent plasma and in 9/27 (33%) evaluable patients receiving usual care. Underlying immunodeficiency was present in 22/60 (37%) and 27/60 (45%) patients in the convalescent plasma and usual care groups, respectively. One patient was thought to have covid-19 disease based on a typical chest computed tomography scan at inclusion, but was later reclassified as non-indicative of SARS-CoV-2 infection, and pulmonary oedema from cardiac origin was diagnosed. Online supplemental table S2 reports other treatments received before and after randomisation until day 14.
An intention-to-treat analysis was performed on 120 patients; two patients in each group were lost to follow-up at the day 28 evaluation but discharged alive before day 28 (figure 1). One patient did not receive a plasma infusion because of sudden worsening after randomisation and transfer to the intensive care unit. Nine patients received two units of convalescent plasma (three based on the protocol and six because of worsening of clinical status leading to admission to the intensive care unit), and 50 received four units of convalescent plasma. Same day transfusion was performed in 78% of patients, whereas 12 (20%) and one (2%) patient received a transfusion one and three days after randomisation, respectively.
Flowchart of CORIPLASM (Efficacy of Convalescent Plasma to Treat COVID-19 Patients, a Nested Trial in the CORIMUNO-19 Cohort) clinical trial. *No SARS-CoV-2 infection. †Received non-invasive ventilation. ICU=intensive care unit
Primary outcomes
Thirteen (22%) patients in the covid-19 convalescent plasma group versus eight (13%) patients in the usual care group had a WHO Clinical Progression Scale score of ≥6 at day 4 (median posterior absolute risk difference 8.0%, 90% credible interval –3.2% to 19.4%; adjusted odds ratio 1.88, 95% credible interval 0.71 to 5.24; table 2, online supplemental table S3, and online supplemental figure S2). The WHO Clinical Progression Scale score on day 4 was analysed as an ordinal outcome in a proportional odds model, giving a median posterior adjusted odds ratio of 1.42 (95% credible interval 0.70 to 2.91), hence showing higher scores in the covid-19 convalescent plasma group, although the difference was not significant. By day 14, patients in the convalescent plasma and usual care groups needed non-invasive or high flow ventilation (n=15 in the convalescent plasma group and n=13 in the usual care group) or additional immunomodulatory treatment in the form of anti-interleukin 6 receptor monoclonal antibody (n=0 in the convalescent plasma group and n=5 in the usual care group), or had died (n=2 in each group). Also, one and five patients died after reaching the primary outcome in the convalescent plasma and usual care groups, respectively. Figure 2 shows the cumulative incidence of assisted ventilation or death. The median posterior adjusted hazard ratio was 1.04 (95% credible interval 0.55 to 1.97), and the posterior probability of a moderate or greater benefit was 0.269 (table 2 and online supplemental table S4). The results were consistent across the range of prior distributions used in the sensitivity analyses (online supplemental figure S3).
Study outcomes in covid-19 convalescent plasma and usual care groups. Cumulative incidence of non-invasive or mechanical ventilation, use of additional immunomodulatory drugs, or death over 14 days (events on day 1 of randomisation occurred on the same day but after randomisation). CrI=credible interval
Secondary outcomes
At day 14, three (5%) and eight (13%) patients had died in the covid-19 convalescent plasma and usual care groups, respectively (adjusted hazard ratio 0.40, 95% confidence interval 0.10 to 1.53) (figure 3 and online supplemental table S5). At day 28, nine (12%) and 12 (20%) patients had died in the convalescent plasma and usual care groups, respectively (0.51, 0.20 to 1.32). The distribution of WHO Clinical Progression Scale scores from day 1 to day 14 did not differ significantly within groups, with a posterior odds ratio of 1.04 (95% credible interval 0.37 to 2.86) for the convalescent plasma group compared with the usual care group in a longitudinal ordinal model. The WHO Clinical Progression Scale scores tended to be higher in the convalescent plasma group between days 3 and 5, and then lower at day 14, with lower mortality (figure 4 and online supplemental table S6), although these findings were not significant. At day 14 and day 28, 38 and 48 patients in the convalescent plasma group and 36 and 45 in the usual care group, respectively, were discharged, with an adjusted day 28 subdistribution hazard ratio of 0.99 (95% confidence interval 0.65 to 1.49) adjusted for age and centre (online supplemental table S7). The incidence of not needing oxygen by day 28 was not different between the groups: 76% and 62% by day 14 and 82% and 71% by day 28 in the convalescent plasma and usual care groups, respectively (subdistribution hazard ratio 1.18, 95% confidence interval 0.73 to 1.91) (online supplemental table S7).
Distribution of World Health Organization Clinical Progression Scale scores during follow-up in covid-19 convalescent plasma and usual care groups
Subgroup analyses
Figure 5 shows the primary outcome at day 14 (need for non-invasive or mechanical ventilation, use of additional immunomodulatory drugs, or death), with no difference in the subgroups. In the 47 patients who had an underlying immunodeficiency, the rate of a WHO Clinical Progression Scale score of ≥6 at day 4 was not significantly different in the covid-19 convalescent plasma group compared with the usual care group (24% v 15%, adjusted odds ratio 1.97, 95% confidence interval 0.53 to 7.39). At day 28, four of 21 patients had died in the convalescent plasma group versus nine of 26 patients in the usual care group (hazard ratio 0.39, 95% confidence interval 0.14 to 1.10) (figure 6). Despite these findings favouring convalescent plasma, we found no evidence of an interaction between immunodeficiency status and treatment (P=0.34): 4/21 patients died in the covid-19 convalescent plasma group versus 9/26 in the usual care group (hazard ratio 0.39, 95% confidence interval 0.14 to 1.10) (figure 6). We found limited mortality in the absence of underlying immunodeficiency (figure 7). Duration of symptoms or use of dexamethasone had no effect on day 28 survival (figure 5). Post hoc analysis of antibody potency in transfused covid-19 convalescent plasma in relation to outcome did not show a significant dose effect (online supplemental table S8).
