Loss Of Clinical Effect Research Articles

P1055 Intravenous to subcutaneous infliximab switch may reduce the risk of immunogenicity related treatment failure and can be used to facilitate immunomodulator withdrawal

Abstract Background Infliximab (IFX) is an effective treatment option for many patients with inflammatory bowel disease. Immunogenicity mediated treatment failure (IMTF) is a common clinical problem usually tackled by addition of an immunomodulator (IMM) and/or IFX dose escalation. Switching stable patients on IV IFX maintenance therapy to SC IFX has been shown to be safe and effective.1 It is hypothesised that SC IFX may reduce the risk of IMTF but there is little data to support this. We aimed to explore whether switching selected patients at risk of IMTF from IV to SC IFX was safe and effective and assess whether this strategy can facilitate treatment de-escalation and IMM withdrawal. Methods The local IBD database was used to identify potentially suitable patients at higher risk of IMTF. This included those on escalated doses of IV IFX, those who had developed low level anti-drug antibodies (ADA), and those on combination therapy in whom it was felt desirable to withdraw IMM. Those who agreed to switch were commenced on SC IFX 120mg fortnightly and followed up clinically and with IFX drug levels (DLs) and ADA at week 8, 24 and 52. Results 29 eligible patients underwent IV to SC IFX switch. Two patients were excluded: one returned to IV IFX and the other stopped IFX completely within 8 weeks of switch. Outcomes for 27 patients were evaluated: 10 with UC, 14 CD, 3 IBD-unclassified. Median age was 38 (IQR 31-49). Median duration of IV IFX was 34 months (IQR 24-54 months). 17 patients were on accelerated IV IFX dosing. All 27 patients remained on SC IFX at one year. Two required a course of steroids for disease flare. Of the 19 patients who had faecal calprotectin (FCP) data available, the mean FCP prior to switch was 66.1 (30-317) and post initiation of SC IFX was 189.6 (30 – 1800), but this did not reach statistical significance (p=0.172). 12/27 patients were on IV IFX plus IMM therapy. 9/12 successfully stopped IMM after switch to SC IFX. Mean DL prior to switch was 7.13 (2.7-12.5) and post switch was 12.07 (1.6-14.5). In those who were on accelerated IV IFX dosing, 15/17 saw an increase in DLs post switch. In the 8 patients who had ADAs prior to switch, all saw a reduction, with 6 having no detectable ADAs post switch. Conclusion Switching from IV to SC IFX in this cohort was safe and effective. Most patients maintained steroid free remission at one year. All those who stopped IMM were successfully maintained on monotherapy at 1 year. 15/17 people treated with escalated IV dosing were successfully switched to standard SC IFX dosing with improvement in mean IFX DLs and without loss of clinical effect.

Individualized approach to elexacaftor/tezacaftor/ivacaftor dosing in cystic fibrosis, in response to self-reported anxiety and neurocognitive adverse events: A case series.

The prevalence of mental health disorders is high among people with Cystic Fibrosis. The psychological symptoms in CF are associated with poor adherence, worse treatment outcomes, and greater health utilization/cost. Mental health and neurocognitive Adverse Events (AEs) have been reported with all available Cystic Fibrosis Transmembrane conductance Regulator (CFTR) modulators in small groups of patients. We report our experience with a dose reduction strategy in 10 of our patients on elexacaftor/tezacaftor/ivacaftor (7.9% of total number of patients) who self-reported developing intense anxiety, irritability, sleep disturbance and/or mental slowness after initiation of full dose treatment. Standard dose elexacaftor/tezacaftor/ivacaftor resulted in 14.3 points improvement in mean Percent Predicted Forced Expiratory Volume in 1s (ppFEV1), and a mean difference in sweat chloride of -39.3mmol/L. We initially discontinued and/or reduced therapy according to the AEs severity, with a subsequent planned dose escalation every 4-6weeks guided by sustainability of clinical effectiveness, absence of AEs recurrence, and patients' preferences. Clinical parameters including lung function and sweat chloride were monitored for up to 12weeks to assess ongoing clinical response to the reduced dose regimen. Dose reduction resulted in resolution of self-reported mental/psychological AEs, without loss of clinical effectiveness (ppFEV1 was 80.7% on standard dose, and 83.4% at 12weeks on reduced dose; sweat chloride was 33.4 and 34mmol/L on standard and reduced dose, respectively). Furthermore, in a subgroup of patients who completed 24weeks of the reduced dose regimen, repeat low dose Computed Tomography imaging showed a significant response when compared to pre-initiation of elexacaftor/tezacaftor/ivacaftor.

