Childhood deaths from acute appendicitis in England and Wales 1963-97: observational population based study.
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Acute Disease↗
Biomedical subjects
G Pledger
Publications and source records attributed to G Pledger.
Proof of efficacy trials: choosing the dose.
It is apparent from current usage of antiepileptic drugs (AEDs) and from retrospective review of their drug development programmes, that the doses currently used in clinical practice differ from those which were used in clinical trials. This raises the question of how dose and titration schedules are selected in early development. An integral component of a drug development programme should be an assessment of dose response. The International Council on Harmonization of Technical Requirements for the Registration of Pharmaceuticals for Human Use [1994. Guidelines for industry: Dose-response information to support drug registration. ICH-E4. Federal Register] regulatory guidelines suggest that, at a minimum, three elements of dosing should be characterised: a maximum well tolerated dose, a minimum effective dose, and an appropriate rate of titration. Several specific designs can be utilised to assess dose response, which fall broadly into four categories, namely free titration, forced titration and dose escalation, parallel dose response, and dose reduction studies. In addition to these standard approaches, concentration-defined trials are an alternative in some circumstances and have been used with success in the development of newer AEDs. The designs chosen to address these elements are dependent upon the phase of development of the drug, and the severity of the disease, however, it is clear that conducting dose response studies earlier in the development programme may reduce the number of failed Phase 3 studies.
Animals↗
Monotherapy trials: presurgical studies.
Presurgical evaluation of patients with refractory partial seizures provides a unique opportunity to perform a placebo-controlled, monotherapy trial. Some patients undergoing presurgical evaluations must have all of their antiepileptic drugs (AEDs) tapered in order to induce seizures and therefore such patients are possible candidates for a placebo-controlled monotherapy trial. Often, EEG monitoring is continued throughout the trial period, thus patients either receiving placebo or whose seizures do not completely respond to the active drug are still evaluated to determine whether or not surgery is feasible, supporting the validity of a trial in this setting. In addition, all patients are, in general, eligible to receive the study drug after the blinded period of the trial, and can therefore be assured of the possible therapeutic benefits of the study. Presurgical inpatients studies have been carried out using felbamate, gabapentin and oxcarbazepine. All patients randomised in these trials were refractory to previous treatment and the studies themselves were short-term and placebo-controlled. These presurgical studies are designed to elucidate AED activity and show statistically significant differences between active and control treatments during short-term therapy, and are therefore of use in fulfilling regulatory requirements. However, these measures of efficacy are distinctly different from those determined during chronic treatment and are therefore not necessarily predictive of clinical usefulness.
Anticonvulsants↗
A multicenter, randomized clinical study to evaluate the effect on cognitive function of topiramate compared with valproate as add-on therapy to carbamazepine in patients with partial-onset seizures.
PURPOSE: This study compares the cognitive effects of topiramate (TPM) with those of valproate (VPA) using efficacious doses of each drug when used as adjunctive therapy to carbamazepine (CBZ). A key question of the study is to what extent a more gradual introduction of TPM improves tolerability and prevents cognitive impairment. METHODS: The study is a multicenter, randomized, observer-blinded, parallel-group clinical trial with VPA or TPM given as first-line add-on therapy to steady-state treatment with CBZ. TPM is introduced at 25 mg and increased with weekly 25mg/d increments to a minimum dosage of 200 mg/d. The target dosage ranges from 200 to 400 mg/d for TPM and is 1800 mg/d for VPA. The study evaluates cognitive function changes from baseline to end point (after 20 weeks of treatment) and during titration (after 8 weeks of treatment). The primary outcome measure is the difference between the treatments (TPM versus VPA) in change from baseline to end point and change from baseline to titration, using a 95% confidence interval approach. RESULTS: For the 10 baseline-to-end point comparisons, one test measuring short-term verbal memory (Rey Auditory Verbal Learning Test) yields a statistically significant difference between the treatments (p = 0.02), showing worsening for TPM and improvement of scores for VPA. The 10 baseline-to-titration comparisons also show one statistically significant difference, again for a test measuring short-term memory (Recognition of Words; p = 0.04), showing a larger change in the negative direction for TPM. None of the mood tests or the test for subjective complaints shows statistically significant differences between the treatments, although more scores are in the negative direction for TPM during titration. CONCLUSION: Although the pattern of changes in the negative direction seems consistent with clinical information, the differences found between the treatments are small. An important finding of our study is that, when the results are compared with those of other studies, it is clear that gradual introduction of TPM can reduce the extent of cognitive impairment (with a maximum of about 0.6 SD).
