Trial Title:
A Cervical Cancer Prevention Program in Kenya
NCT ID:
NCT06411938
Condition:
Cervical Cancer Prevention
Cervical Cancer
Conditions: Official terms:
Uterine Cervical Neoplasms
Conditions: Keywords:
Kenya
cervical cancer
prevention
Study type:
Interventional
Study phase:
N/A
Overall status:
Active, not recruiting
Study design:
Allocation:
N/A
Intervention model:
Single Group Assignment
Intervention model description:
Community-based, non-randomized
Primary purpose:
Prevention
Masking:
None (Open Label)
Intervention:
Intervention type:
Other
Intervention name:
Self-collection of vaginal swabs
Description:
Women will collect vaginal swabs for HPV testing, then undergo standard of care screening
for cervical cancer
Arm group label:
All women and girls eligible for the study
Summary:
Cervical cancer is caused by oncogenic, or "high-risk" (HR) human papillomavirus (HPV),
and is the main cause of cancer-related death among Kenyan women. This malignancy is
theoretically preventable through a combination of screening of adult women and treating
those with cervical premalignancies and vaccination of children and adolescents against
HPV infection. However, only 5% of Kenyan women are regularly screened, and only 14% have
ever been screened, which in Kenya is done by a method known as Visual Inspection with
Acetic Acid (VIA). Possible obstacles to current screening include long travel to
clinics, high costs, poor sensitivity and specificity of VIA, the need for extensive
training for VIA, variability among providers in their interpretation of VIA, lack of
trained personnel, and others. In addition, while safe and effective HPV vaccines have
been available for 15 years, very few (<1%) Kenyan children and adolescents have been
vaccinated. Obstacles to vaccination include high costs, poor delivery infrastructure,
lack of education, long travel to clinics, and others. The investigators began a
community-based program to develop a framework for eradication of cervical cancer by
screening adult women and vaccinating female children. This program is becoming accepted
in the Webuye region of Western Kenya, but there is still a great deal to learn.
Going forward, this initiative will be known as the Kenya Mother-Daughter Cervical Cancer
Eradication Program, or the Mother-Daughter Program (MDP) for short. The investigators
propose a continuation of the MDP that will allow them to accumulate additional data
needed to solidify the overall project and to answer additional questions as described
below. To accomplish this goal the investigators will first enroll an additional 300
adult women to the program. This will increase the strength of the analysis of HR-HPV
testing in detecting premalignant lesions of the cervix, especially in HIV-infected
women. Second, the investigators will identify the positive and negative features of the
MDP from the viewpoint of both the adult women and the girls enrolled in the program.
Third, because anogenital warts (AGWs) may serve as a reservoir for HR-HPV, especially in
women living with HIV/AIDS, the investigators will examine the prevalence, HPV type
distribution, and treatment of these lesions among adult women participating in the MDP.
Detailed description:
Project Framework
The investigators will utilize a modification of the basic framework developed for the
previous MISP (Merck Investigator-Initiated Studies Program) grant that began in 2018.
This framework was successfully implemented in a rural Kenya community setting, and
combines screening of adult women (ages 30 through 55) using HPV DNA testing of
self-vaginal swabs with HPV vaccination of daughters (ages 9 through 14 years) of mothers
attending community meetings.
Rationale for conducting the proposed study
Strategies based on centralized care have been unsuccessful in preventing cervical cancer
in Kenyan women. HR-HPV DNA testing of self-collected vaginal swabs is acceptable and
feasible, and the investigators have now shown that such testing can occur in a community
setting in rural Kenya; other groups have demonstrated similar successes in Africa. In
studies funded by MISP awards, the investigators have shown that essentially all women
invited to community meetings agreed to enroll in the studies, to receive education about
cervical cancer, and to provide a self-collected vaginal swab for HR-HPV DNA testing.
Nearly all women who attended the community meetings were willing to have their female
children vaccinated against HPV. The investigators have also shown that HPV vaccine can
be delivered to western Kenya and can be administered to girls in a community setting.
The investigators wish to continue to use this framework in the next MISP to further
study the utility of this strategy and to address research questions that will elucidate
the barriers to participation and will begin to provide information about the impact of
the program.
