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# Evaluation of risk factors for treatment discontinuation in patients on paliperidone palmitate and risperidone microspheres in France, Germany and Belgium | BMC Psychiatry

### Information source

Data was extracted from the IQVIA Longitudinal Prescription (LRx) databases for France, Germany and Belgium and covered approximately 33%, 60% and 25% of all retail pharmacies respectively. The three countries were selected because the data was collected in a similar way. In addition, the three countries are among the countries with the highest number of patients initiated to PP3M as soon as it becomes commercially available in Europe. The databases contain actual prescription collection data from pharmacy records for anonymized patients. Only pharmaceutical products purchased from retail pharmacies are recorded and no data from hospital pharmacies is entered. Retail pharmacy data was then anonymized by a trusted third party before being transferred to IQVIA. Key patient information includes prescribed and dispensed drug, molecule, brand and generic name, manufacturer, form, strength, dose, package size, method of administration, quantity and the date the prescription was issued. Other data includes gender, physician specialty, concomitant medications, prescription cost, and health insurance status. Age was available in the German and French database but not in the Belgian database. Information on patient diagnosis and disease severity was not available. These databases have been used by IQVIA to study persistence issues in schizophrenia [19] as well as in other psychiatric services [21] and subjects of perseverance [22, 23]. A unique patient identifier was used to ensure that patients visiting different pharmacies within the panel were tracked across all three countries. Only data from pharmacies that submitted data monthly were used.

Ethics approval was not required for this research, as only de-identified/anonymized electronic databases were used. It was therefore not necessary to acquire administrative authorizations and/or licenses to access the clinical/personal data used in this research.

### Patient selection

Two inclusion periods were defined (as shown in Figure 1). To ensure that a sufficient number of patients can be followed for 16 months, we defined the first inclusion period between 28 and one month before the marketing of PP3M. The 16 months consisted of a 12-month follow-up and an additional four-month period to avoid artificial cessation (i.e. mischaracterization of censored patients as having quit). The second inclusion period was defined between the month of commercial availability of PP3M and March 2019 (data lock). The duration of the second inclusion period was different in the three countries, as PP3M became commercially available at different times (February 2017 in France, June 2016 in Germany and November 2016 in Belgium). All patients in the second inclusion period were also followed for 12 months.

For the primary objective, patients newly initiated on paliperidone palmitate and risperidone microsphere during the second enrollment period were selected. Newly initiated patients were those who had not purchased the same drug in the 12 months prior to the index treatment. For the secondary objective, “stable” PP3M patients in the second inclusion period and “stable” PP1M patients in the first inclusion period were selected. Stable patients refer to patients who had purchased a minimum number of boxes of the study drug in the six months prior to the index treatment. According to the PP3M label, patients must show stability on PP1M for at least four months before switching to PP3M. To be comparable to PP1M patients, PP3M patients for whom stabilization can be observed were selected. The minimum number of platelets was defined to cover four months of treatment. Additionally, because continuation of treatment with PP1M was artificially impacted following the availability of PP3M—patients being able to stop PP1M simply to switch to PP3M—patients on PP1M before PP3M became available were selected.

The patient inclusion criteria were: (1) had had at least one transaction of any drug in the six months prior to starting the study drugs; (2) had at least two transactions of any drug on two separate dates within 12 months of initiation; (3) 18 years or older at the index date because the study drugs were not indicated for patients under 18 years of age. Age was not available in the Belgian database, so this inclusion criterion was not applied; (4) patients with no missing or unknown values ​​of the studied variables, with the exception of patients with missing age values ​​in Belgium; (5) patients not purchasing two or more LATs simultaneously.

