Placebo-controlled Pilot Trial Research Articles

Optimal treatment conditions for low-intensity pulsed ultrasound therapy for Alzheimer's disease: applications from mice to humans.

We previously developed a novel therapy with low-intensity pulsed ultrasound (LIPUS) that ameliorates cognitive decline through upregulation of endothelial nitric oxide synthase (eNOS) in mouse models of Alzheimer's disease (AD). In a randomized, double-blind, placebo-controlled pilot trial, we demonstrated that whole-brain LIPUS therapy is safe and tends to suppress the cognitive decline in early AD patients. We herein report the findings of our basic experiments that we performed for the pilot trial in order to apply whole-brain LIPUS therapy to humans, as well. First, we examined the relationship between bone density/thickness and ultrasound transmittance using human temporal bone. Next, based on the results of ultrasound transmittance, we further examined mRNA expression of VEGF, FGF2, and eNOS in response to variable ultrasound frequencies, duty cycles, and sound pressures. There was a significant correlation between bone thickness and transmittance (1.0MHz, P < 0.001), while there was no significant correlation between bone density and transmittance (1.0MHz, P = 0.421). At a frequency of 0.5MHz, the optimum duty cycle was considered to be up to 20%. When the tissue amplitude was in the range of 0.05-0.5MPa, VEGF, FGF2, and eNOS were significantly upregulated by LIPUS. Thus, the conditions necessary for LIPUS therapy for the human brain were identified as sound pressure just below the probe 1.3MPa (tissue amplitude 0.15MPa), duty cycle 5%, and frequency 0.5MHz. We successfully identified the optimal treatment conditions for LIPUS therapy for patients with AD.

A Randomized, Double-Blind, Placebo-Controlled Pilot Trial of the Acute Antisuicidal and Antidepressant Effects of Intranasal (R,S)-Ketamine in Severe Unipolar and Bipolar Depression With and Without Comorbid Alcohol Use Disorder.

A Randomized, Double-Blind, Placebo-Controlled Pilot Trial of the Acute Antisuicidal and Antidepressant Effects of Intranasal (R,S)-Ketamine in Severe Unipolar and Bipolar Depression With and Without Comorbid Alcohol Use Disorder.

A phase II randomised controlled trial of intranasal oxytocin in anorexia nervosa

BackgroundAnorexia nervosa (AN) is an eating disorder (ED) with high mortality rates and limited response to existing treatments, prompting the need to identify effective agents and adjuncts. There is evidence for an emerging role for the neuropeptide oxytocin (OT) in the pathophysiology of AN, with studies showing a perturbed oxytocinergic system in patients with AN. Preliminary evidence has demonstrated that intranasal OT (IN-OT) can produce anxiolytic effects in AN, as well as reducing concern about eating, and dysfunctional attentional biases related to the disorder. IN-OT is a non-invasive treatment option for AN that requires investigation as an adjunct to nutritional rehabilitation. MethodsThis multi-site study (Trial Registration:ACTRN1261000897460) sought to replicate and extend a previous randomised placebo-controlled pilot trial of repeated dose IN-OT in patients with AN hospitalised for nutritional rehabilitation. Patients with AN (N=61) received daily IN-OT (18 IU twice per day) or placebo for four weeks, whilst undergoing inpatient hospital treatment. Outcome measures included ED psychopathology (primary) as measured by the Eating Disorder Examination (EDE) and Body Mass Index (BMI; secondary). Participants were assessed pre- and post-treatment, and at six months following the intervention. The effects of the first and last doses of IN-OT on responses (anxiety ratings and salivary cortisol) to a high-energy snack were also examined. ResultsSixty-one female inpatients (Mage=24.36,SD=7.87) with an average BMI of 16.24 (range: 11.43–18.55), were recruited into the study. No significant differences were found between placebo and OT groups at any of the time points on the outcomes of interest, but significant improvements in almost all psychological parameters in both groups were evident over time. IN-OT did not significantly reduce anxiety nor salivary cortisol in response to a high-calorie snack. ConclusionThis is the largest randomised placebo-controlled trial of repeated dose intranasal OT in people with AN, during refeeding. The therapeutically promising findings of the pilot study were not replicated. Limitations and reasons for the non-replication included relatively large variance, baseline psychopathology scores being higher in this patient group, potential ceiling effects in BMI and ED psychopathology as well as differing comorbidities.