The reasons the investigators want to enroll additional women are as follows: First, the
investigators would also like to evaluate the educational aspect of the Mother-Daughter
Project among women and girls regarding to cervical cancer awareness and prevention
knowledge. Second, the investigators would like to intensively study the acceptability of
the community-based program, and define the obstacles of the program among women who are
newly enrolled. The investigators will interview women and randomly selected children,
and ask them to fill out detailed questionnaires related to these issues. Second,
although the investigators expected to be able to address the issue of sensitivity and
specificity of HR-HPV testing compared to VIA in the first MISP (MISP-I), the
investigators noted an unexpectedly low rate of abnormal VIA in the original 200 women
cohort. The second cohort of 300 women is still undergoing evaluation and the
investigators do not yet know the incidence of abnormal VIA examinations. Thus,
additional women need to be enrolled in a third wave to address this important question.
Third, this program has benefited the community by providing a cancer prevention program
that includes HPV vaccination, to which they have previously not had access to. This
program has engendered trust between the local population and caregivers. Lastly, the
investigators hope to submit a larger application to an organization such as the Gates
Foundation or the NIH for a larger award of several years duration, based on as much
preliminary data as can be generated from this project. The same rationale applies to our
desire to vaccinate additional girls via the MISP mechanism. The investigators have
vaccinated 2000 girls to date and as part of the second MISP (MISP-II). Because aflatoxin
exposure represents a potential public health problem that could thwart efforts to
control HPV-associated malignancies, the investigators will study the serological
response to vaccination in girls with chronic aflatoxin exposure, once they have
completed the vaccine regimen.
The investigators will study the prevalence, HPV type distribution, and treatment
response of AGWs in adult women living in Kenya. AGWs cause considerable morbidity in
women, especially those who are HIV-infected. Few comprehensive studies are available in
women living in sub-Saharan Africa. The investigators and others have previously showed
that HR-HPV are frequently detected in AGWs from immunosuppressed people in the United
States, including some people living with HIV. The investigators will determine the
prevalence of AGWs in women participating in the community based program and test the
hypothesis that the prevalence of AGW will be considerably higher in HIV-infected women.
The investigators will also test the hypothesis that HR-HPV types will be frequently
detected in AGW from HIV-infected women, suggesting that AGWs are a reservoir for HR-HPV
and transmission. The investigators will also explore an objective related to treatment
of AGWs to determine if a higher failure rate in HIV-infected women may be related to
poor control of HIV (a higher HIV viral load) and detection of HR-HPV in the AGWs.
Thus these aims build on the infrastructure the investigators have created in the first
two MISP award cycles. The investigators believe the MDP, a community based approach to
cervical cancer, can become the standard for western Kenya, act as a framework for
HPV-associated cancer control, and can lead to a significant improvement in patient care
as well as providing an opportunity for hypothesis driven research.
The investigators propose a hypothesis driven study that expands our novel
community-based approach to cervical cancer eradication in Kenya. The investigators plan
to enroll 300 additional Kenyan women between the ages of 30 to 55 years. Self-collected
vaginal swabs will be collected during the Community Meetings. Swabs will be tested for
HR-HPV DNA at Moi University using the Roche Cobas Assay. Only women who have not
previously participated in MISP I or II will be enrolled. All women will be asked to
travel to the Webuye Clinic for VIA and pelvic examination, including careful inspection
for AGWs. Regardless of HIV status, women with an abnormal ("positive") VIA will undergo
four-quadrant punch biopsy of the cervix; 20% of women with normal ("negative") VIA will
also undergo cervical biopsy so that the sensitivity and specificity of HR-HPV testing
and VIA can be determined using histologically proven CIN 2/3+ as the gold standard.
The investigators will enroll 2000 girls, ages 9 through 14 into the study and administer
the HPV vaccine at the community meetings. The investigators have shown that vaccination
is feasible in the community setting. In the new study, all women and girls will be asked
to fill out questionnaires that will provide data about the educational aspects and
overall acceptability of the MDP, and obstacles related to its initiation. In addition,
approximately 10% of women and girls will be interviewed at the end of the study to gain
insights into the acceptability of the community-based program compared to the
traditional methods of screening and vaccination. The investigators wish to include the
opinions and desires of the mothers and daughters in designing larger programs in the
future. This MISP, if funded, will help to build on current experiences as well as
answering specific questions related to the hypotheses the investigators have proposed.
Study strategies of the Mother Daughter Project (MDP)
Webuye is a community located in the western region of Kenya, in Bungoma County on the
highway to Uganda. The total population of Webuye sub-county is approximately 25,000; it
is estimated that there are approximately 5,000 to 6,000 women between the ages of 30 and
55 years. A "community entry strategy" has been utilized to introduce the prior studies
and to invite women to community meetings. Prior to study initiation, a female Kenyan
Counselor was trained about cervical cancer, how to educate women about this malignancy,
and how to instruct women in performance of self-collected swabs. Village chiefs, village
elders, women deemed to be community leaders, and leaders of the local churches were then
approached by the Counselor and Study Coordinator to discuss the goals, strategy, and
risks and benefits of the study. Discussions have focused on the importance of early
screening for cervical cancer, the use of self-collected swabs for screening, and
vaccination of children against HPV.
