Developing Individualized Strategies to Prevent Nausea and Vomiting
Status:
Withdrawn
Trial end date:
2015-11-01
Target enrollment:
Participant gender:
Summary
Every year, more than 5 million patients in the US experience postoperative nausea and/or
vomiting (PONV) and in the ambulatory setting post-discharge nausea and/or vomiting (PDNV) is
the most common cause for unanticipated hospital re-admissions. Similarly, millions of
patients suffer from chemotherapy induced nausea and/or vomiting (CINV), and one out of five
patients discontinues chemotherapy for this reason. Thus, the control of nausea and vomiting
remains a major health concern for the investigators society. The investigatorsoverall goal
is to further the understanding of nausea and vomiting and optimize antiemetic selection in
order to facilitate individualized patient care.
Unfortunately, current antiemetics reduce the incidence of nausea by only about one third. As
a result, antiemetics are often combined, exposing patients to adverse events and drug
interactions without evidence for the most effective combination. Moreover, it remains
unclear why such a large amount of inter-individual variability exists in antiemetic
responsiveness. 5HT3, NK1, and GABA receptors are targets for some of the most commonly
prescribed anti-emetics. Furthermore, these receptors have many known genetic polymorphisms,
including several linked to incidence of nausea and vomiting. Thus pharmacogenomic variation
may in part explain interindividual differences in treatment responses and will be tested in
this proposal.
Leveraging the established infrastructure of the UCSF Clinical and Translational Science
Institute, and the support of 6 patient recruitment sites, the investigators will enroll 1280
high risk patients to three oral interventions with distinct mechanisms of action for nausea
and vomiting. Investigating nausea and vomiting in ambulatory surgical patients is an
excellent model for this trial owing to a high incidence, short observational period, and the
ability to standardize and control potentially confounding variables. In this proposal, 100%
of patients will receive a single intraoperative dose of 4 mg ondansetron, which is similar
to the 80% of patients who receive prophylaxis in common practice. Using a factorial design,
these patients will be randomized to receive one out of eight possible combinations of the
three interventions (ondansetron, aprepitant, lorazepam) versus placebo (ond+aprep+lora,
ond+aprep, ond+lora, aprep+lora, ond, aprep, lora, or placebo). Thus, in this proposal 87.5%
(7 out of 8 patients) will have antiemetic coverage for the postdischarge period, which is
considerably higher than in common practice, where only 4% of patients have antiemetic
coverage after discharge. The primary endpoint will be the prevention of nausea and vomiting
within 48 hours after ambulatory surgery. The advantage of the factorial trial design is its
high efficiency to systematically investigate multiple interventions while allowing us to
test for potential interactions. It is also an ideal format for the simultaneous assessment
of pharmacogenomic interactions of antiemetics in this proposal.
To this end, the investigators will collect DNA samples and take advantage of the unique
opportunity to investigate the effects of variation in candidate receptor genes in the
context of the three treatment interventions for PDNV. This approach may in part explain
inter-individual differences in drug efficacy and allow for future screening of at-risk
patients. Specifically, the investigators will be assessing single nucleotide polymorphisms
(SNPs) and copy number variants (CNVs) of targeted receptors for the antiemetics tested.
Aim 1: To determine efficacy of three interventions for the prevention of PDNV.
Hypothesis 1.1: Each intervention reduces the incidence of PDNV.
Hypothesis 1.2: Efficacy of all interventions is independent so that efficacy of a
combination can be derived from the efficacy of the individual interventions.
Aim 2: To determine if drug response for anti-emetics is dependent upon genetic variance.
Hypothesis 2: Efficacy of ondansetron, aprepitant and lorazepam to reduce PDNV differs with
5HT3, NK1, and GABA receptor gene variation, respectively.