Background The CONSORT statement is intended to improve reporting of randomised controlled trials and focuses on minimising the risk of bias (internal validity). The applicability of a trial’s results (generalisability or external validity) is also important, particularly for pragmatic trials. A pragmatic trial (a term first used in 1967 by Schwartz and Lellouch) can be broadly defined as a randomised controlled trial whose purpose is to inform decisions about practice. This extension of the CONSORT statement is intended to improve the reporting of such trials and focuses on applicability. Methods At two, two-day meetings held in Toronto in 2005 and 2008, we reviewed the CONSORT statement and its extensions, the literature on pragmatic trials and applicability, and our experiences in conducting pragmatic trials. Recommendations We recommend extending eight CONSORT checklist items for reporting of pragmatic trials: the background, participants, interventions, outcomes, sample size, blinding, participant flow, and generalisability of the findings. These extensions are presented, along with illustrative examples of reporting, and an explanation of each extension. Adherence to these reporting criteria will make it easier for decision makers to judge how applicable the results of randomised controlled trials are to their own conditions. Empirical studies are needed to ascertain the usefulness and comprehensiveness of these CONSORT checklist item extensions. In the meantime we recommend that those who support, conduct, and report pragmatic trials should use this extension of the CONSORT statement to facilitate the use of trial results in decisions about health care.

https://www.bmj.com/content/bmj/337/bmj.a2390.full.pdf

Improving the reporting of pragmatic trials: an extension of the CONSORT statement.

Clinical Trials: A Practical Approach

From the Departments of Anesthesiology (I.G., J.M.B.) and Pharmacology and Tox- icology (I.G.), the Departments of Mathe- matics and Statistics and Community Health and Epidemiology (D.T.), the De- partment of Psychology (R.R.H.), and the Department of Medicine (Division of En- docrinology) (R.L.H.), Queen's Universi- ty, Kingston, Ont.; and the Departments background The available drugs to treat neuropathic pain have incomplete efficacy and dose-limit- ing adverse effects. We compared the efficacy of a combination of gabapentin and mor- phine with that of each as a single agent in patients with painful diabetic neuropathy or postherpetic neuralgia. methods In this randomized, double-blind, active placebo-controlled, four-period crossover trial, patients received daily active placebo (lorazepam), sustained-release morphine, gabapentin, and a combination of gabapentin and morphine — each given orally for five weeks. The primary outcome measure was mean daily pain intensity in patients re- ceiving a maximal tolerated dose; secondary outcomes included pain (rated according to the Short-Form McGill Pain Questionnaire), adverse effects, maximal tolerated dos- es, mood, and quality of life. results abstract

/pdf/morphine-gabapentin-or-their-combination-for-neuropathic-35gy6x35u9.pdf

Morphine, Gabapentin, or Their Combination for Neuropathic Pain

https://www.thelancet.com/pdfs/journals/lancet/PIIS0140-6736(07)60460-7.pdf

The SANAD study of effectiveness of carbamazepine, gabapentin, lamotrigine, oxcarbazepine, or topiramate for treatment of partial epilepsy: an unblinded randomised controlled trial