Community meetings and self-collected vaginal swabs
The Counselors will invite local women ages 30 through 55 years and their 9 through 14
year-old daughters/grand-daughters to meetings in Webuye. These meetings have been very
successful; approximately 30 to 40 women attend each meeting, and many bring their
daughters as well. The instructional brochure that the investigators developed for the
proper self-collection method (available in both English and Swahili) will again be
shared with participants. Women will obtain the swab in a private setting at the meeting.
Self-collected swabs will be gathered by the Counselor, then a delivery person will
transport the swabs (dry, no added medium) at ambient temperature to Moi Teaching and
Referral Hospital (MTRH) laboratories in Eldoret, Kenya (about 60 km away). Swabs will be
tested for HR-HPV DNA using the Roche Cobas Assay, a test that provides specific HPV 16
or 18 detection as well as detection of any of 12 additional oncogenic types (HPV types
31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, 68). Results of the Cobas Assay will be
entered into a RedCap database that the investigators previously created for the first
MISP. Results of the Roche Cobas Assay will be delivered electronically to the
Counselor's tablet, who will discuss these results with women at subsequent community
meetings.
VIA and cervical biopsy
All women will be asked to go to the Webuye Clinic for VIA, which is the current standard
of care for cervical cancer screening in Kenya. Regardless of HIV status, women with an
abnormal ("positive") VIA will undergo four-quadrant punch biopsy of the cervix; 20% of
women with normal ("negative") VIA will also undergo cervical biopsy. All women with
abnormal VIA examinations will then be treated according to established local algorithms.
In the event of suspected cancer, the participant will be sent to the Gynecologic Cancer
Clinic at MTRH.
In our vision for the future, women will be triaged to the local clinic for VIA only if
they have a positive Cobas Assay, taking advantage of the high (>99%) negative predictive
value of the Cobas Assay previously established in studies of HIV-uninfected women in the
U.S.A., where the test is now FDA-approved for primary cervical cancer screening.
However, the Roche Cobas Assay has not been adequately tested in HIV-infected women
living in any country, or in HIV-uninfected women living in sub-Saharan Africa utilizing
self-collected vaginal swabs.
Biopsy of AGWs
A pelvic examination will be performed, and AGWs (vulvar, introital, vaginal, perineal,
perianal) will be identified by clinical inspection. A detailed anatomical chart will be
utilized to document the location and size of suspected AGWs. Women with lesions
suspicious for AGW will be scheduled for gynecologist review. If the gynecologist
believes the lesions are consistent with AGW, he/she will perform excision biopsy under
local anesthesia with 1% lidocaine injected into the base of the lesion. The entire
lesion will be removed if smaller than 5 mm in diameter, and the remaining lesions will
be treated with cryotherapy, per Kenya standard. Following cleansing of the affected
area, lidocaine 1% will be injected into the base of the AGW, the excision will be
performed with sterile instruments, generally scissors. The sample will be place in
buffered formalin and sent to the Pathology Department at Moi University, where
paraffin-embedded sections will be prepared. One section from each biopsy specimen will
be stained with hematoxylin and eosin for histological confirmation, and additional
sections will be used for DNA in situ hybridization assays (Dako Laboratories or another
suitable system) using either a combined HPV 6/11 probe mix, an HPV 16/18 probe mix, or
an HPV 31/33/35/39/45/52/58 probe mix. Sections will be scored positive or negative for
each of the three probe mixes. This work will likely be performed at Indiana University
School of Medicine, Indianapolis, IN, unless the investigators can train technicians at
Moi University in this methodology.
Follow-up visits for AGWs and cervical cancer screening
Women in the study who have AGWs biopsied and treated will be asked to return in six
months to the Webuye Clinic to determine if warts have recurred. Women will be asked to
return to the Webuye Clinic for cervical cancer screening in one year if HIV-infected or
in three years if HIV-uninfected.