Effects of motor imagery and action observation on respiratory function in mild smokers: a randomized single-blind controlled pilot trial

Background: Motor imagery (MI) and action observation (AO) training can activate brain areas involved in planning, adjusting, and automating voluntary movement in a manner similar to that when these activities are being performed. Aim: The main objective of this study was to assess the effects of MI and AO training on respiratory function in mild smokers. Methods: A single-blind placebo-controlled pilot trial was designed. A total of 27 mild smokers were randomized into three groups: MI (n = 9), AO (n = 9), and sham observation (SO; n = 9) groups. The MI and AO groups performed mental training of breathing exercises while the SO group observed a landscape without a human agent. The primary outcomes were pulmonary function parameters (forced expiratory volume during the 1st s [FEV1], forced vital capacity [FVC], FEV1/FVC ratio, maximum voluntary ventilation [MVV], and peak expiratory flow [PEF]), and the secondary outcomes were maximal inspiratory/expiratory pressures (MIP/MEP) and perceived fatigue. All outcome measures were assessed at baseline and post-intervention. Results: Regarding the pulmonary function parameters, only the AO group showed significant within-group differences in FEV1 (mean differences [MD] = 0.37 L (0.17 – 0.56), P = 0.001), FVC (MD = 0.1 L (0.02 – 0.16), P = 0.008), and PEF (MD = 0.74 L/s (0.29 – 1.18), P = 0.002) with a small-to-moderate effect size. No differences were found in FEV1/FVC ratio and MVV. With regard to the maximal static pressures, only the AO group showed significant within-group differences in MEP with a small effect size (MD = 11.22 cm H2O (0.19 – 22.2), P = 0.046). Finally, both AO and MI groups showed significantly greater perceived fatigue with regard to SO group with a large effect size (P &lt; 0.05). Conclusion: AO training has a slight impact on some pulmonary function parameters, such as FEV1, FVC, or PEF, as well as on MEP when applied in isolation and in a single session. Relevance for Patients: Although it is still early to draw some solid conclusions, AO training could be used in combination with respiratory exercises to see if the effect is greater than exercises in isolation. The study of movement representation strategies on pulmonary function is a field that has been sparingly explored so far. This paper offers some interesting data to be considered for further research.

Dalfampridine as a promising agent in the management of hereditary spastic paraplegia: A triple-blinded, randomized, placebo-controlled pilot trial

Limited but encouraging results support the use of dalfampridine in patients with hereditary spastic paraplegia (HSP). Our aim was to investigate the effects of dalfampridine on walking speed, muscle length, spasticity, functional strength, and functional mobility in patients with HSP. In this triple-blinded, randomized, placebo-controlled pilot trial, four patients with HSP received dalfampridine (10 mg twice daily) in addition to physiotherapy (twice a week), and four patients received placebo in addition to physiotherapy for eight weeks. The group allocation was masked from the assessor, treating physiotherapists, and patients. The primary outcome was the Timed 25-foot Walk Test (T25FWT) at the end of the eight-week treatment. The secondary outcome measures were functional mobility, functional muscle strength, muscle length, and spasticity. The improvement in the T25FWT values was significantly higher in the experimental group than in the control group (p < 0.05). All patients in the experimental group exceeded the proposed minimally important clinical difference for T25FWT. The degrees of improvement in most muscle length and spasticity assessments and functional muscle strength were also higher in the experimental group (p < 0.05). No significant difference was observed between the groups regarding functional mobility (p > 0.05). No adverse events or side effects were noted. This pilot trial yields encouraging evidence that the combination of dalfampridine and physiotherapy may enhance muscle parameters and improve walking speed in patients with HSP. However, further research involving larger sample sizes and more comprehensive assessments is needed to validate these results and establish the clinical benefits of this treatment approach.Trial registration ID: NCT05613114 (https://clinicaltrials.gov/), retrospectively registered on November 14, 2022.