Subgroup analyses. Day 14 primary outcomes (need for non-invasive or mechanical ventilation, use of additional immunomodulatory drugs, or death) in covid-19 convalescent plasma and usual care groups. Dashed line indicates overall estimate of treatment effect. Because only one patient was receiving antiviral agents at randomisation, no subgroup analysis according to antiviral agents was done. CI=confidence interval
Overall survival during follow-up in patients with no underlying immunodeficiency in covid-19 convalescent plasma and usual care groups. CI=confidence interval
Adverse events
Adverse events were reported in 44 (73%) and 36 (60%) patients in the covid-19 convalescent plasma (n=124 events) and usual care (n=103 events) groups, respectively (incidence rate ratio 1.06, 95% confidence interval 0.63 to 1.77; online supplemental table S9). We found serious adverse events in 30 (50%) and 26 (43%) patients in the convalescent plasma (n=46 events) and usual care (n=48 events) groups, respectively (incidence rate ratio 0.84, 95% confidence interval 0.46 to 1.54). We found 10 sepsis related events with usual care (six with convalescent plasma) and four incidences of acute pulmonary oedema with convalescent plasma (none with usual care).
Causes of death were covid-19 related acute respiratory distress syndrome (n=3 in the convalescent plasma group and n=10 in the usual care group), cardiac origin (n=2 convalescent plasma, n=0 usual care), sepsis (n=2 convalescent plasma, n=3 usual care), gastrointestinal (n=0 convalescent plasma, n=1 usual care), vascular (n=1 convalescent plasma, n=0 usual care), and one of unknown origin (convalescent plasma).
Discussion
Principal findings
In this CORIPLASM trial, we found no difference in early outcomes between the covid-19 convalescent plasma and usual care groups for patients admitted to hospital for covid-19 disease not requiring assisted ventilation. The survival rate at day 14 and day 28 was higher in the convalescent plasma group but this finding was not significant.
The lack of efficacy associated with covid-19 convalescent plasma agrees with the results of most prospective randomised clinical trials of patients admitted to hospital for covid-19 disease.19 Only a small number of randomised studies have reported better survival after treatment with convalescent plasma,20 21 whereas several other trials, notably the large RECOVERY (Randomised Evaluation of COVID-19 Therapy) trial,22 found no evidence of survival benefit with convalescent plasma. Large retrospective studies in the US reported evidence of reduced mortality associated with treatment with covid-19 convalescent plasma in patients admitted to hospital with covid-19.23 24 The reasons for these discrepancies might be related to the characteristics of the convalescent plasma, time to treatment from first symptoms, treatment modalities, and patient characteristics.
Our study included a substantial proportion of patients with underlying immunosuppression. Similar to previous findings,25 we found that these patients with covid-19 have a worse prognosis, as seen in the usual care group. Several studies have suggested that convalescent plasma might be particularly effective in patients who lack an immune response, particularly a humoral response. We reported previously that treatment with covid-19 convalescent plasma was associated with a favourable outcome in patients who were immunosuppressed (mainly B cell haematological malignancies treated with anti-CD-20 monoclonal antibodies).6 Further evidence was provided by two independent exposed and non-exposed studies with propensity score in patients with underlying immunosuppression. Hazard ratios of 0.52 (95% confidence interval 0.29 to 0.92) and 0.50 (0.34 to 0.72) were reported in favour of convalescent plasma treatment, respectively.6 7 This reduction in mortality was similar to patients with immunosuppression randomised to the convalescent plasma group in the CORIPLASM trial.
Comparison with other studies
Most other randomised trials published so far did not report subgroup analyses for patients with underlying immunosuppression. One exception is the REMAP-CAP (Randomized, Embedded, Multifactorial Adaptive Platform Trial for Community Acquired Pneumonia) trial that investigated convalescent plasma in critically ill patients with covid-19.22 Although the overall results of this study did not provide evidence of the efficacy of covid-19 convalescent plasma in these patients, a prespecified subgroup analysis showed a potential benefit of convalescent plasma in patients with immunodeficiency. Another randomised trial performed in patients with a diverse range of clinical conditions reported a significant effect of covid-19 convalescent plasma on clinical improvement and survival in the subgroup of 56 individuals with cancer.26 Finally, a meta-analysis incorporating the CORIPLASM trial has confirmed the potential benefit of covid-19 convalescent plasma in individuals with immunosuppression with mild-to-moderate covid-19 disease, based on greater statistical power because of the large number of individuals with immunosuppression included in the meta-analysis (1487 from randomised trials, 265 from case series, and 368 from cohorts).27
An antibody dose effect has been reported in several randomised studies3 28 as well as in the early access programme in the US.23 In the CORIPLASM trial, 800-880 mL of covid-19 convalescent plasma were transfused to patients randomised to the convalescent plasma group. In most studies so far, patients most often received 250-500 mL of convalescent plasma, except in the CAPSID (A Clinical Trial of Convalescent Plasma Compared to Best Supportive Care for Treatment of Patients With Severe Covid-19) trial where patients received 700-750 mL of convalescent plasma.24 28 The CAPSID trial reported a significant antibody dose effect for several outcomes, including survival at day 28. By contrast, the CORIPLASM protocol recommended four covid-19 convalescent plasma units provided by different donors for each patient, which resulted in less variation in mean antibody content in transfused convalescent plasma from patient to patient. This difference in transfusion practice might explain why we did not see an antibody dose effect in our study. Furthermore, convalescent plasma for the CORIPLASM study was collected early in the covid-19 crisis when vaccination was not available and before the occurrence of relevant SARS-CoV-2 variants.
