Escalation Group Research Articles

A randomised controlled trial of the efficacy and safety of allopurinol dose escalation to achieve target serum urate in people with gout

ObjectivesTo determine the efficacy and safety of allopurinol dose escalation using a treat-to-target serum urate (SU) approach.MethodsA randomised, controlled, parallel-group, comparative clinical trial was undertaken. People with gout receiving at...

Optimal regimens of sulfamethoxazole-trimethoprim for chemoprophylaxis of Pneumocystis pneumonia in patients with systemic rheumatic diseases: results from a non-blinded, randomized controlled trial

BackgroundSulfamethoxazole-trimethoprim (SMX/TMP) is a standard drug for the prophylaxis of Pneumocystis pneumonia (PJP) in immunosuppressed patients with systemic rheumatic diseases, but is sometimes discontinued due to adverse events (AEs). The objective of this non-blinded, randomized, 52-week non-inferiority trial was to quest an effective chemoprophylaxis regimen for PJP with a low drug discontinuation rate. Results at week 24 were reported.MethodsAdult patients with systemic rheumatic diseases who started prednisolone ≥0.6 mg/kg/day were randomized into three dosage groups: a single-strength group (SS, SMX/TMP of 400/80 mg daily), half-strength group (HS, 200/40 mg daily), and escalation group (ES, started with 40/8 mg daily, increasing incrementally to 200/40 mg daily). The primary endpoint was non-incidence rates (non-IR) of PJP at week 24.ResultsOf 183 patients randomly allocated at a 1:1:1 ratio into the three groups, 58 patients in SS, 59 in HS, and 55 in ES started SMX/TMP. A total of 172 patients were included in the analysis. No cases of PJP were reported up to week 24. Estimated non-IR of PJP in patients who received daily SMX/TMP of 200/40 mg, either starting at this dose or increasing incrementally, was 96.8–100% using the exact confidence interval as a post-hoc analysis. The overall discontinuation rate was significantly lower with HS compared to SS (p = 0.007). The discontinuation rates due to AEs were significantly lower with HS (p = 0.006) and ES (p = 0.004) compared to SS. The IR of AEs requiring reduction in the dose of SMX/TMP (p = 0.009) and AEs of special interest (p = 0.003) were different among the three groups with significantly higher IR in SS compared to HS and ES.ConclusionsAlthough there were no PJP cases, the combined group of HS and ES had an excellent estimated non-IR of PJP and both were superior in safety to SS. From the perspective of feasibility and drug discontinuation rates, the daily half-strength regimen was suggested to be optimal for prophylaxis of PJP in patients with systemic rheumatic diseases.Trial registrationThe University Hospital Medical Information Network Clinical Trials Registry number is UMIN000007727, registered 10 April 2012.

Gut microbiota and tacrolimus dosing in kidney transplantation.

Tacrolimus dosing to establish therapeutic levels in recipients of organ transplants is a challenging task because of much interpatient and intrapatient variability in drug absorption, metabolism, and disposition. In view of the reported impact of gut microbial species on drug metabolism, we investigated the relationship between the gut microbiota and tacrolimus dosing requirements in this pilot study of adult kidney transplant recipients. Serial fecal specimens were collected during the first month of transplantation from 19 kidney transplant recipients who either required a 50% increase from initial tacrolimus dosing during the first month of transplantation (Dose Escalation Group, n=5) or did not require such an increase (Dose Stable Group, n=14). We characterized bacterial composition in the fecal specimens by deep sequencing of the PCR amplified 16S rRNA V4-V5 region and we investigated the hypothesis that gut microbial composition is associated with tacrolimus dosing requirements. Initial tacrolimus dosing was similar in the Dose Escalation Group and in the Stable Group (4.2±1.1 mg/day vs. 3.8±0.8 mg/day, respectively, P=0.61, two-way between-group ANOVA using contrasts) but became higher in the Dose Escalation Group than in the Dose Stable Group by the end of the first transplantation month (9.6±2.4 mg/day vs. 3.3±1.5 mg/day, respectively, P<0.001). Our systematic characterization of the gut microbial composition identified that fecal Faecalibacterium prausnitzii abundance in the first week of transplantation was 11.8% in the Dose Escalation Group and 0.8% in the Dose Stable Group (P=0.002, Wilcoxon Rank Sum test, P<0.05 after Benjamini-Hochberg correction for multiple hypotheses). Fecal Faecalibacterium prausnitzii abundance in the first week of transplantation was positively correlated with future tacrolimus dosing at 1 month (R=0.57, P=0.01) and had a coefficient±standard error of 1.0±0.6 (P=0.08) after multivariable linear regression. Our novel observations may help further explain inter-individual differences in tacrolimus dosing to achieve therapeutic levels.