2081P The therapeutic effect of anti-inflammatory tripeptide cream on hand-foot syndrome related to anticancer drugs: A prospective, randomized, placebo-controlled pilot trial

2081P The therapeutic effect of anti-inflammatory tripeptide cream on hand-foot syndrome related to anticancer drugs: A prospective, randomized, placebo-controlled pilot trial

Theta burst stimulation add on to dialectical behavioral therapy in borderline-personality-disorder: methods and design of a randomized, single-blind, placebo-controlled pilot trial

Specialized psychotherapeutic treatments like dialectical behavioral therapy (DBT) are recommended as first treatment for borderline personality disorder (BPD). In recent years, studies have emerged that focus on repetitive transcranial magnetic stimulation (rTMS) in BPD. Both have independently demonstrated efficacy in the treatment of BPD. Intermitted theta burst stimulation (iTBS), a modified design of rTMS, is thought to increase the excitability of neurons and could be a supplement to psychotherapy in addition to being a standalone treatment. However, no studies to date have investigated the combination of DBT and rTMS/iTBS. This study protocol describes the methods and design of a randomized, single-blinded, sham-controlled clinical pilot study in which BPD patients will be randomly assigned to either iTBS or sham during four consecutive weeks (20 sessions in total) in addition to standardized DBT treatment. The stimulation will focus on the unilateral stimulation of the left dorsolateral prefrontal cortex (DLPFC), which plays an important role in the control of impulsivity and risk-taking. Primary outcome is the difference in borderline symptomatology, while secondary target criteria are depressive symptoms, general functional level, impulsivity and self-compassion. Statistical analysis of therapy response will be conducted by Mixed Model Repeated Measurement using a 2 × 2-factorial between-subjects design with the between-subject factor stimulation (TMS vs. Sham) and the within-subject factor time (T0 vs. T1). Furthermore, structural magnetic resonance imaging (MRI) will be conducted and analyzed. The study will provide evidence and insight on whether iTBS has an enhancing effect as add-on to DBT in BPD.Trial registration: drks.de (DRKS00020413) registered 13/01/2020.

Randomized, double-blinded, placebo-controlled pilot study: efficacy of faecal microbiota transplantation on chronic fatigue syndrome

BackgroundChronic fatigue syndrome (CFS) is a disabling illness of unknown aetiology. Disruption of gut microbiota may play a role in several neurological disorders. In this study, the effect of faecal microbiota transplantation (FMT) on fatigue severity and health-related quality of life (HRQOL) in patients with CFS was evaluated.MethodsRandomized, placebo-controlled pilot trial. Patients and researchers were blinded to treatment assignment. 11 patients with CFS (10 female and 1 male, mean age 42.2 years and mean duration of CFS 6.3 years) were randomly assigned to receive either FMT from a universal donor (n = 5) or autologous FMT (n = 6) via colonoscopy. Patients’ HRQOL was assessed by using visual analog scale (VAS) and self-reporting questionnaires Modified Fatigue Impact Scale (MFIS), 15D and EQ-5D-3L. Patients’ HRQOL was evaluated at baseline, and 1 and 6 months after the FMT.ResultsThe baseline VAS scores in the FMT and placebo groups were 62.4 and 76.0 (p = 0.29). 1-month scores were 60.0 and 73.7 and 6-months scores 72.8 and 69.5, respectively. Total MFIS scores in the FMT and placebo groups were 59.6 and 61.0 at the baseline (p = 0.80), 53.5 and 62.0 at 1 month and 58.6 and 56.2 at 6 months. Compared to the baseline scores, differences at 1 and 6 months were statistically insignificant both in VAS and in MFIS. The 15D and EQ-5D-3L profiles did not change after the FMT or placebo. FMT-related adverse events were not reported.ConclusionFMT was safe but did not relieve symptoms or improve the HRQOL of patients with CFS. Small number of study subjects limits the generalizability of these results.Trial Registration ClinicalTrials.gov Identifier NCT04158427, https://register.clinicaltrials.gov, date of registration 08/08/2019.

A Pilot Study on the Effectiveness of Prazosin as a Treatment of Post-Traumatic Stress Disorder-Related Nightmares in Women with Bulimia Nervosa.

