Aggregated N-of-1 trials for unlicensed medicines for small populations: an assessment of a trial with ephedrine for myasthenia gravis.

BACKGROUND: Inexpensive medicines with a long history of use may currently be prescribed off-label for rare indications. Reimbursement is at the discretion of health insurance companies, and may be unpredictable. The example addressed was ephedrine as add-on treatment for myasthenia gravis. Stakeholders from academia, a patient organization, the Dutch National Health Care Institute (NHCI) and Dutch Medicines Evaluation Board (MEB) advised on the trial design. The NHCI and MEB agreed to provide scientific advice on the suitability of the evidence generated by the trial, for regulatory decisions. This paper describes the feasibility of the trial and the utility of its aggregated results. RESULTS: The trialists experienced the trial as feasible. Retrospective interviews showed that the trial as performed was acceptable to patients. The treatment effect in the primary outcome measure, muscle strength, was statistically significant when inferred to the population level, though the effect size was modest. Secondary outcomes were statistically significant in a preplanned, fixed effects analysis within the four patients. The NHCI advised that it could potentially make reimbursement decisions based on the Fitting Evidence framework, should the trialists decide to apply for reimbursement. The MEB advised that for a licensing decision, the N-of-1 design is a last-resort option for demonstrating treatment benefit in a rare disease. N-of-1 trials alone do not provide enough evidence on potential risk. The MEB found the current trial inconclusive. It suggested doing a 2-armed trial of longer duration, possibly with a different outcome measure (postponement of corticosteroid use). It suggested engaging a consultancy or commercial sponsor, should the trialists decide to seek market authorization of the drug. CONCLUSIONS: In theory, evidence from aggregated N-of-1 trials is suitable for use in licensing and reimbursement decisions. The current example illustrates differences in interpretation of N-of-1 results by health authorities. In the era of personalized medicine, consensus is required on the interpretation of data from study designs geared to small groups. Demonstrating effectiveness of inexpensive medicines in small populations may require involvement of non-commercial parties, to preserve affordability.

Ephedrine treatment for autoimmune myasthenia gravis.

We studied the effect and safety of ephedrine as add-on treatment for patients with myasthenia gravis with acetylcholine receptor antibodies (AChR MG), who do not sufficiently respond to standard treatment. Four patients with AChR MG were included in a placebo-controlled, double-blind, and randomised, multiple crossover series of n-of-1 trials. Each n-of-1 trial consisted of 3 cycles, in which two 5-day intervention periods were followed by 2 days washout. In each cycle, ephedrine 50 mg daily in 2 doses was compared with placebo in the alternate treatment period. Primary outcome was a change in QMG score. Add-on treatment with ephedrine compared with placebo improved QMG score by 1.0 point (95% confidence interval 0.21-1.79), which was significant for the group of trial patients as well as for the population treatment effect. Ephedrine also showed a significant trial average treatment effect for all secondary outcomes, improving MG Composite by 2.7, MG-ADL by 1.0 and VAS score for muscle strength by 1.1. Adverse events were mild and included palpitations, tremor and restlessness. Although all ECGs were normal, ephedrine prolonged the corrected QT interval. Ephedrine as add-on treatment for myasthenia gravis resulted in a small but consistent reduction of symptoms and weakness in patients with moderate disease severity.

Ephedrine as add-on therapy for patients with myasthenia gravis: protocol for a series of randomised, placebo-controlled n-of-1 trials.

INTRODUCTION: Myasthenia gravis (MG), a rare neuromuscular disease, is often initially treated using acetylcholinesterase inhibitors. Patients who do not respond adequately depend on the use of corticosteroids or other immunosuppressive medication, but these may have serious side effects. Clinical observations suggest that ephedrine can diminish, postpone or even prevent the need for immunosuppressive therapy when added to acetylcholinesterase inhibitors or low-dose prednisone. In the Netherlands, ephedrine is not licensed for MG nor is reimbursement guaranteed. MG is a rare condition, and ephedrine might be indicated only in a subset of patients. Thus, randomised controlled trials comparing large groups are difficult to conduct. We, therefore, aim to aggregate data from a small series of n-of-1 trials (also known as single patient trials) to assess the effect of ephedrine as add-on treatment for MG. METHODS AND ANALYSIS: Single-centre, placebo-controlled, double-blind, randomised, multiple crossover n-of-1 studies in 4 adult patients with generalised MG who show inadequate improvement on pyridostigmine and/or immunosuppressive drugs. Each n-of-1 trial has 3 cycles of two 5-day intervention periods. TREATMENT: 25 mg ephedrine or placebo, twice daily. MAIN OUTCOME MEASURE: Quantitative Myasthenia Gravis (QMG) test. STATISTICAL ANALYSIS: fixed effects linear model for QMG for all patients combined. SECONDARY OUTCOME MEASURES: Clinical: effects on MG-Composite and MG-Activities of Daily Living (MG-ADL) scales; QMG at individual level; adverse events. Acceptability of trial design: number of patients eligible and enrolled; number of treatment cycles completed; patients' and caregivers' experiences. ETHICS AND DISSEMINATION: This study was approved by the Medical Ethics Committee of Leiden University Medical Center, No. P14.108. Results of the trial will be reported in a peer-reviewed publication. Regulatory stakeholders will comment on the suitability of the trial for market authorisation and reimbursement purposes. TRIAL REGISTRATION NUMBER: This study is registered under EudraCT number 2014-001355-23, protocol no. 40960, V.1.0, registration date 27 March 2014.

