1.     INTRODUCTION

Chemotherapy-induced nausea and vomiting (CINV) is one of the factors significantly affecting the patient’s Quality of life and reduces compliance to chemotherapy medication. When the antiemetic prophylaxis is not given, the incidence of CINV is as high as 90% with highly emetogenic regimens(HEC) and 30-90% with Moderately Emetogenic regimens (MEC) (1). With extensive research work in this area, control of vomiting is better than nausea control. (2).  Chemotherapy-induced nausea and vomiting are divided mainly into 3 phases: acute phase – on the day of chemotherapy (0-24 hrs), delayed phase (25-120hrs) following chemotherapy, and anticipatory phase. The acute phase is mediated by serotonin through 5-HT3, whereas the delayed phase is due to substance P through NK 1 receptor in the brain (3). Anticipatory nausea/vomiting is due to the conditional-response to previous chemotherapy cycles mediated by various physiological and pathological mechanisms (4). The current guidelines approach CINV prophylaxis and management according to their emetogenic potential (1). The chemotherapy regimens are classified into 4 levels according to their emetogenic potential: Highly emetogenic ->90%, moderately emetogenic -30 % to 90%, low-10% to 30%, minimal-<10% (1). At present, 5-HT 3 receptor antagonists, dexamethasone, NK 1 receptor antagonists are used for the prevention of CINV. The 5HT3 receptor antagonists act both centrally (in the area posterma) and peripherally (in the intestine) to prevent emesis. Currently approved agents in this category are Ondansetron, Palonosetron, Granisetron, Dolasetron (5). Dexamethasone is used as a prophylactic antiemetic, but its exact mechanism is unknown (6). The neurokinin (NK) 1 receptor antagonists currently available are aprepitant, fosaprepitant, netupitant. They generally prevent the delayed phase of CINV (6). Even with the antiemetic prophylaxis still, patients experience nausea and vomiting, especially nausea during cancer chemotherapy. Studies assessing the patient’s Quality of life using the Functional Living Index Emesis (FLIE) questionnaire signifies that CINV had a negative impact on the Quality of life (QOL) of the patient (7). The cost of NK receptor antagonist is also high and creates a cost burden on a patient in a low socioeconomic status (8). So, an alternative cheaper agent is needed. Olanzapine, an atypical antipsychotic, is used as an antiemetic agent through its ability to block the multiple neurotransmitters in the brain such as dopamine, histamine, serotonin, acetylcholine (9). It is recently added to guidelines (National Comprehensive Cancer Network) as one of the components of a four-drug combination to manage the CINV due to highly emetogenic chemotherapeutic agents. Olanzapine (10 mg) is also recommended for use in CINV due to moderately emetogenic agents (1). However, recent studies have suggested using a low dose (5mg) to reduce sedation with the same efficacy in patients undergoing cancer chemotherapy (10). Pregabalin, a gabapentinoid, acts on the alpha 2 delta subunit of the presynaptic calcium channel and inhibits the release of many excitatory neurotransmitters, including substance P, dopamine, serotonin, glutamate and norepinephrine(11). A meta-analysis had shown that pregabalin reduced the incidence of postoperative nausea and vomiting (12). But, there is no evidence suggesting the role of pregabalin in the management of CINV. However, it is observed that gabapentin, which is another gabapentinoid, has shown some efficacy in the reduction of CINV(13). Based on our experience, it has been observed that the combination of add-on pregabalin and olanzapine had a better outcome in the management of CINV compared to other regiments. So, in this study, we have planned to evaluate the interaction effect of pregabalin (75mg) and Olanzapine (5mg) in the management of CINV.

Unmet need and justification for the present study - Olanzapine at a dose of 10 mg can cause unwanted sedation. A recent study has suggested that the dose can be reduced to 5mg without reducing efficacy (28). The standard treatment guidelines recommend using NK 1 receptor antagonist, but it has many drug-drug interactions as they have the property of inhibiting  CYP-3A4 and CYP2C9 enzymes in a dose-dependent manner (24).  Moreover, their cost burden is a significant concern inhibiting their use in patients with low socioeconomic status (8). So the search for an alternative treatment regimen that is cheaper and less CYP interaction is needed. Despite the newer antiemetic regimens, the control of nausea is not optimal. We theoretically consider that there might be a synergism as one drug (pregabalin) will reduce the release of neurotransmitters, and another drug (Olanzapine) will block the action of the released neurotransmitters. However, there is no clinical trial which has evaluated the interaction effect of pregabalin and olanzapine in the management of CINV. So in this study, we will check the role of pregabalin (75 mg), olanzapine and  combination of Olanzapine (5mg) and pregabalin (75mg) (interaction effect) in the management the CINV

1.     MATERIALS AND METHODS

Study design 

A Factorial 2*2 double-blinded, add-on placebo-controlled clinical trial.

Study site

Department of Pharmacology and Radiotherapy of AIIMS, Bhubaneshwar.