Objectives Post-traumatic stress disorder (PTSD) symptoms are reported in over 36% of individuals with bulimia nervosa. To date, none of the clinical trials have examined nightmare reduction in this population.We evaluated the effectiveness of prazosin in bulimic females experiencing PTSD-related nightmares. We hypothesized that prazosin will decrease nightmares, normalize cortisol levels and secretory patterns, and improve sleep. Methods Our seven-week prospective, randomized, double-blind, placebo-controlled crossover pilot trial recruited eight adult women. Each participant received three weeks of prazosin and a placebo, separated by a one-week washout period. The order of treatment was counterbalanced across participants.Self-reports, clinician-administered scales, and salivary cortisol was collected to measure outcomes. Results A significant treatment effect was seen in nightmare intensity on the Clinician-Administered PTSD Scale (CAPS-I) (p=0.026) and a marginally significant effect on nightmare frequency (p=0.069). The only significant main effectof treatment on self-reported sleep parameters was on nightmares. Cortisol secretory patterns did not change, but on average, study participants had significantly higher cortisol levels compared to normative values. ANOVA showed a significant main effect of time for cortisol (F(4, 28) = 6.15, p=.001) but no within or between groups significant effects (ps>.179). Follow-up tests showed the effect of time was linear (F(1, 7) = 10.77, p=.013). Conclusion Prazosin significantly reduced intensity and marginally reduced the frequency of PTSD-related nightmares in bulimia nervosa but did not affect subjective sleep efficiency, quality, cortisol levels, or diurnal cortisol secretory pattern. Larger trials using objective sleep measures are warranted to replicate these findings.

The Effect of Crackers Enriched with Camelina Sativa Oil on Omega-3 Serum Fatty Acid Composition in Older Adults: A Randomized Placebo-Controlled Pilot Trial

BackgroundCamelina sativa oil is one of the richest dietary sources of omega-3, with polyunsaturated fatty acids amounts of over 50%, linolenic acid content of around 40–45%, and linoleic acid of about 15%. Moreover, this oil is a valuable source of antioxidants which provide oxidative stability. All those features raise interest in considering Camelina oil as an alternative and sustainable oil source providing stable omega-3-rich emulsions for functional food production.ObjectivesThe present study aimed to investigate the effects of Camelina oil-enriched crackers on serum omega-3 concentration, inflammatory markers and serum lipid profile.DesignRandomized placebo-controlled pilot trial. Setting: Research and Development Center (Complife Italia s.r.l.).ParticipantsSixty-six free-living older volunteers (aged≥65 years).InterventionOlder adults were enrolled and randomly assigned to one of two groups: the camelina group or the placebo group. Subjects consumed daily 35 g of crackers (Camelina enriched crackers or placebo ones) twice daily for 12 weeks.MeasurementsSerum polyunsaturated fatty acid profile, inflammatory status and serum lipid panel parameters were recorded pre and post-intervention.ResultsIn the camelina group, alpha-linolenic acid serum concentration was significantly higher (p<0.01) compared to the placebo group at the end of the study. Concerning inflammatory plasma markers, a significant mean pro-inflammatory interleukin-18 plasma concentration decrease in the placebo group compared to the camelina one was observed (p<0.05). No significant differences in other mean inflammatory markers concentrations post-intervention were noted in either group. Lastly, examining the change in lipid profile, it is noteworthy that a higher reduction of total cholesterol, low-density lipoprotein and triglycerides in the camelina group postintervention, despite the lack of statistical significance.ConclusionCamelina oil significantly elevated the serum alpha-linolenic acid concentration with no significant changes in inflammatory markers and lipid profile.

Sirolimus suppresses circulating fibrocytes in idiopathic pulmonary fibrosis in a randomized controlled crossover trial.