The Effect of a Slower than Standard Dose Escalation Scheme for Dipyridamole on Headaches in Secondary Prevention Therapy of Strokes: A Randomized, Open-Label Trial (DOSE)

Background: Combination therapy with acetylsalicylic acid and dipyridamole is first-line treatment in secondary prevention of strokes. Approximately 40% of patients report headache as a side effect of dipyridamole. Dose escalation of dipyridamole reduces this side effect. In practice, different dose escalation schemes are used. In theory, slower dose escalation than a standard scheme reduces headaches even more. This study aimed to find the best dose escalation scheme for prevention of headaches as a side effect of dipyridamole in the secondary prevention of strokes. Methods: In this randomized, open-label, 4-week trial, 114 patients who had an ischemic stroke or transient ischemic attack were randomized to receive either a standard or slow dose escalation scheme of dipyridamole. Participants were asked to report the four most common side effects of dipyridamole in a study diary on study days 1, 3, 5, 7, 14, 21 and 28. They were asked to score headache intensity on a visual analog scale (VAS). Participants were unaware that the trial was focused on headaches. Primary end point was to determine if a slow dose escalation scheme reduces the percentage of patients with headaches. Secondary objective was to determine the number of patients who discontinued treatment with dipyridamole because of headaches. Results: Overall 37 patients (38%) of the final population reported headache, 19 (39%) in the standard dose escalation group and 18 (37%) in the slow dose escalation group (p = 1.0). In the standard dose escalation group patients scored headaches (VAS >4) on an average of 3.3 days and patients in the slow dose escalation group on 3.6 days (p = 0.82). Mean VAS scores on study days 1, 3, 5, 7, 14 and 21 ranged from 1.4 to 3.7 in both groups. These scores did not differ significantly. However, on day 28 patients scored a significantly lower mean VAS score in the standard dose escalation group than in the slow dose escalation group (2.5 vs. 4.8; p = 0.05). In the standard dose escalation group 6 patients (11%) discontinued treatment because of side effects of dipyridamole and 3 patients (6%) in the slow dose escalation group (p = 0.49, Fisher's exact test). Conclusion: We showed that slower than standard dose escalation of dipyridamole in combination therapy with acetylsalicylic acid does not reduce headaches as a side effect. The use of such schemes should be discontinued in clinical practice. Slow dose escalation might, however, reduce the number of patients who discontinue treatment, but further research is needed to confirm this.

Mesalamine Dose Escalation Reduces Fecal Calprotectin in Patients With Quiescent Ulcerative Colitis

Among patients with quiescent ulcerative colitis (UC), lower fecal concentrations of calprotectin are associated with lower rates of relapse. We performed an open-label, randomized controlled trial to investigate whether increasing doses of mesalamine reduce concentrations of fecal calprotectin (FC) in patients with quiescent UC. We screened 119 patients with UC in remission on the basis of Simple Clinical Colitis Activity Index scores, FC >50 μg/g, and intake of no more than 3 g/day mesalamine. Participants taking mesalamine formulations other than multimatrix mesalamine were switched to multimatrix mesalamine (2.4 g/day) for 6 weeks; 52 participants were then randomly assigned (1:1) to a group that continued its current dose of mesalamine (controls, n= 26) or a group that increased its dose by 2.4 g/day for 6 weeks (n= 26). The primary outcome was continued remission with FC <50 μg/g. Secondary outcomes were continued remission with FC <100 μg/g or <200 μg/g (among patients with pre-randomization values above these levels). The primary outcome was achieved by 3.8% of controls and 26.9% of the dose escalation group (P= .0496). More patients in the dose escalation group reduced FC to below 100 μg/g (P= .04) and 200 μg/g (P= .005). Among the patients who were still in remission after the randomization phase, clinical relapse occurred sooner in patients with FC >200 μg/g compared with those with FC <200 μg/g (P= .01). Among patients with quiescent UC and increased levels of FC, increasing the dose of mesalamine by 2.4 g/day reduced fecal concentrations of calprotectin to those associated with lower rates of relapse. Clinicaltrials.gov number: NCT00652145.

