Clinical Trial Details
— Status: Not yet recruiting
Administrative data
NCT number |
NCT05801198 |
Other study ID # |
452/RNEC/2022 |
Secondary ID |
|
Status |
Not yet recruiting |
Phase |
Phase 2
|
First received |
|
Last updated |
|
Start date |
March 1, 2024 |
Est. completion date |
December 31, 2026 |
Study information
Verified date |
March 2023 |
Source |
King Faisal Hospital Rwanda |
Contact |
Edgar Kalimba, MD |
Phone |
+250788531514 |
Email |
Edgar.mk[@]kfhkigali.com |
Is FDA regulated |
No |
Health authority |
|
Study type |
Interventional
|
Clinical Trial Summary
The investigators believe that to effectively achieve malaria elimination in Rwanda, it is
critical to target the human reservoirs of Plasmodium falciparum using local and readily
available Artemisia tea. Asymptomatic infections detectable by PCR are important reservoirs
because they often persist for months and harbor gametocytes, the parasite stage infectious
to mosquitoes. Lessons learnt from this study will be of critical importance for health
decision makers with regard to potential malaria control. MSc and PhD students will be
trained and the impact of this research project will be enormous on the socioeconomic
transformation of Rwanda.
Description:
According to the World Health Organization (WHO) world malaria 2021 report, there were 241
million cases of malaria in 2020, with 627 000 estimated deaths during the same year - an
increase of 69 000 deaths over the previous year. The African continent continues to carry a
disproportionately high share of the global malaria burden. In 2020 the Region was home to
95% of all malaria cases and 96% of deaths. Children under 5 years of age accounted for about
80% of all malaria deaths in the Region. Despite admirable progress in the first 15 years of
this century, there has been setbacks with regard to achieving malaria elimination.
Malaria is a parasitic vector-transmitted infection caused by Plasmodium species. Four main
human species are: P. falciparum, the most virulent and predominant specie in Sub-Saharan
Africa, P. Ovale, P. vivax and P. malariae, and one zoonotic specie P. knowlesi. It is a
disease responsible for catastrophic health and socio-economic impact mainly due to
Plasmodium falciparum, which is responsible for substantial morbidity and mortality
especially in children under five years and pregnant women.
When a Plasmodium-carrying Anopheles mosquito takes a blood meal on an individual, saliva is
injected together with the sporozoites, which migrate to the liver, thereby beginning a
cycle. Once humans become infected, the hepatic cycle lasts 10 to 14 days (in the case of P.
falciparum), after which thousands of asexually reproducing merozoites are released into the
peripheral blood where they invade and develop inside mature erythrocytes. The blood stage
parasites are those that cause the symptoms of malaria. In a continuous pattern, during
asexual replication in the blood stream, a small proportion of the parasites undergo sexual
development that lasts approximately 10 days in the case of P. falciparum, resulting in the
production of transmissible gametocyte forms. These gametocytes responsible for parasite
transmission from humans to the mosquito vector, are insensitive to most conventional
antimalarial drugs and are often long-lived (population lifespan of up to 55 days following
successful antimalarial therapy), thereby ensuring malaria transmission over several weeks.
Disrupting malaria transmission therefore requires the development of new anti-gametocyte
drugs with safety profiles that allow for population-wide treatment campaigns.
Rwanda has made great strides during the last two decades by investing strategically in
health system strengthening, increasing access to care by establishing community based health
insurance, resulting in substantial declines in disease burden. However, since 2012, the
country has been experiencing a persistent upsurge of malaria. From 2012 to 2018, malaria
incidence increased significantly from 48 per 1000 to 403 per 1000, an almost 10x increase.
By 2019-2020, the number of cases was reduced by more than half, to 198 per 1000. Although
transmission is heterogeneous in Rwanda, the entire population is considered at risk of
malaria. The primary Plasmodium (P.) species found in Rwanda, the agent responsible for this
disease, is P. falciparum, but P. malariae and P. ovale have also been identified and this is
mostly in the cosmopolitan main city of Kigali that receives frequent travelers and tourists.
