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The human papilloma virus is a major cause of human malignancies especially cervical cancer in women. Within the American population, HPV types 16 and 18 have been implicated in over 80% of cervical cancer cases. In fact, cervical intraepithelial neoplasia has been ranked the 14th most frequent type of cancer in the US while it is the 3rd most common cause of death among all cancer types. Previously, HPV vaccine has been designed and approved for use in younger women without considering the health benefits the vaccine could have in women older than 27 years. This study determines the efficacy of HPV quadrivalent vaccine, Gardasil in reducing the prevalence of cervical cancer by reducing the rate of infection. In the study, a randomized control trial design will be employed with the study involving a total of 2000 study subjects; half receiving the intervention agent (qHPV vaccine), and the remaining half, the placebo (physiological saline). The anticipated outcome in the two year study commencing February 2015 through to March 2017 will be a decrease in the number of new infections with HPV women older than 27 years following vaccination with qHPV vaccine. The results will be used to design a better intervention program to facilitate mass vaccination to aid in lowering the spread of HPV and the associated cancers, especially cervical cancer.
Background and Rationale
The human papilloma virus is the causative agent of various viral human warts and cancers with HPV types 16, 18, 31, 33 and 45 being the primary cause of cervical intraepithelial neoplasia (CIN) and associated genital warts . HPV is a virus that is predominantly transmitted through sexual contact with infected partners. According to reports by center for disease control and prevention , males and females are susceptible to infection by over 40 HPV types. In addition to infection on the genitals, HPV has been shown to infect other body organs especially the mouth and throat. While most victims seldom notice HPV infection, the virus is majorly transmitted via oral, vaginal, or anal sexual contact . The CDC report of 2004 has identified different cancer types associated with HPV, considering majority of cervical cancers being caused by HPV infection of which HPV types 16 and 18 account for over 80% of the cases, while HPV infections are implicated in approximately 50% of vulval cancers . Penile cancer, vaginal cancer, esophageal cancer, and anal cancer are other cancers of which HPV is largely implicated .
With respect to reports by the National Institute of Health (2010), cervical cancer is the most widespread type of cancer, which is categorized as 14th in terms of frequency among the women in United States. The same report points at a mortality rate reflecting over 300,000 death annually due to cervical cancer, with cervical cancer being classified as the third most prevalent of all cancers affecting women . Projections on the prevalence of HPV infections and cervical cancer incidence in developing countries show higher morbidity and mortality rates.
Several diagnostic approaches have been designed to detect precancerous and cancerous lesions, of which detection of precancerous lesions with Pap smears allows for early treatment before progression to cancerous states [3; 4]. According to Winer et al., (2003), precancerous lesions may be treatable but women aged between 25 and 40 years are prone to re-infection with HPV due to their increased sexual activity. Despite the decrease in the number of cervical cancer cases in the last four decades, women are Even if the numbers of cervical cancer have decreased in the last 40 years, active women are predisposed at a higher risk of acquiring the tumor viruses, and hence cervical cancer . Approximately 12,000 women report HPV-related cervical cancer every year in the US , while NIH (2010) report higher incidences of cervical cancer, and associated mortality rates within some American populations based on the accessibility of cervical cancer screening services.
Currently, there is a limitation of available data relating to the prospective risks of detecting CIN and/or precancerous cervical lesions within the US population. Moreover, the previous studies on the subject are age-limited bringing in the concept of age limiting in the design of HPV vaccine considering that by the time majority of women are aged 26 years, exposure to HPV infection may have occurred. Previously, the HPV vaccine was designed to be age-limited based on the fact that majority of scientists has insufficiently tested the efficacy of the vaccine amongst the older women population prior to its approval . In the recent past, the Food and Drug Administration has shown negation to the expansion of use of HPV vaccine in women older than 26 years. The conclusion of this study will enumerate the effectiveness of HPV vaccines among women older than the current age threshold to mitigate the incidence of cervical cancer in women older than 27 years of age.
The study aims at determining the effectiveness of HPV vaccine to reduce the incidence of cervical cancer among females 27 years of age or older who are HPV negative at baseline
The study will be geared towards answering the question: what is the effectiveness of the HPV vaccine in reducing the incidence of cervical cancer in women aged 27 years or older?
The study subjects who will receive the HPV vaccine will have a significantly lower incidence of cervical cancer than subjects who will not receive the vaccine.
To determine the effectiveness of HPV vaccine in reducing the incidence of cervical cancer among females 27 years of age or older who are HPV negative at baseline.
The study population for this study will encompass women aged 27 years or more, who are negative of HPV infection at baseline to evaluate the efficacy of HPV vaccine in reducing the prevalence of cervical cancer in women within the American population. Previous studies, such as the FUTURE II Study Group (2007), studies the efficacy of the same vaccine but within a different study population targeting women aged between 16 and 26 years.
The study will follow a quantitative study design of which the study participants will be randomized in the double-blind placebo controlled clinical trial. The intervention group will be treated with the quadrivalent HPV vaccine, the Gardasil, which is effective against HPV types 6, 11, 16, and 18 (Gardasil & Merck). On the other hand, the control group will receive physiological saline. The study will run for a period of 24 months commencing in February 2015 through to March 2017.
During the selection of study subjects, the previous criterion  will be used, where inclusion will be based on computer generated sequences to facilitate randomization. Cervical screening and enrollment will be performed at two study sites including Prince George's Community Hospital and the INOVA Fairfax Hospitalinto. The inclusion criteria will be all women aged above 27 years of age, who will give informed consent, while they meet the requirement of being negative of HPV infection during the screening. The exclusion criteria will be women below 27 years of age, women who test positive of HPV infection irrespective of age limit, and all women who do not give informed consent of participation.
