Clinical Response Changes Research Articles

A prospective, multicenter study to evaluate the effectiveness and safety of prochlorperazine in patients suffering from vestibular migraine

Background: Prochlorperazine is commonly used for managing vertigo and dizziness-associated vestibular disorders. This study was designed to evaluate the effectiveness and safety of prochlorperazine in Indian patients with vestibular migraine. Methods: In this prospective, multicenter, open-label, single-arm study, VM patients received 5 mg of prochlorperazine thrice daily for 5 days. The primary endpoint measured changes in clinical response using the scale for vestibular vertigo severity level and clinical response evaluation from baseline to days 6, 15, and 30. Secondary endpoints included symptom severity improvement and changes in SVVSLCRE from baseline up to day 30. Safety and tolerability were also assessed. Statistical analysis used the Wilcoxon signed-rank test and student-paired t-test. Results: Out of 259 enrolled patients, 254 (98.1%) completed the study with a mean (standard deviation) age of patients was 42.22 (10.7) years; 72.2% were females. Significant improvements in clinical response and symptom severity were observed at all follow-up periods. 81.5% of patients showed VM symptom improvement by day 6, with 77.2% exhibiting moderate to good changes in SVVSLCRE scores. 83.4% experienced milder vestibular symptoms after 6 days. Furthermore, a significant difference (p<0.001) in mean values was observed from baseline at different follow-up periods. 11 (4.3%) adverse events (AEs) were reported, with headache being the most common (2, 0.8%); all AEs were unrelated to the study drug, and patients reported good tolerability. Conclusions: Prochlorperazine showed significant improvement in clinical response and symptom severity with acceptable safety and tolerability in VM patients.

Major depressive disorder: association with vitamin C levels and role of vitamin C supplementation in pharmacotherapy

Background: Oxidative stress has a well-documented role in pathophysiology of depression. Decrease in levels of vitamin C, an antioxidant, has also been reported in major depressive patients. This study was conducted to assess the association of vitamin C deficiency with major depressive disorder and any change in clinical response to antidepressant therapy with vitamin C co-administration vis-a-vis baseline vitamin C level status.Methods: This study was a prospective, interventional, parallel, randomized and open label study. Sixty patients diagnosed as a case of major depressive disorder in accordance to ICD-10 criteria were enrolled after taking a written informed consent. Two clinical scales namely Hamilton depression rating scale (HDRS) and clinical global impression- illness severity (CGI-S) scale were used for assessment and monitoring.Results: Vitamin C deficient subjects had relatively severe disease as assessed by HDRS and CGI-S scales. A highly significant (p<0.001) reduction was observed in HDRS and CGI-S scores in vitamin C deficient and insufficient groups with supplementation. A statistically insignificant (p>0.05) reduction was seen in HDRS and CGI-I scores in vitamin C sufficient group while also showing a comparatively milder disease.Conclusions: Vitamin C deficiency was found to have a direct relation with severity of illness, as those patients who had insufficient and sufficient vitamin C levels at recruitment were found to exhibit milder symptoms compared to those who were vitamin C deficient. With treatment, greater improvement was observed in those patients who were deficient at the outset.

Pharmacogenomics in kidney transplant recipients and potential for integration into practice.

Pharmacogenomic biomarkers are now used in many clinical care settings and represent one of the successes of precision medicine. Genetic variants are associated with pharmacokinetic and pharmacodynamic changes leading to medication adverse effects and changes in clinical response. Actionable pharmacogenomic variants are common in transplant recipients and have implications for medications used in transplant, but yet are not broadly incorporated into practice. From the Clinical Pharmacogenetics Implementation Consortium and Dutch Pharmacogenetics Working Group guidelines, and PharmGKB databases, 12 pharmacogenomic genes with 30 variants were selected and used to create diplotypes and actionable pharmacogenomic phenotypes. A total of 853 kidney allograft recipients who had genomic information available from a genome-wide association study were included. Each recipient had at least one actionable pharmacogenomic diplotype/phenotype, whereas the majority (58%) had three or four actionable diplotypes/phenotypes and 17.4% had five or more among the 12 genes. The participants carried actionable diplotypes/phenotypes for multiple medications, including tacrolimus, azathioprine, clopidogrel, warfarin, simvastatin, voriconazole, antidepressants and proton-pump inhibitors. Pharmacogenomic variants are common in transplant recipients, and transplant recipients receive medications that have actionable variants. Genomics of Transplantation, clinicaltrials.gov (NCT01714440).