Adolescent↗
Topiramate as add-on therapy: pooled analysis of randomized controlled trials in adults.
PURPOSE: Six double-blind, placebo-controlled trials were conducted with topiramate (TPM) initiated as adjunctive therapy in adults with treatment-resistant partial-onset seizures with or without secondary generalization. METHODS: Because protocols and study populations were similar, data from the studies were pooled and analyzed for 527 patients treated with TPM and 216 treated with placebo. RESULTS: Seizures were reduced > or =50% in 43% of TPM-treated patients and in 12% of placebo-treated patients (p < 0.001); 5% of TPM-treated patients, but no placebo-treated patients, were seizure free during 11-19 weeks of double-blind treatment (p < 0.001). The therapeutic effect was consistent regardless of seizure type, age, gender, baseline seizure rate, or concomitant antiepileptic drug (AED). With 100 mg/day TPM as a starting dosage and weekly dosage increments of 100-200 mg/day added to maximally tolerated dosages of AEDs, the most common treatment-emergent adverse events (TEAEs) were dizziness, somnolence, fatigue, psychomotor slowing, nervousness, paresthesia, ataxia, memory difficulty and speech problems. These central nervous system effects were generally mild to moderate in severity, usually occurred early in treatment, often during titration, and resolved with continued treatment. Other notable TEAEs were weight loss and, in a small percentage of patients, renal calculi.
Adolescent↗
A double-blind, randomized trial of topiramate in Lennox-Gastaut syndrome. Topiramate YL Study Group.
OBJECTIVE: To evaluate the efficacy and safety of topiramate as adjunctive therapy for Lennox-Gastaut syndrome in a multicenter, double-blind, placebo-controlled trial. BACKGROUND: Conventional antiepileptic drugs are frequently ineffective against multiple-seizure types of Lennox-Gastaut syndrome. METHODS: Ninety-eight patients >1 year to <30 years of age, with slow spike-and-wave patterns on EEG, seizure types including drop attacks, and either a history of or active atypical absence seizures, were assigned to an 11-week, double-blind treatment phase with either topiramate or placebo. Topiramate was titrated to target doses of approximately 6 mg/kg/d. RESULTS: For drop attacks, the most severe seizures associated with this syndrome, the median percentage reduction from baseline in average monthly seizure rate was 14.8% for the topiramate group and -5.1% (an increase) for the placebo group (p = 0.041). Topiramate-treated patients demonstrated greater improvement in seizure severity than did placebo-treated patients based on parental global evaluations (p = 0.037). The percentage of patients with a > or = 50% reduction from baseline in major seizures (drop attacks and tonic-clonic seizures) was greater in the topiramate group (15/46 or 33%) than in the control group (4/50 or 8%; p = 0.002). The most common adverse events in both groups were CNS related; there were no discontinuations from topiramate therapy due to adverse events. CONCLUSIONS: Topiramate adjunctive therapy was effective in reducing the number of drop attacks and major motor seizures and in improving seizure severity as determined by parental global evaluation.
Adolescent↗
Medical examiners employed by health authorities should audit death certificates.
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Coroners and Medical Examiners↗
A randomized, placebo-controlled study of topiramate in primary generalized tonic-clonic seizures. Topiramate YTC Study Group.
