Evaluation of the ShangRing vs. Mogen Clamp for Early Infant Male Circumcision (EIMC) in Sub-Saharan Africa

The study will evaluate the safety and acceptability of the topical anesthesia-based, no-flip ShangRing technique vs. Mogen clamp for Early Infant Male Circumcision (EIMC) in neonates and infants up to 60 days of life.

The study will consist of 2 phases; a pilot phase and a field study. In the pilot phase, male infants of up to 60 days of life will be enrolled in three sub-Saharan countries, specifically Kenya, Tanzania, and Uganda. Infants will be randomized in 1:1 fashion to undergo EIMC using either the Mogen clamp or no-flip ShangRing technique using topical anesthesia. Upon completion of the pilot trial and assuming satisfactory safety results, a larger non-comparative field study of ShangRing EIMC will be initiated, as performed by non-physician providers in routine practice settings in the three sub-Saharan African countries.

Total study duration will be 3 years. The pilot phase is anticipated to encompass a total of 1 year. Completion of the field study is expected to take 2 years.

Study Endpoints include:

1. To compare the rates of adverse events (AEs) with the ShangRing or Mogen clamp
2. To compare pain control, time to complete wound healing and parent satisfaction with EIMC using the ShangRing or Mogen clamp
3. To compare operative time and provider preference.
4. To assess the rate of spontaneous ring detachment with the ShangRing as a method to decrease the need for follow-up visits after circumcision.
5. To assess the subpreputial microbiome of the infants prior to and after the initiation of circumcision

Three correlative studies will be conducted:

1. Penile microbiome study: In the pilot trial, the subpreputial microbiome of the infants undergoing circumcision will be assessed to better understand the spectrum of bacteria that may exist and play a role in infant circumcision.
2. Demand creation study: During both the pilot phase and the field study, it will be assessed whether device-driven EIMC can be safely and effectively integrated into maternal and child health services as a method to promote demand creation.
3. Cost impact study: During both the pilot phase and the field study, a comparative cost analysis of EIMC with ShangRing versus Mogen clamp will be performed, in addition to a cost analysis of ShangRing EIMC as performed in routine clinical settings in the field study. The costing of demand creation will also be assessed.

Male circumcision (MC) has been shown to reduce HIV incidence in men by 50-60% in three randomized trials, and observational studies of men circumcised in infancy or childhood have shown long-term protection from HIV acquisition in adulthood. MC also reduces the risk of human papilloma virus, herpes simplex virus type 2 in men; and Trichomonas vaginalis and bacterial vaginosis infections in their female partners, genital ulcer disease in both sexes, and reduces the risk of cervical and penile cancers. In children, circumcision also provides immediate benefits by protecting against urinary tract infections, phimosis, and balanitis.

Though HIV prevention may be achieved through continued scale-up of MC in adolescents and adults, long-term sustainability will likely be better achieved through early infant male circumcision (EIMC). EIMC is technically simpler, safer, and less expensive compared to MC performed in older children or adults. In addition, EIMC has the benefit of more rapid wound healing and does not carry the risk of premature resumption of sexual activity before complete wound healing that has been reported in 7 to 28% of adult men after circumcision which may increase transmission to female partners. In several African countries, EIMC services have been found to be highly acceptable among parents and other caregivers.The long-term benefits of EIMC have led experts to recommend population-wide neonatal circumcision, as the benefits accrued over a child's life greatly outweigh any short-term risks, and delaying circumcision until adulthood places the child at risk of disease acquisition before the procedure can be performed. Despite these advantages, however, EIMC has not been significantly deployed in African countries. Part of the barrier to wider use of EIMC stems from the scarcity of trained providers and resources in sub-Saharan Africa. Device-assisted MC has therefore been proposed to simplify the procedure, enable safe task-shifting, and reduce the burden on healthcare providers, thus increasing the availability of EIMC services. While several devices are currently in use for patients of various ages, the use of a single device requiring only topical anesthesia across all age ranges would dramatically simplify supply chain logistics, streamline personnel training, and most importantly enhance patient/parent acceptability and demand uptake.