Exposure-Response Assessment in Pediatric Drug Development Studies Submitted to the US Food and Drug Administration.

Exposure-response (E-R) modeling provides a quantitative tool to leverage adult data to support pediatric trial design and drug approval. The pediatric E-R studies submitted to US Food and Drug Administration (FDA) between 2007 and 2018 were surveyed in the context of various types of trial designs supporting drug approval in the pediatric population. The applications of E-R evaluation in pediatric drug development programs are mainly focused on three areas: (i) supporting pediatric extrapolation when the E-R relationships are similar between the pediatric and adult populations; (ii) dose selection to balance the risk-benefit profile based on the change in efficacy and safety response with different exposure levels; and (iii) approval of a new formulation, new dosing regimen, or new route of administration, where E-R evaluation helps quantify the change in clinical response between the old and new strategies. E-R modeling will continue to play an expanded role in pediatric drug development in the future.

Peak Lymphocyte Count after CAR T Infusion Is a Clinically Accessible Test That Correlates with Clinical Response in Axicabtagene Ciloleucel Therapy for Lymphoma

Peak Lymphocyte Count after CAR T Infusion Is a Clinically Accessible Test That Correlates with Clinical Response in Axicabtagene Ciloleucel Therapy for Lymphoma

Protocol for a double-blind, randomised, placebo-controlled pilot study for assessing the feasibility and efficacy of faecal microbiota transplant in a paediatric Crohn’s disease population: PediCRaFT Trial

IntroductionCrohn’s disease (CD) is a chronic inflammatory condition with transmural involvement of the gastrointestinal tract. Extraintestinal manifestations are common, and the disease burden on patients and the healthcare system is...

Clinico-pathological responses in reproductive system and its associated lymph nodes of bucks challenged with Corynebacterium pseudotuberculosis and its mycolic acid extract

Caseous lymphadenitis (CLA) is a chronic bacterial disease that causes economic losses in small ruminant throughout the world. Corynebacterium pseudotuberculosis is the causative agent of CLA characterized by large abscesses internally/externally, abortions, weight loss, and decreased wool production in sheep and goat farming. There is paucity of information on Corynebacterium pseudotuberculosis and its immunogen mycolic acid responses in male goat during the course of CLA. As a result, this study was designed to investigate the clinical responses and pathological changes of the reproductive tract and its associated lymph nodes in male goats following inoculation with Corynebacterium pseudotuberculosis and its immunogen mycolic acids. A total of 12 healthy crossbred Boer male goats aged 16–20 months were divided into three groups, 1, 2, and 3, of four in each group. Group 1 (control group) was inoculated with 2 ml of sterile phosphate-buffered solution (PBS) via intradermal route, group 2 was inoculated with 2 ml 1 × 109 colony forming unit (cfu) of C. pseudotuberculosis intradermally and group 3 was inoculated with 2 ml of mycolic acid (1 g/ml) intradermally. The bucks were observed and assessed for changes in clinical responses daily for 60 days post challenged. At the end of the experiment, animals were slaughtered and organs of the reproductive tract and lymph nodes were harvested for histopathological investigations. In this study, all experimental bucks survived throughout the study period with some evidence of clinical manifestation such as pyrexia, weight loss, and enlargement or rupture of the lymph nodes. Microscopically, C. pseudotuberculosis and mycolic acid challenged groups showed significant cellular changes in the reproductive system and lymph nodes. Group 2 showed abscessation of the lymph nodes while group 3 did not indicate any abscess formation in the lymph nodes. For mycolic acid extract, the result revealed only mild to moderate clinic-pathological responses in bucks with no abscess formation in the lymph nodes. The result obtained added knowledge in the field of CLA research in small ruminants. In conclusion, this research revealed that C. pseudotuberculosis has a negative effect on reproductive performances of bucks and affects the clinical responses and abscess formation.