Real-World clinical outcomes of asthma patients switched from reslizumab to mepolizumab or benralizumab.

Approximately 3%-10% of asthma patients will remain uncontrolled despite maximum, optimal conventional therapy. Treatment of severe refractory asthma often involves the use of targeted biological therapy. Randomised controlled trials have shown improvements in clinical parameters with these treatments but real-world data is lacking. The clinical parameters, frequency of exacerbations, number of hospital admissions, asthma control questionnaire score (ACQ), forced expiratory volume in one second (FEV1) and maintenance oral corticosteroid (OCS) dose of twenty asthma patients switched from reslizumab to benralizumab or mepolizumab at 1 year prior and 6 months after switching were compared, with adjustments for time. The mean frequency of exacerbations (0.35 v 0.3) and the mean ACQ were essentially unchanged (1.6 v 1.5) following the switch. The number of hospital admissions was one in the 6 months post switch compared to one in 1-year pre switch. 25% of patients were on maintenance OCS before and after switching but one patient required an increased dose post switch resulting in an increase in the mean maintenance OCS dose (1.6 mg to 2.4 mg). The mean FEV1 was unchanged (80% v 77.9%) six months post switching. Regarding asthma control (n = 19), 47.4% were controlled pre and post switch (ACQ < 1.5), 36.8% remained uncontrolled despite switching, 10.5% improved control while 5.3% disimproved. We present real-world clinical outcomes of asthma patients switched from reslizumab to either benralizumab or mepolizumab without a loss of clinical effectiveness in the majority.

O030 / #531 DEEP BRAIN STIMULATION SCALP EROSION RISK REDUCTION WITH NOVEL SURGICAL TECHNIQUE: TRACK 2: BRAIN STIMULATION FOR TREATMENT RESISTANT DEPRESSION, PAIN, AND PARKINSON'S DISEASE

Deep Brain Stimulation (DBS) has a low risk profile with complication rates reported as less than ten percent. Most complications occur around the time of the surgery, but scalp erosion typically presents in a delayed fashion. An erosion can expose the underlying hardware significantly increasing the risk of infection. If present, infection often requires the complete removal of the DBS system and therefore loss of clinical effect. Scalp erosions occur most commonly at the surgical cap site followed by the extension connector site.

S0505 The Effect of Retreatment and Treatment Cessation in Clinical Studies of Prucalopride in Patients With Chronic Idiopathic Constipation

INTRODUCTION: Prucalopride is a selective serotonin type 4 (5-HT4) receptor agonist indicated for the treatment of chronic idiopathic constipation (CIC) in adults. To assess how prucalopride can be used in clinical practice, we evaluated the effect of re-treatment and treatment cessation on complete spontaneous bowel movements (CSBMs) and adverse events (AEs) using data from two randomized, double-blind, placebo-controlled trials in adults with CIC. METHODS: The effect of re-treatment was assessed in one trial with two 4-week treatment periods (TPs; prucalopride 4mg once daily or placebo) with a drug-free period of 2 weeks or 4 weeks between TPs. During both TPs, the proportion of responders (patients with a mean of ≥3 CSBMs/week) and the incidence of AEs were assessed. In a dose-finding trial, the effect of treatment cessation on these endpoints was assessed during a 4-week drug-free run-out period, which followed a 4-week dose-finding period (prucalopride 0.5, 1, 2 or 4 mg once daily or placebo). Both trials enrolled patients with a mean of <3 CSBMs/week at baseline. RESULTS: In the re-treatment trial (Table 1; responder analysis: placebo, n = 205; prucalopride, n = 189) the proportion of responders in TP2 was similar to that in TP1 and was significantly higher (P ≤ 0.001) with prucalopride 4mg than with placebo (weeks 1–4: TP1, 38.6% vs 10.7%; TP2, 36.0% vs 11.2%; Figure 1); 71.2% (52/73) of prucalopride responders in TP1 responded in TP2. The most common AEs (headache, diarrhea, nausea, abdominal pain) occurred at a lower frequency during TP2 than TP1. In the dose-finding trial (N = 234; 43–48 patients per treatment group [Table 1]), the proportion of responders during the 4-week TP was higher with prucalopride 0.5–4 mg (23.4–55.6%) than with placebo (13.3%). The mean number of CSBMs/week was higher in the prucalopride groups than in the placebo group during the 4-week TP, but was similar between all groups 4 weeks after stopping treatment (Figure 2). Gastrointestinal AEs that were possibly or definitely related to prucalopride treatment were less frequent during the run-out phase than during the TP. CONCLUSION: Over 70% of patients who initially responded to prucalopride responded again when re-treated with prucalopride after a 2- or 4-week drug-free period. The incidence of AEs was lower during re-treatment with prucalopride than during initial treatment. Cessation of prucalopride treatment resulted in a loss of clinical effect after 7 days, indicated by a reduction in the mean number of CSBMs/week.Table 1.: Baseline demographics and disease characteristics of participants in the re-treatment and dose-finding trialsFigure 1.: Proportion of responders during TP1 and TP2 of the re-treatment trial.Figure 2.: Mean number of CSBMs per week in patients with CIC during the 4-week TP and the 4-week run-out period of the dose-finding trial.