Several studies have shown that plasma provided by convalescent donors who were vaccinated strongly increased anti-SARS-CoV-2 antibody titres and seroneutralisation ratios and also increased cross reactivity with a broader spectrum for variants to which the donor had not been exposed.12 29 High titre plasma from these convalescent donors who were vaccinated might have increased clinical efficacy. Early intervention with covid-19 convalescent plasma has been associated with improved outcome.3 4 Patients in our study had a median duration of symptoms of seven days at the time of inclusion, a short time period compared with most trials of patients admitted to hospital. Prespecified subgroup analyses, however, did not favour increased efficacy of convalescent plasma associated with a shorter time since onset of symptoms. The high number of patients with underlying immunosuppression, for whom seroconversion is not expected early on, might have contributed to this finding. Also, and as found in other covid-19 trials, early admission to hospital might be associated with more severe disease.8 22
Patients in the covid-19 convalescent plasma group tended to have worsening pulmonary clinical conditions than patients in the usual care group early after transfusion. The occurrence of early transient pulmonary worsening after transfusion of convalescent plasma has also been reported elsewhere,30 and might be related to antibody dependent enhancement involving immune complex mediated inflammatory immunopathology in infected tissues.31 Also, an antibody dependent Fc receptor mediated infection of tissues macrophages (and circulating monocytes) might result in a massive inflammatory response, as recently reported,32 which could also contribute to pulmonary worsening after transfusion of convalescent plasma.
These early outcomes are seldom reported in clinical studies, and distinguishing early pulmonary worsening from transfusion associated circulatory overload, transfusion related acute lung injury, or overall disease worsening, possibly started before transfusion, can be challenging. The transfusion of four units of plasma might have contributed to circulatory overload in some patients. Further spacing of administration of convalescent plasma (ie, 1 unit/day over four days) could reduce this risk. Early worsening did not prevent subsequent improvement and increased survival as early as day 14 after randomisation, although this effect was not significant. Antibody mediated SARS-CoV-2 uptake by monocytes and macrophages triggering inflammatory cell death and inhibition of viral replication might be a mechanism for subsequent improvement in disease.33
Limitations of this study
Our study had some limitations. The relatively small size of the trial limited the ability to appropriately assess outcomes, such as patient mortality, but we did access treatment with covid-19 convalescent plasma in immunosuppressed patients. Also, information on patient serostatus at inclusion was often not available. Although the mean antibody ratio in transfused convalescent plasma in our study was well above the US Food and Drug Administration threshold for high titre convalescent plasma (Euroimmun anti-SARS-CoV-2 immunoglobin G ratio >3.5),34 transfusion of higher titre plasma from convalescent donors who were vaccinated might improve efficacy.3 12 23 26
The emergence of the omicron variant of the SARS-CoV-2 virus with its BA.1-BA.5 subvariants has highlighted the risks associated with immune resistant SARS-CoV-2 and loss of efficacy of available monoclonal antibodies.11 Whereas several months are necessary to produce one or more new monoclonal antibodies more suited to changes in circulating viral strains, convalescent plasma, particularly from donors who are vaccinated, has shown increased resilience to immune resistant SARS-CoV-2 variants,12 30 increased scalability because of the existing collection infrastructure, as well as increased adaptability. The time between the onset of a covid-19 variant and the availability of convalescent plasma from donors infected with the variant disease is about four weeks.
Conclusions
The results of the CORIPLASM trial, along with recent data from other trials and cohort studies, support further evaluation and consequent use of convalescent plasma in patients who are immunocompromised for whom treatment options are limited. Recent guidelines from the Association for the Advancement of Blood and Biotherapies suggest transfusion of covid-19 convalescent plasma in addition to standard of care for patients admitted to hospital with covid-19 and pre-existing immunosuppression.
Researchers investigated whether ketamine may induce changes in the brain that are similar to psychosis.
They found that ketamine increases background noise, which may interfere with how the brain processes sensory signals.
The researchers conducted their study on rats, meaning that further research is needed to see how the findings may apply to humans.
Schizophrenia is characterized by changes in how a person perceives reality, including experiencing persistent delusions, hallucinations, and disorganized thinking. The condition affects around 24 millionTrusted Source people globally.
The exact cause of schizophrenia remains unknown. However, studies suggest that the condition may arise from environmental, psychological, and genetic factors.
A drug known as ketamine induces a mental state similar to psychosis in healthy individuals by inhibiting NMDA receptorsTrusted Source in the brain. This creates an imbalance of excitatory and inhibitory signals in the central nervous system, which affects sensory perception.