Switching from reference infliximab to CT-P13 in patients with inflammatory bowel disease: 12 months results.

BackgroundBiological agents, such as infliximab, have transformed the outcomes of patients with immune-mediated inflammatory diseases. The advent of biosimilar treatment options such as CT-P13 promises to improve the availability of biological therapy, yet real-world switching data are currently limited. Here, we assess the effectiveness and safety of switching to CT-P13 from infliximab reference product (RP) in patients with inflammatory bowel disease.Materials and methodsThis was a prospective single-center observational study in patients with moderate to severe Crohn’s disease (CD) and ulcerative colitis (UC). All patients were switched from infliximab RP (Remicade) to CT-P13 treatment and followed up for up to 12 months. The efficacy endpoint was the change in clinical response assessed at 3-monthly intervals, according to the Harvey–Bradshaw score and partial Mayo score for patients with CD and UC, respectively. C-reactive protein (CRP) was also measured. Adverse events were monitored and recorded throughout the study.ResultsA total of 98 patients with inflammatory bowel disease (67 CD/31 UC) were included. A total of 83.6% (56/67) of patients with CD were in remission at the time of the switch and 62.7% were in remission at 12 months. The Harvey–Bradshaw score showed a significant change at 12 months (P=0.007) but no significant change was observed in median CRP at this timepoint (P=0.364). A total of 80.6% (25/31) of patients with UC were in remission at the time of the switch and 65.3% (18/28) were in remission at 12 months. No significant changes in the median partial Mayo score (P=0.058) or CRP (P=0.329) were observed at 12 months. Serious adverse events related to medication were reported in 11 (11.2%) patients.ConclusionSwitching from infliximab RP to CT-P13 is efficacious and well tolerated in patients with CD or UC for up to 12 months.

The infliximab biosimilar in the treatment of moderate to severe plaque psoriasis

The infliximab originator's patent recently expired, leading to the production of biosimilar versions of the drug. The biosimilars' efficacy was not tested on patients with psoriasis but most regulatory authorities approved their use in psoriasis because of an extrapolation of data from studies conducted in other diseases. We sought to describe the use of the infliximab biosimilar (Remsima; CT-P13) in patients with psoriasis. Objective (Psoriasis Area and Severity Index) and subjective (visual analog pain scale) measurements of disease activity were collected in 2 cohorts of patients with moderate to severe plaque psoriasis: cohort 1 patients switched from the infliximab originator to the infliximab biosimilar; and cohort 2 patients were infliximab-naïve and started on the infliximab biosimilar. We observed no changes of Psoriasis Area and Severity Index and visual analog pain scale scores in 30 patients who switched from the infliximab originator to the biosimilar. Four of 5 infliximab-naïve patients who started infliximab biosimilar treatment achieved 75% improvement or better from baseline Psoriasis Area and Severity Index score at the end of the induction phase. Number of patients and length of follow-up was limited. Patients with psoriasis taking infliximab originator treatment can switch to the infliximab biosimilar without experiencing a significant change in clinical response or additional adverse events. The use of the infliximab biosimilar could reduce the growing pressure on health care budgets.

Inflammation-induced phenoconversion of polymorphic drug metabolizing enzymes: hypothesis with implications for personalized medicine.