Drug interaction resources: mind the gaps.

SUMMARYDrug interactions can lead to significant toxicity or loss of clinical effect. The risks increase with the number of drugs the patient takesGeneral and specialised drug interaction resources are available. Access to up-to-date electronic resources is encouragedThere are gaps in the information on interactions for new drugs, those with complicated metabolism and drugs with limited use. It may be necessary to use multiple resources to find the informationWhen assessing information about interactions, clinicians should evaluate the relevance for each patient. In high-risk situations, expert advice can be valuableClinicians should report new or unusual drug interactions to the Therapeutic Goods Administration

Regional Differences In Potential Savings For The Medical Treatment Of Advanced Prostate Cancer In The German Health Care System

Gonadotropin-releasing hormone analogues (GnRH-analogues) are well established for treating advanced prostate cancer. In 2015 and 2016, four GnRH-analogues were available in Germany: Buserelin, Goserelin, Leuprorelin and Triptorelin. Only Leuprorelin had generics. Four of 17 regions of physicians’ associations (KV) in the statutory health insurance (SHI) had quotas promoting Leuprorelin in 2015 and 2016 (“Quota-KVs”). Four regions introduced quotas in 2017 (“New-KVs”). This research investigates the regional differences in market penetration and potential savings. QuintilesIMS provided monthly SHI prescription data per region, sickness fund and package for 2015 and 2016. Pharmacy sales prices and defined daily doses (DDD) were used for sales respectively volume. Total sales were 207.7m (212.3m) Euro and volume was 37.6m (38.3m) DDD in 2015 (2016). The average quarterly market share (sales) of Leuprorelin differed regionally between 60.5% and 75.7%. Within the Leuprorelin market, the average generics’ share varied between 5.9% and 33.6%. In the “Quota-KVs”, the average share was 23.9% compared to 12.2% in the “New-KVs” and 14.3% in the remaining nine. Leuprorelin generics had a more cost-effective average price level (4.51 Euro/DDD) than other Leuporelin products (5.38 Euro/DDD) and GnRH-analogues (6.02 Euro/DDD). SHI could have saved 20.6m Euro or 4.9% of sales in 2015 and 2016, when the highest quarterly market shares (DDD) of Leuprorelin in a KV (79.7%) and generics within Leuprorelin (45.8%) would have been achieved over all quarters and KVs. Average potential savings per KV varied between 2.0% and 6.9%. Average potential savings would have been 3.5% in “Quota-KVs” and 5.7% in “New-KVs” as well as the remaining nine. The analysis shows a low market share for generics and a strong deviation between regions. Quotas push market penetration for generics. Regions with lower shares have recently introduced them. Substantial savings can be achieved without any loss of clinical effectiveness.

Antimicrobial-resistant Bacteria Arising from the Use of Colistin Sulfate in the Livestock (Antimicrobial-resistant Bacteria).