HPV vaccination of girls enrolled in the study
Women will be instructed at the community meetings in the efficacy, safety and potential
adverse effects of HPV vaccination. Vaccination against HPV will be offered to girls
(2000 in all) ages 9 through 14 of women attending the community meetings. The second
dose of the HPV vaccine will be administered six to twelve months after the first dose at
subsequent community meetings. Careful records will be kept, and all families will be
given a record of the vaccine administration. This is especially important because Kenya
began a facility-based HPV vaccine program for 10 year-old girls in 2019, but few girls
have been vaccinated to date. Our approach is important because many girls will not be
able to attend school to receive the vaccine, or have the means to travel to local
facilities for vaccination; it is therefore important that community-based opportunities
for vaccination are an option in Kenya. In addition, the government program vaccinates
girls at age 10 and does not include 9-year-olds so our project will be important for
these girls.
Questionnaires
A detailed questionnaire (in Swahili and English) will be developed to 1) determine
knowledge and beliefs of mothers about HPV and cervical cancer, which will be
administered at the beginning of the study and at the end of the study, and 2) capture
the opinions of mothers and daughters regarding all aspects of the program. Mothers will
be asked about the self-collected swabs, travel to community meetings and the Clinic,
acceptability of HPV vaccination of daughters. Daughters will be asked to answer
questions related to vaccination; how the community-based approach compared to a
school-based program, and other questions. Children will fill out the questionnaire with
help from their mothers.
The aims of this project will be accomplished during a two-year period. Key personnel
will be trained in the first four months of the project. The remainder of the first year,
and the second year will be devoted to community meetings, vaccinations, and VIA
examinations, AGW biopsy and treatments, and follow up visits.
The investigators (Drs. Brown, Ermel, Tong, Tonui, and Omenge) will be responsible for
analyzing the study data.
Sample size consideration and analysis plan for Objective 1: Determine if High-Risk
(HR)-HPV DNA testing of self-collected vaginal swabs, collected in a community setting
can be used as a triage step cervical cancer screening in HIV-infected Kenya women.
Hypothesis: HIV-infected women with negative HR-HPV DNA tests uniformly have either 1)
normal VIA examinations, or 2) falsely abnormal VIA examinations.
The investigators will evaluate HR-HPV DNA testing of self-collected vaginal swabs as a
triage step for VIA among HIV-infected rural Kenyan women. Our hypothesis is that
HIV-infected women with negative HR-HPV DNA tests will have normal VIA examinations or
falsely-abnormal VIA examinations (all women with abnormal VIA exams will undergo
cervical biopsy).
Sample size consideration: The investigators will enroll 300 adult women in this study.
The investigators expect 30% (90 women) to be HIV-infected. Of the 90 HIV-infected women,
the investigators expect 39% (35 women) to have a positive HR-HPV DNA test and 61% (55
women) to have a negative HR-HPV DNA test, based on the data from the pilot study. Of the
35 women with a positive HR-HPV DNA test, the investigators expect that 30% (11 women)
will have an abnormal VIA, and of these 11 women, 50% (6 women) will have biopsy proven
CIN2/3+. Of the 55 women with a negative HR-HPV DNA test, the investigators expect that
4% (2 women) will have an abnormal VIA, and of these 2 women, 1 woman will have biopsy
proven CIN 2/3+. Thus, the investigators expect among 90 HIV-infected women, 17% women
with positive HR-HPV DNA tests and 2% women with negative HR-HPV DNA tests will have
biopsy proven CIN2/3+.
To analyze the test characteristics of HPV DNA testing of self-collected vaginal swabs,
the investigators will combine the data from the proposed sample of 300 women with the
sample of 300 women that has been enrolled in the Merck Investigator Studies Program
(MISP) II to a total sample of 600 women to test this hypothesis. The enrollment and HPV
DNA testing procedures are identical between the two studies, which allows us to merge
the two study populations to increase statistical power. Of the 600 women, the
investigators expect 180 (30%) women to be HIV-infected. Among the 180 HIV-infected
women, the investigators expect 70 women (39%) to have a positive HR-HPV DNA test and
among them 17% (12 women) to have biopsy proven CIN2/3+, and 110 women (61%) to have a
negative HR-DNA test and among them 2% (2 women) to have biopsy proven CIN2/3+.
Our proposed sample size of 180 HIV-infected women (90 HIV-infected women from the
current proposed sample of 300 women plus 90 HIV-infected women from the already enrolled
300 women in the MISP-II) will provide 89% power to detect a significant difference in
biopsy-proven (CIN2/3+) VIA abnormality between HR-HPV DNA positive and HR-HPV DNA
negative HIV-infected women at a two-sided 0.05 significance level based on Fisher's
exact test.