Experts believe that similar changes in NMDA receptors could be linked to perception changes in schizophrenia. How this may be the case, however, has remained unknown.
Recently, researchers examined how ketamine affects sensory perception in the brains of rats.
They found that ketamine increased “background noise” in the brain, making sensory signals less defined or pronounced. This, they noted, may explain the distorted perception of reality among people with schizophrenia or psychosis.
Dr. Sam Zand, a psychiatrist based in Las Vegas, not involved in the study, commented on these findings, telling Medical News Today that they “suggest that dysfunction in NMDA receptors may play a role in the development of psychosis.”
“The study provides new insights into the mechanism by which ketamine may induce psychotic symptoms. The findings may help to inform the development of new treatments for psychosis that target NMDA receptors or brain noise,” he added.
For the study, the researchers looked at the effects of ketamine on sensory perception in seven male lab rats. To do so, they first implanted rats with electrodes to record electrical activity in their brains.
They then simulated their whiskers and recorded the brain’s responses before and after ketamine.
More specifically, the researchers monitored how ketamine affects beta and gamma oscillations in a neural network that transmits signals from sensory organs to the brain.
Beta oscillations are brainwaves that range from 17–29 Herz (Hz), while gamma waves range from 30–80 Hz. The frequencies are crucial for processing sensory information.
In the end, the researchers found that ketamine increased power in both beta and gamma oscillations even before they stimulated the rats’ whiskers.
They also found, however, that post-stimulus and after ketamine administration, the amplitude of the rats’ beta and gamma oscillations decreased, which is linked to impaired perception.
They further noted that ketamine increased noise in gamma frequencies, which is also linked to an impaired ability to process sensory signals.
The researchers suggested that their findings mean that the distorted reality experienced in psychosis and schizophrenia may be triggered by more background noise, which in itself may be caused by malfunctioning NMDA receptors causing an imbalance of inhibition and excitation in the brain.
“The discovered alterations in thalamic and cortical electrical activity associated with ketamine-induced sensory information processing disorders could serve as biomarkers for testing antipsychotic drugs or predicting the course of disease in patients with psychotic spectrum disorders,” says Dr. Sofya Kulikova, senior research fellow at the HSE University in Perm, Russia, one of the study authors.
MNT spoke with Dr. Howard Pratt, psychiatrist and behavioral health medical director at Community Health of South Florida, not involved in the study, about its limitations. He emphasized that:
“The limitations of these findings are really that while we have clear correlation, we don’t yet have causation. Conditions like psychosis have numerous causes, which could be, for example, elevations in dopamine, which is the target of treatment with people carrying a diagnosis of schizophrenia. I look forward to seeing what happens when the research goes beyond animal studies.”
We also spoke with Dr. James Giordano, Pellegrino Center professor of neurology and biochemistry at Georgetown University Medical Center, not involved in the study, about the study’s limitations.
“A major limitation of the study is that it only investigated ketamine-induced effects, and thus, while useful and viable for gaining insights to ketamine’s activity in a rat model, may not provide direct translation to understand non–drug–induced dissociative, and psychotic states in humans,” he cautioned.
“It may be, for example, that the effects produced by ketamine in humans, while certainly being dissociative, and having certain characteristics of psychosis, are not completely representative or identical to the neurological mechanisms involved in other types of psychosis and schizophreniform disorders,” Dr. Giordano further noted.
When asked about the study’s implications, Dr. Giordano explained that “[t]hese findings are useful in that demonstration of ketamine’s actions at defined brain networks may enable better understanding — and improved clinical applications — of its effects in humans.”
“Additionally, by illustrating the roles of these brain nodes and networks involved in mediating dissociative states, we may develop improved insights — and possible treatments for — certain types of drug-induced psychoses, and perhaps other psychotic conditions, such as forms of schizophrenia, as well,” he concluded.
Background: Patients with metastatic urothelial carcinoma have a dismal prognosis and few treatment options after first-line chemotherapy. Responses to second-line treatment are uncommon. We assessed nivolumab, a fully human IgG4 PD-1 immune checkpoint inhibitor antibody, for safety and activity in patients with metastatic or surgically unresectable urothelial carcinoma whose disease progressed or recurred despite previous treatment with at least one platinum-based chemotherapy regimen.
Methods: In this multicentre, phase 2, single-arm study, patients aged 18 years or older with metastatic or surgically unresectable locally advanced urothelial carcinoma, measurable disease (according to Response Evaluation Criteria In Solid Tumors v1.1), Eastern Cooperative Oncology Group performance statuses of 0 or 1, and available tumour samples for biomarker analysis received nivolumab 3 mg/kg intravenously every 2 weeks until disease progression and clinical deterioration, unacceptable toxicity, or other protocol-defined reasons. The primary endpoint was overall objective response confirmed by blinded independent review committee in all treated patients and by tumour PD-L1 expression (≥5% and ≥1%). This trial is registered with ClinicalTrials.gov, number NCT02387996, and is completed. Follow-up is still ongoing.