Fibrocytes are bone marrow-derived circulating cells that traffic to the injured lungs and contribute to fibrogenesis. The mTOR inhibitor, sirolimus, inhibits fibrocyte CXCR4 expression, reducing fibrocyte traffic and attenuating lung fibrosis in animal models. We sought to test the hypothesis that short-term treatment with sirolimus reduces the concentration of CXCR4+ circulating fibrocytes in patients with idiopathic pulmonary fibrosis (IPF). We conducted a short-term randomised double-blind placebo-controlled crossoverpilot trial to assess the safety and tolerability of sirolimus in IPF. Subjects were randomly assigned to sirolimus or placebo for approximately 6 weeks, and after a 4 week washout, assigned to the alternate treatment. Toxicity, lung function, and the concentration of circulating fibrocytes were measured before and after each treatment. In the 28 study subjects, sirolimus resulted in a statistically significant 35% decline in the concentration of total fibrocytes, 34% decline in CXCR4+ fibrocytes, and 42% decline in fibrocytes expressing ɑ-smooth muscle actin, but no significant change in these populations occurred on placebo. Respiratory adverse events occurred more frequently during treatment with placebo than sirolimus; the incidence of adverse events and drug tolerability did not otherwise differ during therapy with drug and placebo. Lung function was unaffected by either treatment with the exception of a small decline in gas transfer during treatment with placebo. As compared with placebo, short-term treatment with sirolimus resulted inreduction of circulating fibrocyte concentrations in subjects with IPF with an acceptable safety profile. gov identifier number NCT01462006FUNDING. NIH R01HL098329 and American Heart Association 18TPA34170486.

Beneficial effect of Gyejibokryeong-hwan on climacteric syndrome with blood stasis pattern: A randomized, double-blinded, placebo-controlled clinical pilot trial

BackgroundGyejibokryeong-hwan (GBH), a herbal mixture that is widely used for climacteric syndrome, is studied for its efficacy; however, no study evaluated the GBH indication, which is a blood-stasis pattern based on traditional Chinese medicine theory. MethodsThis was a randomized, double-blinded, placebo-controlled clinical pilot trial. Fifty subjects with climacteric syndrome were recruited and randomly assigned to GBH group or placebo group. Subjects were administered GBH or placebo granules for 4 weeks followed by 4 weeks of observation period. For the primary outcome, the Menopause Rating Scale (MRS) was evaluated. For the secondary outcomes, quality of life, degrees of abdominal resistance and tenderness, blood-stasis pattern questionnaire and degree of upward movement of Qi were evaluated. ResultsAfter 4-week intervention, the mean change of total MRS score significantly decreased in the GBH group compared to the placebo group (p = 0.037). The quality of life related to physical health (p = 0.008) and blood-stasis pattern (p = 0.018) significantly improved in the GBH group but not in the placebo group. ConclusionOur findings provide evidence of the feasibility of recruiting subjects with GBH indications and show that GBH may have clinical efficacy for the treatment of menopausal symptoms, especially urogenital symptoms, without any significant adverse events. Trial registrationThis trial was registered at Clinical Research Information Service (CRIS identifier: KCT0002040).

1513 Anti-IL17A, Ixekizumab, for treatment-resistant chronic venous leg ulcers: A phase II randomized, double-blind, placebo-controlled pilot trial

1513 Anti-IL17A, Ixekizumab, for treatment-resistant chronic venous leg ulcers: A phase II randomized, double-blind, placebo-controlled pilot trial

Plasma, urine, and stool metabolites in response to dietary rice bran and navy bean supplementation in adults at high-risk for colorectal cancer.

Dietary intake of whole grains and legumes and adequate physical activity (PA) have been associated with reduced colorectal cancer (CRC) risk. A single-blinded, two-arm, randomized, placebo-controlled pilot trial was implemented to evaluate the impact of a 12-week dietary intervention of rice bran + navy bean supplementation and PA education on metabolite profiles and the gut microbiome among individuals at high risk of CRC. Adults (n=20) were randomized 1:1 to dietary intervention or control. All participants received PA education at baseline. Sixteen study foods were prepared with either heat-stabilized rice bran + navy bean powder or Fibersol®-2 as a placebo. Intervention participants consumed 30 g rice bran + 30 g navy bean powder daily; those in the control group consumed 10 g placebo daily. Non-targeted metabolite profiling was performed by UPLC-MS/MS to evaluate plasma, urine, and stool at 0, 6, and 12 weeks. Stool was also analyzed for primary and secondary bile acids (BAs) and short chain fatty acids (SCFAs) by UPLC-MS/MS and microbial community structure via 16S amplicon sequencing. Two-way ANOVA was used to compare differences between groups for metabolites, and mixed models were used to compare differences between groups for BAs, SCFAs, and alpha and beta diversity measures of microbial community structure. Across biological matrices, the intervention resulted in changes to several amino acid and lipid metabolites, compared to control. There was a 2.33-fold difference in plasma (p<0.001) and a 3.33-fold difference in urine (p=0.008) for the amino acid S-methylcysteine at 12 weeks. Fold-differences to 4-methoxyphenol sulfate in plasma and urine after 6 and 12 weeks (p<0.001) was a novel result from this combined rice bran and navy bean intervention in people. A 2.98-fold difference in plasma (p=0.002) and a 17.74-fold difference in stool (p=0.026) was observed for the lipid octadecenedioylcarnitine at 12 weeks. For stool BAs, 3-oxocholic acid was increased at 12 weeks compared to control within a subset of individuals (mean difference 16.2 ug/uL, p=0.022). No significant differences were observed between groups for stool SCFAs or microbial community structure. Dietary intake of rice bran + navy beans demonstrates beneficial modulation of host and gut microbial metabolism and represents a practical and affordable means of increasing adherence to national guidelines for CRC control and prevention in a high-risk population.