Weekly Inotuzumab Ozogamicin (InO) In Adult Patients With Relapsed Or Refractory CD22-Positive Acute Lymphoblastic Leukemia (ALL)

▪ BackgroundInO is a humanized anti-CD22 antibody conjugated to calicheamicin. CD22 is expressed on a majority of B-cell ALL. An initial study suggested InO efficacy and tolerability in ALL (Cancer. 2013 Aug 1;119(15):2728-36). AimsTo optimize the InO dose and weekly schedule, and evaluate safety and efficacy in CD22+ relapsed/refractory ALL. MethodsThis phase 1, dose-escalation and expansion study enrolled pts aged ≥18 y with CD22+ refractory/relapsed ALL and no central nervous system disease. InO was administered in 28-d cycles (Table), up to 6 cycles. The final dose was to be determined based on dose-limiting toxicities (DLT) and efficacy, using the MDACC EffTox V2.10 software. Adverse event (AE) severity was assessed per CTCAE V3. DLTs included the following InO -related events in Cycle 1: gr ≥4 nonhematologic AE; prolonged myelosuppression; gr 3 nonhematologic AE >7 d; any AE resulting in permanent InO discontinuation. Complete response (CR) was defined as <5% bone marrow blasts without peripheral blasts, ANC ≥1,000/µL, platelets >100,000/µL and no extramedullary disease; CRi defined as CR without ANC or platelet recovery. ResultsWe report data for 37 pts: median age was 56 y (23-75 y); 65% were male; 17 (46%) pts were in salvage 1, 9 (24%) in salvage 2, and 10 (27%) in salvage ≥3; 7 (19%) pts had prior allogeneic stem cell transplant (SCT); 6 (16%) pts were Ph+; CD22 found on a median of 98% blasts (31.1-100%); median WBC was 5.18×103/mm3 (0.5-67.2×103/mm3). The expansion cohort (n=13) was comprised of pts with higher peripheral blast counts (PBC) and higher risk cytogenetics as compared to the dose escalation group (n=24): median PBC of 4158/µL (0-38,976/µL) and 18/µL (0-10,189/µL), respectively; aberrant baseline cytogenetics were reported in 10/13 (77%) expansion pts including 2 pts Ph+ and 2 pts t(4;11) and 11/24 (46%) escalation pts. Median follow-up in surviving pts was 4.1 mo (1-12.6 mo). Thirty-two pts discontinued InO: 14 due to PD, relapse or resistant disease, 11 proceeded to SCT, 6 due to AEs (1 pt each: gr 3 acute renal failure, gr 2 ascites, gr 2 increased gamma-glutamyl transpeptidase (GGT), gr 5 graft failure, gr 2 constitutional symptoms and gr 2 veno-occlusive disease (VOD)) and 1 to receive maintenance therapy. InO-related ≥gr 3 AEs (≥10% of pts) were thrombocytopenia (30%) and neutropenia (19%). Other ≥gr 3 hepatic AEs included increased ALT (5.4%) and increased GGT (3%). Gr 2 AEs include ascites (2 pts) and VOD (2 pts). Sixteen deaths were reported: ALL (n=11), sepsis following SCT (n=3), graft failure (n=1) and gut GVHD and liver dysfunction (n=1). The RP2D was determined as 1.8 mg/m2/cycle based on efficacy and safety in the dose escalation patients (1 DLT; 89% CR+CRi rate; all remissions were minimal residual disease (MRD) negative (<1 blast out of 104 mononuclear cells by flow cytometry) with a dose reduction to 1.6 mg/m2/cycle upon achievement of CR/CRi. The dose reduction was recommended due to AEs leading to discontinuation and the observation of increased InO exposure with successive cycles in prior studies.The remission rate (CR+CRi) for the dose escalation pts (n=24) was 79% (95% CI: 58, 93) and 46% (95% CI: 19, 75) for the dose expansion pts (n=13); 18/19 (95%) escalation pts with CR/CRi and 4/6 (67%) expansion pts with CR/CRi achieved MRD negativity. Overall, the median time to remission and MRD negativity was 29 d (20-85d) and 34 d (22-141d), respectively. Minimum InO concentrations in responders were higher than in pts failing treatment. Summary/ConclusionThe RP2D was confirmed as 1.8 mg/m2/cycle, InO had a tolerable safety profile primarily characterized by hematologic, gastrointestinal and hepatic AEs. Single-agent InO demonstrated encouraging clinical activity in this relapsed/refractory population; preliminary efficacy results appear dynamically related to exposure and circulating blasts. Further exploration in CD22+ ALL is ongoing. [Display omitted] Disclosures:DeAngelo:Pfizer Inc: Membership on an entity's Board of Directors or advisory committees. Off Label Use: This abstract presents findings from a phase I study of inotuzumab ozogamicin in patients with relapsed/refractory CD22+ acute lymphoblastic leukemia; this drug is investigational and is not approved for use in any indication in any country. Stock:Pfizer Inc: Research Funding. Liedtke:Millennium: The Takeda Oncology Company: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding. Schiffer:Amgen Inc: Research Funding; Pfizer Inc: Research Funding. Ananthakrishnan:Pfizer Inc: Employment. Boni:Pfizer Inc: Employment. Luu:Pfizer Inc: Employment. Liau:Pfizer Inc: Employment. Vandendries:Pfizer Inc: Employment. Advani:Pfizer Inc: Research Funding.

