Real-world assessment of treatment with extended-release topiramate (Trokendi XR^®) and comparison with previous immediate-release topiramate treatment

The protocol for this retrospective, multisite medical chart review was approved by a central IRB (Sterling Institutional Review Board, Atlanta, GA, USA). Recruitment letters were sent to Trokendi XR prescribers identified from purchased prescriber data (Symphony Health Solutions, Conshohocken, PA, USA). Participating physicians received an administrative fee for providing randomly selected medical charts of patients meeting inclusion criteria. The target sample size in this pilot study was 500 patients treated with Trokendi XR for any indication for which FDA had approved a topiramate-containing product – i.e., epilepsy, migraine, obesity. This sample size was expected to produce cohorts of at least 100 patients per therapeutic use.

Patient/medical chart inclusion criteria were patient age ≥6 years at the first Trokendi XR prescription (defined as the index date), index date between 1 August 2013 and 30 June 2014, a visit record documenting initiation of Trokendi XR therapy, and at least one post-initiation visit. For eligible patients, data were extracted from the complete medical chart (progress notes, visit information, laboratory reports, hospital visit information, medication lists). Experienced clinical research nurses abstracted medical charts; data extraction methods were HIPAA-compliant. Data were captured using a standardized optical character recognition collection form; all collected information was de-identified to ensure patient confidentiality. Trained nurse abstractors underwent an inter-rater reliability assessment and were required to score at least 90% to continue abstracting. Data abstraction forms were reviewed, verified, and committed to a final database. Descriptive statistics were used to analyze data for cohorts defined by the disorder being treated with Trokendi XR (epilepsy, migraine, obesity). Patients prescribed Trokendi XR to treat both epilepsy and migraine were assigned to the Epilepsy cohort; patients in whom Trokendi XR was used to treat migraine and obesity simultaneously were assigned to the Migraine cohort. Data abstraction for all patients included patient age and gender, date of initial Trokendi XR prescription (index date), date of Trokendi XR discontinuation (if applicable), Trokendi XR dosage (most recent), and TEAEs attributed to Trokendi XR. Information on previous and concomitant medication (including TPM-IR) use was also collected. Migraine and seizure data were abstracted.

Persistence rates were determined for records in which Trokendi XR treatment status was known (continuing at the last visit or discontinued). Duration of Trokendi XR treatment in the Epilepsy and Migraine cohorts was calculated from the index data to the stop date (if a patient discontinued) or date of the last visit with documentation of continuing Trokendi XR treatment.

Although the planned analysis for estimating response to Trokendi XR in epilepsy was the change from pre-index monthly seizure frequency, most charts did not provide sufficient information to determine monthly seizure frequency. The treatment effect in the Epilepsy cohort was therefore estimated as the change in proportion of patients who reported seizures (yes/no) in the first post-index interval versus interval before index visit. Mean monthly (28 day) migraine frequency was calculated for each patient with evaluable data. Median change from pre-index migraine frequency was analyzed by McNemar's test. A separate analysis limited to patients with evaluable migraine frequency at both pre- and post-index visits determined median percent change in mean monthly migraine frequency (patients with 0 preindex migraines were excluded from the analysis):

Median percent change from pre-index migraine frequency was analyzed with Wilcoxon signed rank test.

TEAEs were defined as AEs that started or worsened after the index visit and were attributable to Trokendi XR. Incidences of TEAE were determined for patients overall and separately for treatment cohorts (Epilepsy, Migraine, Obesity) to examine potential differences based on target disorder. The incidence of ‘any cognitive symptom’ was the proportion of patients reporting one or more cognitive symptoms (e.g., word-finding difficulty, slowed thinking/speech, memory problems, concentration/attention difficulty).

For a post-hoc comparison of TPM-IR and Trokendi XR, the final database was searched for records with a documented history of previous treatment with TPM-IR (Topamax or generic) which ended before or simultaneously with the initiation of Trokendi XR therapy. The primary analysis of interest was TEAE occurrence during Trokendi XR versus previous TPM-IR treatment. Changes in seizure and migraine occurrence associated with Trokendi XR treatment were also determined as exploratory analyses.

This pilot study was the first evaluation of Trokendi XR use in real-world clinical practice. In this patient sample, Trokendi XR was used most commonly for migraine prevention and exhibited the treatment effects and types of TEAEs expected of topiramate. Trokendi XR was associated with a significantly lower incidence of TEAEs versus previous TPM-IR, largely due to the markedly lower incidence of cognitive symptoms and paresthesia with Trokendi XR.

