Developing Individualized Strategies to Prevent Nausea and Vomiting

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.