Phenoconversion transiently converts genotypic extensive metabolizers (EMs) into phenotypic poor metabolizers (PMs) of drugs, potentially with corresponding changes in clinical response. This phenomenon, typically resulting from coadministration of medications that inhibit certain drug metabolizing enzymes (DMEs), is especially well documented for enzymes of the cytochrome P450 family. Nonclinical evidence gathered over the last two decades also strongly implicates elevated levels of some proinflammatory cytokines, released during inflammation, in down-regulation of drug metabolism, especially by certain DMEs of the P450 family, thereby potentially causing transient phenoconversion. Clinically, phenoconversion of NAT2, CYP2C19, and CYP2D6 has been documented in inflammatory conditions associated with elevated cytokines, such as human immunodeficiency virus infection, cancer, and liver disease. The potential of other inflammatory conditions to cause phenoconversion has not been studied but experimental and anecdotal clinical evidence supports infection-induced down-regulation of CYP1A2, CYP3A4, and CYP2C9 as well. Collectively, the evidence supports a hypothesis that certain inflammatory conditions associated with elevated proinflammatory cytokines may cause phenoconversion of certain DMEs. Since inflammatory conditions associated with elevated levels of proinflammatory cytokines are highly prevalent, phenoconversion of genotypic EM patients into transient phenotypic PMs may be more frequent than appreciated. Since drug pharmacokinetics, and therefore the clinical response, is influenced by DME phenotype rather than genotype per se, phenoconversion (whatever its cause) can have a significant impact on the analysis and interpretation of genotype-focused clinical outcome association studies. There is a risk that focusing on genotype alone may miss important associations between clinical outcomes and DME phenotypes, thus compromising future prospects of personalized medicine.

SAT0260 Biomarkers Associated with Rheumatoid Arthritis Disease Activity Including Joint Damage Correlate with Changes in Clinical Response in Subjects Treated with Mavrilimumab at Doses above 10 Mg

BackgroundMavrilimumab is a human monoclonal antibody targeting the alpha subunit of GM-CSF receptor and was recently evaluated in RA subjects in a phase 2a study (EARTH). Results reported from the...

FRI0280 Impact of Disease Duration before Starting Adalimumab Treatment on Work Productivity in Japanese Patients with Rheumatoid Arthritis; Analysis of 24-Weeks Data from the Anouveau Study

BackgroundTreatment with adalimumab (ADA) has been reported to improve work productivity and reduce indirect cost due to work impairment in patients with rheumatoid arthritis (RA). The impact of disease duration...

Radiological and clinical findings of 25 patients with invasive pulmonary aspergillosis: retrospective analysis of 2150 liver transplantation cases

The purpose of this study was to evaluate the radiological and clinical findings of invasive pulmonary aspergillosis (IPA) after liver transplantation. This study included 25 consecutive liver transplant recipients with histologically confirmed IPA after liver transplantation. Radiological examinations performed for diagnosis were available in all patients. Clinical findings and changes in clinical response and radiological findings after treatment were also evaluated. 3 main radiological findings were identified: nodules, 64% (16/25); masses, 36% (9/25); and consolidations in a patchy pattern, 20% (5/25). A tree-in-bud pattern was found in 12% (3/25) of patients. In 8 (32%) of 25 patients, we found a combination of 2 or more of these signs: 5 (20%) patients presented with concurrent nodules accompanied by patchy consolidations and/or tree-in-bud, and 3 (12%) patients showed masses accompanied by large consolidations. A halo sign was observed in 20 (80%) of 25 patients. Hypodense sign and cavitary lesions were encountered in 17 (68%) of 25 patients. Follow-up radiological findings after treatment showed improvement in 18 patients, no change in 4 patients and progression in 3 patients. There were three aspergillosis-associated deaths during the follow-up period. The onset time of IPA was a median of 31 days after transplantation. The most common symptom at diagnosis was fever (n=15). None of the 25 patients had leukopaenia at the time of the diagnosis of IPA. The most common radiological findings of IPA after liver transplantation are multiple nodules with or without halo sign, masses and consolidations, which usually appear about 1 month after transplantation.