Findings: Between March 9, 2015, and Oct 16, 2015, 270 patients from 63 sites in 11 countries received nivolumab, and 265 were evaluated for activity. Median follow-up for overall survival was 7·00 months (IQR 2·96-8·77). Confirmed objective response was achieved in 52 (19·6%, 95% CI 15·0-24·9) of 265 patients. Confirmed objective response was achieved in 23 (28·4%, 95% CI 18·9-39·5) of the 81 patients with PD-L1 expression of 5% or greater, 29 (23·8%, 95% CI 16·5-32·3) of the 122 patients with PD-L1 expression of 1% or greater, and 23 (16·1%, 95% CI 10·5-23·1) of the 143 patients with PD-L1 expression of less than 1%. Grade 3-4 treatment-related adverse events occurred in 48 (18%) of 270 patients-most commonly grade 3 fatigue and diarrhoea, which each occurred in five patients. Three deaths were attributed to treatment (pneumonitis, acute respiratory failure, and cardiovascular failure).
Interpretation: Nivolumab monotherapy provided meaningful clinical benefit, irrespective of PD-L1 expression, and was associated with an acceptable safety profile in previously treated patients with metastatic or surgically unresectable urothelial carcinoma.
POLARIX trial supports a favorable risk-benefit profile for polatuzumab vedotin, ODAC members say
Despite the concerns of FDA staff, agency advisors endorsed the inclusion of polatuzumab vedotin (Polivy) in a modified version of R-CHOP for adults with previously untreated large B-cell lymphoma.
By a vote of 11-2 on Thursday, the agency’s Oncologic Drugs Advisory Committee (ODAC) said findings from the phase III POLARIX trialopens in a new tab or window supported a favorable risk-benefit assessment for including the CD79b-directed antibody-drug conjugate as part of the first-line regimen.
During the meeting, FDA reviewers noted that while POLARIX met its primary endpointopens in a new tab or window of progression-free survival (PFS) in patients with previously untreated diffuse large B-cell lymphoma (DLBCL), that improvement was “modest,” and was accompanied by no improvement in overall survival (OS), as well as other secondary efficacy endpoints.
However, ODAC members on the whole were convinced that this version of the standard-of-care regimen of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine [Oncovin], and prednisone), in which vincristine was replaced by polatuzumab vedotin (pola+R-CHP), achieved a clinically meaningful improvement in PFS relative to standard R-CHOP.
“I believe this gain in progression-free survival is clinically meaningful for patients, and also leads to a reduction in the need for subsequent therapy,” said Grzegorz Nowakowski, MD, of the Mayo Clinic Comprehensive Cancer Center in Rochester, Minnesota, in explaining his “yes” vote. “And there were no major adverse toxicity signals, which would have been detrimental in this study.”
“However,” he added, “I would consider this regimen to be an option, rather than a standard, in the setting of a lack of overall survival difference from R-CHOP.”
Ravi A. Madan, MD, of the National Cancer Institute in Bethesda, Maryland, pointed out that R-CHOP has historically “been a regimen very hard to improve on, largely because of its roughly 70% efficacy rate.”
“The data reviewed today with R-CHP and polatuzumab does meet its endpoint of PFS relative to R-CHOP, and while PFS is not always meaningful, in this case I think it is,” he added. “And while the data are not as robust as we’re used to seeing in oncology settings, I’m not convinced you can have a robust improvement on a highly effective regimen such as R-CHOP without designing an impractically large study.”
That approval was based on a study of 80 patients randomized 1:1 to polatuzumab vedotin plus BR or BR alone for 6 cycles. At the end of therapy, the complete response rate in the combination arm was 40% compared with 18% with BR.
POLARIX — the confirmatory trial to determine polatuzumab vedotin’s clinical benefit — included 879 patients with previously untreated intermediate- or high-risk DLBCL randomized to pola+R-CHP or R-CHOP, and met its primary endpoint, with a statistically significant improvement in PFS with pola+R-CHP relative to standard R-CHOP (HR 0.73, 95% CI 0.57-0.95, P=0.02).
Although the difference in PFS was statistically significant, during the ODAC meeting, FDA reviewer Maryam Yazdy, MD, of the Division of Hematologic Malignancies 2 at the Office of Oncologic Diseases, noted that the effect size — a 4.1% absolute improvement in PFS at 1 year, and 6.5% at 2 years — “was modest.”
“Furthermore, it remains challenging to assess the contribution of pola+R-CHP,” given the fact that the activity of the drug it replaced — vincristine — is uncertain in the R-CHOP regimen, Yazdy said.
She also pointed out that there was no significant difference in secondary efficacy endpoints, such as complete response and patient-reported outcomes, and, most importantly, OS.
With a follow-up of 39.7 months, polatuzumab vedotin plus R-CHP failed to show improved OS, with an HR of 0.94 (95% CI 0.67-1.33), and an HR of 1.02 in the largest histological subgroup, DLBCL not otherwise specified.
“The lack of improvement in overall survival, particularly in the context of frontline therapy for diffuse large B-cell lymphoma, is a reflection of safety and efficacy, and adds to the uncertainty in benefit/risks,” Yazdy said.
The Relevance of PFS and OS
Christopher Flowers, MD, of the University of Texas MD Anderson Cancer Center in Houston, who was an investigator for POLARIX, argued that not only was the PFS result “clinically meaningful,” but that PFS, rather than OS, may be a more relevant endpoint in this first-line setting.
He pointed to an individual patient-level analysisopens in a new tab or window of 13 randomized trials showing that OS as an endpoint in first-line DLBCL would require more than a decade of follow-up. “In my view, this is an unacceptably long time to wait to determine whether a new therapy benefits patients,” Flowers said. “With that said, PFS as an endpoint measures and reflects what is meaningful for patients.”
