Primary Objective: To assess whether CYP450 genotype guided dosing of TCAs results in faster attainment of therapeutic plasma concentrations compared to dosing as usual. . Secondary Objectives: * To assess whether genotype guided dosing results in…
ID
Source
Brief title
Condition
- Mood disorders and disturbances NEC
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Primary outcome measure: Time to TCA plasma concentration in the therapeutic
range (primary outcome measure). Blood for plasma concentration measurements
will be taken in the morning, at 12 (+/-) 1 hours after the last evening dose.
When a patient attains a plasma level within the therapeutic range at steady
state, the primary endpoint has been reached (for nortriptyline 0.05*0.15 mg/l;
for clomipramine: 0.15*0.30 mg/l (clomipramine plus desmethylclomipramine) and
for imipramine 0.15-0.25 mg/l (imipramine plus desipramine).
Secondary outcome
a. Reduction of depressive symptoms after 7 weeks of treatment (defined as the
baseline HDRS score minus the HDRS score at the 7 weeks assessment.) rated by a
blinded investigator.
b. Highest level of side effects based on the Antidepressant Side Effect
Checklist (ASE, Uher et al. 2009) and the FIBSER (Frequency, Intensity, and
Burden of Side Effects Rating FIBSER (Wisniewski et al. 2006)) rated by the
patient.
c. Economic Evaluation:
The impact of the intervention on the quality of life of patients will be
assessed both by the EuroQol 5 dimensions with 5 levels (EQ5D5L) and the The
Short Form (36) Health Survey (SF36) at weeks 0, 2,4,6,13 and 26 following
randomization.
Cost analysis: The cost analysis consists of two main parts. First, at
patient level, volumes of care related to MDD and TCA therapy will be measured
by means of the iMTA Medical Consumption Questionnaire. This questionnaire
measures all relevant health care related costs like outpatient visits at any
medical specialist and hospitalizations. In addition the medication use will be
derived from the electronic patient records. Loss of productivity due to
illness or recovery, will be estimated based on patient reported absences from
paid (or unpaid) labour measured with the Productivity Cost Questionnaire.
The second part of the cost analysis consists of determining the cost prices
for each volume of consumption. The standard cost prices from the 'Dutch
Guidelines for Cost Analyses* and www.medicijnkosten.nl will be used. For units
of care where no standard prices are available real costs prices will be
determined on the basis of full cost pricing. Productivity losses will be
valued by means of the friction cost method. In the end volumes of care will be
multiplied with the cost prices for each volume of care to calculate costs.
Background summary
Tricyclic Antidepressants (TCA*s) are the cornerstone of treatment for patients
with severe Major Depressive Disorder (sMDD). Current dosing is guided by
repeated measurements of blood levels. Compared to patients with a normal
metabolization function, for those with increased cytochrome P450 (CYP450)
enzyme activity it takes longer to reach a therapeutic drug level. As a
consequence patients have a prolonged treatment period, increased risk of
suicidal behaviour and eventually lower remission rates. For those with reduced
CYP450 activity higher rates of side effects are expected. An innovative TCA
dosing strategy, taking the genetic variants of the CYP2D6 and CYP2C19 genes
into account may help to reduce the above mentioned problems. Up till now, the
current guidelines for CYP450 pharmacogenetics based TCA dosing have not been
systematically evaluated for effectiveness and cost-effectiveness in larger
groups of patients. Such evaluation is necessary before broad implementation of
these guidelines can be advocated. We hypothesize that for patients with
genotypes reflecting deviant CYP450 enzyme activity, genotype informed dosing
results in faster attainment of therapeutic drug levels, lower rates of side
effects, earlier symptom relief and lower levels of health- and working related
costs
Study objective
Primary Objective:
To assess whether CYP450 genotype guided dosing of TCAs results in faster
attainment of therapeutic plasma concentrations compared to dosing as usual. .
Secondary Objectives:
* To assess whether genotype guided dosing results in lower rates of adverse
effects compared to dosing as usual.
* To assess whether genotype guided dosing results in earlier reductions of
depressive symptoms compared to dosing as usual.
* To assess the value of an early TCA blood level (12 hours after the first
dose) as a potential predictor of time to therapeutic plasma concentration,
treatment response and side effects.
* To explore the contribution of other clinical (psychomotor retardation) and
biological factors (measures of metabolomics) and the changes within these
factors during treatment as predictors of time to therapeutic plasma
concentration, treatment response and side effects.
* To compare the healthcare costs and work related costs of genotype based
dosing to dosing as usual.
Study design
This study is a randomized controlled clinical trial. As we aim to approach
actual clinical practice (which is important for generalisation and
implementation of the results), prescribing physicians will be unblinded for
the CYP2C9 and CYP2D6 genotype and the resulting metabolization phenotype.
Intervention
Using a genetic test, genetic variants that have an impact on the metabolizing
capacity of CYP2D6 and CYP2C19 will be determined. These variants explain
90-95% of the cases with changes in CYP2D6 and CYP2C19 enzyme activity.
Dedicated genotyping assays or copy number variant methods will be used to
detect the genetic variants.
Based on the drug choice (imipramine, nortriptyline or clomipramine) and based
on the latest allele definition tables (see KNMP kennisbank achtergrondteksten)
patients in the intervention group will be classified into a metabolic
phenotype category (PM,IM,EM or UM). Initial TCA dosing of 100 patients will
take place according to the dosing guidelines by the KNMP
(https://kennisbank.knmp.nl). These patients will be compared to 100 matched
patients who will be dosed based on the conventional dosing guideline
(farmacotherapeutisch kompas).
Study burden and risks
There is a low burden for participating patients: 4 extra samples of blood will
be drawn: one for genotyping, two for storage and one for an extra TCA level
determination (12 hrs after the first dose). Extra questionnaires will be
adminisered for cost effectivity analyses. We expect an extra time investment
of about 330 minutes per patient. Risks are minimal. We expect a lower risk for
side effects for participants in the intervention group as the dose will be
adapted to the individual's metabolising capacity. The extra monitoring in all
groups also will increase safety compared to standard psychiatric care.
Reinier Postlaan 6
Nijmegen 6525 GC
NL
Reinier Postlaan 6
Nijmegen 6525 GC
NL
Listed location countries
Age
Inclusion criteria
Patients are in- and outpatients, having a primary diagnosis of severe major
depressive disorder (SCID-I diagnosis in agreement with DSM-5 criteria and a
Hamilton Rating Scale for Depression score * 19 (HRSD-17-item version), aged
18-65 years, who, according to their physician, are eligible for treatment with
a TCA (Nortriptyline (NOR), Clomipramine (CLOMI) or Imipramine (IMI)). The
choice of the specific TCA is at the discretion of the physician in attendance.
Exclusion criteria
(1) Psychotic depression (2) Bipolar I or II disorder. (3) Schizophrenia or
other primary psychotic disorder.(4) Drug or alcohol dependence in the past 3
months. (5) Mental Retardation (IQ < 80). (6) For women: pregnancy or
possibility for pregnancy without adequate contraceptive measures. (7)
Breast-feeding. (8) Serious medical illness affecting the CNS, including but
not restricted to M Parkinson, SLE, brain tumour, CVA. (9) Relevant medical
illness as contra-indication for TCA use, such as recent myocardial infarction.
(10) Other drugs influencing the pharmacokinetics of the TCAs as based on a
list of interacting drugs. In case of psychotropic co-medication only a
benzodiazepine in a dose equivalent up to 4 mg lorazepam will be allowed.
Design
Recruitment
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| ClinicalTrials.gov | NCT03548675 |
| CCMO | NL63514.091.17 |