Study type

Study topic

Human medicinal product

Study type

Non-interventional study

Scope of the study

Effectiveness study (incl. comparative)
Safety study (incl. comparative)

Data collection methods

Secondary use of data
Non-interventional study

Non-interventional study design

Cohort
Study drug and medical condition

Name of medicine

XELJANZ

Study drug International non-proprietary name (INN) or common name

TOFACITINIB CITRATE

Anatomical Therapeutic Chemical (ATC) code

(L04AA29) tofacitinib
tofacitinib

Medical condition to be studied

Colitis ulcerative
Rheumatoid arthritis
Population studied

Short description of the study population

As this study aims to assess the effectiveness and safety of Recombinant Zoster Vaccine (RZV) among patients receiving ongoing treatment with tofacitinib, we will identify current users of tofacitinib rather than new users or initiators as the source population to identify patients with and without RZV vaccine.

A patient will be considered to be a current user of tofacitinib if they have a tofacitinib on-treatment period on or after 20 October 2017. The date of tofacitinib dispensing will serve as the first day of the on-treatment period. The duration of the on-treatment period will be defined by the days’ supply for the dispensing plus a grace period of 30 days to account for non-adherence. A patient will continue to be considered a current user if the time between the
current and subsequent dispensing of tofacitinib is less than or equal to the days’ supply plus 30 days. Otherwise, the on-treatment period will cease at the end of the 30-day grace period, and the patient will no longer be considered a current user of tofacitinib. (It should be noted that discontinuation of tofacitinib is not a censoring criterion. Patients who were previously included in one of the exposure cohorts while they were on-treatment for tofacitinib will continued to be followed if their tofacitinib on-treatment period ends.) If the patient restarts
treatment with tofacitinib (ie, has another on-treatment period) after the end of a previous on-treatment period, the patient may be included in the study if they continue to meet the other eligibility criteria.

If there are consecutive dispensings of tofacitinib with overlapping days’ supply, the duration of the on-treatment period will be the sum of the days’ supply from each dispensing plus 30 days if the dose of tofacitinib is the same for both dispensings, as it is likely that this represents an early refill. However, if the dose of tofacitinib is different for the subsequent dispensing, the end date for the earlier dispensing will be set to the day prior to the
dispensing date of the subsequent dispensing when calculating the duration of the on-treatment period.

Once patients who are current users of tofacitinib on or after 20 October 2017 have been identified, the source population will be restricted to those who are 18 years and older and have a diagnosis of UC or RA on or after 20 October 2016.

Age groups

  • Adult and elderly population (≥18 years)
    • Adults (18 to < 65 years)
Study design details

Study design

This is a non-interventional observational cohort study to evaluate the effectiveness and safety of RZV in real-world patients with ulcerative colitis (UC) or rheumatoid arthritis (RA) receiving ongoing treatment with tofacitinib.

Main study objective

The primary objective for effectiveness in this study is:
To estimate and compare the incidence rate of HZ among patients with UC or RA being treated with tofacitinib who receive two doses of RZV relative to the incidence rate among patients with UC or RA being treated with tofacitinib who do not receive RZV.

The secondary objective for effectiveness in this study is:
To estimate and compare the incidence rate of HZ among patients with UC or RA being
treated with tofacitinib who receive at least one dose of RZV relative to the incidence rate among patients with UC or RA being treated with tofacitinib who do not receive RZV.

The secondary objectives for safety in this study are:
1. To estimate and compare the incidence rate of UC disease flares among patients with UC being treated with tofacitinib who receive at least one dose of RZV relative to the incidence rate among patients with UC being treated with tofacitinib who do not receive RZV.
2. To estimate and compare the incidence rate of RA disease flares among patients with RA being treated with tofacitinib who receive at least one dose of RZV relative to the incidence rate among patients with RA being treated with tofacitinib who do not receive RZV.

Setting

The source population will consist of adult patients 18 years and older treated with tofacitinib with moderately to severely active UC or RA between 20 October 2017 (the date of RZV approval in the US) and 31 July 2023 (or most recent available data at the time the data are extracted). Severity of UC and RA will not be measured directly; rather, it will be assumed based on the indications for tofacitinib treatment.

Comparators

Optum will identify a cohort of patients without exposure to RZV among patients who are current users of
tofacitinib. To minimize the immortal time bias that may be introduced when exposure is defined based on information accrued during follow-up, these patients will be randomly drawn from time-matched vaccination risk sets that are defined as sequential 4-week windows during which they were eligible for inclusion in the RZV cohorts, but without any RZV exposure during the window. Matching within this narrow caliper of calendar time
limits the potential immortal time introduced by using future information (ie, lack of RZV receipt) to classify patients at the time of cohort entry. A cohort entry date will be randomly selected from this time window. In addition, other factors, such as duration of tofacitinib use, will be considered for matching upon feasibility, which will be described in the statistical analysis plan (SAP).

To construct the vaccination risk sets, separate 4-week windows will be created, starting on the study initiation date (20 October 2017) through the end of the study period. Among patients who are current tofacitinib users within a given 4-week window, patients without any RZV exposure who meet the study inclusion criteria and exclusion criteria at the beginning of the 4-week window will be identified. These patients will be eligible to be
sampled as comparator patients for each RZV initiator identified with receipt of a second RZV dose during the same 4-week window.

Up to 2 comparators for each RZV initiator will be selected, matched on data source (the Optum Research Database or the Optum Medicare Advantage and and Medicare Part D Database) and other factors considered upon feasibility. Patients will be sampled with replacement. This process will be repeated for each 4-week window during the study period; as such, it is possible that a patient could be sampled as a comparator multiple times
during the study.

Outcomes

The primary outcome for this study is the occurrence of new herpes zoster (HZ) infection. The secondary outcome for this study is disease flare: UC flare within the UC cohorts and RA flare within the RA cohorts.

Data analysis plan

There will be 4 propensity score models that, separately, will estimate propensity scores that discriminate between (1) receipt of two doses of RZV and non-receipt of RZV in UC cohorts, (2) receipt of two doses of RZV and non-receipt of RZV in RA cohorts, (3) receipt of at least one dose of RZV and non-receipt of RZV in UC cohorts, and (4) receipt of at least one dose of RZV and non-receipt of RZV in RA cohorts. If there are confounders identified that would only be appropriate to include in one model and not the other, separate propensity score models for the outcomes HZ and disease flare will be considered. Once the final models have been generated, propensity scores will be estimated for each patient.