Voltage-gated calcium channels are required for many key functions in the body. In this review, the different subtypes of voltage-gated calcium channels are described and their physiologic roles and pharmacology are outlined. We describe the current uses of drugs interacting with the different calcium channel subtypes and subunits, as well as specific areas in which there is strong potential for future drug development. Current therapeutic agents include drugs targeting L-type Ca(V)1.2 calcium channels, particularly 1,4-dihydropyridines, which are widely used in the treatment of hypertension. T-type (Ca(V)3) channels are a target of ethosuximide, widely used in absence epilepsy. The auxiliary subunit α2δ-1 is the therapeutic target of the gabapentinoid drugs, which are of value in certain epilepsies and chronic neuropathic pain. The limited use of intrathecal ziconotide, a peptide blocker of N-type (Ca(V)2.2) calcium channels, as a treatment of intractable pain, gives an indication that these channels represent excellent drug targets for various pain conditions. We describe how selectivity for different subtypes of calcium channels (e.g., Ca(V)1.2 and Ca(V)1.3 L-type channels) may be achieved in the future by exploiting differences between channel isoforms in terms of sequence and biophysical properties, variation in splicing in different target tissues, and differences in the properties of the target tissues themselves in terms of membrane potential or firing frequency. Thus, use-dependent blockers of the different isoforms could selectively block calcium channels in particular pathologies, such as nociceptive neurons in pain states or in epileptic brain circuits. Of important future potential are selective Ca(V)1.3 blockers for neuropsychiatric diseases, neuroprotection in Parkinson's disease, and resistant hypertension. In addition, selective or nonselective T-type channel blockers are considered potential therapeutic targets in epilepsy, pain, obesity, sleep, and anxiety. Use-dependent N-type calcium channel blockers are likely to be of therapeutic use in chronic pain conditions. Thus, more selective calcium channel blockers hold promise for therapeutic intervention.

The Physiology, Pathology, and Pharmacology of Voltage-Gated Calcium Channels and Their Future Therapeutic Potential

Summary

: Purpose: Gabapentin (GBP), lamotrigine (LTG), tiagabine (TGB), topiramate (TPM), vigabatrin (VGB), and zonisamide (ZNS) are all in use as “add-on” treatment for patients with refractory epilepsy. There have been no comparative randomized controlled trials allowing an evidence-based choice between these drugs. We report a series of meta-analyses of randomized placebo-controlled add-on trials in which these drugs have been tested in patients with partial epilepsy. This work provides an estimate of each drug's efficacy and tolerability compared with placebo. These estimates are compared across drugs to give broad estimates of comparative efficacy and tolerability.



Methods: Trial reports were found by searching Medline, by searching through journals by hand, and by contacting the pharmaceutical industry. The outcomes chosen were the proportion of patients who (a) have a 350% reduction in seizure frequency (50% responders); (b) withdrew from the study (any reason); or (c) reported the following side effects: ataxia, dizziness, fatigue, nausea, or somnolence. Overall odds ratio (OR) with 95% confidence intervals (CIS; 50% responders) or 99% CIS; side effects) were calculated.



Results: Twenty-nine trials were included, representing 4,091 randomized patients. The ORs for 50% response (95% CI) were GBP, 2.29 (1.53–3.43); LTG, 2.32 (1.47–3.68); TGB, 3.03 (2.01–4.58); TPM, 4.07 (2.87–5.78); VGB, 3.67 (2.44–5.51); and ZNS, 2.7 (1.36–4.47). ORs for discontinuation were GBP, 1.36 (0.75–2.49); LTG, 1.19 (0.79–1.79); TGB, 1.81 (1.21–2.70); TPM, 2.56 (1.64–4.00); VGB, 2.58 (126–5.27); and ZNS, 4.23 (1.71–10.49).



Conclusions: We have clear evidence that each of these drugs is better than placebo at preventing seizures. When results are compared across drugs, the confidence intervals overlap, and we have no conclusive evidence of differences in efficacy or tolerability. Despite this, the agent that appears most effective may be twice as effective as the agent that appears least effective, and the agent that appears most likely to cause discontinuation may be 4 times more likely to do so than the treatment that appears least likely to do so. Comparative randomized studies are needed further to evaluate these drugs.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1528-1157.1997.tb01251.x

The new antiepileptic drugs: a systematic review of their efficacy and tolerability.