Despite the gains made, recent upsurges and concerns about growing drug resistance calls for
more dynamic, accessible, cost effective and adaptive mechanisms to combat, and potentially
eliminate malaria all together. Over the past decade, several public health measures
attempting to eradicate malaria were instituted, but this goal remains elusive to date and
the country, and like most of sub-Saharan Africa, Rwanda continues to face a high burden of
malaria mortality and morbidity.
In Rwanda, and many other African household setting, families frequently have both younger
children and elderly grandparents living together. When a household member has Plasmodium
reservoirs, this puts both the younger children and older more vulnerable family members at
risk for recurrent severe malaria infections. The significance of asymptomatic household
carriers in sustaining transmission of malaria was evidenced both in South East Asia and in
Africa.
Malaria control measures that are currently deployed include the selective use of various WHO
recommended strategies like control of mosquito breeding, timely diagnosis, and management of
cases, as well as use of chemoprophylaxis for highly vulnerable population groups such as
children under 5, pregnant women and visitors from non-endemic zones. This has provided some
gains in reducing malaria burdens globally in recent years and, generating increased hopes
for malaria elimination/eradication in the near future. However, such gains are severely
threatened by the emergence and worldwide spread of both insecticide and antimalarial drug
resistance. Resistance to Artemisinin combination therapy (ACTs), the first line treatment
recommended by WHO is evident in Southeast Asia and has also been reported in African
countries. Eliminating malaria will therefore necessitate the development of innovative
approaches and tools, including new treatment options and vector control measures.
During 2021, the WHO recommended the use of the RTS, S/S2 malaria vaccine for the prevention
of P. falciparum malaria in children living in regions with moderate to high transmission as
defined by WHO. However, phase 3 trials showed relatively little efficacy, and the fact that
the vaccine itself is unlikely to meet the goal of malaria eradication by itself. With
further vaccine candidates in the pipeline that are being evaluated in vaccine trials, there
is hope that alternative parasite targets and vaccination strategies will continue to be
developed. Another recent positive is from combined RTS, S/S2 vaccine and chemoprevention
that showed that this approach was non-inferior to chemoprevention alone in preventing
uncomplicated malaria. The combination of these interventions resulted in a lower incidence
of uncomplicated malaria, severe malaria, and death from malaria than each intervention
alone.
More recently, a novel vaccine R21 has been undergoing phase 2 trials. Despite being similar
to RTS, S2, it fuses together a hepatitis B antigen and half the circumsporozoite protein - a
larger portion than in RTS, S2. The developers believed that this combination would be at
least as effective as RTS, S, but less expensive. In a double-blind, randomized, controlled,
phase 2b trial a low-dose circumsporozoite protein-based R21 vaccine, was given to children
aged 5-17 months in Nanoro, Burkina Faso, with two different doses of adjuvant Matrix-M (MM).
R21/MM appears safe and significantly immunogenic in this cohort of African children, and
shows promising efficacy.
More vaccine trials have been conducted with radiation-attenuated Plasmodium falciparum
sporozoite (PfSPZ) vaccine, hypothesized to provide protection against P. falciparum
infection in malaria-naïve adults and children. Preclinical studies show that T cell-mediated
immunity is required for protection and is readily induced in humans after vaccination. There
was, however, no significant protection against P. falciparum infection in any dose group at
6 months which was the primary end point of the study.
Asymptomatic malaria is prevalent in endemic regions and throughout all seasons and
identifying them often requires the use of highly sensitive diagnostic tools, including
molecular approaches such as PCR. Eliminating malaria in areas with stable malaria
transmission will therefore require the sustainable use of integrated vector-parasite
approaches targeting both the human asymptomatic reservoirs and vector reservoirs, while
paying attention to toxicity from drugs, and ensuring resistance is not further worsened.
Literature shows that asymptomatic reservoirs can be eliminated in mass treatment programs.