Effects of Selenium Supplementation on Incidence and Severity of Preeclampsia: A Randomized, Double-Blind, Placebo-Controlled Pilot Trial

Background: Preeclampsia is a serious hypertensive condition of pregnancy associated with high maternal and fetal morbidity and mortality. In this study, the effect of selenium supplementation on the incidence and severity of preeclampsia in pregnant women was evaluated. Methods: The present double-blind, placebo-controlled, parallel study was registered at Fatemieh Hospital of Hamadan, Iran. One hundred eighty women in the first trimesters of pregnancy were assigned to either selenium (SG, n = 90) or placebo (PG, n = 90) groups. SG and PG received 100 μg of selenium supplement or placebo per day, respectively. Results: In this study, no significant difference was observed between two groups in terms of age, body mass index, and serum selenium before the intervention (P &gt; 0.05). The incidence of preeclampsia in the SG and PG was 9 and 5, respectively (P = 0.28). There was no statistically significant difference between sex and Apgar score of neonates in the two groups (P = 0.73). The mean birth weight, systolic and diastolic blood pressure in the SG was significantly higher than PG (P = 0.003, 0.01, and 0.007, respectively). The mean gestational age in the SG was insignificantly lower than the PG (P = 0.41). After the study, preeclampsia incidence was not significant between the groups (P = 0.28). Conclusion: The administration of 100 μg of selenium supplementation in pregnant women, had no effect on decreasing preeclampsia, but it may reduce the severity of preeclampsia.

Single low-dose ketamine infusion for women with prenatal depressive symptoms undergoing cesarean delivery: A pilot randomized trial.

Ketamine is approved for antidepressant therapy, but evidence regarding its use in women with perinatal depression is lacking. Herein, we investigated the effects of low-dose ketamine in women with prenatal depressive symptoms and tested the feasibility of a future large randomized trial. This was a randomized, double-blind, placebo-controlled pilot trial. Sixty-six women with prenatal depressive symptoms who were scheduled for elective cesarean delivery were randomized to receive either low-dose ketamine (0.5 mg/kg) or placebo (normal saline). The study drugs were intravenously infused over a 40-minute period after clamping the umbilical cord. The primary outcome was depression score assessed with the Edinburgh Postnatal Depression Scale at 48 h postpartum. Among other and safety outcomes, occurrence of nausea or vomiting was observed, pain intensity was assessed with the numeric rating scale. The feasibility of implementing the protocol was also evaluated. A total of 64 parturients were included in the intention-to-treat analysis. The depression score at 48 h did not differ between groups: median 9 (interquartile range 6 to 13) with ketamine vs. 8 (6 to 10) with placebo; median difference 1, 95% CI -1 to 3; P = 0.608. The pain intensity at 4 h postpartum was less severe in the ketamine group (median difference -1, 95% CI -1 to 0, P = 0.002). Among safety outcomes, intraoperative nausea or vomiting was less common in patients given ketamine (0.0% [0/33] with ketamine vs. 21.2% [7/33] with placebo, P = 0.011). Recruitment was satisfactory and the protocol was acceptable to participants and clinicians. A single low-dose ketamine infusion did not decrease the depression score at 2 days, but reduced intraoperative nausea and vomiting and lowered pain intensity at 4 h after cesarean delivery among women with prenatal depressive symptoms. The study protocol is feasible for a large randomized trial. The study was registered with ClinicalTrials.gov (identifier: NCT03336541; 08/11/2017).