He noted that the design of previous randomized trials supports an HR of 0.75 — representing a 5%-7% improvement in PFS at 2 years — as an indicator of clinical benefit, and that POLARIX met this standard.
“When we think about treatment for large B-cell lymphoma, first-line therapy offers the best chance for cure,” Flowers said. “With R-CHOP as the only FDA-approved therapy, there remains an unmet need to reduce relapse and progression in first-line patients.”
“At MD Anderson, we see approximately 500 newly diagnosed patients with large B-cell lymphoma every year,” he added. “An improvement in PFS of 5%-7% means that 25 t0 35 of those patients might avoid relapse of disease or the need for subsequent treatment.”
This argument was particularly compelling for several ODAC members.
“I think the importance of this drug — what Dr. Flowers and others have been saying — is that as frontline therapy, if we can cure more patients, that’s a win,” said Anthony Sung, MD, of Duke University School of Medicine in Durham, North Carolina. “I think if we can say to our patients, you have a greater chance of being cured with this regimen, I think that many patients would take it, and I think as a provider I would prescribe it.”
However, Mikkael A. Sekeres, MD, MS, of the Sylvester Comprehensive Cancer Center at the University of Miami in Florida, was unconvinced.
Sekeres, one of the two “no” votes, was particularly troubled by the fact that the initial lymphoma diagnosis in POLARIX was not confirmed by independent central review, nor was disease progression.
“I felt this trial didn’t meet the basics of a large clinical trial in hematological malignancies,” he said. “There wasn’t confirmation of the diagnosis, and there wasn’t confirmation of whether or not patients actually progressed before they were removed from the trial.”
“Progression-free survival, in and of itself, in a disease that has comparatively lower mortality rates is okay, as long as it has supportive data, but I couldn’t trust whether or not a patient has truly progressed on this study,” he added.
While the FDA is not required to follow the advice of its advisory committees, it usually does.
Patients with either atherosclerotic CVD, heterozygous familial hypercholesterolemia or both who were assigned bempedoic acid with maximally tolerated statin therapy had significant decreases in LDL levels without a higher incidence of overall adverse events compared with those assigned placebo, according to results from the CLEAR Harmony trial published in The New England Journal of Medicine.
“Our latest study shows that bempedoic acid could be another addition to the arsenal of cholesterol-lowering treatments available to patients,” Kausik K. Ray, MD, MPhil, professor at Imperial College London School of Public Health, said in a press release. “What we have is a new class of drug that could be given to patients who are already taking statins and could help them to further reduce their cholesterol levels and, thus, potentially cut their risk of heart attacks and strokes.”
In this phase 3 trial, researchers analyzed data from 2,230 patients with ASCVD, heterozygous familial hypercholesterolemia or both, were on maximally tolerated statin therapy and had a fasting LDL level of at least 70 mg/dL. Patients were assigned 180 mg once-daily bempedoic acid (Esperion Therapeutics; n = 1,488; mean age, 66 years; 74% men) or placebo (n = 742; mean age, 67 years; 71% men).
The primary endpoint was overall safety, which was determined by changes in safety laboratory variables and the incidence of adverse events. The principal secondary endpoint was the percentage change in LDL from baseline to week 12.
Follow-up visits that included fasting blood samples were conducted at 4, 8, 12, 24, 36 and 52 weeks.
At baseline, the mean LDL level was 103.2 mg/dL for all patients in the study.
The bempedoic acid and placebo groups had similar incidence of adverse events (78.5% vs. 78.7%, respectively) and serious adverse events (14.5% vs. 14%, respectively). Patients assigned bempedoic acid had a higher incidence of adverse events leading to regimen discontinuation compared with those assigned placebo (10.9% vs. 7.1%; P = .005). This was also seen in the incidence of gout (1.2% vs. 0.3%; P = .03).
At 12 weeks, patients assigned bempedoic acid had a mean reduction in LDL of 19.2 mg/dL, which represented a –16.5% change from baseline (difference compared with placebo = –18.1 percentage points; 95% CI, –20 to –16.1).
Findings regarding safety and efficacy were consistent despite background statin therapy intensity.
“Some of the adverse effects, such as increases of uric acid and gout, are problems that health care providers can recognize with routing blood tests and that can be managed,” Christie M. Ballantyne, MD, FACC, FACP, FAHA, FNLA, professor of medicine, chief of the section of cardiovascular research and director of the Center for Cardiovascular Disease Prevention at Baylor College of Medicine, said in a press release. “So the bigger picture is understanding the types of side effects that can develop, whether they can be managed and the benefit of the drug on LDL levels in patients who are at high risk for cardiovascular events and who still have higher levels of LDL-C than are optimal on the highest dose of statin that they can tolerate.” – by Darlene Dobkowski
Preclinical data suggest that antiprogestins inhibit the growth of luminal breast carcinomas that express higher levels of progesterone receptor isoform A (PRA) than isoform B (PRB). Thus, we designed a presurgical window of opportunity trial to determine the therapeutic effects of mifepristone in patients with breast cancer, based on their high PRA/PRB isoform ratio (MIPRA; NCT02651844).
Patients and Methods:
Twenty patients with luminal breast carcinomas with PRA/PRB > 1.5 (determined by Western blots), and PR ≥ 50%, naïve from previous treatment, were included for mifepristone treatment (200 mg/day orally; 14 days). Core needle biopsies and surgical samples were formalin fixed for IHC studies, while others were snap-frozen to perform RNA sequencing (RNA-seq), proteomics, and/or Western blot studies. Plasma mifepristone levels were determined using mass spectrometry. The primary endpoint was the comparison of Ki67 expression pretreatment and posttreatment.