Efficacy of combination of Ezetimibe 10 mg and rosuvastatin 2.5 mg versus rosuvastatin 5 mg monotherapy for hypercholesterolemia in patients with type 2 diabetes.

BackgroundStatins are used to treat hypercholesterolemia in patients with type 2 diabetes mellitus, but many of these patients fail to achieve the target LDL-C level. Recent reports have suggested that a synergistic effect can be obtained by concomitant administration of the cholesterol absorption inhibitor ezetimibe and a statin. However, in patients with type 2 diabetes who are already being treated with satins, it remains unclear whether it is more effective to add ezetimibe or to increase the statin dose. Therefore, this study was performed to examine the effects of these two regimens on LDL-C and lipoproteins.MethodsThe subjects were type 2 diabetic patients under treatment with rosuvastatin (2.5 mg daily), who had LDL-C levels ≥80 mg/dL. They were randomly allocated to a group that received add-on therapy with ezetimibe at 10 mg/day (combination group, n = 40) or an increase of the rosuvastatin dose to 5 mg/day (dose escalation group, n = 39). These two groups were compared at baseline and after 12 weeks of treatment.ResultsThe percent change of LDL-C was −31% in the combination group and −12% in the dose escalation group. Both groups showed a significant decrease, but the decrease was greater in the combination group. In both groups, there was a significant decrease in the levels of small dense LDL-C, oxidized LDL and remnant-like lipoprotein cholesterol. For all of these parameters, the percent changes were greater in the combination group. Only the combination group showed a significant decrease of triglycerides. Multivariate analysis was performed to identify factors associated with reaching an LDL-C level <80 mg/dL. As a result, add-on therapy with ezetimibe was extracted as a factor related to improvement of LDL-C.ConclusionsCompared with increasing the dose of rosuvastatin, the combination of rosuvastatin and ezetimibe not only achieves quantitative but also qualitative improvement of serum lipid levels in type 2 diabetic patients, suggesting that this combination could suppress the progression of atherosclerosis.Trial registrationUMIN000011005

THU0132 Comparison of dose escalation of infliximab and the addition of tacrolimus in rheumatoid arthritis patients with an inadequate response to infliximab and methotrexate combination therapy

BackgroundThe treatment of rheumatoid arthritis (RA) has been transformed in by the development of novel agents focusing on biological factors. The idea of “treat to target” has emerged. Early aggressive...