During the study the ration of the intervention vaccine to the placebo will be 1: 1 administered via parallel assignment in order to maintain the blinding. In addition to that, the placebo and vaccine will be concealed through the pharmaceutical company, so that the investigators will receive two identical syringes, one containing Gardasil, and the other physiological saline. In the study, 3 doses of either the intervention vaccine (Gardasil) or placebo (physiological saline) will be administered to the study subjects with respect to the group each participant is assigned. Parenteral administration will be through an intramuscular injection into the deltoid region of the non-dominant arm in line with a 0, 1 and 6 months schedule . The study will follow a randomized clinical trial design because the design minimizes selection bias through randomization of the participants, and educe generalized results among the study population of women aged 27 year age or older. RCTs are also known to reduce spurious casualties in the course of the study .
The study will encompass 2000 study participants, all of which will be randomized and double-blinded during the selection and during the administration of the intervention and placebo. Within this group, 1000 subjects will be exposed to the intervention vaccine, while the remaining 1000 subjects will receive the placebo, forming the control group. Another important inclusion factor is women with intact cervixes.
Specifically, the inclusion criteria will include women aged 27 years or older. This is as opposed to the age limit criteria used by Winer et al. (2003), who used women aged between 18 and 20 years with a smaller sample size. The large sample size increases the degree of representativeness, as is depicted in a RCT study by Vicus, Sutradhar, Lu, Elit, Kupets and Paszat (2014) , who involved 11546 participants. In addition to age as an inclusion factor, the women living in either Fairfax and/or Montgomery counties will be included in the study as a measure to lower commuting expenses. Sexually active women with only one partner will also be included in the study, as will be women who had never received HPV vaccine before. Moreover, women with a negative Pap smear will be included. Women with incompetent cervixes will also be excluded in the study.
Although the women will be required to undergo pregnancy tests estimating hCGH in the urine, postmenopausal women will not be subjected to the pregnancy test. Sexually active women will be required to remain negative of pregnancy by abstaining from sexual contact or using effective contraception before receiving the first dose of the study intervention agent. In addition, the included study subjects will be required to remain not pregnant for at least two months following the completion of the three doses. Lastly, it is following an informed consent from each participating study subject that the study will commence.
Treatments to Compare
As defined by the study design, the study will follow a randomized control trial design of which there will be an intervention group, and a control or placebo group. The treatments include the qHPV vaccine, Gardasil, which will be considered the intervention vaccine, and physiological saline, which will be considered the placebo. The frequency of administration will be as per the schedule of a 0, 1 and 6 months schedule, followed by a patient follow up. The study agents will be administered parenterally via intramuscular injection on the deltoid region of the non-active arm. Of the 2000 study subjects, half will form the intervention group, while the other half will form the control group to receive the placebo.
In the course of the study, the primary endpoints will be determined following assessment of cervical tissues using Pap smear. The 2001 Bethesda System will be employed for determination of vaginal and/or cervical cytological characteristics. Serological and histological samples will be collected prior to, and/or 6 months and 12 months after administration of the intervention doses.
As with the study by Vicus et al., (2014), which used 1052 study subjects, this study will encompass a total of 2000 participants aged 27 years or older, where half will receive the intervention vaccine, and the remaining half will receive the placebo as a control group. This large sample size is meant to bring in better representativeness of the population understudy in order to make conclusive and representative inferences of the effectiveness of Gardasil qHPV vaccine in reducing the prevalence of cervical cancer in older women.
Statistical Analysis Plan
The collected data will be analyzed using the statistical package for social scientists (SPSS) version 17.0, whereby descriptive statistics will be used to enumerate demographic information regarding the study population . The Chi-square test will be used to evaluate the association between the obtained results from the RCT considering that it is a statistical test suitable for analyzing measures at sets of categorical levels in order to determine how the observed differences between the intervention group and placebo group arose . The results from the Chi-square test will be used to make inferences and conclusions pertaining to the effectiveness of Gardasil in lowering the prevalence of cervical cancer among older women.
The study will commence following approval by the institutional review board of the university and the health institutions identified as the study sites. Every study subject will be recruited and included in the study following provision of through information regarding the procedures of the study, how samples will be collected, tested, risks and the benefits of participation and the results to the participant, the investigator, and the health care institution. Moreover, the participants will be informed that their consent or refusal to join in the study will not affect the quality of health care service they were seeking then or any other time. Participants will also be briefed on their rights to participate or withdraw from the study at any time of their choice.
In addition, they will be informed that all the data collected will be coded for anonymity and confidentiality will be maintained at every level. The collected data will be collated and stored in the departmental cabinets for safety and monitoring in course of analysis, and that the results will be shared with the participants, the health care institutions involved in the study, and the ministry of health to help improve the quality of women health by mitigating the prevalence of cervical cancer through vaccination. Witten informed consent will then be obtained from recruits who consent having understood all that pertains the study procedures, risks and benefits.
Study Management Plan
The principal investigator will be the student under supervision of doctorate-holding university lecturers. The student will be in charge of all collected relevant data to the study. Research assistants will include qualified registered gynecologist to assist in sample collection, and a laboratory technologist to assist in testing during the screening of HPV infection. A pharmacist working together with the principal investigator will be charged with administration of the study intervention agent and placebo, and monitoring of the effects of the agent vis-à-vis the prevalence of cervical cancer in terms of new infections recorded in the intervention group.
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