Erosive oesophagitis: outcome of repeated long term maintenance treatment with low dose omeprazole 10 mg or placebo

Aims—To investigate the efficacy of dailymaintenance treatment with omeprazole 10 mg in reducing the relapserate of healed erosive oesophagitis.
Methods—Three hundred patients with erosiveoesophagitis (grade 2 or greater) received omeprazole 20 mg daily for12 weeks, followed by 40 mg daily for a further 12 weeks if required.After healing, patients were randomised to double blind treatment with omeprazole 10 mg daily or placebo for up to 18 months. On relapse thetreatment cycle was repeated.
Results—The cumulative healing rate at 12 weeksin the initial healing period was 95%, and 96% and 98% on rehealingcourses after relapse in the first and second maintenance periodsrespectively. After 12 weeks of treatment, 98% of patients were freefrom heartburn and 97% were free of all reflux related symptoms.Relapse in the subgroup of patients who relapsed in both maintenanceperiods was infrequent on omeprazole 20 mg daily: only 9% at twoyears. Gastrin concentrations rose above normal in one third ofpatients. One patient had linear hyperplasia of endocrine cells andanother had micronodular hyperplasia. There were no side effectsdefinitely attributable to omeprazole.
Conclusion—Maintenance treatment with omeprazole10 mg daily keeps about 60% of patients with erosive oesophagitis inprolonged remission. Patients relapsing once are likely to do so again; they can subsequently be treated effectively with omeprazole 20mg daily.

Keywords:erosive oesophagitis; long term maintenancetreatment; omeprazole

     

Advantages of multi-arm non-randomised sequentially allocated cohort designs for Phase II oncology trials

Background Efficient trial designs are required to prioritise promising drugs within Phase II trials. Adaptive designs are examples of such designs, but their efficiency is reduced if there is a delay in assessing patient responses to treatment.Methods Motivated by the WIRE trial in renal cell carcinoma ({"type":"clinical-trial","attrs":{"text":"NCT03741426","term_id":"NCT03741426"}}NCT03741426), we compare three trial approaches to testing multiple treatment arms: (1) single-arm trials in sequence with interim analyses; (2) a parallel multi-arm multi-stage trial and (3) the design used in WIRE, which we call the Multi-Arm Sequential Trial with Efficient Recruitment (MASTER) design. The MASTER design recruits patients to one arm at a time, pausing recruitment to an arm when it has recruited the required number for an interim analysis. We conduct a simulation study to compare how long the three different trial designs take to evaluate a number of new treatment arms.Results The parallel multi-arm multi-stage and the MASTER design are much more efficient than separate trials. The MASTER design provides extra efficiency when there is endpoint delay, or recruitment is very quick.Conclusions We recommend the MASTER design as an efficient way of testing multiple promising cancer treatments in non-comparative Phase II trials.Subject terms: Adaptive clinical trial, Randomized controlled trials     

A 12-week clinical trial determining the efficacy of synthetic conjugated estrogens, A (SCE), in the treatment of vasomotor symptoms in menopausal women

OBJECTIVE: To compare the clinical effects of a new oral synthetic conjugated estrogens, A (SCE), versus placebo in a clinically relevant population on the reduction in the mean number of moderate to severe vasomotor symptoms. DESIGN: A total of 120 healthy pre- and postmenopausal women (72 active, 48 placebo) were enrolled into a randomized, placebo-controlled, double-blind, multi-center clinical trial. Women of all races were enrolled, using minimal inclusion and exclusion criteria. Each subject received either orally administered SCE, in doses of 0.3 mg, 0.625 mg or 1.25 mg per day, or placebo. Analysis of variance was performed on the primary efficacy variable (change from baseline to weeks 4, 8, and 12 in the mean number of moderate to severe vasomotor symptoms). RESULTS: Changes in moderate to severe vasomotor symptoms in the intent to treat population showed statistically significant differences between the active and placebo treatments at week 4 (P < .022), week 8 (P < .010), and week 12 (P < .010). By week 12, the mean percentage reduction in moderate to severe vasomotor symptoms was 81%, from an average baseline of 96.8, to 16.5 hot flashes per week for the active treatment group. The overall incidence of expected estrogen-related adverse effects was modest. Laboratory tests and vital sign measurements did not reveal clinically significant changes or abnormalities from screening to the final visit in either treatment group. CONCLUSIONS: The results of this study confirm the efficacy and safety of SCE in the treatment of moderate to severe vasomotor symptoms in menopausal women. In addition, the study also demonstrated that the use of more liberal entry criteria did not materially affect the efficacy outcome.     