The investigators are requesting the HPV vaccine to vaccinate 2000 girls ages 9 through
14; two doses of vaccine will be required. Thus, the investigators request 4000 vaccine
doses.
Injection Site Reactions The protocol team should be contacted within 24 hours for any
Grade 3 or 4 adverse experiences (AE) (e.g., injection site reactions, elevated
temperatures following vaccination that occur at any point during study participation)
thought definitely, possibly, or probably related to vaccination. Further vaccines should
not be given to that participant prior to consultation with the Site Co- Investigator,
Dr. Omenge Orang'o, phone number 0722 609132. For injection reactions judged to be
life-threatening, the protocol team should be notified immediately. The person receiving
the vaccine should be brought to a clinic immediately for evaluation and treatment. No
additional vaccinations shall be given to that participant.
Other Adverse Events
The following guidelines will be used for the management of AEs that are felt to be at
least possibly related to vaccines:
- Grade 1 or 2 Toxicity/AE Participants who develop a Grade 1 or 2 AE may continue
study vaccine. If a participant experiencing a Grade 1 or 2 AE chooses to
permanently discontinue study treatment or study participation, the AE will be
documented.
- Grade 3 or 4 AE Participants who develop a Grade 3 or 4 AE that is at least possibly
related to vaccine should be reevaluated for that toxicity until the AE returns to
Grade ≤2. The study vaccine may be given at the discretion of the site investigator.
If the same Grade 3 or 4 AE recurs and is considered by the investigator to be
possibly, probably, or definitely related to the study vaccine, the study vaccine
will be permanently discontinued. If, in the investigator's opinion, the AE has NOT
been caused by the study vaccine or if the event is an asymptomatic laboratory
abnormality, study treatment may continue.
Cryotherapy- and LEEP (loop electro-excisional procedure)-Related Complications These
complications will be documented and reported to the PIs as well as Merck. A brief
summary of treatment for these complications is provided below.
Vaginal Bleeding Bleeding post cervical biopsy will first be controlled with direct
pressure using a dry swab. If this is not sufficient, then a swab with Monsel's solution
will be applied to stop the bleeding. When postoperative bleeding occurs, it usually
appears 4-6 days after treatment and often from the posterior lip of cervix. This
bleeding can usually be controlled in the clinic by fulguration, applying Monsel's paste,
or using a silver nitrate applicator stick. Rarely, placement of a suture at the bleeding
site is necessary. The risk of post-treatment infection is very small and can likely be
reduced even more by delaying surgical treatment until any woman with a likely diagnosis
of pelvic inflammatory disease, cervicitis, vaginal trichomoniasis, or bacterial
vaginosis has been adequately treated and recovered.
Vaginal Infection The chance of postoperative infection is lessened by (1) only
performing cryotherapy or LEEP when there is no evidence of bacterial STIs (sexually
transmitted infections) and (2) advising women to abstain from vaginal intercourse for 6
weeks post procedure.
In addition, participants are to be advised of the symptoms of infection and encouraged
to return to the clinic if the symptoms occur. If a participant presents postoperatively
with a malodorous discharge, it should be cultured if possible and empirical treatment
prescribed with antibiotics that are effective for pelvic inflammatory disease.
Criteria for eligibility:
Criteria:
Inclusion Criteria:
- Kenyan girls ages 9 through 14,
- willing to sign informed consent to be vaccinated
- are able to return for the second HPV vaccine dose.
- Kenyan women between the ages of 30 to 55 years
- willing to sign informed consent to be vaccinated
- are able to travel to the Webuye Clinic for VIA.
Exclusion Criteria:
- girls who are not willing or able to return for the second HPV vaccine dose;
- women who are not willing to sign informed consent
- women who are not willing or able to travel to the Webuye Clinic for VIA.
Gender:
Female
Gender based:
Yes
Gender description:
Girls ages 9-15 will be vaccinated against HPV per Kenya Guidelines Adult women 30-55
will be tested for HPV and undergo cervial cancer screening per Kenya Guidelines
Minimum age:
9 Years
Maximum age:
55 Years
Healthy volunteers:
Accepts Healthy Volunteers
Locations:
Facility:
Name:
Indiana University
Address:
City:
Indianapolis
Zip:
46202
Country:
United States
Start date:
April 2, 2024
Completion date:
May 2026
Lead sponsor:
Agency:
Indiana University
Agency class:
Other
Collaborator:
Agency:
Academic Model Providing Access to Healthcare (AMPATH)
Agency class:
Other
Source:
Indiana University
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT06411938