Rapamycin and inulin for third-dose vaccine response stimulation (RIVASTIM): Inulin – study protocol for a pilot, multicentre, randomised, double-blinded, controlled trial of dietary inulin to improve SARS-CoV-2 vaccine response in kidney transplant recipients

IntroductionKidney transplant recipients (KTRs) are at an increased risk of hospitalisation and death from COVID-19. Vaccination against SARS-CoV-2 is our primary risk mitigation strategy, yet vaccine effectiveness in KTRs is...

Duvelisib for Critically-Ill Patients with COVID-19 Disease: An Investigator-Initiated, Randomized, Placebo-Controlled Double-Blind Pilot Trial

Background: Severe and critical COVID-19, including acute respiratory distress syndrome (ARDS), cardiomyopathy, and shock, have been associated with a 28-day mortality exceeding 50%. While dexamethasone (dex) improves survival in such patients and highlights a role for anti-inflammatory therapy, mortality remains high especially in those who do not respond initially. Phase II/III studies of the PI3K-d/g inhibitor duvelisib in patients with chronic lymphocytic leukemia or follicular lymphoma have demonstrated that duvelisib significantly downregulates expression of inflammatory cytokines and chemokines (e.g. G-CSF, GM-CSF, macrophage inflammatory protein-1 α and β). These same inflammatory molecules are upregulated in ARDS and COVID-19. Several murine models of acute lung inflammation and sepsis have demonstrated improved markers of inflammation and survival of mice treated with PI3K inhibitors. The original SAR-CoV-1 coronavirus had demonstrated the ability to hijack the PI3K signaling machinery in order to persist within human airway cells. Additionally, in the context of neoplasia, duvelisib polarizes macrophages to the M1 phenotype which has antimicrobial effector functions in contrast to the pro-inflammatory M2 phenotype. In the context of chimeric antigen receptor T (CAR T) therapy, the DiPersio lab has identified duvelisib as a potent mediator of cytokine release syndrome (CRS) without T-cell inhibition, an overlapping concept with COVID-19. We hypothesized that duvelisib could attenuate COVID-19 ARDS and CRS through M1 macrophage polarization, reduction in cytokine signaling/production, and elimination of viral persistence. Methods: We conducted a multicenter, double-blind, placebo-controlled trial in which 28 patients were randomized 1:1 to duvelisib 25mg twice daily or placebo for 10 days. Eligible patients were 18 years or older hospitalized with a primary diagnosis of COVID-19 disease with either respiratory failure (≥ 50% lung involvement by imaging, invasive or non-invasive mechanical ventilation, or extracorporeal membrane oxygenation), new cardiomyopathy, and/or shock requiring vasopressor support. All patients were required to be receiving or have received dex 6mg daily or equivalent for at least 48 hours without improvement. All patients received prophylaxis for Pneumocystis jiroveci. We monitored viral load daily using quantitative RT-PCR to assess for changes in viral replication following initiation of therapy. Primary endpoint was 28-day survival. Secondary endpoints included: 60-day survival; duration on ventilator and vasopressors; hospital and ICU length of stay; viral kinetics; and adverse events. Correlatives included impact on cytokine expression measured by multiplex panel, viral kinetics by RT-PCR, and flow-cytometry to assess immune populations at various time points during therapy. Results: Baseline and disease characteristics were well-balanced with the exception of baseline renal replacement therapy (Table 1). At day 29, 67% of those in the duvelisib arm and 62% of those in the placebo arm were alive. Secondary efficacy endpoints were comparable between the two cohorts. There was a trend toward improved 60-day OS in the duvelisib arm (60% vs. 46%, p = 0.36, Figure 1) and some patients in the treatment arm were noted to have quick radiographic and clinical improvements. Of those on ECMO at initiation 3/5 (60%) in the duvelisib arm and 1/4 (25%) in the placebo arm were successfully weaned. Adverse events (AEs) occurred at similar rates between arms. Among AEs of special interest previously reported with the use of duvelisib, one patient developed colitis ultimately deemed to be stercoral colitis and unrelated to treatment. No CMV reactivation or Pneumocystis jiroveci pneumonia occurred. Eighty percent of overall deaths were due to respiratory failure from disease progression. In the placebo arm, one patient died of Pseudomonas pneumonia and one died of cholecystitis. Conclusion: In our pilot study, duvelisib did not show improvement in 28-day survival in a critically-ill, steroid-refractory population. However, there was a trend toward improved 60-day OS. No added toxicity was observed in those receiving duvelisib. Based on comparable safety, notable improvements in select patients, and a continued unmet need in this population, we believe larger studies are justified. Correlative data will also be presented. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Effect of vitamin D3 supplementation on cellular immunity and inflammatory markers in COVID-19 patients admitted to the ICU