In the past, diverse mass treatment strategies (Mass drug administration (MDA)) have been
proposed and tried proving to rapidly reduce malaria particularly in regions with seasonal
malaria transmission in parts of Africa and in China. Unfortunately, the use of ACTs in
community-directed treatment of asymptomatic malaria poses a challenge, not only from drug
resistance, but also the observation of potentiation of gametocyte proliferation upon ACT
administrations. Contrarily to the above reported challenges of ACTs to be used in MDA, in
vitro studies demonstrated that Artemisia annua and Artemisia afra infusions or powdered
leaves were efficacious, where both clearly demonstrated potent inhibition of parasitemia and
gametocytemia. It has also been shown that Artemisia annua contains not only artemisinin but
also other components that demonstrate a synergistic complex anti-malaria effect. Artemisia
afra does not contain any artemisinin. In a recent human double-blind clinical trial and in
other previous studies both plants were reported to stably cure malaria, including
ACT-resistant cases as well as killing transmissible gametocyte forms. Their chemo protective
potential was also observed in these and other studies.
We believe that to effectively achieve malaria elimination in Rwanda, it is critical to
target the human reservoir of P. falciparum using local and readily available Artemisia
infusions. Asymptomatic infections detectable by PCR are an important reservoir because they
often persist for months and harbor gametocytes, the parasite stage infectious to mosquitoes.
III. Research objectives General objective; To provide a proof of concept that Artemisia
infusions, both annua and afra, are efficient and sufficient to eliminate residual Plasmodium
reservoirs following malaria treatment. The investigators will determine the current
prevalence of human Plasmodium reservoirs in our community and in our post malaria treated
patients, both the wild type, and mutated/resistant strains at King Faisal Hospital and
associated health facilities. We will further determine those associated with mutation in the
Kelch13 gene or other candidate genes implicated in treatment failure.
Specific objectives;
1. Provide a proof of concept that Artemisia infusions are efficient and sufficient to
empty human Plasmodium reservoirs in asymptomatic volunteers in community and following
malaria treatment.
2. Investigate P. falciparum household clusters in Under Five old malaria patients as well
as in individuals infected with strains carrying mutations associated with resistance to
treatment, and explore how engineering a Malaria Family Registry can be used as a tool
for better disease control in Rwanda
3. To assess the safety of Artemisia afra and Artemisia annua by monitoring urine chemistry
tests, kidney (urea, creatinine and electrolytes), and liver function tests
(transaminases, bilirubin).
4. To investigate the prophylactic potentials of Artemisia infusions once reservoirs have
been cleared.
5. Assess utilization and acceptability of Artemisia herbal medicine in Rwandan
communities.
6. Study the socio-economic impact of human Plasmodium reservoir drainage in Rwandan
community.
IV. Methodology
Study setting The study will be conducted on patients seeking medical care for malaria at
King Faisal Hospital, associated health facilities, CHUB, as well as in the community
targeting asymptomatic Plasmodium carriers.
Study design The study will be conducted as a proof of concept open randomized controlled
trial using permuted block randomization/random varying sizes. The investigators will recruit
at least 125 participants within 14 days following completion of standard malaria treatment.
Patients will be asked to sign informed consent and a PCR/RT-PCR will be performed to test
for P. falciparum reservoirs. We will use a Real Time PCR (qPCR) cut off cycle threshold (CT
value) above or equal to 40, which has been established based on negative African control and
European controls that have never been exposed to malaria before. Blood samples from the
recruited participants will also be investigated for single nucleotide polymorphisms (SNPs)
in the Kelch13 gene by sequencing the propeller domain of this gene within which point
mutations associated with Artemisinin resistance have been reported. In case of absence of
SNP in K13, the search for other gene mutation associated with treatment failure will be done
by whole genome sequencing and further addressed by laboratory parasite culture assays. From
the screened participants, one hundred (100) with residual parasites (induced reservoirs)
will then be assigned into 3 groups: two intervention groups and 1 control group
Sample size determination The investigators are planning a study of independent cases and
controls with 1 control for 2 cases. Preliminary data indicates that the failure rate among
controls is ≥ 0.75. If the true failure rate for treated subjects is ≤ 0.25, we need to study
at least 40 treatment subjects and 20 controls in order to detect such a difference with a
95% power at a 0.05 significance level. We will thus require 40 patients in each intervention
group and 20 controls, a total of 100. For us to randomize 100, we plan to screen at least
125 patients during our set recruitment period. Based on the fact that under 5 children are
the most vulnerable with the highest malaria associated mortality and morbidity and will not
participate in our clinical trials, we will recruit them as index cases for our household
clusters survey. Household members of these children will thus be screened using PCR to
establish status of plasmodium reservoirs and to ascertain if there are any mutations of
significance within the plasmodium circulating in the home. Confirmed reservoirs in adult
household members who consent will be treated with Artemisia tea.