The finding that Trokendi XR was used most commonly in migraine patients was not unexpected since topiramate is the most commonly prescribed migraine preventive in the USA [9,27] The Migraine cohort appeared to be a difficult-to-treat population with a high disease burden as demonstrated by chronic migraine as the most common diagnosis, previous use of migraine preventives, and proportion of patients in whom Trokendi XR was added to another migraine preventive.

Population characteristics were consistent with labeling for topiramate formulations, i.e., children and adults in Epilepsy cohort, adolescents and adults in the Migraine cohort, adults only in the Obesity cohort. Trokendi XR use was skewed toward females across all cohorts, particularly in the Migraine and Obesity cohorts*. In the Migraine cohort, the gender bias reflects, in large part, the higher prevalence of migraine, especially chronic migraine and migraine without aura, in females [28–30]. The gender distribution in the obesity cohort is consistent with a study of national prescription databases showing that 85% of patients prescribed antiobesity drugs are females [31]. The high comorbidity of depression, anxiety, and sleep problems with migraine and comorbidity of depression and migraine with epilepsy in this sample mirror rates reported in epidemiologic studies [32–35].

It is presumed that q.d. Trokendi XR and b.i.d. TPM-IR would exhibit equivalent efficacy if compared in randomized controlled trials since the two formulations have been shown to be bioequivalent at steady state [24]. In this evaluation of real-world treatment effects, initiation of Trokendi XR in the Migraine cohort was associated with a clinically significant response (≥50% reduction in mean monthly migraine frequency) in 55% of patients, with 100% reduction in 24% of patients. In randomized, placebo-controlled trials of b.i.d. TPM-IR, 50% response rates ranged from 22 (chronic migraine) [36] to 49% (episodic migraine) [37], with 6% of patients with episodic migraine experiencing 100% reduction [37].

Our analysis found that nearly two-thirds of patients were continuing Trokendi XR therapy at the last visit and half (49%) had persisted with Trokendi XR for at least 6 months, the minimum recommended duration for migraine prophylaxis [38]. The 6-month persistence rate with TPM-IR has been ≤40% with TPM-IR in medical and pharmacy administrative claims [27,39,40].

Weight data were not collected for an analysis of effectiveness in the Obesity cohort since topiramate is only FDA-approved for weight management based on weight loss in combination with phentermine. In the Epilepsy cohort, the initiation of Trokendi XR was associated with a substantial reduction in the proportion of patients reporting seizures. Persistence rates in the Obesity and Epilepsy cohorts suggest that 75–80% had a treatment response that merited continued treatment with Trokendi XR.

Because the primary impediment to an adequate trial of TPM-IR has historically been TEAEs, notably cognitive symptoms, TEAE occurrence with Trokendi XR was of particular interest in this study. In our primary analysis, the overall incidence of TEAEs was relatively low (<25%); cognitive symptoms or paresthesia were reported in ≤5% of patients. Migraineurs accounted for a disproportionate share of TEAEs overall, with more than 80% of cognitive symptoms and paresthesia reported by the Migraine cohort.

The 192 medical charts with information on patients’ history of previous TPM-IR treatment provided a relatively large sample for a post-hoc, exploratory test of the hypothesis that Trokendi XR would be better tolerated than TPM-IR. In this patient subset, incidences of TEAEs overall, cognitive symptoms and paresthesia were significantly lower during Trokendi XR versus previous TPM-IR treatment. Compared with non-migraine patients, migraineurs were markedly more susceptible to TEAEs with TPM-IR, accounting for 90% of cognitive symptom occurrences, for example. Migraine patients garnered the greatest benefit in terms of improved tolerability with Trokendi XR. The significant tolerability benefit of Trokendi XR versus previous TPM-IR treatment could not be attributed to dosage differences.

Although q.d. dosing of Trokendi XR would be expected to have a favorable influence on efficacy versus b.i.d. TPM-IR, the difference between Trokendi XR and previous TPM-IR treatment may have been magnified due to an inadequate trial of TPM-IR therapy. Side effects, which typically emerge during the initiation/titration of topiramate therapy [41], were the most common reason for TPM-IR discontinuation. Patients may therefore not have achieved maximal therapeutic effect before TPM-IR was discontinued.