BACKGROUND AND OBJECTIVE: Topiramate is effective as adjunctive treatment of partial-onset seizures in adults. The efficacy and safety of topiramate as adjunctive therapy for the treatment of primary generalized tonic-clonic (PGTC) seizures were investigated in a randomized, double-blind, placebo-controlled study. METHODS: Eighty patients, 3 to 59 years old, who experienced three or more PGTC seizures during an 8-week baseline phase were randomly assigned to treatment with either topiramate (n = 39) or placebo (n = 41). Topiramate was titrated to target doses of approximately 6 mg/kg/day over 8 weeks and maintained for another 12 weeks. RESULTS: The median percentage reduction from baseline in PGTC seizure rate was 56.7% for topiramate patients and 9.0% for placebo patients (p = 0.019). The proportion of patients with 50% or higher reduction in PGTC seizure rate was 22/39 (56%) and 8/40 (20%) for the topiramate and placebo groups, respectively (p = 0.001). The median percentage reduction in the rate of all generalized seizures was 42.1% for topiramate patients and 0.9% for placebo patients (p = 0.003). The proportions of patients with 50% or higher reductions in generalized seizure rate were 18/39 (46%) and 7/41 (17%) for the topiramate and placebo groups, respectively (p = 0.003). The most common adverse events were somnolence, fatigue, weight loss, difficulty with memory, and nervousness. Treatment-limiting adverse events occurred in one patient in the topiramate group (anorexia and weight loss) and one in the placebo group (granulocytopenia and thrombocytopenia). CONCLUSION: Topiramate is well-tolerated and effective for the adjunctive treatment of PGTC seizures.
Adolescent↗
A double-blind, randomized trial of topiramate as adjunctive therapy for partial-onset seizures in children. Topiramate YP Study Group.
OBJECTIVE: To evaluate the efficacy and safety of topiramate 6 mg/kg/day in children (age 2 to 16 years) as adjunctive therapy for uncontrolled partial-onset seizures with or without secondarily generalized seizures in a multicenter, randomized, double-blind, placebo-controlled trial. METHODS: Patients with at least six partial-onset seizures during the 8-week baseline phase were treated with either topiramate (n = 41) or placebo (n = 45) for 16 weeks. RESULTS: Topiramate-treated patients had a greater median percent reduction from baseline in average monthly partial-onset seizure rate than placebo-treated patients (33.1% versus 10.5%, p = 0.034), a greater proportion of treatment responders (i.e., patients with a > or = 50% seizure rate reduction; 16 of 41 [39%] versus 9 of 45 [20%], p = 0.080), and patients with a > or = 75% seizure rate reduction (7 of 41 [17%] versus 1 of 45 [2%], p = 0.019), and better parental global evaluations of improvement in seizure severity (p = 0.019). Emotional lability (12% versus 4%), fatigue (15% versus 7%), difficulty with concentration or attention (12% versus 2%), and forgetfulness/impaired memory (7% versus 0%) were more frequent among topiramate-treated than placebo-treated patients. Most treatment-emergent adverse events were mild or moderate in severity. No topiramate-treated patients discontinued the study due to adverse events. CONCLUSIONS: Topiramate was safe and effective in the treatment of partial-onset seizures in children.
Adolescent↗
A note on the number needed to treat.
The concept of the average number of patients needed to treat to prevent a single bad outcome is becoming increasingly popular among clinicians. Defined as the inverse of the absolute risk reduction (delta), its sample estimate is denoted as NNT. Here we discuss the mathematical and statistical properties of NNT and show that simple calculations, like taking sums of different NNTs, can give nonsensical results. The implication for a meta-analysis expressed in NNTs is that we can best calculate the combined NNT by taking the inverse of the combined estimate for delta. Simulations illustrate the better performance of the combined NNT estimate on the delta-scale (NNT(P)) in comparison with the combined estimate of NNT on the NNT-scale (NNT(O)), even in cases where it is reasonable to take sums. The calculations are illustrated using data from anti-epileptic trials.
Anticonvulsants↗
Topiramate monotherapy for partial onset seizures.