The Food Safety Commission of Japan (FSCJ) conducted a risk assessment on antimicrobial-resistant bacteria arising from the use of colistin sulfate, which is used as a feed additive and veterinary medicinal products in the livestock. Both Salmonella and E. coli were considered as potential antimicrobial-resistant bacteria to be selected under the use of colistin sulfate in the livestock. As only limited reports were available on the colistin-resistance in Salmonella, FSCJ conducted a risk assessment focusing on E. coli as a hazard, on which the information was rather available. In the release assessment, the degree of possible selection of the hazard was evaluated as "Medium". Considering proper cooking of the livestock products, the degree of possible human exposure to the resistant bacteria via livestock products was evaluated as "Low". The degree of possible reduction or loss of clinical effectiveness was evaluated as "High" considering the current situation of colistin use in human medicine. From the above, the overall estimation of the risk was "Medium".

Should Mental Health Interventions Be Locally Grown or Factory-Farmed?

Should Mental Health Interventions Be Locally Grown or Factory-Farmed?

Impact of Combined Low-Level Mupirocin and Genotypic Chlorhexidine Resistance on Persistent Methicillin-Resistant Staphylococcus aureus Carriage After Decolonization Therapy: A Case-control Study

The clinical importance of low-level mupirocin resistance and genotypic chlorhexidine resistance remains unclear. We aimed to determine whether resistance to these agents increases the risk of persistent methicillin-resistant Staphylococcus aureus (MRSA) carriage after their use for topical decolonization therapy. A nested case-control study was conducted of MRSA carriers who received decolonization therapy from 2001 through 2008. Cases, patients who remained colonized, were matched by year to controls, those in whom MRSA was eradicated (follow-up, 2 years). Baseline MRSA isolates were tested for mupirocin resistance by Etest and chlorhexidine resistance by qacA/B polymerase chain reaction. MRSA carriers with high-level mupirocin resistance were excluded. The effect of the primary exposure of interest, low-level mupirocin and genotypic chlorhexidine resistance, was evaluated with multivariate conditional logistic regression analysis. The 75 case patients and 75 control patients were similar except that those persistently colonized were older (P = .007) with longer lengths of hospital stay (P = .001). After multivariate analysis, carriage of combined low-level mupirocin and genotypic chlorhexidine resistance before decolonization independently predicted persistent MRSA carriage (odds ratio [OR], 3.4 [95% confidence interval {CI}, 1.5-7.8]). Other risk factors were older age (OR, 1.04 [95% CI, 1.02-1.1]), previous hospitalization (OR, 2.4 [95% CI, 1.1-5.7]), presence of a skin wound (OR, 5.7 [95% CI, 1.8-17.6]), recent antibiotic use (OR, 3.1 [95% CI, 1.3-7.2]), and central venous catheterization (OR, 5.7 [95% CI, 1.4-23.9]). Combined low-level mupirocin and genotypic chlorhexidine resistance significantly increases the risk of persistent MRSA carriage after decolonization therapy. Institutions with widespread use of these agents should monitor for resistance and loss of clinical effectiveness.

DB02-01 - Drug treatment is not necessary for maintenance treatment of depression

Prolongation or lifelong pharmacotherapy has emerged as the main therapeutic tool for preventing relapse in depression. However, outcome after discontinuation of antidepressants is unfavourably affected by the duration of their administration. Loss of clinical effects, despite adequate compliance, has also emerged as a vexing clinical problem. Use of intermittent pharmacotherapy with follow-up visits is another therapeutic option, that, however, entails the problems of resistance and of discontinuation syndromes.In recent years, several controlled trials have suggested that a sequential use of pharmacotherapy in the treatment of the acute episode and psychotherapy in its residual phase may improve long-term outcome. Antidepressant drugs may be tapered and discontinued during the course of psychotherapy. The sequential treatment of depression not fall within the realm of maintenance strategies. It is an intensive, two-stage approach, which is based on the fact that one course of treatment with a specific tool (whether pharmacotherapy or psychotherapy) is unlikely to provide solution to the complex array of symptoms of patients with mood disorders.