Objectives: To evaluate the efficacy and tolerability of the newly developed antiepileptic drugs gabapentin, lamotrigine, tiagabine, topiramate, vigabatrin, and zonisamide in patients with refractory partial epilepsy. Design: Systematic review of published and unpublished randomised controlled trials of add-on treatment with new antiepileptic drugs. Subjects: 20 published and eight unpublished trials representing 3883 patients with refractory partial epilepsy. Main outcome measures: Proportion of patients who (a) showed 50% or greater reduction in frequency of seizures (50% responders) and (b) withdrew from each study for any reason. Results: Odds ratios (95% confidence intervals) relative to placebo for 50% responders were 2.29 (1.53 to 3.43) for gabapentin, 2.32 (1.47 to 3.68) for lamotrigine, 3.03 (2.01 to 4.58) for tiagabine, 4.22 (2.80 to 6.35) for topiramate, 3.68 (2.45 to 5.51) for vigabatrin, and 2.47 (1.36 to 4.47) for zonisamide. Odds ratios for withdrawal were 1.36 (0.75 to 2.49) for gabapentin, 1.19 (0.79 to 1.79) for lamotrigine, 1.81 (1.21 to 2.70) for tiagabine, 2.42 (1.43 to 4.11) for topiramate, 2.58 (1.26 to 5.27) for vigabatrin, and 5.70 (1.76 to 18.49) for zonisamide. Comparing results for each drug showed that all of the 95% confidence intervals overlapped, indicating that they were not significantly different in terms of efficacy and tolerability. Conclusions: All six drugs were significantly better than placebo at reducing frequency of seizures. These results do not allow an evidence based choice between these drugs as we have no conclusive indication of differences in efficacy or tolerability. Key messages At present there is insufficient evidence to guide a choice between these new treatments We systematically reviewed randomised placebo controlled studies of supplementary gabapentin, lamotrigine, tiagabine, topiramate, vigabatrin, and zonisamide Each drug was significantly better than placebo at preventing seizures, but none was significantly different from the others in terms of efficacy or tolerability, though the confidence intervals were wide Randomised trials comparing active treatments are needed to further evaluate these drugs

/pdf/new-antiepileptic-drugs-a-systematic-review-of-their-3gcd12ekvl.pdf

New antiepileptic drugs: a systematic review of their efficacy and tolerability.

Background The majority of epileptic patients have a good prognosis and their seizures can be well controlled with the use of a single antiepileptic agent, but up to 30% develop refractory epilepsy, especially those with partial seizures. In this review we summarize the current evidence regarding a new antiepileptic drug, topiramate, when used as an add-on treatment for drug-resistant partial epilepsy. Objectives To evaluate the efficacy and tolerability of topiramate when used as an add-on treatment in patients with drug resistant partial epilepsy. Search strategy (a) The Cochrane Library (1999 Issue 1); (b) The controlled trial register of the Cochrane Epilepsy Group; (c) Johnson and Johnson, makers of topiramate; (d) Experts in the field. Selection criteria Randomized placebo controlled add-on trials of topiramate in patients with drug resistant epilepsy. Data collection and analysis Two reviewers independently selected trials for inclusion and extracted the relevant data. The following outcomes were assessed: (a) 50% or greater reduction in seizure frequency; (b) treatment withdrawal (any reason); (c) side effects. Primary analyses were intention to treat. Summary odds ratios (OR) were estimated for each outcome. Dose response was evaluated in regression models. Main results Six trials were included representing 743 randomized patients. Efficacy Overall OR (95% CIs) for 50% or greater reduction in seizure frequency compared to placebo 4.06 (2.86-5.78). Dose regression analysis shows increasing efficacy with increasing dose, but found no advantage for doses over 400 mg per day. Global effectiveness: treatment withdrawal OR (95% CIs) compared to placebo 2.57 (1.65-4.00). Side effects: OR (99% CIs)compared to placebo, dizziness 1.99 (1.20-3.29); fatigue 2.52 (1. 47-4.32); nausea 2.84 (1.36-5.93); somnolence 2.89 (1.72-4.85) and 'thinking abnormally' 3.71 (2.02-6.80) were significantly associated with topiramate. Reviewer's conclusions Topiramate has efficacy as an add-on treatment in patients with drug resistant partial epilepsy. However, trials reviewed were of relatively short duration, and provide no evidence for the long term efficacy of topiramate. Results cannot be extrapolated to monotherapy or patients with other epilepsy types.

Topiramate for drug-resistant partial epilepsy.