Results:
A 49.62% decrease in Ki67 staining was observed in all surgical specimens compared with baseline (P = 0.0003). Using the prespecified response parameter (30% relative reduction), we identified 14 of 20 responders. Mifepristone induced an increase in tumor-infiltrating lymphocytes; a decrease in hormone receptor and pSer118ER expression; and an increase in calregulin, p21, p15, and activated caspase 3 expression. RNA-seq and proteomic studies identified downregulated pathways related to cell proliferation and upregulated pathways related to immune bioprocesses and extracellular matrix remodeling.
Conclusions:
Our results support the use of mifepristone in patients with luminal breast cancer with high PRA/PRB ratios. The combined effects of mifepristone and estrogen receptor modulators warrant clinical evaluation to improve endocrine treatment responsiveness in these patients.
Discussion
MIPRA was the first clinical trial in which patients were categorized according to their PR isoform ratio. In this single-arm study, we demonstrated that mifepristone inhibited the proliferation of breast carcinomas with higher levels of PRA than of PRB. The study met the primary endpoint of a 30% reduction in Ki67 between CNB and surgery. Morphologic evaluation, transcriptomic, and proteomic studies support the therapeutic effect of mifepristone, and suggest that responses may be underestimated with the unique measurement of Ki67. Although transcriptomic studies have been performed to reinforce Ki67 data in different breast cancer WOT studies (28), to the best of our knowledge, this is the first study in which paired samples were characterized by proteomics.
Originally, we estimated that we had to evaluate 100 patients to reach 20 who met the inclusion criteria. However, we recruited 140 patients because, in some cases, the biopsy failed to have sufficient cancer cells, and the sensitivity of WB was not sufficient to obtain a reliable result.
Following the design of a similar study (29), we did not include a placebo group to compare the intrinsic variation in Ki67 expression between CNB and surgical samples. In trials in which control patients have been included, some authors reported a slight increase in Ki67 expression (30–33), while others reported a decrease between the surgical sample and the CNB that never exceeded 20% (12, 34), which is below the decrease obtained in this study (49%). Ki67 evaluation, as a primary endpoint, has become the gold standard in WOT studies (35–37). Our results are similar to those originally reported for tamoxifen treatment in patients with ER+ breast cancer (30, 38). In line with other studies, such as the IMPACT (39), POETIC (40), and neoMONARCH (28) trials, MIPRA patients received mifepristone for only 2 weeks to avoid surgery delays.
Although a decrease in tumor size determined by ultrasound was not expected, it was achieved in several cases, even considering that the first ultrasound measurement was registered 49 days (median) before the surgical sample at the time of CNB. Considering that luminal tumors may increase in size by 0.17%–0.21% per day (41), the real decrease in size might be even higher than the one recorded.
Six of the 20 tumors did not meet the prespecified criteria for treatment response. As Ki67 evaluation was the primary endpoint, we named these tumors as unresponsive. Three of these patients had very low Ki67 levels on CNB, suggesting that a possible therapeutic effect might have been masked. Moreover, RNA-seq analysis performed using four of six unresponsive tumors showed the activation of pathways similar to those in responsive tumors. GSVA showed a clear inhibitory effect for patients M090 and M073 and less sharp suppression for M094, whereas M105 had a different response. Several morphologic signs of drug response were also observed in three of six unresponsive cases, and the analysis was performed blinded to the Ki67 data.
RNA-seq and MS studies identified downregulated pathways related to cell proliferation, and although the individual MKI67 mRNA (Ki67 gene) or protein did not appear to be one of the deregulated candidates, proliferating cell nuclear antigen and MCM2–7 proteins, which are also considered surrogate markers of cell proliferation, were downregulated. This highlights the importance of simultaneously evaluating several biomarkers to improve the data accuracy. As Ki67 and RNA-seq/proteomic data originated from different CNB or surgical samples, inclusion of both analyses increased the robustness of our data.
Common enriched pathways found in both proteomic and RNA-seq studies were those related to the innate immune system and those related to cell-matrix organization. This agrees with the increase in TILs observed in most mifepristone-treated tumors and with recent preclinical findings showing that mifepristone may prime PRA-H tumors for a second treatment with an immune checkpoint inhibitor (26), and with those from Werner and colleagues, who suggested the use of antiprogestins to increase immune infiltrates in tumors by targeting PR (42). Proteins related to PD1 signaling were found in the Cyt extracts of mifepristone-treated tumors. Calreticulin/calregulin, a protein related to immunogenic cell death (43), was highly expressed in the cell membranes of several mifepristone-treated samples (IHC assays). Similar immune signatures were observed in trials using CDK4/6 inhibitors (44). However, it may be argued that the CNB procedure elicits an inflammatory effect. In the NeoMONARCH study, CNB and surgical samples were collected after 14 days of single or combined treatment, and an increase in immune-related pathways was only observed in the combined treatment group, ruling out the possible assumption (45).