Analgesic effectiveness of caudal levobupivacaine and ketamine

BackgroundKetamine is used increasingly in paediatric anaesthetic practice to prolong the action of a caudal block. This study was designed to determine if adding S(+)-ketamine 0.5 mg kg−1 allows a lower concentration of levobupivacaine to be used for caudal anaesthesia without loss of clinical effectiveness. MethodsOne hundred and sixty-four children (ASA I or II) aged 3 months–6 yr were randomly allocated to receive 1 ml kg−1 of levobupivacaine 0.15% with 0.5 mg kg−1 S(+)-ketamine (Group 1), levobupivacaine 0.175% with 0.5 mg kg−1 S(+)-ketamine (Group 2), or levobupivacaine 0.2% (Group 3) by the caudal route. Pain, motor block, sedation, and requirement for postoperative analgesia were assessed up to 6 h after operation. ResultsThere was no significant difference between the groups in effectiveness at first surgical incision. Significantly lower analgesic requirements were reported in Group 2 compared with Group 3 at wakeup, 180 and 360 min after operation. Time to first rescue analgesia was longer in Group 2 compared with Group 1 or 3. Kaplan–Meier survival analysis of analgesia free time demonstrated a significant advantage of Group 2 over Groups 1 and 3 (log rank P=0.05). The incidence of postoperative motor block was not significantly different between the groups. No excess sedation or dysphoric reactions were observed in the ketamine groups. ConclusionsThe addition of 0.5 mg kg−1 S(+)-ketamine to levobupivacaine 0.175% for caudal analgesia for lower abdominal and urological surgery is significantly more effective in providing postoperative analgesia than levobupivacaine 0.15% with 0.5 mg kg−1 S(+)-ketamine or levobupivacaine 0.2%.

Treatment of recurrent depression

Approximately eight out of ten people experiencing a major depressive episode will have one or more further episodes during their lifetime: a recurrent major depressive disorder. Prolongation or lifelong pharmacotherapy has emerged as the main therapeutic tool for preventing relapse in depression. However, outcome after discontinuation of antidepressants does not seem to be affected by the duration of their administration. Loss of clinical effects, despite adequate compliance, has also emerged as a vexing clinical problem. Use of intermittent pharmacotherapy with follow-up visits is another therapeutic option that would leave patients with periods free of drugs and side effects, in consideration of the fact that a high proportion of patients would discontinue the antidepressant anyway. However, the problems of resistance (the fact that a drug treatment may be associated with a diminished chance of response in those patients who successfully responded to it, but discontinued it) and of discontinuation syndromes are a substantial disadvantage of this therapeutic option. In recent years, several controlled trials have suggested that a sequential use of pharmacotherapy in the treatment of the acute episode and psychotherapy in its residual phase may improve long-term outcome. However, patients should be motivated for psychotherapy and skilled therapists should be available. It is important to discuss with the patient the various therapeutic options and to adapt strategies to the specific needs of patients.

Can long-term treatment with antidepressant drugs worsen the course of depression?

The possibility that antidepressant drugs, while effectively treating depression, may worsen its course has received inadequate attention. A review of the literature suggesting potential depressogenic effects of long-term treatment with antidepressant drugs was performed. A MEDLINE search was conducted using the keywords tolerance, sensitization, antidepressive agents, and switching. This was supplemented by a manual search of Index Medicus under the heading "antidepressant agents" and a manual search of the literature for articles pointing to paradoxical effects of antidepressants. A number of reported clinical findings point to the following possibilities: very unfavorable long-term outcome of major depression treated by pharmacologic means, paradoxical (depression-inducing) effects of antidepressant drugs in some patients with mood and anxiety disturbances, antidepressant-induced switching and cycle acceleration in bipolar disorder, occurrence of tolerance to the effects of antidepressants during long-term treatment, onset of resistance upon rechallenge with the same antidepressant drug in a few patients, and withdrawal syndromes following discontinuation of mood-elevating drugs. These phenomena in susceptible individuals may be explained on the basis of the oppositional model of tolerance. Continued drug treatment may recruit processes that oppose the initial acute effects of a drug and may result in loss of clinical effect. When drug treatment ends, these processes may operate unopposed, at least for some time, and increase vulnerability to relapse. The possibility that antidepressant drugs may worsen the course of depression needs to be tested, even though its scientific exploration is likely to encounter considerable methodological and ideological difficulties. The clinical implications of this hypothesis in depression are considerable. Antidepressant drugs are crucial in the treatment of major depressive episodes. However, appraisal of paradoxical effects that may occur in susceptible patients during long-term treatment may lead to more effective use of the drugs.

