PDNVF: Developing Individualized Strategies to Prevent Nausea and Vomiting

Sponsor

University of California, San Francisco (Other)

Overall Status

Withdrawn

CT.gov ID

NCT01393288

Collaborator

National Cancer Institute (NCI) (NIH)

Enrollment

Locations

Arms

Duration (Months)

Patients Per Site

Patients Per Site Per Month

Study Details

Study Description

Brief 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.

Condition or Disease	Intervention/Treatment	Phase
Postoperative Nausea and Vomiting Genetic Polymorphisms	Drug: Ondansetron Drug: Lorazepam Drug: Aprepitant	N/A

Study Design

Study Type:

Interventional

Actual Enrollment :

0 participants

Allocation:

Randomized

Intervention Model:

Factorial Assignment

Masking:

Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

Primary Purpose:

Prevention

Official Title:

Developing Individualized Strategies to Prevent Nausea and Vomiting

Study Start Date :

Nov 1, 2013

Primary Completion Date :

Nov 1, 2014

Study Completion Date :

Nov 1, 2015

Arms and Interventions

Arm	Intervention/Treatment
Placebo Comparator: Ondansetron	Drug: Ondansetron 8 mg ondansetron ODT or placebo, 1 hour pre-operatively, before discharge, evening of day of surgery, morning of postoperative day (POD) 1, lunch POD 1, evening POD 1, and morning of POD 2
Placebo Comparator: Lorazepam	Drug: Lorazepam 1 mg Lorazepam or placebo 1 hour preoperatively, before discharge, evening of day of surgery, morning of postoperative day (POD) 1, lunch of POD 1, evening of POD 1, and morning of POD 2.
Placebo Comparator: Aprepitant	Drug: Aprepitant 40 mg Aprepitant or placebo 1 hour preoperatively and before discharge (placebo for postoperative days 1-2)

Arm

Intervention/Treatment

Placebo Comparator: Ondansetron

Drug: Ondansetron

8 mg ondansetron ODT or placebo, 1 hour pre-operatively, before discharge, evening of day of surgery, morning of postoperative day (POD) 1, lunch POD 1, evening POD 1, and morning of POD 2

Placebo Comparator: Lorazepam

Drug: Lorazepam

1 mg Lorazepam or placebo 1 hour preoperatively, before discharge, evening of day of surgery, morning of postoperative day (POD) 1, lunch of POD 1, evening of POD 1, and morning of POD 2.

Placebo Comparator: Aprepitant

Drug: Aprepitant

40 mg Aprepitant or placebo 1 hour preoperatively and before discharge (placebo for postoperative days 1-2)

Outcome Measures

Primary Outcome Measures

Incidence of post-discharge nausea and vomiting (PDNV) [48 hours post-discharge]

Eligibility Criteria

Criteria

Ages Eligible for Study:

21 Years to 70 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

adult (i.e. at least 21 years of age) ambulatory surgery patients, with a duration of 1-4 hours
able to understand, read, and write in English, are ASA physical status 1-3, and are high risk PDNV patients (with 3 or more of the following risk factors:
female gender
age < 50
history of PONV and/or currently prone to motion sickness, and expectation of post-op opioid use).

Exclusion Criteria:

patients not at high risk for PDNV (as described above)
patients <21 years of age
planned inpatient surgical patients
planned total intravenous anesthesia, sedation, or regional technique without inhaled anesthetic
inability to provide informed consent in English
pregnant or breastfeeding
persistent and/or current nausea/vomiting.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of California, San Francisco	San Francisco	California	United States	94115
2	University of Kansas Medical Center	Kansas City	Kansas	United States	66160
3	University of Kentucky Hospital	Lexington	Kentucky	United States	40506
4	Brigham & Women's Hospital	Boston	Massachusetts	United States	02215
5	Cleveland Clinic	Cleveland	Ohio	United States	44195
6	Ohio State University Medical Center	Columbus	Ohio	United States	43210