Computed Tomography and Clinical Features of Invasive Pulmonary Aspergillosis in Liver Transplant Recipients

The aim of this study was to evaluate the computed tomography (CT) and clinical features of invasive pulmonary aspergillosis (IPA) in liver transplant recipients. This study included 25 consecutive liver transplant recipients with histologically confirmed IPA after liver transplantation. CT examinations performed for diagnostic evaluation were available for all patients. CT features were retrospectively evaluated by 2 radiologists. Clinical features and the changes in clinical response and CT features after treatment were also evaluated. Three main CT features were identified: nodules 64% (16 of 25), masses 36% (9 of 25), and consolidations in a patchy pattern 20% (5 of 25). A tree-in-bud pattern was found in 12% (3 of 25) of patients. In 8 (32%) of the 25 patients, we found a combination of 2 or more of these signs: 5 (20%) patients presented with concurrent nodules accompanied by patchy consolidations and/or tree-in-bud, and 3 (12%) patients showed masses accompanied by large consolidations. A halo sign was observed in 20 (80%) of the 25 patients. A hypodense sign and cavitary lesions were encountered in 17 (68%) of the 25 patients. Follow-up CT scans after treatment showed improvement in 18 patients, were unchanged in 4 patients, and showed progression in 3 patients. There were 3 aspergillosis-associated deaths during the follow-up period. The onset time of IPA was a median of 31 days after transplantation. The most common symptom at diagnosis was fever (n=19). None of the 25 patients had leukopenia at the time of the diagnosis of IPA. The most common CT features of IPA in liver transplant recipients are multiple nodules with or without halo sign, masses, and consolidations, which usually appear approximately 1 month after transplantation.

What Is the Efficacy and Safety of Colistin for the Treatment of Ventilator-Associated Pneumonia? A Systematic Review and Meta-Regression

Experience with intravenous and aerosolized forms of colistin for the treatment of ventilator-associated pneumonia (VAP) in patients without cystic fibrosis is limited. We aimed to assess the safety and efficacy of colistin for the treatment of VAP. We searched MEDLINE and Cochrane Database of Systematic Reviews for studies comparing colistin vs other antibiotics for treatment of VAP in patients without cystic fibrosis. QUOROM guidelines were followed, the I(2) method was used for heterogeneity, and a random-effects model for odds ratio (OR) estimates. Six controlled studies met the inclusion criteria. Clinical response did not differ significantly between colistin and control groups (OR, 1.14; 95% confidence interval [CI], .74-1.77; P = .56; I(2) = 0%). The efficacy of colistin was independent of study design (prospective OR, 0.89 [95% CI, .48-1.66; P = .71; I(2) = 0%]; retrospective OR, 1.45 [95% CI, .79-2.68; P = .23; I(2) = 0%]); randomized trials OR, 0.86 [95% CI, .43-1.74; P = .68; I(2) = 0%]). There was no indication of a significant change in clinical response after controlling for concomitant antibiotic treatment (intercept, 0.121; slope, 0.0315; P = .95). Treatment with colistin vs controls did not affect hospital mortality (OR, 0.92; 95% CI, .50-1.67; P = .78; I(2) = 34.59%) or nephrotoxicity (OR, 1.14; 95% CI, .59-2.20; P = .69; I(2) = 0%). Fourteen single-arm studies have been analyzed, and the results were in concordance with the findings of the controlled studies. Our results suggest that colistin may be as safe and as efficacious as standard antibiotics for the treatment of VAP.

Statistical Test for Ordered Categorical Data in Clinical Trials

In clinical trials, subjects are often classified into ordered categories (eg, worsening, no change, and improvement) based on their post-treatment clinical response changes from baseline. The usual approach in using a multinomial model for assessing treatment effects between treatment groups is not efficient because it demands intense computation to evaluate the corresponding probabilities across these ordered categories. In this study, we propose to model the response probabilities via a parametric form, and the comparison of these probabilities is translated into the comparison of the associated model parameters. Maximum likelihood estimates are then derived and the required sample size for achieving a desired statistical power at a prespecified level of significance is also obtained. A simulation study is performed to evaluate finite sample size performance. An example concerning the evaluation of the efficacy of a test treatment for subjects with moderate to severe Crohn disease that is refractory to steroids and immunosuppressants is presented to illustrate the proposed method.