BACKGROUND The majority of epileptic patients have a good prognosis and their seizures can be well controlled with the use of a single antiepileptic agent, but up to 30% develop refractory epilepsy, especially those with partial seizures. In this review we summarise the current evidence regarding a new antiepileptic drug, gabapentin, when used as an add-on treatment for drug-resistant partial epilepsy OBJECTIVES To evaluate the efficacy and tolerability of gabapentin when used as an add-on treatment for patients with drug-resistant partial epilepsy. SEARCH STRATEGY We searched the Cochrane Epilepsy Group trial register, the Cochrane Controlled Trials Register of The Cochrane Library Issue 4, 1998. In addition, we contacted Parke Davis (manufacturers of gabapentin) and experts in the field to seek any ongoing studies or unpublished studies. SELECTION CRITERIA Randomized placebo controlled double blind add-on trials of gabapentin in patients with drug-resistant partial epilepsy. DATA COLLECTION AND ANALYSIS Two reviewers independently selected trials for inclusion and extracted the relevant data. The following outcomes were assessed: (a) 50% or greater reduction in seizure frequency; (b) treatment withdrawal (any reason); (c) side effects. Primary analyses were intention to treat. Sensitivity best and worst case analyses were also undertaken. Summary odds ratios were estimated for each outcome. Dose response was evaluated in regression models, and Number Needed to Treat (NNTs) were calculated for individual doses. MAIN RESULTS Four trials were included representing 750 randomized patients. EFFICACY Overall odds ratio (OR) (95% Confidence Interval (CI)) for 50% or greater reduction in seizure frequency compared to placebo 2.22 (1.49 - 3.32). Dose regression analysis shows increasing efficacy with increasing dose, with 28.5% (21.5 - 36.7) of patients responding to 1800mg of gabapentin compared to placebo, NNT 6.7 (3.0 - 10.5). Global effectiveness: treatment withdrawal OR (95% CI) compared to placebo 1.40 (0.76 - 2.55); Side effects: OR (99% CI) compared to placebo. dizziness 2.26 (1.28 - 3.99); fatigue 2.29 (1.11 - 4.74); somnolence 2.04 (1.21 - 3.45) were significanty associated with gabapentin. REVIEWER'S CONCLUSIONS Gabapentin has efficacy as an add-on treatment in patients with drug-resistant partial epilepsy. However, trials reviewed were of relatively short duration, and provide no evidence for the long term efficacy of gabapentin. Results cannot be extrapolated to monotherapy or patients with other epilepsy types.

Gabapentin for drug-resistant partial epilepsy.

Gabapentin, lamotrigine, tiagabine, topiramate, vigabatrin, and zonisamide are all administered as add-on therapy for treatment of patients with refractory epilepsy. To date, no comparative randomized trials have been performed that could potentially allow an evidence-based choice to be made between these antiepileptic drugs (AEDs). We report a series of meta-analyses of placebo-controlled, randomized add-on trials in patients with partial epilepsy. Results of these meta-analyses are compared, thus giving broad estimates of the comparative efficacy and tolerability of these AEDs. The efficacy outcome is the odds ratio for the number of patients with a ≥50% reduction in seizure frequency. Reported side effects are also used as tolerability outcomes, and study withdrawal is used as a global outcome measure. Results are summarized as odds ratios with 95% confidence intervals (CIs). When each outcome is compared among drugs, the 95% CIs overlap. Therefore, no conclusive evidence of a difference in efficacy or tolerability between these AEDs was derived, even though the apparently most effective agent (topiramate) may be twice as effective as the apparently least effective agent (lamotrigine). Comparative randomized studies are needed to further evaluate these drugs.

Z A Kadir

Papers

The new antiepileptic drugs: a systematic review of their efficacy and tolerability.

New antiepileptic drugs: a systematic review of their efficacy and tolerability.

Topiramate for drug-resistant partial epilepsy.

Gabapentin for drug-resistant partial epilepsy.

Clinical administration of new antiepileptic drugs: an overview of safety and efficacy