Clinical Trial Details
— Status: Withdrawn
Administrative data
| NCT number |
NCT00809692 |
| Other study ID # |
10898 |
| Secondary ID |
|
| Status |
Withdrawn |
| Phase |
N/A
|
| First received |
|
| Last updated |
|
| Start date |
September 2007 |
| Est. completion date |
September 2008 |
Study information
| Verified date |
January 2021 |
| Source |
Children's Mercy Hospital Kansas City |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
A critical first step to address the "pharmacodynamic information gap" in pediatrics resides
with the development of methods capable of accurately measuring the time dependent effects of
xenobiotic exposure in a manner sufficient to enable an integrative analysis of drug action
which incorporates both pharmacokinetic and pharmacogenetic determinants. The proposed study
will evaluate laser Doppler flowimetry, a necessary initial step in developing an "ideal"
pharmacodynamic surrogate endpoint that ultimately could be used in infants, children and
adolescents to fully characterize the impact of development on the pharmacokinetic (PK) /
pharmacodynamic (PD) / pharmacogenetic (PG) determinants of drug effect for agents capable of
modulating the cellular response to histamine.
Description:
The overall goal of this research is to develop and validate non-invasive approaches suitable
for use in pediatrics that are sufficient to directly evaluate genotype-phenotype
associations as determinants of the concentration-effect profile of drugs capable of altering
microvascular function. The specific goal of this project will be to assess whether
microvascular blood flow determined by a previously validated laser Doppler technique can be
used as a reliable surrogate endpoint capable of functionally discriminating the effects of
polymorphisms in the genes which are quantitatively important for histamine
biotransformation. The investigators hypothesize that microvascular blood flow velocity can
be used as a valid surrogate marker to discriminate the functional consequences of allelic
variants in the enzymes primarily responsible for the biotransformation of histamine.
The project includes two parts:
1. Validation of histamine iontophoresis (with measurement of microvascular blood flow by
laser Doppler flowimetry) in a pediatric cohort as a pharmacologic provocation test
capable of reliably characterizing the normal physiologic response of the cutaneous
microvasculature to this xenobiotic addressed by a study in 50 children with a diagnosis
of allergic disease or other "allergic" conditions where treatment with antihistamines
represents the medical "standard of care". Subjects will concomitantly (on contralateral
extremities) receive histamine challenges by the "gold standard" cutaneous prick test
(time dependent response assessed by serial assessment of wheal and flare reactions) and
by a previously described iontophoresis technique (time dependent response by serial
assessment of microvascular blood flow using a validated laser Doppler
technique).Additionally, DNA will be isolated from these subjects for genotyping as
described in part 2).
2. Assessment of microvascular response to histamine challenge as a surrogate marker
capable of functionally discriminating genotype-phenotype associations for
polymorphically expressed genes that are quantitatively important in regulating the
biotransformation and pharmacologic inactivation of histamine addressed first by
genotyping 150 additional subjects who have an established diagnosis of allergic disease
where treatment with antihistamines represents the medical "standard of care". Genotype
data for candidate genes of primary interest, histamine-N-methyltransferase (HNMT) and
diamine oxidase (DAO), will thus be available from a total of 200 subjects. Based upon
known genotype-phenotype associations for HNMT (the enzyme primarily responsible for
histamine biotransformation), two cohorts of subjects will be selected from those
studied using an extreme discordant phenotype approach: subjects predicted, based upon
genotype, to have reduced HMNT activity (i.e., those with 1 or 0 functional alleles) and
subjects predicted to have normal enzyme activity (i.e., those with two functional
alleles). These study participants will then receive a transcutaneous histamine
challenge delivered by iontophoresis, followed by repeated assessment of microvascular
reactivity reflected by time-averaged measurement of blood flow velocity using an
established laser Doppler technique. Statistical analysis of blood flow velocity and
other parameters from the laser Doppler assessment will be used as the primary outcome
measurement for comparison of the two study cohorts with respect to expression of HNMT
and DAO and the functional consequences thereof, using histamine response as the
surrogate assessment of phenotype.