Study population For the clinical approach, the study will recruit adults between 18 and 65
years for the Artemisia tea proof of concept intervention between 15th April 2023 until 30th
June 2026. However, based on the fact that under 5 children are the most vulnerable with the
highest mortality, the under 5 post malaria treated children will be included as index cases
for our household clusters survey and family registry development. Although children will not
be included during this initial proof of concept study, we intend to develop galenic
formulations appropriate to pediatric age group at a later stage.
For de community approach, asymptomatic household members will be screened using PCR/RT-PCR
to establish status of Plasmodium reservoirs and to ascertain if there are any mutations
within the residual Plasmodium circulating in the home. Based on this, a family registry
around the young children index cases will be built as a tracking tool, and Artemisia tea
given to the adults with a goal to eliminate the household cluster reservoirs. We will then
track over at least a 6 months' period to see if any differences in children whose household
clusters were treated with the infusions and those who were not with regard to malaria
infections. This will be tested as an additional potential malaria surveillance and control
measure.
To further investigate if Artemisia infusions could possess prophylactic potential, we intend
to pursue the study with the already enrolled participants by changing the posology. The 75%
of participants with reservoir emptied will be randomized in 3 groups: the first group of 12
participants will proceed with Artemisia tea one cup (335 ml) of 10g/L (A. afra) or 10g/L (A.
annua) every day; the second group of 12 participants will receive Artemisia tea one cup (335
ml) of 10g/L (A. afra) or 10g/L (A. annua) once every week; the last group of 6 participants
will be the controls. If the Artemisia infusions with either A. afra or A. annua block
Plasmodium reservoir fill up in more than 75% of the participants compared to less than 25%
of controls, then the study will have a 95% power to detect a difference between the
prophylactic group and the controls at a significance level of 0.025.
To monitor for toxicity, kidney and liver function tests will be investigated at the
beginning and after 14 days of Artemisia tea, as well as monthly during the prophylactic
phase of at least 6 months.
To address acceptability and impact of the research interventions, appropriate surveys will
be conducted.
Data management and analysis All data will be handled using standard confidentiality
principles and managed with EpiInfo and analyzed using STATA 17 software packages.
Participants will be described based on their socio-demographic characteristics as means and
standard deviations for continuous variables or proportions for categorical variables. An
intention-to-treat (ITT) analysis using two sample proportion will be used to determine the
chances of the plasmodium reservoir being emptied. Survival analysis with cox regression will
be carried out to evaluate the plasmodium reservoir emptying time and time for recrudescence
/ reinfection. Data will be compared between groups using either the Chi-square or Fischer
exact test after checking for the smallest expected value. Mean change from baseline Means
will be compared using either a parametric (student t or ANOVA) or a non-parametric
(Mann-Whitney/Wilcoxon or Kruskal-Wallis) test after checking for normality of distribution
and equality of variances.
Ethical considerations All study participants will have a detailed explanation about the
study and requested to freely sign a written informed consent. Ethics clearance has been
approved by the Rwanda National Ethics committee (120/RNEC/2022 May 2022, Amended October
2022). Rwanda Food and Drug Authority clearance application has been initiated.