[Pitfalls in the treatment of neuropathic pain in patients with cancer]. / Valkuilen in de behandeling van neuropathische pijn bij patiënten met kanker.

Three patients with cancer experienced severe side-effects after starting anti-neuropathic pain therapy. All patients, 1 woman and 2 men aged between 69 and 71, fell or had problems with balance. These side-effects diminished after reducing the doses or stopping the medication. It seems that side-effects in patients with cancer are more common and more severe than in other populations with neuropathic pain, such as patients with diabetic neuropathy or postherpetic neuralgia. There is little research into the treatment of neuropathic pain in patients with cancer. In this patient group it is advisable to monitor the patient at least once a week for an optimal treatment and to prevent severe side-effects, especially in the first weeks after starting the treatment.

Non-compliance on the part of the professional community with a national guideline: an argumentative policy analysis.

In 1997, the National Health Insurance Board of the Netherlands (CVZ) introduced a guideline for the use of a new anti-epileptic drug, Lamotrigine. The goal was to limit the use of this relatively expensive drug to patients with difficult-to-treat epilepsy. A survey had shown that only a minority of neurologists were familiar with the guideline, and even fewer applied it in practice. In the present study, interviews were held with stakeholders to obtain a better understanding of why this policy measure failed. The results indicate that the problem definitions of policy maker and practicing neurologists differed widely, and that the policy measure was conflicting with certain professional beliefs. In such cases, the theory of argumentative policy predicts that policy is unlikely to succeed, unless policy makers take actions to ensure a greater congruence in interpretative frames between them and their target population.

Improving the process of antibiotic therapy in daily practice: interventions to optimize timing, dosage adjustment to renal function, and switch therapy.

BACKGROUND: Timely administration of the first dose, dosage adjustment to renal function, switch from intravenous to oral administration, and streamlining are important aspects of rational antibiotic prescription. The goals of this study were to investigate all of these variables, compare them with predefined quality standards, and implement improvement with specific interventions. METHODS: At the departments of internal medicine, surgery, and neurology and the emergency department of a tertiary referral university medical center, all consecutive patients receiving therapeutic antibiotics were enrolled. Dosages, timing of first doses, dosing intervals, administration routes, and adjustment of the chosen drug to clinical data were investigated. After the preintervention period, barriers to change were identified, followed by specific interventions and a postintervention measurement. RESULTS: In the preintervention and postintervention periods, 247 and 250 patients were enrolled, receiving 563 and 598 antibiotic prescriptions, respectively. The mean time from the order to first dose at the wards improved from 2.7 to 1.7 hours in potentially severe cases (P =.003). Dosage adjustment to renal function remained unchanged at 45% vs 52% (P =.09) of cases where necessary. Switching of therapy from intravenous to oral improved from 46% to 62% (P =.03) and was performed a mean of 1.6 days earlier (P =.002). Streamlining was performed correctly in most cases, and thus no interventions were necessary. CONCLUSIONS: Timing of antibiotic therapy and switch therapy may be improved with a combination of interventions. To improve poor adjustment of dosing to renal function, other strategies are needed. In our setting, streamlining was already correct in most cases.

Increase in drug use after admission to Dutch nursing homes.

OBJECTIVE: To study changes in drug use after admission to Dutch nursing homes. SETTING: Six nursing homes near the city of Nijmegen, The Netherlands. DESIGN: Prospective longitudinal study. METHODS: All patients who had been newly admitted to the nursing home were included in the study. Age, gender, residence of the patients before admission, and indication were registered. All prescriptions were registered with start-date and end-date. The nomenclature and subcategory definitions used were those of the World Health Organisation Nordic Anatomical Therapeutic Chemical classification index (ATC) codes. Patients had a follow-up of six weeks. RESULTS: There was a minor, but statistically significant, increase in the mean number of drugs from 5.6 on admission to 5.8 six weeks later. Patients referred from a hospital and patients with a somatic indication were prescribed the highest number of drugs. On admission 5.5% of the patients were not on medication at all, 48% were using 1-2 drugs, and 46% had been prescribed 6 or more drugs. Six weeks after admission, a significant increase in drug use was found in drugs for the nervous system, and drugs for the sensory organs. CONCLUSION: Increase in drug use does not necessarily have to reflect bad prescribing practices. However, in this frail population, continuous drug review is needed to guarantee quality of prescribing and reduce unnecessary polypharmacy.

International interlaboratory quality control program for measurement of antiretroviral drugs in plasma.

An international interlaboratory quality control program for measurement of antiretroviral drugs was initiated. The first round was confined to protease inhibitors and showed large variability in the performance of participating laboratories. The results demonstrate the need for and utility of an ongoing quality control program in this area of bioanalysis.