THU0213 The Combination Therapy with Dose Escalation and Interval Shortening of Infliximab Makes Better Response to Patients with Rheumatoid Arthritis who Were Loss of Efficacy Against Infliximab

BackgroundThe anti-TNF agents prevents joint destruction, and brought drastic change on rheumatoid arthritis treatment, but some patients have to discontinue these drugs due to inadequate response. In Infliximab (IFX) standard...

Sorafenib Dose Escalation in the Treatment of Advanced Hepatocellular Carcinoma

Objective: Although sorafenib has shown survival benefits in patients with hepatocellular carcinoma (HCC), many patients require discontinuation or dose reduction due to adverse events (AEs). We applied a dose escalation scheme to increase patient compliance and avoid AEs. Methods: Of 267 HCC patients treated with first-line sorafenib, 25 at increased risk of AEs, including those with advanced liver cirrhosis, a history of liver transplantation, or cytopenia, received the dose escalation scheme. They started on a reduced dose of sorafenib which increased to the standard dosage according to tolerance in each patient. We analyzed the efficacy and safety of the dose escalation scheme. Results: Patients with risk factors showed a lower disease control rate, shorter survival, and more frequently grade 3/4 AEs. Among patients presenting risk factors, the dose scheme did not affect the efficacy of sorafenib or survival, but reduced the incidence of grade 3/4 AEs. Rates of sorafenib discontinuation and dose reduction related to AEs were also lower in the dose escalation group. Dose escalation to the standard dose of sorafenib was achieved in 16 of the 25 patients in the dose escalation group (64.0%). After 2 weeks, the dose intensity of sorafenib did not differ between the two dose schemes. Conclusions: The sorafenib dose escalation scheme may increase patient compliance and tolerance to prolonged treatment, thus enhancing the efficacy of sorafenib in patients at high risk of AEs or with poor tolerance. Further prospective analyses are needed to determine the usefulness of the dose escalation scheme.

Outcomes after escalation of infliximab therapy in ambulatory patients with moderately active ulcerative colitis.

Infliximab (IFX) therapy escalation during maintenance treatment occurs frequently in clinical practice in patients with ulcerative colitis (UC). Outcomes for these patients have not been described. To describe the prevalence of, and outcomes after, IFX escalation during maintenance therapy in patients with moderate-severe UC. Retrospective observational study of clinical outcomes in ambulatory patients with moderate-severe UC treated with maintenance IFX. Fifty-six ambulatory patients received IFX for moderate-severe UC; fifty (89%) responded and proceeded to maintenance therapy. Mean duration of maintenance therapy was 14 months, with mean follow-up of 38 months. Twenty-seven patients (54%) required IFX therapy escalation after a mean of six maintenance infusions. Clinical remission was noted in 36% of the entire cohort (18/50) at 12 months; 19% in the escalation group and 56% in the non-escalation group. Patients who required IFX escalation were less likely to be in clinical remission at 12 months (OR 0.2, 95% CI 0.1-0.6, P = 0.01) when compared with those who did not. During the follow-up period, 27% of patients required a colectomy, and the mean time to colectomy was 17 months. Patients in the escalation group required a colectomy in 33% of cases, compared with 21% of non-escalation patients. A significant proportion of ambulatory patients with UC treated with maintenance infliximab required therapy escalation over time. This was associated with lower remission, and higher colectomy, rates.

Efficacy and safety of rapid escalation of cabergoline in comparison to conventional regimen for macroprolactinoma: A prospective, randomized trial

