Clinical Trial Details
— Status: Not yet recruiting
Administrative data
| NCT number |
NCT06411938 |
| Other study ID # |
MISP 101003 |
| Secondary ID |
|
| Status |
Not yet recruiting |
| Phase |
N/A
|
| First received |
|
| Last updated |
|
| Start date |
May 2024 |
| Est. completion date |
May 2026 |
Study information
| Verified date |
May 2024 |
| Source |
Indiana University |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial 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.
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 MISPII 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.