Treatment of recurrent depression: a sequential psychotherapeutic and psychopharmacological approach.

The chronic and recurrent nature of major depressive disorder is receiving increasing attention. Approximately eight of ten people experiencing a major depressive episode will have at least one more episode during their lifetime, i.e. recurrent major depressive disorder. In the 1990s, prolonged or lifelong pharmacotherapy emerged as the main therapeutic tool for preventing relapses of depression. This therapeutic approach is based on the effectiveness of antidepressant drugs compared with placebo in decreasing relapse risk and on the improved tolerability profile of the newer antidepressants compared with their older counterparts. However, outcome after discontinuation of antidepressant therapy does not seem to be affected by the duration of administration. Loss of clinical effects, despite adequate compliance, has also emerged as a vexing clinical problem. The use of intermittent pharmacotherapy with follow-up visits is an alternative therapeutic option. This leaves patients with periods free of drugs and adverse effects and takes into account that a high proportion of patients would discontinue the antidepressant anyway. However, the problems of resistance (that a drug treatment may be associated with a diminished chance of response in subsequent treatments in those patients whose symptoms successfully responded to it but who discontinued it) and of discontinuation syndromes are substantial disadvantages of this therapeutic approach. In recent years, several controlled trials have suggested that sequential use of pharmacotherapy in the treatment of the acute depressive episode and psychotherapy in its residual phase may improve long-term outcome. Patients, however, need to be motivated for psychotherapy, and skilled therapists have to be available. Despite an impressive amount of research into the treatment of depression, there is still a paucity of studies addressing the specific problems that prevention of recurrent depression entails. It is important to discuss with the patient the various therapeutic options and to adapt strategies to the specific needs of patients.

A Systematic Approach to Delegation in Out-patient Physiotherapy

Summary This paper describes the result of a pilot study carried out in a district general hospital to examine the effects of introducing a systematic approach to delegation in out-patient physiotherapy. Physiotherapists and assistants were set to work in teams. Both new and experienced assistants were trained to carry out the treatments found on analysis to be suitable for delegation, and formal communications were arranged. Measurements were taken before and during the pilot study of productivity, costs, outcomes and patient satisfaction and were compared. There was an increase in productivity per physiotherapist and a reduction in costs. There was no loss of clinical effectiveness or efficiency and patient satisfaction remained similar before and after the changes. The physiotherapists, after experiencing initial difficulties due to fears of loss of control of patients' care and feelings of guilt through giving up care, found the system operated successfully as they built up their trust in assistants.

Cyproterone acetate/ethinyl estradiol in the treatment of acne. A comparative dose-response study of the estrogen component

The investigators compared 2 mg cyproterone acetate (CPA) in combination with either 0.035 mg or 0.050 mg ethinyl estradiol (EE 2) (Diane®-35 versus Diane®-50) in the treatment of acne. Both formulations of Diane® were highly effective in improving acne, even in women who had been refractory to other types of medication. Cycle control with both formulations was excellent and adverse effects were generally mild and confined to the first two cycles of treatment. Mean plasma lipid levels increased with both treatments, yet most individual values remained within normal limits after one year of therapy while the LDL-cholesterol/HDL-cholesterol ratio was stable throughout the study period. Plasma testosterone and DHEA-S levels paralleled the decline in the clinical severity of the acne. There was no loss of clinical effectiveness with Diane∗-35 and it provided the advantage of a 30% decrease in the amount of estrogen.

A rapid one-step kit for the routine preparation of basic 99 mTc penicillamine

Basic (pH 8.4) 99 m Tc penicillamine (TPEN) is an excellent agent forimaging renal functional morphology. The radiopharmaceutical development of this renal-scanning agent has progressed from daily, “on-demand”, preparation through a two-step kit with short shelf life to the presently reported rapid, one-step, freeze-dried kit, without loss of clinical effectiveness. Renal uptake is comparable to the earlier preparations, and the freeze-dried kit has a shelf life in excess of 2 months.