This study seeks to accomplish three major goals. First, the study would evaluate the safety of the ShangRing vs. the Mogen clamp for EIMC. The ShangRing is the only MC device requiring topical anesthesia that is capable of being used across all age ranges from newborns to adults; its use would dramatically simplify supply chain logistics, streamline personnel training, and most importantly enhance patient/parent acceptability and demand uptake. The Mogen clamp is a pre-existing device already in use for EIMC in Africa and will serve as an important comparator. The use of an EIMC device that enables safe task-shifting would allow the integration of circumcision services into pre-existing maternal and child health (MCH) service infrastructure and would thereby further facilitate rapid scale-up of MC services throughout Africa. A penile microbiome study will also be performed to better understand the spectrum of bacteria present at the time of EIMC. Next, the study attempts to ascertain whether device-driven EIMC can be safely and effectively integrated into MCH services as a method to promote demand creation. As sub-Saharan countries have deployed MC services on a national basis, the issue of insufficient patient demand has begun to take greater prominence as a barrier to achieving the goal of 20.8 million MC as proposed by the World Health Organization (WHO) and the Joint United Nations Program on HIV/AIDS (UNAIDS). The study will therefore examine the ability of EIMC to stimulate demand for circumcision through MCH services as well as identify potential barriers and strategies for wider scale programmatic roll-out. Finally, the study will also attempt to assess the economic burden of device-driven EIMC. In a context of limited resources, understanding the economic burden of a device-driven EIMC program will be critical in ascertaining its long-term feasibility and sustainability in sub-Saharan Africa.

All subjects will be recruited for the study at the following designated study sites:

Kenya: Homa Bay County Teaching and Referral Hospital, Homa bay; Jaramaogi Oginga Odinga Teaching and Referral hospital, Kisumu County; Nyanza Reproductive Health Society - UNIM Research and Training Centre (URTC) on the grounds of the Lumumba sub-County Hospital, Kisumu County.

Tanzania: Iringa Regional Referral Hospital, Iringa; Ilulu Hospital, Ilula; Mafinga Hospital, Mafinga; Ngome Health Center, Iringa.

Uganda: Rakai District Hospital, Rakai; Kalisizo Hospital, Kyotera; Kakuuto Health Centre IV, Kyotera; Lyantonde District Hospital, Lyantonde, Masaka Regional Referral Hospital, Masaka.

Subjects will be registered to take part in the study through their parents/legally acceptable representatives (LARs) who will be required to sign an informed consent after they agree to the enrollment of their infant. Parents/LARs are first familiarized with the procedures and provided with the information on the risks and benefits of EIMC using WHO/JHPIEGO guidelines.

Each infant will be enrolled in this study for a total of 42 days in the pilot phase and 28 days in the field study (or longer if wound healing is incomplete). Circumcision will take place on day 0, and weekly follow-up visits will be conducted until complete wound healing is documented for the pilot study. For the field study, follow-up will occur on days 7 and 28 only, with additional follow up visits if complete wound healing has not been achieved.

Participation in this study is voluntary. Any parent/LAR is free to discontinue their infant's participation at any point in time. When further participation in the study is not desired, even while the ring is still on, treatment will be administered as if the infant was in the study. However, participation for the entire length of the study is encouraged until the infant is fully healed.

The study doctor or his designee can stop an infant's participation in a study if:

* Continuing in the study could harm the infant
* The study is stopped.

Clinical data will be obtained and recorded using either 1) electronic Clinical Research Forms (eCRFs) that are loaded on mobile tablets or 2) paper forms. The information that will be obtained includes questionnaires, medical history, physical exam findings, details of the EIMC procedure, and clinical follow-up parameters. Once an eCRF is completed, the data will be encrypted on the collecting devices and submitted through a secure connection to the database server. No copy of the information will be left on the electronic device after it has been transferred to the database server. This will ensure that there will be no risk of unauthorized access to the data even in the case of device misplacement. All devices that will be used to collect data shall, upon completion of the day's activity, be locked in the study cabinets in a locked room. All electronic data will be backed-up on paper, and security will be ensured by storing the data in a locked cabinet. Data access will only be provided to primary researchers or their designees, and the data set will only be used for the research question asked.

Informed consent forms and participant contact information will not be obtained using electronic media but will instead be obtained using written forms that will be stored in locked cabinets at the study sites.

-Pilot Phase A total sample size of 460 eligible infants in Kenya, 460 eligible infants in Uganda, and 460 eligible infants in Tanzania will be enrolled, assuming successful recruitment and follow-up of a total of 1200 (87%) patients, or 400 patients per country. The anticipated accrual rate is 115 infants per month across the three countries. Infants will be randomized in a 1:1 fashion using a randomization software to EIMC with the ShangRing or the Mogen clamp, resulting in 200 infants receiving ShangRing circumcision and 200 receiving Mogen clamp per site.

