Clinical Trial Details
— Status: Terminated
Administrative data
| NCT number |
NCT03933007 |
| Other study ID # |
P170409J |
| Secondary ID |
2018-002542-37 |
| Status |
Terminated |
| Phase |
Phase 4
|
| First received |
|
| Last updated |
|
| Start date |
September 10, 2019 |
| Est. completion date |
February 28, 2024 |
Study information
| Verified date |
May 2024 |
| Source |
Assistance Publique - Hôpitaux de Paris |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
Gout, secondary to sodium urate crystal deposition, is responsible of recurrent inflammatory
painful flares. Efficacy of colchicine which is the first line drug for the treatment and
prophylaxis of gout flare varies and only half of treated patients experience good response.
This study aims to optimize colchicine prescription for the treatment and prophylaxis of gout
flare.
Current data suggest that efficiency of colchicine relies on its maximum blood concentration
(Cmax).
In this study, the investigators hypothesize that responders to colchicine treatment have
higher colchicine Cmax than non-responder patients following the recommended dose regimen (1
mg then 0.5 mg 1 hour later).
The individual pharmacokinetics (PK) of colchicine remains poorly investigated while the
assessment of individual drug metabolisms can be performed.
The hypothesis of this study stands that several factors contribute to the variability of
colchicine Cmax. The analysis of individual PK profile and a well-characterized metabolism of
colchicine will permit a personalized treatment regimen for the treatment and prophylaxis of
gout flares.
Description:
Gout flare is driven by interleukin (IL)-1β production and can be treated by colchicine,
NSAID, corticoid or IL-1β blockers (PMID 27457514).
Colchicine is an alkaloid compound that disrupts cytoskeletal functions through inhibition of
microtubule polymerization and consequently interferes with the intracellular assembly of the
inflammasome NLRP3 complex that mediates activation of IL-1β (PMID 16407889).
Efficacy of colchicine treatment in gout flare varies between 37.5 and 64% (PMID 3314832;
20131255). Previous study suggests that colchicine efficiency relies on its blood maximum
concentration (Cmax) (PMID 20131255). However this hypothesis needs to be confirmed.
The hypothesis of this study stands that colchicine Cmax varies with individual colchicine
pharmacokinetics and that this individual variation may explain the variation response of
colchicine treatment.
Absorption of orally administrated colchicine varies between 24 et 88% with an average of
45%. Thus, following oral administration of 1.8 mg colchicine over 1 hour to healthy young
adults, under fasting condition, the colchicine Cmax (mean 6.2 ng/ml) is reached within a
median of 1.8 hours (range 1.0-2.5) (PMID 20131255).
Colchicine is demethylated to two metabolites, 2-O-demethylcolchicine and
3-O-demethylcolchicine (2- and 3-DMC, respectively). In vitro studies have shown that hepatic
cytochrome P450 3A4 (CYP3A4) is involved in the metabolism of colchicine to 2- and 3-DMC.
Colchicine is also a substrate of liver and intestinal P-glycoprotein (P-gp) transporter.
Colchicine is eliminated in urine and stools. 40-65% of orally administrated colchicine is
recovered unchanged in urine. Enterohepatic recirculation and biliary excretion account for
around 50% of colchicine elimination. The mean half-live elimination is 20 to 40 hours.
Thus, blood concentration of colchicine depends on kidney and hepatic functions, intestinal
absorption and secretion, the presence of drug-drug interactions and individual
characteristics of CYP3A4 and P-gp activities (PMID 21480191).
The individual CYP3A4 and P-gp activities can be assessed with specific probe and/or
substrate of these proteins in the so-called phenotyping assay. Thus, using micro dose of
midazolam and fexofenadine the activity of CYP3A4 and P-gp, respectively, can be determined
and subsequently the individual pharmacokinetic profile of colchicine characterized (PMID
24722393).
CYP3A4 activity is given by the ratio of hydroxy-midazolam/midazolam assessed 2 hours after
an oral administration of 1 mg midazolam (PMID 24722393).
P-gp activity is given by the area under the curve (AUC) of a short kinetic that measures
fexofenadine concentrations at 2, 3 and 6 hours after its oral administration of 120 mg (PMID
24722393).
These CYP3A4 and P-gp activities will be correlated with blood colchicine concentrations
determined at different time points after an oral administration of 1.5 mg over 1 hour under
fasting condition.
The CYP3A4 and P-gp phenotyping will be proposed to all gouty patients who experienced gout
flare and who fulfilled the inclusion and exclusion criteria.
Participants will have 3 visits :
- V0: inclusion visit of patients who had untreated gout flare. Signed consent to the
study will be collected and blood analysis performed. A blood collection and biobank of
serum will be done using the blood harvested for gout care. Colchicine will be initiated
at 1.5 mg over 1 hour (1 mg + 0.5 mg)
- V1: treatment efficiency will be assessed 48 h after V0 using Visual Analogue Scale
(VAS) (0-100) pain measurement. Patients who will have an improvement of VAS more than
50% of baseline VAS will be considered as responders to colchicine. In contrast an
improvement less than 50% of baseline VAS will be considered as non-responders. Gout
flare treatment will be adapted according to patient response. Colchicine treatment will
be stopped after gout flare resolution
- V2: this visit will be appointed 1 month after V1 (far enough after resolution of gout
flare). During this visit, the CYP3A4 and P-gp phenotyping will be performed. Patients
will receive colchicine (1.5 mg over 1 hour) and midazolam (1 mg) and fexofenadine (120
mg) orally. A kinetic of blood samples will be harvested with a total of 8 time points
from T0 prior to drug administration to T6 6 hour post-drug administration. At the end
of the phenotyping kinetic, urate-lowering therapy will be introduced according to usual
care and dosage. This visit is the last visit of the protocol and patients will be
followed-up as usual care.
Plasma concentrations of colchicine, midazolam, hydroxymidazolam and fexofenadine will be
quantified by liquid chromatography-tandem mass spectrometry (PMID 24295116).
Plasma concentrations of colchicine will then correlate to CYP3A4 and P-gp activities
estimated by midazolam and fexofenadine metabolism, respectively.
The phenotyping will be performed in 34 colchicine responder and 34 colchicine non-responder
patients.
