Real World Evaluation of an Albendazole-Ivermectin Coformulation Safety and Effectiveness

Официальное название

A Pragmatic Phase III Multicentre Clinical Trial to Evaluate the Safety and Effectiveness of a Single Dose of an Albendazole-Ivermectin Coformulation vs Albendazole for Preventive Chemotherapy of Soil-Transmitted Helminth Infections in School-Aged Children

Обзор

An open-label, randomized by school, two-arm pragmatic trial, will be conducted involving two study sites in Sub-Saharan-Africa (SSA), Ghana and Kenya, to evaluate safety and effectiveness of the newly developed fixed dose combination (FDC) of albendazole (ALB) and ivermectin (IVM) as a single dose to treat Soil-Transmitted Helminths (STH), compared to the standard dose ALB single dose for the treatment and control of STH (REALISE study: Real World Evaluation of an Albendazole-Ivermectin Coformulation Safety and Effectiveness). The general objectives are to validate the benefits of FDC through this pragmatic trial in a context of mass drug administration (MDA) programme to evaluate the safety as a primary endpoint and effectiveness profile as a secondary endpoint, in a large population of school-aged children.

Подробное описание

In the REALISE study a total of 20,000 children will be enrolled approximately in both countries for the safety cohort, 10,000 children in around 30 schools per country (5,000 per treatment arm). For the effectiveness cohort, REALISE study is planned to assess a total of approximately 4,500 participants in both countries, 2,250 children per country (75 children for each of the 30 schools and 1,125 children per treatment arm).

The REALISE study will have two study arms:

* Treatment arm 1: Single dose of a tablet of FDC 400 mg/18 mg IVM or 400 mg ALB/9 mg IVM, administered according to the following age criteria:

1. For children from 5-14 years old (included) at the time of screening visit: 1 tablet of FDC 400 mg ALB/9 mg IVM. 2. For children from 15-17 years old (included) at the time of screening visit: 1 tablet of FDC 400 mg ALB/18 mg IVM. * Treatment arm 2: Single dose of a tablet of ALB 400 mg (active control arm).

Randomization will occur at the school level, and each eligible participant within a school will receive only one of the study treatments. Given the variable number of children in the Ghanaian and Kenyan schools, and that conducting the intervention for only a fraction of the school is not feasible, it may be possible to exceed the intended trial sample size. Efforts will be made to minimize this

The Primary objective of the trial will be to evaluate and compare safety of a FDC against ALB alone via MDA in two study areas in Kenya and Ghana in the seven days after first treatment intervention. Thus, as a primary outcome, the adverse effects will be monitored through a specific surveillance system established in schools, hospitals and health centers as health facilities. Safety surveillance will be performed for seven days after each MDA, allowing for the identification of AEs and SAEs in subpopulations (in terms of gender, age, body weight, comorbidities, and additional risk factors) for better estimation of safety.

This surveillance will consist of active surveillance at day 0, day 1, day 2 and day 7 post-intervention to record any AEs and SAEs presented by participants during the conducting study with drug intake. In addition, the trial will include passive surveillance monitoring AEs and SAEs through diary cards given to the subjects, and in hospitals and health centres near the schools involved in the study for six days after the intervention until day 7 (end of the safety surveillance period) to avoid the loss of possible AEs and SAEs underreported, in case the participant does not attend school during the surveillance period.

The Secondary objective will be to evaluate the effectiveness of one round of MDA with FDC compared to ALB against STH T. trichiura by microscopy, to address the reduction of the prevalence of this species in the FDC and ALB arms. Thus, the secondary outcome will be measured at the school level, prior to the first intervention (baseline), at 21 days post intervention and within the month prior to the second yearly intervention which is at s11 months.

Moreover, the trial will include Exploratory objectives to evaluate the effectiveness of one round of MDA with FDC compared to ALB against S. Stercolaris by serology to address the outcome of the seroprevalence reduction of this species in the FDC arm and ALB arm and to evaluate the effectiveness of one round of MDA with FDC compared with ALB against Hookworms and A. lumbricoides to determine the reduction of the prevalence of these species through microscopy.

The frequency of scabies also will be measured as an exploratory objective in the effectiveness cohort at baseline and 21 days after the intervention.

Genetic monitoring is an exploratory objective to address the impact of the two treatment arms on the genetic structure of the populations of parasites. This genetic analysis will measure on the one hand the genetic diversity as an estimation of the effective population size and a proxy for successful control programmes, as seen for other parasites (it is expected that diversity will be lower in populations closed to elimination. In addition, the genetic differentiation between baseline parasites and the parasites collected after the interventions will be evaluated. Thus, the investigators will be able to evaluate the impact of both treatments in genetic selection and potentially identify genes associated with treatment failure and anthelmintic resistance. On the other hand, the investigators will measure the genome-wide association to see the relationship between parasite genetics and parasite clearance in response to treatments.

As part of the exploratory endpoints, the investigators will estimate alpha and beta diversity as well as the composition of the microbiome at phylum, family and genus level for each sample and time point. Investigators will assess differences between infected and uninfected participants at baseline by comparing the diversity and relative abundance of the different bacteria between baseline and 21 days after the intervention, comparing the effect of the two treatment arms in the microbiome composition. Moreover, the investigators will also explore the recovering of the initial microbiome composition between month 11 post-intervention and baseline, particularly in those participants that were not newly infected after 11 months.