PURPOSE: Evaluation of topiramate (TPM) as monotherapy in patients with uncontrolled partial onset seizures. METHODS: A total of 48 patients were evaluated in a double-blind, parallel-group trial. During a 56-day baseline period, patients had at least eight partial onset seizures while being treated with one or two standard antiepileptic drugs (AEDs). After 1-2 weeks of open-label treatment with TPM 100 mg/day, patients were randomly assigned, in equal proportions, to receive double-blind therapy with TPM 100 or 1,000 mg/day in a 5-week conversion and an 11-week monotherapy period. The study endpoint was completion of 112 study days (success) or fulfillment of one or more exit criteria: doubling of average 28-day or highest 2-day baseline seizure rate, a generalized tonic-clonic seizure (GTCS) if none had occurred at baseline, or significant prolongation of generalized seizure duration. RESULTS: Time until exit was longer (p = 0.002) and success frequency was higher (p = 0.005) with TPM 1,000 as compared with 100 mg/day. Seizure-rate reductions of > or = 50, > or = 75, or 100% were achieved by 46, 25, and 13% of the 1,000-mg/day group, respectively, as compared with 13, 8, and 0% of the 100-mg/day group, respectively. Most adverse events (AE) were mild or moderate in severity. CONCLUSIONS: Monotherapy with TPM 1,000 mg/day for partial onset seizures with or without secondarily generalized seizures was effective, with a favorable safety profile.
Adult↗
Double-blind, placebo-controlled study of topiramate in patients with refractory partial epilepsy.
The efficacy and safety of topiramate 400 mg/day as adjunctive therapy to traditional antieleptic drugs for partial onset seizures with or without secondary generalization were assessed in a double-blind, parallel-group, placebo-controlled trial. Forty-seven patients with at least one seizure per week during an 8 week baseline were randomly assigned to topiramate (N = 23) or placebo (N = 24) double-blind treatment for a 3 week titration and an 8 week stabilization period. Median percent reduction from baseline in monthly seizure frequency during the double-blind phase was not significantly greater in the topiramate group than in the placebo group (41% vs. 1%; P = 0.065). Nevertheless, other efficacy variables evidenced statistically significant differences in favor of topiramate: a greater number of treatment responders (> or = 50% reduction in seizures; 35% vs. 8%; P = 0.033); better investigator (P = 0.002) and patient (P = 0.021) global assessments; and greater reductions in secondarily generalized seizures compared to placebo (P = 0.002). The most commonly reported topiramate treatment-emergent adverse events were somnolence, fatigue, abnormal vision, weight decrease, and anxiety. Most adverse events were mild or moderate in severity. Among 7 withdrawals due to limiting adverse events, 6 were CNS-related (in 5 topiramate-treated patients). Results of this trial strongly suggest that topiramate 400 mg/day is effective and well tolerated in the treatment of refractory partial epilepsy.
Adolescent↗
Double-blind, placebo-controlled trial of topiramate as add-on therapy in patients with refractory partial seizures.
In a double-blind, randomized, parallel-group trial, we compared topiramate (TPM) with placebo as add-on therapy in patients with refractory partial epilepsy. TPM was titrated either to the target dosage of 800 mg/ day [400 mg twice daily (b.i.d)] or to the maximal tolerated dose if lower. Twenty-eight (28) patients were randomized to each treatment group. In the intent-to-treat analysis, the net median percent reduction relative to placebo in average monthly seizure rate was 54% for patients in the TPM group (p < 0.001). None of the placebo-treated patients and 43% of the patients treated with TPM experienced > or = 50% reduction in seizures (p = 0.001), and 36% of patients assigned to TPM had a 75-100% reduction in seizures (p < 0.01). Secondarily generalized seizures were also significantly reduced in the TPM group (p = 0.044). The most common adverse events (AE) reported in the TPM group were fatigue, impaired concentration, weight loss, dizziness, and paresthesias. AE occurring either during the rapid titration of TPM or at high dosages led 21% of TPM-treated patients to withdraw from the study. Half of these occurred during the titration study period. No serious AE or clinically important changes in clinical laboratory measures were observed. The present study further establishes the favorable profile and good benefit/risk ratio of TPM in resistant partial epilepsy.
Adolescent↗
Double-blind, placebo-controlled trial of topiramate (600 mg daily) for the treatment of refractory partial epilepsy.