This sample size exceeds the recommendations from the World Health Organization for the comparative trial component of the clinical evaluation of MC devices, which is based on an ability to rule out an adverse event (AE) rate of about 5% or more with a new use of a device that has already been shown to be previously safe in a larger group of men in randomized controlled trials (RCTs) and demonstration studies. The primary endpoint will be safety as determined by the rate of moderate to severe AEs using an intention to treat analysis.

Sample size justification: The goal of this study is to determine if the AE rate using ShangRing is not inferior to that for Mogen clamp. The control arm is the Mogen clamp and the anticipated moderate/severe AE rate is 2%. It is felt that the benefits of ShangRing in terms of convenience and acceptability will allow a non-inferiority margin of 2% (absolute). A sample size of 1200 infants (600 per arm), with one formal interim analysis for futility, has approximately 80% power with a (one-sided) alpha = 0.05. The null hypothesis for the non-inferiority test is that the moderate/severe AE rate for the ShangRing is at least 2% (absolute) greater than that of Mogen clamp, which is assumed to be 2%. The alternative hypothesis is that the rate of the ShangRing is less than 2% great than that of the Mogen clamp.

-Field Study The WHO recommends that the field study component of clinical assessment involve at least 500 clients per country in two countries of intended use. As such, we will aim to recruit a maximum of 600 infants in Kenya, 600 infants in Uganda and 600 infants in Tanzania, assuming successful recruitment and follow-up of a total of 1500 (83%) patients, or 500 patients per country. Once a total of 500 infants have completed follow up in each country, recruitment will stop as the necessary sample size will then had been achieved.

Sample size justification: A sample size of 1500 patients will have a 95% confidence interval margin-of-error of 0.007 to 0.010 for the moderate/severe AE rate estimate, assuming the observed rate is between 0.02 and 0.04. This provides adequate precision for the estimate of the severe AE rate in order to make decisions as to whether this device is safe when used in the field.

AEs will be pre-specified based on WHO/JHPIEGO definitions of the nature and severity of AEs, and classified as related or unrelated to EIMC.

-Statistical considerations and data analysis AE rates, pain control, wound healing, and parent/provider satisfaction between groups will be compared using chi-square tests, two-group t-tests. If the variable distributions violate the underlying assumptions of these tests, the corresponding non-parametric tests will be used (e.g. Wilcoxon rank sum test, Fisher's exact test). Analyses will be for all sites, and site-specific. Multivariable models will be used to adjust for imbalances in baseline characteristics significant at p\<0.10 using logistic regression to estimate adjusted odds ratios of moderate/severe AEs by arm. For outcomes with an incidence \<10%, the modified Poisson regression will be used to estimate adjusted prevalence rate ratios.

A formal interim analysis will be conducted after 200 circumcisions have been completed. The analysis will be for futility only. If after 200 infants have been enrolled and followed for 42 days it is found that the (non-inferiority) p-value is 0.97 or greater (corresponding to a z-statistic of 1.91 or greater) the trial will be recommended to stop due to futility.

Eligibility Criteria:
Inclusion Criteria:

1. Male infants from 24 hours up to 60 days of life
2. Gestational age ≥37 weeks
3. Normal birth weight (≥2.5 Kg)
4. No illness requiring medical treatment
5. No penile abnormality requiring surgical repair (e.g. hypospadias, chordee)
6. No family history of bleeding disorders
7. Consent provided by at least one parent/legally acceptable representative (LAR) of the infant

   1. Parent or LAR must be able to understand study procedures and requirements of study participation;
   2. Parent or LAR must agree to return the client to the study site for the full schedule of follow-up visits after his circumcision;
   3. Parent or LAR must have a cell phone or access to a cell phone

Exclusion Criteria:

* Not meeting one or more of the inclusion criteria
* Consent not provided by parents/legally acceptable representatives of the infant
* If parent(s)/legally acceptable representative(s) decline(s) the procedure or is/are uncomfortable with the procedure
* Babies \<6 weeks of age to mother without previous T.T. vaccination during ANC visits for that pregnancy
* Babies \>6 weeks of age without DPT vaccination
* Any other valid health-related issues as judged by the health workers