### Continuation of treatment

A patient was considered to be on continuous treatment either until treatment was discontinued or interrupted for a period longer than a predefined allowed interval. The allowed gap is the maximum time (after the previous prescription date) that a patient must be back at the pharmacy to be considered continuing treatment. The allowed deviation was defined as follows:

$$left[mathrm{coverage};mathrm{period};mathrm{of};1;mathrm{unit}right] times left[mathrm{number};mathrm{of};mathrm{units};mathrm{in};mathrm{the};mathrm{last};mathrm{purchase}right]+left[mathrm{grace};mathrm{period}right]$$

(1)

The time to discontinuation of treatment was calculated as follows:

$$begin{array}{c}left[mathrm{Time};mathrm{between};mathrm{initiation};mathrm{and};mathrm{last};mathrm{purchase};mathrm{before};mathrm{treatment};mathrm{stop}right]+left[mathrm{coverage};mathrm{period};mathrm{of};1mathrm{unit}right] times left[mathrm{number};mathrm{of};mathrm{units};mathrm{in};mathrm{the};mathrm{last};mathrm{purchase}right]end{array}$$

(2)

The period of coverage was based on the European Medicines Agency’s Summary of Product Characteristics (SPC). The grace period reflects the additional time allowed beyond the coverage period for deviations from the theoretical prescription frequency. In the base case, the grace period was defined as the coverage period of 1 unit plus 150% of the dosing window to avoid a missed dose. It was calculated so that if a patient buys a unit drug from pharmacies not included in the databases, the patient would still be considered on continuous treatment. The window for administration of risperidone microspheres was not mentioned in the SPC and was set at half that of PP1M. A sensitivity analysis was conducted on all products, applying an equal grace period of 120 days (equivalent to the longest grace period in the base case). Coverage and grace period durations have been summarized in Table 1.

### Data extracted

Among the selected patients, data on gender, any product purchased between six months before and three months after the indexing date, the date of the transactions, the dosage and the specialty of the prescribers of the drugs under study were extracted from the three databases and merged. Age was extracted only from the French and German databases, as it was not available in Belgium.

Previous treatments, ie products purchased six months before the index date, were classified as an index drug; other LATs; oral PA; and no AP. Patients who did not purchase any other APs during the first three months after the index, with the exception of oral risperidone or oral paliperidone, were referred as patients on monotherapy. The other patients were called patients on combination therapy. The recommended monthly dose of the three study drugs was similar according to the SmPC (50 mg). Patients were grouped into patients who received an average dose of 125mg / 30 days. Prescriber specialties were grouped into psychiatrist only, general practitioner (GP) only, psychiatrists and GP and other specialties. In France and Germany, hospital prescriptions issued in pharmacies do not contain information on the specialty of the prescribers. In these cases, the prescriptions were assumed to come from a psychiatrist.

### statistical analyzes

The main objective was to assess the risk factors for stopping treatment in patients newly initiated on paliperidone palmitate and risperidone microspheres.

#### Patient characteristics

Patient characteristics such as sex, age, prior treatment and specialty of prescribers were used as categorical variables and presented as numbers (percentage) for all patients and by country.

#### Discontinuation Risk Factors

Multilevel survival regression using the Cox proportional hazards regression model with mixed effects (frailty model) was used to identify risk factors for treatment discontinuation. Level one variables were gender, age, study drug, prior treatment, number of distinct molecules purchased, dosage, combination therapy, and specialty of prescribers. Country was used as a level two grouping variable. All variables were tested with univariate analyzes and were incorporated into the multivariate analysis when the p-the value was p– value

#### Kaplan Meier analyzes time to discontinuation

To determine the median time from initiation to discontinuation of treatment and the percentage of patients discontinuing study medications during 12-month follow-up, Kaplan Meier survival analyzes were performed. Analyzes were performed by significant risk factors identified from multivariate Cox regression. Sensitivity analyzes of survival analyzes using a different grace period were performed.

For secondary objective – comparison of continuation of treatment between stable patients with PP3M and PP1M.

A similar set of analyzes of patient characteristics and risk factors for treatment discontinuation was performed to compare treatment continuation between patients with PP3M and PP1M. To visualize the difference in time to discontinuation between patients with PP1M and PP3M, a Kaplan Meier survival analysis was performed.

The SAS Statistical Analysis System (SAS for XP PRO, version 9.4 TS2 M3; SAS Institute Inc., Cary, NC, USA) was used to perform the analyses. For all statistical tests, p