Introduction:Cabergoline (CAB) is conventionally started at a dose of 0.25-0.5 mg once a week with dose escalation at 1to 3months intervals. Previously, we and others have shown that rapid escalation and high doses of CAB can lead to normalization of serum PRL as early as 8.2 weeks in 93% of the patients. We hypothesize that rapid escalation of CAB doses, may help in both the earlier normalization of PRL and also significant shrinkage of tumor mass.Study Design:Randomized, prospective, interventional trial.Subjects and Methods:Forty two patients (male or female) with macroprolactinoma were randomized to conventional (group A) or rapid escalation (group B) of CAB dosing. In group B, CAB was started at a dose of 0.5 mg twice a week followed by a weekly hike of 1 mg/week, based on serum PRL and then monthly. The end point of the present study was a composite of normoprolactinemia and tumor shrinkage ≥50% from baseline. PRL and visual field analysis (weekly), other hormonal work up periodically and magnetic resonance imaging (sella) was performed monthly.Results:A total of 19 patients in each group completed a minimum follow-up of 6 months. There was a reduction of 72.7 ± 26.2% in group A and 84.1 ± 15.0 in group B (P = 0.24) within a week of CAB therapy. The duration of CAB treatment to normalize PRL was 10.2 ± 9.2 week(2-36) in group A and 7.2 ± 6.2 weeks(1-24) in group B (P = 0.28). There was no difference in the tumor shrinkage in either of the groups (92.3% [46.7-100%] in group A and 90.5% [66.6-100%] reduction in group B). The composite end point was achieved in 14 patients in group A (73.6%) and 16 patients in group B (84.2%) (P = 0.69). The composite end point was achieved in 13.1 ± 9.5 weeks (group A) versus 16.5 ± 14.1 weeks (group B) (P = 0.61).Discussion:This is first head to head comparative trial showing that a rapid hike of CAB dose is not associated with earlier normalization of PRL or reduction in tumor volume as compared to conventional monthly hike. There is no difference in the number of patients or duration required to achieve the composite end point. We obtained much earlier PRL normalization (8.4 weeks) as compared to previous studies (36-72 weeks), probably because PRL was not assessed as frequently as in the present study. Rapid escalation of CAB was well tolerated.Conclusion:A weekly or a conventional 4 weekly escalation of CAB have a similar efficacy with regards to the achievement of normoprolactinemia and significant tumor shrinkage for macroprolactinoma.

CYP3A5*3 Affects Plasma Disposition of Noroxycodone and Dose Escalation in Cancer Patients Receiving Oxycodone

The aim of this study was to evaluate the plasma dispositions of oxycodone and its demethylates and dose escalation based on genetic polymorphisms of CYP2D6, CYP3A5, ABCB1, and OPRM1 in cancer patients receiving oxycodone. Sixty-two Japanese cancer patients receiving oxycodone extended-release tablets were enrolled. Predose plasma concentrations (C(12)) of oxycodone, noroxycodone, and oxymorphone were determined at the titrated dose. Daily oxycodone escalation rate was evaluated as the opioid escalation index (OEI). Genetic variants did not significantly alter oxycodone C(12). Oxymorphone C(12) and its ratio to oxycodone C(12) were significantly higher in CYP2D6 extensive metabolizers than in intermediate metabolizers but did not affect dose escalation. In contrast, noroxycodone C(12) and its ratio to oxycodone C(12) were significantly higher in the CYP3A5*1 carrier group than in the *3/*3 group. The OEI was significantly higher in the CYP3A5*3/*3 group than in the *1 carrier group. No significant difference was observed in the OEI in the other genetic variants. Noroxycodone C(12) was higher in the dose escalation group as compared to the nonescalation group and significantly affected the incidence of dose escalation. In conclusion, CYP3A5*3 altered the plasma disposition of noroxycodone, which was inversely affecting the dose escalation in cancer patients receiving oxycodone.

Escalation Regimen of Cilostazol for Acute Brain Infarction

Several reports have indicated that cilostazol is effective in the prevention of recurrence after cerebral infarction. However, cilostazol is inferior in tolerability for the adverse events than other anti-platelet agents. The goal of this study was to determine whether cilostazol escalation oral administration affects its tolerability. One hundred sixty-eight patients hospitalized for brain infarction with cilostazol treatment in our stroke center from 2006 to 2008 were enrolled in this study. During this term, we had two teams in our center and used different regimens. One of which used 100 mg b.i.d. regimen of cilostazol (Standard group) and the other used 50 mg b.i.d. for the initial 4 days, followed by a dose of 100 mg b.i.d. of it (Escalation group). Patient's information such as baseline characteristics, adverse events, were collected and statistically analyzed retrospectively. Seventy-nine patients were enrolled in Standard group and 87 patients in Escalation group. Comparison between these groups demonstrated that Escalation group had fewer patients who discontinued treatment (p=0.001) and a lower incidence of headache (p=0.004). This type of dose escalation regimen of cilostazol may be superior to the standard regimen in tolerability.