Retrospective chart reviews have well-recognized limitations, including incomplete documentation, ambiguous and contradictory information, and variability in the information recorded by different healthcare providers. For methodological rigor, the study reported here used ‘best practices’ [42] – for example, carefully designed abstraction tool and coding manual; decision-making rules for ambiguous information and missing data; trained nurse abstractors; and inter-rater reliability assessments. For this pilot study, analyses did not impute missing seizure or migraine frequency data, which could lead to biased estimates of treatment effect, particularly in the smaller and more selected subset of patients previously treated with TPM-IR. Compared with randomized controlled trials, chart reviews may underestimate TEAE occurrence since TEAEs are most likely to be recorded when they are considered drug-related and required intervention, counseling, and/or follow-up. However, the tolerability of TPM-IR and Trokendi XR were compared within a subset of patients treated with both drugs under the same circumstances by the same clinicians, thereby minimizing the bias of TEAE under-reporting. Persistence with Trokendi XR therapy was based on prescriptions recorded in patient charts but subsequent adherence in terms of prescription fills and dosing instructions could not be analyzed due to the lack of relevant documentation in patient charts.

Observations from this chart review are supported by results of studies showing migraineurs’ greater susceptibility to topiramate-associated side effects, (e.g., cognitive symptoms and paresthesia) versus non-migraine patients treated with markedly higher TPM-IR dosages [11,12]; significantly less negative impact of Trokendi XR versus TPM-IR on an objective measure of verbal fluency in healthy volunteers [26]; and improved verbal fluency scores and increased patient satisfaction with topiramate therapy in chronic migraine patients switched from b.i.d. TPM-IR to q.d. Trokendi XR [43]. In addition, a pilot study analyzing medical and pharmacy claims comparing adherence and persistence patterns in parallel groups of patients treated with Trokendi XR or TPM-IR found a significant difference favoring Trokendi XR [44]. Prospective studies and larger datasets are needed to confirm these signals suggesting a more favorable profile of q.d. Trokendi XR versus b.i.d. TPM-IR.

Our data document the utility of Trokendi XR in the diverse patient populations encountered in clinical practice. The subset analysis supported the potential for better tolerability of Trokendi XR versus TPM-IR, particularly in migraineurs, which may have clinical implications in terms of overall treatment effectiveness, persistence and disease burden. Use of topiramate as the most commonly prescribed migraine preventive is based on a large body of evidence documenting its efficacy, a safety profile from more than 20 years’ clinical experience, and its more favorable weight profile versus other migraine preventives. Findings from this pilot study raise important considerations regarding the role of q.d. Trokendi XR relative to b.i.d. TPM-IR for which generics are available. An analysis of medical and pharmacy claims data for patients initiating migraine prophylaxis (TPM-IR, β blockers, tricyclic antidepressants) showed that patients who discontinued their first preventive were unlikely to restart therapy, add, or switch to alternative preventives during the 1-year observation period [27]. The fact that the majority of discontinuations occurred within the first 90 days points to intolerable side effects as a likely contributor to early drug failure. Because the experience of drug failure risks eroding patient confidence and contributing to disillusionment with therapy, the first trial of migraine prophylaxis is especially critical to patient acceptance of prophylaxis as an effective strategy for managing migraine headaches. Based on the evidence, albeit preliminary, that q.d. Trokendi XR is better tolerated than b.i.d. TPM-IR and may be more effective in promoting adherence/persistence with treatment, migraine patients who are candidates for Trokendi XR treatment include those who have previously failed TPM-IR or another migraine preventive. However, Trokendi XR candidates should also include those in whom migraine prophylaxis is being initiated since Trokendi XR may produce a more favorable trajectory for migraine preventive therapy.

*Use of any topiramate formulation in women should take into consideration evidence that topiramate exposure during pregnancy increases the risk of cleft lip and/or palate and infants small for gestational age.

The study was conducted by Indegene Total Therapeutic Management under a research contact with Supernus Pharmaceuticals, Inc., Rockville, MD, USA. All authors participated in the study design and execution; data collection, analysis and interpretation and manuscript preparation and review. W O'Neal, EE Hur and T Liranso are employees of Supernus Pharmaceuticals, Inc. B Patel was an employee of Indegene Total Therapeutic Management at the time of the study. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Editorial assistance was provided by V Ilacqua of ID&A and was funded by Supernus Pharmaceuticals Inc.

All data used in this study were de-identified, pre-existing, and retrospective. Informed consent was not required of patients.

This work is licensed under the Attribution-NonCommercial-NoDerivatives 4.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/4.0/