Apoptosis has not been identified as a hierarchical pathway involved in the success of endocrine therapies, showing only mild increases after tamoxifen or fulvestrant treatment (46). However, in preclinical studies in which mifepristone induced almost complete tumor regression involving differentiation and/or tissue remodeling, a significant increase in apoptosis was observed after 24 or 48 hours of mifepristone administration (47). Thus, we expected to find an increase in apoptotic cells in mifepristone-treated tumors. In the MIPRA trial, a modest increase in apoptosis was observed morphologically, as confirmed by IHC and proteomic studies, in which an increase in several proapoptotic proteins was observed.
In our study, we also included patients with advanced stages that were naïve to any other treatment for this cancer, which makes this study unique compared with other trials using mifepristone, in which patients who failed to respond to other treatments were included. Romieu and colleagues (8) and Klijn and colleagues (6) enrolled patients with tamoxifen resistance. Perrault and colleagues identified PR+ patients who received no other treatment for recurrence but were previously treated for their primary tumors (7). In preclinical models, most endocrine-resistant tumors are PRB-H (3), which may partially explain the poor responses observed in the aforementioned clinical trials.
Different reasons may explain why some patients in our cohort were unresponsive to mifepristone, and they should be considered in future studies. Two of the unresponsive tumors, M026 and M105, and the responsive M140 tumor were classified as PRA-H based on the WB of the Nuc extract; however, in the three tumors, the Cyt fraction was PRB-H. It may be suggested that tumors in which both the Nuc and Cyt fractions are PRA-H may represent the best candidates for mifepristone treatment, as they truly represent the total protein ratio. Tumor M140 showed good responsiveness in the Ki67 assay, a decrease in tumor size, an increase in the immune bioprocess pathways and apoptosis, but unexpectedly, an increase in proliferative pathways. This may be because the frozen CNB sample also contained adjacent nontumor mammary cells, which may have masked the mifepristone-induced effects.
Among Ki67 responsive patients, a HER2+ patient (CNB evaluation) was cataloged as negative in the surgical sample by the Hospital Pathology Department. We also found a decrease in membrane staining for HER2 (IHC), and HER2/ERBB2 was one of the downregulated proteins reported in the Cyt extracts (proteomics). Similar observations were made by Lee and colleagues, who used TLP to show a decrease in HER2-related genes in TLP-treated tumors. Moreover, they proposed that HER2+ luminal tumors might respond best to antiprogestin therapy (12).
IHC for p53 indirectly detects p53 mutations (48). The only tumor that was positive for p53 was sensitive to mifepristone, as was the case with T47D xenografts that have a pathogenic p53 mutation (49) and respond to mifepristone treatment (50). RNA-seq analysis allowed us to investigate possible mutations in the eight tumors studied. It is worth mentioning the missense mutation in ESR1, which, as reported previously, is associated with endocrine resistance (27). As this patient was responsive to mifepristone, the effect of mifepristone treatment in patients with activated ESR1 mutations deserves further investigation.
The decrease in ER observed by IHC was consistent with the possible displacement of ER from the nuclear compartment to the cytoplasm, as observed in proteomic studies. ER is usually phosphorylated at Ser118 in response to MAPK activation or estradiol binding, whereas Ser167 is phosphorylated by Akt, RSK, and casein kinase II in addition to MAPK (51, 52). As we only observed a decrease in pSer118ER expression following mifepristone treatment, it can be speculated that mifepristone treatment compromises MAPK-mediated ER signaling.
As mentioned previously, mifepristone, in addition to its antiprogestin action, exerts antiglucocorticoid effects (53). Taking advantage of the immunomodulatory effects of mifepristone, an ongoing clinical trial intends to exploit this property therapeutically using high mifepristone doses in patients with breast cancer (NCT03225547). Using experimental PRA-H tumor models, we showed that mifepristone inhibits tumor growth even when tumors are transplanted into immunosuppressed mice (26). Moreover, in vitro, mifepristone exerts antiproliferative effects only in PRA-H+ cells (16), suggesting that the direct antiprogestin effect of mifepristone is the prevailing effect, without ruling out a contribution from its antiglucocorticoid or its antiandrogenic effects (reviewed in ref. 15).
In summary, our clinical study showed that preclinical findings are valid in patients with breast cancer, suggesting that mifepristone can be used for the treatment of luminal PRA-H breast cancer. Further studies are needed to evaluate the effects of combined treatment with antiprogestins and tamoxifen in PRA-H patients. Preclinical studies have suggested that a stronger response can be obtained with this combination (54). Aromatase inhibitors or ER degraders may not work together with mifepristone, because they inhibit PR expression. Because we have already shown that lymph node metastases maintain the same PR isoform ratio as the primary tumor (15), it may be speculated that this treatment might prove suitable in an adjuvant setting, or alternatively, in a neoadjuvant setting, if further immunotherapy is suggested. Ongoing studies are currently evaluating the combination of mifepristone and CDK4/6 inhibitors in preclinical PRA-H models. Finally, because WB does not seem to be an ideal method for discriminating PRA-H patients in hospital facilities, companion diagnostic tools to improve screening should be developed.
Strengths
Originality, proof of concept after years of preclinical research, primary endpoint met, combination of approaches: standard Ki67 supported by exhaustive morphologic evaluation, IHC validation, WB, transcriptomics, and proteomics. Most secondary outcomes were met, including studies based on frozen samples and studies using different formalin-fixed samples. The evaluation of mifepristone in plasma guarantees treatment compliance.
Limitations
This study had a small number of patients, no placebo group, limited material from CNB for further analysis, and a short treatment period.
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