Estudio comparativo de la efectividad y tolerabilidad de un procedimiento de escalado lento de dosis de rivastigmina en pacientes con demencia tipo Alzheimer leve o moderada: estudio SCALEX

To determine and to compare the tolerability and effectiveness of a slow escalation of the dose of rivastigmine in patients with Alzheimer's disease with respect to using it with a faster escalation. We conducted a multi-centre, naturalistic, open-label, randomised trial with 429 hospital outpatients diagnosed with Alzheimer-type dementia (according to DSM-IV and NINCDS-ADRA criteria) and in whom treatment with rivastigmine was clinically indicated. Two study groups were established: slow escalation and fast escalation (in accordance with usual clinical practice); effectiveness and tolerability variables were analysed in the two groups, as was the proportion of patients who reached therapeutic doses (> 6 mg/day). The scores obtained on the CGI, MMSE, NPI and Barthel index scales were analysed, together with adverse events and reactions concerning spontaneous communication, and scores on the UKU scale. The slow escalation group displayed slightly higher percentages of sub-therapeutic anticipated interruptions than the fast escalation group (chi-square test; p < 0.05). On comparing the two treatment groups, no statistically significant differences were observed for the evolution of the scores on the different scales of effectiveness; no statistically significant differences were found between the two groups in the safety and tolerability analyses (chi-square test, exact test; p > 0.05) for most of the parameters that were studied (adverse reactions in spontaneous communication and the modified UKU scale). Slow escalation of the dose of rivastigmine did not display greater effectiveness or tolerability in comparison to an escalation applied in accordance with usual clinical practice.

Response to low-dose ketoconazole and subsequent dose escalation to high-dose ketoconazole in patients with androgen-independent prostate cancer

4646 Background: High dose ketoconazole (HDK) in combination with steroids has been recognized as an effective secondary hormonal therapy in androgen independent prostate cancer (AIPC). However, HDK causes more severe adverse events than low dose ketoconazole (LDK). Relatively little is known about the efficacy of LDK in AIPC. We evaluated the efficacy of LDK and of subsequent dose escalation from LDK to HDK as secondary hormonal therapy in patients with AIPC. Methods: We retrospectively identified patients with AIPC in a single institution treated with LDK (200 mg PO TID) as secondary hormonal therapy with or without concomitant steroids. Additionally, patients were identified who received dose escalation to HDK (400 mg PO TID) after experiencing a rising prostate-specific antigen (PSA). Results: 138 patients were eligible for the study. Median age was 64 years (range: 41–84); median PSA at initiation of ketoconazole was 37.4 ng/ml (range: 0.8–2279). Patients received LDK as either second (25.4%), third (50.0%) or fourth (21.7%) line hormonal therapy. Thirty-nine of 138 patients (28.3%, 95% CI 20.9%–36.6%) treated with LDK treatment experienced PSA declines ≥50%. Median duration of LDK was 6.4 months in responders and 2.9 months in non-responders. Dose escalation to HDK subsequently was performed in 55 (40%) patients, seven of whom (12.7%) demonstrated a subsequent PSA decline ≥50% (5 LDK responders and 2 LDK non-responders, respectively). Overall time to progression with LDK with or without dose escalation was 3.5 months (range 0.1+–61 months). The most common reversible adverse effect on LDK was grade 1 or 2 fatigue (12.3%). 41.8% of dose escalation group experienced either aggravation or development of toxicities. The most common toxicities on HDK were nausea (16.4%) and fatigue (14.5%). Conclusions: LDK is associated with a PSA response rate comparable to HDK as secondary hormonal therapy in patients with AIPC, and appears to be less toxic. Few patients responded to the dose escalation from LDK to HDK but durable additional responses occurred in some. No significant financial relationships to disclose.