Vitamin D as an immunomodulator has not been studied in patients with severe COVID-19. This study aimed to estimate the efficacy of vitamin D3 supplementation on cellular immunity and inflammatory markers in patients with COVID-19 admitted to the intensive care unit (ICU). A single-center, double-blind, randomized, placebo-controlled pilot trial was conducted (N = 110). Patients were randomly assigned to receive a weekly oral dose of 60,000 IU of vitamin D3 followed by daily maintenance doses of 5000 IU (n = 55) or placebo (n = 55). Primary outcomes were lymphocyte counts, natural killer (NK) and natural killer T (NKT) cell counts, neutrophil-to-lymphocyte ratio (NLR), and serum levels of inflammatory markers on 7th day of treatment. On day 7, patients in the vitamin D3 group displayed significantly higher NK and NKT cell counts and NLR than those in the placebo group did. The mortality rate (37% vs 50%, P = 0.16), need for mechanical ventilation (63% vs 69%, P = 0.58), incidence of nosocomial infection (60% vs 41%, P = 0.05) did not significantly differ between groups. Vitamin D3 supplementation, compared with placebo, significantly increased lymphocyte counts, but did not translate into reduced mortality in ICU.Trial Registration: ClinicalTrials.gov Identifier: NCT05092698.

Effect of an enzyme-containing mouthwash on the dental biofilm and salivary microbiome in patients with fixed orthodontic appliances: a randomized placebo-controlled pilot trial.

Mouthwashes containing oral antiseptics or enzymes are suggested suitable for controlling biofilm accumulation in patients with fixed appliances and thereby limiting unwanted side effects during the orthodontic treatment. To evaluate the effect of an enzyme-based mouthwash on the amount of dental biofilm and the composition of the salivary microbiome in patients undergoing treatment with fixed orthodontic appliances. Randomized double-blind placebo-controlled trial. In total, 35 young adolescents (14-18 years) under treatment with fixed appliances were consecutively enrolled and randomly allocated to an experimental or a placebo group by opening a computer-generated numbered envelope. The subjects were instructed to rinse twice daily during an intervention period of 8 days with experimental mouthwash or placebo without active enzymes. Unstimulated whole saliva samples were collected at baseline and after 8 days. The participants and examiner were blinded for the allocation. The primary outcome was the Orthodontic Plaque Index (OPI) and the secondary was the composition of the salivary microbiome. In total, 28 adolescents (21 females and 7 males) completed the trial and there were no differences in age, clinical, or microbial findings between the test (n = 14) and the placebo group (n = 14) at baseline. We found a decreased OPI in the test group after 8 days and the difference was statistically significant compared with the placebo group (P < 0.05). There were no significant treatment effects on the richness and global composition of the salivary microbiome. In total, one participant in the test group claimed nausea and abandoned the project. In total, two participants did not like the taste of the mouthwash but used it as instructed. No other adverse events or side effects were reported. Short-term pilot trials may by nature be sensitive for selection and performance biases and are not designed to unveil persisting effects. Daily use of enzyme-containing mouthwash reduced the amount of dental biofilm in adolescents under treatment with the fixed orthodontic appliances, without affecting the composition of the salivary microbiota. Approved by the Regional Ethical Board, Lund, Sweden (Dnr 2020-05221). NCT05033015.