Superwarfarin poisoning

Superwarfarins consist of two classes of compounds, the 4-hydroxycoumarins and the indandiones. These compounds have replaced warfarin as an anticoagulant rodenticide. This article is a summary of the clinical effects produced by accidental and deliberate ingestions of superwarfarins. Most accidental ingestions occur in childhood and result in a benign outcome. Deliberate overdoses usually involve repeated ingestions of large quantities of superwarfarins that have resulted in prolonged laboratory evidence of interference with clotting; serious bleeding has been rare. This article suggests an approach to the management of patients with accidental and deliberate anticoagulant rodenticide ingestions.     

Restriction fragment length polymorphisms of the insulin gene hypervariable region in gestational onset diabetes mellitus

Restriction fragment length polymorphisms in the insulin gene hypervariable region are compared among 93 women with gestational onset diabetes mellitus and 146 women with normal glucose tolerance during pregnancy. No significant differences in gene or genotype frequencies were observed in the overall sample (p greater than 0.50). However, an increased frequency of one allele (class 1) was observed among nonoverweight patients with gestational onset diabetes mellitus with elevated fasting plasma glucose levels compared with age-, race-, and parity-matched control subjects (p = 0.061). These data suggest that gestational onset diabetes mellitus is a heterogeneous disorder with respect to both genotypic and phenotypic characteristics, and that restriction fragment length polymorphisms near the insulin gene may serve as a molecular marker for susceptibility to gestational onset diabetes mellitus only in some women.     

To add or not to add a new treatment arm to a multiarm study: A decision-theoretic framework

Multiarm clinical trials, which compare several experimental treatments against control, are frequently recommended due to their efficiency gain. In practise, all potential treatments may not be ready to be tested in a phase II/III trial at the same time. It has become appealing to allow new treatment arms to be added into on-going clinical trials using a “platform” trial approach. To the best of our knowledge, many aspects of when to add arms to an existing trial have not been explored in the literature. Most works on adding arm(s) assume that a new arm is opened whenever a new treatment becomes available. This strategy may prolong the overall duration of a study or cause reduction in marginal power for each hypothesis if the adaptation is not well accommodated. Within a two-stage trial setting, we propose a decision-theoretic framework to investigate when to add or not to add a new treatment arm based on the observed stage one treatment responses. To account for different prospect of multiarm studies, we define utility in two different ways; one for a trial that aims to maximise the number of rejected hypotheses; the other for a trial that would declare a success when at least one hypothesis is rejected from the study. Our framework shows that it is not always optimal to add a new treatment arm to an existing trial. We illustrate a case study by considering a completed trial on knee osteoarthritis.     

Reducing sample sizes in two-stage phase II cancer trials by using continuous tumour shrinkage end-points

Reducing the number of patients required for a clinical trial is important for shortening development time. Phase II cancer trials assess the tumour-shrinking effect of a novel compound through a binary end-point formed from the percentage change in total lesion diameter. We compare single-arm two-stage designs which use the binary end-point to those which directly use the continuous end-point.Using the continuous end-point results in lower expected and maximum sample sizes. For larger trials the reduction is around 37%. This assumes that the dichotomisation point of the continuous end-point is chosen to give the best sample size, with the trial design using the binary end-point performing even worse otherwise. We consider a previous trial designed using a Simon two-stage design and show that if the continuous end-point had been used, the expected and maximum sample sizes of the trial would be reduced by around 50%.Using the continuous end-point in a two-stage cancer trial results in large sample size reductions. The methods discussed in this paper work best when the number of complete responses is low, as is true in several types of cancer. We discuss what could be done if this is not the case.     

Sensitization of pancreatic cancer cells to radiation by cerium oxide nanoparticle-induced ROS production

Side effect of radiation therapy (RT) remains the most challenging issue for pancreatic cancer treatment. In this report we determined whether and how cerium oxide nanoparticles (CONPs) sensitize pancreatic cancer cells to RT. CONP pretreatment enhanced radiation-induced reactive oxygen species (ROS) production preferentially in acidic cell-free solutions as well as acidic human pancreatic cancer cells. In acidic environments, CONPs favor the scavenging of superoxide radical over the hydroxyl peroxide resulting in accumulation of the latter whereas in neutral pH CONPs scavenge both. CONP treatment prior to RT markedly potentiated the cancer cell apoptosis both in culture and in tumors and the inhibition of the pancreatic tumor growth without harming the normal tissues or host mice. Taken together, these results identify CONPs as a potentially novel RT-sensitizer as well as protectant for improving pancreatic cancer treatment.From the Clinical EditorPancreatic tumors remain some of the most notoriously treatment-unresponsive malignancies. Cerium oxide nanoparticles may be capable of sensitizing such cells to radiotherapy, as demonstrated in this study.