Ask the Experts

Q Is it appropriate to adjust body surface area (BSA) and intravenously administered vasoactive medication dosage against daily weight changes in the intensive care unit (ICU)? Because of these significant changes, is admission weight acceptable? Is there such a thing as “dry weight”? If so, how is it defined and measured?A Nancy Faulkner, RPh, BS, replies:BSA is not an appropriate parameter by which to calculate or modify inotropic and vasopressor drug infusion doses in the ICU. BSA is not a kinetic variable; it remains nearly constant regardless of changes in patient weight. Weight is a good kinetic variable for predicting drug concentration, dose, and therapeutic response. It better reflects changes in volume of distribution of the “size of the tank” into which drugs are distributed. Drug doses for the inotropic vasopressor agents, which have wide therapeutic ranges and short durations of action, should be calculated on body weight. BSA is generally reserved for dosing agents with narrow therapeutic indices, such as oncologic drugs.The significant question becomes whether to respond to changes in patient body weight when calculating doses. The controversy is an issue only for initial dosing. The drugs under consideration—dobutamine, dopamine, isoproterenol, phenylephrine, epinephrine and norepinephrine—are all short-acting medications that are titrated to achieve a desired pharmacologic response. Changes in weight because of fluid overload, dehydration, or organ system (cardiac, renal, pulmonary, hepatic) function may result in changes in volume of distribution of drugs accompanied by changes in clinical response. The infusion rate is adjusted according to standard guidelines, or nomograms, until the appropriate response is reestablished. When considering the initial rate of infusion for these compounds, determine the dosing weight by using the following considerations:\batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} \[Dosing\ weight=IBW\ [(ABW-IBW)\ {\times}\ 0.4]\] \end{document}A practical method is simply to split the difference between ABW and IBW. Patients who can be identified as having abnormal fluid weight on admission to the ICU should probably be dosed on actual body weight, because the volume of distribution is larger than normal at this point. Vasopressors will distribute into the fluid compartments and initial doses could be too low unless one accounts for this possibility.“Dry weight” is a parameter used in hemodialysis, where the maximum amount of weight (fluid) that can be removed is measured by blood pressure response. The lowest weight achieved before the patient becomes hypotensive is considered the dry weight. It is not of practical utility for drug dosing.A reference list supporting the contentions of this article is not available due to the paucity of research defining the “best” dosing weight for intravenous vasoactive drugs. The research question is not compelling because the safety and efficacy profiles of these compounds do not demand dosing precision. Practitioners empirically support the various pharmacokinetic and pharmacologic-based approaches described here.

Magnetic Resonance Imaging and Deep Brain Stimulation

To determine whether cranial magnetic resonance imaging (MRI) is associated with deep brain stimulation (DBS) lead displacement or program interference. In vitro and in vivo studies were performed with the Itrel II implantable pulse generator (IPG) (Model 7424; Medtronic, Minneapolis, MN), Medtronic 3387 and 3389 leads, and a 1.5-T GE Horizon LX scanner (General Electric, Milwaukee, WI). In the in vivo study, two MRI volumetric data sets were compared for each of five patients undergoing staged, bilateral, DBS electrode placement in the thalamic or subthalamic nucleus. The data sets were acquired shortly after the initial implantation and during stereotactic planning for the second implantation (1-8 mo between acquisitions). An additional thalamotomy-treated patient was included as a control patient. Volumetric data were analyzed in a blinded manner, using AnalyzeAVW 3.0 software (Biomedical Imaging Resource, Mayo Clinic, Rochester, MN), to determine lead movement. In the in vitro study, the IPG and leads were positioned in the magnetic field in various configurations and were systematically assessed for movement. In vivo, the majority of measured deviations (88%) were within the standard error of measurement (1.4 mm). The maximal measured deviation was 3 mm (2% occurrence). Excellent tremor control with stimulation was demonstrated, which did not change after MRI. In vitro, the DBS leads demonstrated no deflection when introduced into the magnetic field. Similarly, no changes in IPG battery strength, lead impedance, or program settings were observed. MRI was not associated with significant DBS electrode movement or changes in clinical responses. Other IPG models and components and MRI scanners should be evaluated, to develop specific guidelines for MRI among individuals with implanted DBS systems.