Participants

Patients above 18 years old of either sex diagnosed with any malignancy who were planned to receive the first or repeated cycle of the drug regimen containing highly emetogenic chemotherapeutic agents. (cisplatin-based regimen or anthracycline + cyclophosphamide based regimen).

Study groups

a)     Add-on pregabalin (75 mg per day )

b)    Add-on olanzapine (5 mg/day)

c)     Add-on pregabalin (75 mg per day) and olanzapine (5 mg/day)

d)    Add-on placebo group.

Sample size calculation

We calculated sample size by using Web power statistical power online tool (38) (https://webpower.psychstat.org/models/means04/) based on the mean VAS score for olanzapine and pregabalin combination group as 2, olanzapine alone as 3, pregabalin alone as 5.5, and the placebo group as 8 with a common variance of 1.5. The alpha error assumed is 0.5. A total sample size of 104 equally distributed among the four groups(each group 26) will be powered at 80% to achieve our objective to determine the interaction effect between olanzapine and pregabalin.

Randomisation

In this factorial design, the subjects will be allocated randomly to one of the four-arm by simple randomization technique, and followed for the response of VAS score in nausea.

Blinding & Allocation concealment

This study is a  double-blinded randomised clinical trial. Blinding will be maintained by using a similar-looking placebo. The assessor will be blinded regarding the groups of Allocation of the participant. The assessor will not be involved in the analysis of data and interpretation of results. Allocation concealment will be done by allotting numbers to the randomisation chart generated. These numbers will be labelled on the drug containers.

Participant recruitment

            Once the participant who is planned for highly emetogenic cancer chemotherapy consents for the study, an assessment of eligibility will be done by

·       History and physical examination

·       ECOG performance status

·       Liver & renal function tests and serum electrolytes

Administration of Treatment

After checking for the eligibility criteria, the baseline "nausea and vomiting" questionnaire is filled. Based on the allocation, either two starch-filled placebo capsules or two capsules of pregabalin 75mg and olanzapine 5mg or a capsule of pregabalin 75mg and starch-filled placebo capsules, or a capsule containing Olanzapine 5mg and a starched filled capsule along with the standard of care ondansetron 8 mg and dexamethasone 8 mg will be given to the participant one hour before the administration of chemotherapeutic agents. The participants will be given three more capsules of each drug or starched fille placebo and instructed to take them daily (one capsule per day) for next three days before going to bed.

Assessment of outcomes

After 24 hours, the patient will be contacted over the phone and enquired about the nausea severity (VAS score) and vomiting episodes. This process will be repeated for four more days. At the end of the 5^th day, the patient will be asked to visit the Department of Pharmacology to evaluate the compliance and administer the FLIE questionnaire to assess the effect of the intervention on patient Quality of life.

Assessment of Adverse event

The participant will be asked for the occurrence of an adverse event with a non-leading question initially. It will be followed with leading questions to assess the specific adverse events pertaining to the experimental drugs as follows. Undesired sedation and increased appetite will be assessed daily in terms of VAS scoring.   Any disturbance in vision.

Statistical analysis

 The statistical analysis will be done using R 4.1. The continuous data like VAS score, age, etc., will be expressed as mean (SD). The categorical variables like presence or absence of nausea/vomiting, sex, etc., will be represented as proportions.

For interaction analysis, a linear regression technique with interaction effect of grouping variables will be used to analyze the interaction between pregabalin and olanzapine. The dependent variable will be VAS score (either cumulative or individual day). The VAS score in the group that received a combination of Olanzapine and pregabalin will be compared with the groups that didn’t receive combination treatment (a group that received placebo alone, pregabalin alone and Olanzapine alone) by ANOVA test with post hoc analysis or Kruskal wallis test with post hoc test. The VAS score in groups that received the olanzapine (which include the group that received Olanzapine alone and a group that received the combination of Olanzapine + pregabalin )  will compared with groups that did not receive the Olanzapine (a group that received the placebo and pregabalin alone ), same for VAS score difference in the group that received pregabalin (which includes groups that received pregabalin alone and a group that received the combination of Olanzapine + pregabalin ) with the groups that did not receive the pregabalin using t -test.

For secondary outcome measurement, the response rate in proportion between groups will be compared as compared for the categorical outcome using chi-square test.

The VAS scores for nausea and vomiting over five days will be assessed using mixed-effect models for longitudinal data. Both intention-to-treat analysis and per-protocol analysis will be performed along with the sensitivity analysis for the primary outcome. Replacement of the missing values will be dealt with using multiple imputation techniques or an expectation-maximisation algorithm. Adverse events analysis will be performed using chi-square analysis.

Ethical Consideration

The study will be done as per the National ethical guidelines for biomedical and health research involving human participants established by ICMR in 2017. The declaration of Helsinki will also be followed in our study. The benefits and harms of participating in the research and the freedom to withdraw from the study at any moment will be explained to participants. From each participant, a full voluntary written informed consent will be obtained. The recruitment of study subjects will be done after obtaining written permission from the IEC (Institutional Ethics Committee). The study will be registered in the Clinical trial registry of India.