Вмешательства

• Препарат Pre-screening Phase
  The entire school population will be invited to participate in the study. The purpose of this phase is to confirm participant eligibility for enrolment in the study based on the inclusion and exclusion criteria. Given the context in which the clinical trial is being conducted, in many instances, group meetings with the parents/guardians of potential participants in the community or at school might be necessary as part of the informed consent process. This consent process may be performed up to t
• Препарат Screenig Phase
  The purpose of the screening visit is to confirm subject eligibility for enrolment in the study based on the inclusion/exclusion criteria. Screening visits in a particular school can be performed between 14 and 7 days before the intervention (Day 0). To continue with the screening activities, participants must have signed written consent from their parent or legal guardian, and in the case of participants aged 12 years or older, they must also have a signed assent form before any specific study
• Препарат Randomization
  Only when the screening process is finalized in a particular school, and the list of eligible participants is closed, with at least 100 eligible participants, will the school be a candidate for randomization. Once the screening process is finalized, the investigator or designee will notify the ISGlobal Trial Statistician, who will provide the School Randomization ID allocated based on the randomization lists created before the trial starts. School Randomization ID will be assigned sequentially p
• Препарат Baseline Effectiveness Cohort
  Before the administration of the study drug at school, participants selected for the Effectiveness Cohort will perform an additional study visit during which they will provide the study team with a stool sample for STH analysis. A dried blood spot (DBS) sample will also be taken to test for S. stercoralis. Sampling of the baseline effectiveness cohort will be conducted within 7 days before the start of the school study intervention. In addition to the delivery of the stool/blood sample, partici
• Препарат Day 0 Trial Intervention
  Within seven days after the first sample for the baseline effectiveness cohort is collected, the school's mass administration of the allocated drug will take place. All participants included in the list of eligible subjects from a particular randomized school will receive a single dose of the medication administered to their school (FDC or ALB). Before the administration, participants will be asked about any medical condition that has arisen since the last study visit, in which case information
• Препарат Active Surveillance (study visit Day 1, Day 2 and Day 7)
  Active safety surveillance will be performed at school during the trial intervention on day 0 until day 7 post-intervention. The assessment will include recording of all AEs and SAEs presented by study participants from the intake of the study drugs, and for two additional days (Day 1 and Day 2 study visits). During active surveillance, participants will be visited by a study physician at school during the study intervention, on day one and day two, and they will be questioned about any potentia
• Препарат Passive Surveillance
  Passive surveillance will be carried out by monitoring AEs in health facilities near the schools involved in the study for six days after the intervention until Day 7 (end of the safety surveillance period). Although AE will be actively monitored during the scheduled study visits, this passive surveillance will allow for the identification of AEs and potential SAEs that might occur and remained underreported in case the participant does not attend school during the active safety surveillance per
• Препарат Post-Treatment Effectiveness Evaluation
  Post-treatment effectiveness evaluation will be performed by measuring the prevalence of STH at two time points: 21 days after the intervention (± 7 days) and 11 months after intervention (± 28 days). Additionally, the reduction in S. stercoralis seroprevalence will be evaluated 11 months after the intervention. These participants will be tested for STH by Kato-Katz at the two post-treatment time points (day 21 and month 11) and for S. stercoralis by NIE ELISA at 11 months. The diagnostic test

Первичные конечные точки

• AEs and SAEs record of participants treated with FDC compared to ALB. [Срок оценки: 7 days, active surveillance (Day 0 (1 hour), Day 1, Day 2 and Day 7 post-intervention) and passive surveillance (From Day 0 up to Day 6 post-intervention)]

Вторичные конечные точки (1)

• Reduction in T. trichiura prevalence in participants treated with FDC compared with ALB. [Срок оценки: Baseline, 21 days and 11 months post-intervention]

Критерии участия

Критерии включения

Individuals of both sexes that attend the selected schools in the trial areas in Ghana and Kenya that meet the following criteria:

• Age: 5 to 17 years old (included).
• Height: over 110 cm.
• Parental acceptance to participate in the study by obtaining written informed consent approved by the Ethics Committee. Written assent will also be obtained from children according to the local national legislation (12-17 years old).

Критерии исключения

• Epidemiological risk of being infected by Loa loa, defined as those who have visited any of the following countries: Angola, Cameroon, Central Africa Republic, Chad, Congo, Democratic Republic of the Congo, Equatorial Guinea, Ethiopia, Gabon, Nigeria and Sudan.
• Serious medical illness, defined as participants showing symptoms of acute illness which could hamper the participation in the trial, such as high-grade fever, severe diarrhoea, neurological symptoms or others, per investigator's criteria.
• Any condition prevents the appropriate evaluation and follow-up of the participant, per the investigator's criteria.
• Known hypersensitivity to any component of either study treatment.
• Pregnant or first week post-partum: female participants who are post-menarche must have a negative urine pregnancy test at screening.

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Да

Дизайн исследования

Распределение

Рандомизированное

Модель

Параллельные группы

Маскирование

Простое слепое

Основная цель

Лечение

Центры проведения

Ghana · 1 центр

• Ghana Health Service (GHS) — Accra

Kenya · 1 центр

• Kenya Medical Research Institution (KEMRI) — Nairobi

Идентификаторы

NCT: NCT06282315 · REALISE

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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