The aim of this study is to investigate the use of cobicistat to reduce the required dose and dose frequency of tofacitinib in the treatment of RA.
ID
Source
Brief title
Condition
- Autoimmune disorders
- Joint disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
To investigate the bioequivalence of tofacitinib 5mg and cobicistat 150 mg QD
(intervention) compared to tofacitinib 5mg BID alone (control) with regard to
the relevant steady state pharmacokinetic parameters (average concentration at
steady state (Cavg,ss )/Area Under the Curve (AUC0-24), as defined by a 90%
confidence interval of the geometric mean ratio falling entirely between 75%
and 125%.
Secondary outcome
* To construct a mechanistic population pharmacokinetic model describing the
quantitative effect of cobicistat on tofacitinib pharmacokinetics;
* To describe the relevant pharmacokinetic parameters (Cavg,ss, AUC0-24,
Cmax,ss, tmax,ss, Ctrough and t1/2) after administration of tofacitinib 5mg and
cobicistat 150 mg QD compared to tofacitinib 5mg BID alone;
* To evaluate the safety and tolerability of tofacitinib 5mg and cobicistat 150
mg QD compared to tofacitinib 5mg BID alone;
* To provide a suitable dosing scheme of tofacitinib and cobicistat for a
future clinical non-inferiority study, based on the developed pharmacokinetic
model, in case tofacitinib 5mg and cobicistat 150 mg QD is not equivalent to
tofacitinib 5mg BID alone in this study;
* To evaluate the efficacy of both regimes by DAS28-CRP;
* To establish which regimen is preferred by patients based on medication QD or
BID.
Background summary
Tofacitinib is a relatively new drug for treatment of rheumatoid arthritis (RA)
and psoriatic arthritis (PsA), which appears to have at least similar efficacy
and safety as currently available biological disease modifying anti-rheumatic
drugs (bDMARD), though it has directly been compared to adalimumab only. As the
yearly costs per patient of tofacitinib treatment at the 5mg BID dose are
significant (approximately ¤12,000 per patient per year), interventions that
might reduce this cost are of interest in order to keep health care costs in
control.
Because tofacitinib is mainly metabolized by CYP3A4, the manufacturer
recommends halving the dose of tofacitinib from 5mg BID to 5mg QD in patients
using concomitant medication which strongly inhibits CYP3A4 in order to
maintain a similar drug concentration and safety. This creates the opportunity
to halve the required dose (and thus cost) of tofacitinib, by deliberately
adding a CYP3A4 inhibitor to tofacitinib treatment. One such CYP3A4 inhibitor
is cobicistat, which is already registered as a pharmacokinetic enhancer (or
booster) in the EU and used for this purpose in human immunodeficiency virus
(HIV) treatment without significant adverse events.
Besides the obvious benefit of lower costs, halving the dose may also improve
medication adherence as only one dose per day is required (versus BID without a
booster) and medication adherence is negatively associated with dosing
frequency. Furthermore, CYP3A4 inhibition will lead to more predictable
pharmacokinetics of tofacitinib as natural variation in CYP3A4 activity is
reduced. This has the potential for an improved safety/efficacy ratio.
Study objective
The aim of this study is to investigate the use of cobicistat to reduce the
required dose and dose frequency of tofacitinib in the treatment of RA.
Study design
We will perform an open-label, within-subject sequential trial of tofacitinib
where patients meeting eligibility criteria receiving tofacitinib 5mg BID will
switch to the combination of tofacitinib 5mg combined with cobicistat 150mg QD
during 2 -6 weeks.
Intervention
Reference treatment
All patients are using the conventional dose of tofacitinib which is
tofacitinib 5mg BID orally.
Intervention treatment
For 2-6 weeks, patients will switch to tofacitinib 5mg orally together with
150mg cobicistat orally QD.
Study burden and risks
The risks associated with this study are limited. It is plausible and in
accorcance with the SPC that the dosage of tofacitinib can be reduced when its
metabolization is inhibited by cobicistat. Possible risks are adverse effects
related cobicistat treatment and possible interactions with other medications.
The burden for patients participating in this study is mainly time-investment
associated with the study visits and the number of blood samples.
Geert Grooteplein 10 864
Nijmegen 6525 GA
NL
Geert Grooteplein 10 864
Nijmegen 6525 GA
NL
Listed location countries
Age
Inclusion criteria
* Rheumatoid arthritis (either 2010 ACR RA and/or 1987 RA criteria and/or
clinical diagnosis of the treating rheumatologist, fulfilled at any time point
between start of the disease and inclusion) or Psoriatic arthritis (either
Classification Criteria for Psoriatic Arthritis (CASPAR) and/or diagnosed with
peripheral SpA of the psoriatic arthritis subtype by a rheumatologist)
* Patients using tofacitinib for * 2 weeks in the standard dose of 5mg BID.
* Patient informed consent, *18 years old and mentally competent
* Ability to measure the outcome of the study in this patient (e.g. patient
availability; willing and being able to undergo repeated serum samples)
* Ability to read and communicate well in Dutch
Exclusion criteria
* Concomitant use of inducers or potent inhibitors of CYP3A4 or moderate
inhibitors of CYP3A4 and potent inhibitors of CYP2C19, or medication sensitive
to changes in metabolism as a result of cobicistat co-treatment, as assessed
with the KNMP *G-standaard* unless an alternative is listed in Table 1.
* Known contra-indications for treatment with cobicistat in line with the
summary of product characteristics
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2018-000766-11-NL |
| CCMO | NL65634.091.18 |
| Other | NL7766 |
| OMON | NL-OMON26019 |