PURPOSE: We wished to evaluate adjunctive therapy for partial-onset seizures with topiramate (TPM) for efficacy and safety in a double-blind, placebo-controlled, randomized, parallel-group study. METHODS: Sixty outpatients with epilepsy (47 men and 13 women, mean age 32.9 years) were studied. All had a documented history of partial-onset seizures with or without secondarily generalized seizures. After an 8-week baseline during which patients had at least one seizure per week, 30 patients each were randomized to TPM 300 mg twice daily (b.i.d.) or placebo for 12 weeks. RESULTS: TPM was significantly superior to placebo, as indicated by all efficacy assessments: greater median percent reduction from baseline in the average monthly seizure rate (46 vs. -12%, p = 0.004); greater number of treatment responders (patients with > or = 50% reduction in seizure rate) (47 vs. 10%, p = 0.001), and better investigator (p = 0.002) and patient (p = 0.010) global assessments of treatment. Among TPM-treated patients, the most commonly reported adverse events (AE) were headache, somnolence, fatigue, dizziness, and abnormal thinking. Most AE were mild or moderate in severity. CONCLUSIONS: The results of the present trial indicate that TPM 600 mg/day is effective in the treatment of refractory partial-onset seizures with or without secondarily generalized seizures.
Adolescent↗
Topiramate placebo-controlled dose-ranging trial in refractory partial epilepsy using 600-, 800-, and 1,000-mg daily dosages. Topiramate YE Study Group.
We conducted a multicenter, double-blind, randomized, parallel, placebo-controlled trial in 190 patients to evaluate the safety and efficacy of three dosages of topiramate (600, 800, and 1,000 mg/day) as adjunctive therapy for patients with refractory partial epilepsy. During an 18-week double-blind treatment period, median percent reductions from baseline in average monthly seizure rates were 1% for placebo, 41% for topiramate 600 mg/day and topiramate 800 mg/day, and 38% for topiramate 1,000 mg/day. There was a 50% or greater reduction from baseline in seizure frequency in 9% of patients in the placebo group and in 44% for topiramate 600 mg/day, 40% for topiramate 800 mg/day, and 38% for topiramate 1,000 mg/day. No placebo patients were improved by 75 to 100% in seizure frequency, whereas 20% of the topiramate patients were improved to this degree. All intent-to-treat drug-placebo comparisons including seizure reduction, percent responders, and investigator and patient global evaluations significantly (p < or = 0.02) favored topiramate. Treatment-emergent adverse events consisted mainly of neurologic symptoms commonly observed during antiepileptic drug (AED) therapy. Sixteen percent of patients on topiramate discontinued therapy due to adverse events. Results of this study indicate that topiramate is a highly efficacious and generally well tolerated new AED. When large groups of patients are compared, incremental efficacy in the add-on setting is not observed at topiramate dosages above 600 mg/day; however, higher doses may prove beneficial to individual patients who tolerate them.
Adolescent↗
Hospital investigation of men and women treated for angina.
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Adult↗
Childhood deaths from intussusception in England and Wales, 1984-9.
OBJECTIVE: To assess the incidence of potentially avoidable factors contributing to death of children with intussusception. DESIGN: Review of children who died with intussusception in England and Wales between 1984 and 1989 from data of the Office of Population Censuses and Surveys, case notes, coroners' records, and necropsy reports. MAIN OUTCOME MEASURES: Unambiguous objective criteria such as failure to diagnose intussusception within 24 hours of admission. RESULTS: 33 children died of acute intussusception in England and Wales between 1984 and 1989 compared with 67 in the previous six years. Their median age was 7 months (range 2 months to 12 years), and two thirds were boys. Half of the deaths occurred at home or soon after arrival at hospital but 15 patients had surgery. Potentially avoidable factors contributing to death were identified in 20 (61%) children, all but three of whom had ileocolic intussusception. These factors were excessive delay in diagnosis, inadequate intravenous fluid and antibiotic therapy, delay in recognising recurrent or residual intussusception after hydrostatic reduction, and surgical complications. Of the 13 patients in whom no avoidable factors were identified, there were nine of 11 children with isolated small bowel intussusception, who tended to have atypical presentations. CONCLUSION: Although the mortality from intussusception has declined, there remains ample opportunity for improved management.
Child↗
Epidemiology of indications.
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Health Policy↗