TITLE: An implementation toolkit for the use of hydroxyurea in the treatment of sickle cell anemia in Ugandan children.
Principal Investigators: Principal Investigators: 1. Dr. Robert O. Opoka, MBChB, M.Med, MPH, PhD Associate Professor, Department of Paediatrics and Child Health College of Health Sciences, Makerere University 2. Dr. Angela L. Rollins, PhD Associate Research Professor, Psychology Department, Indiana University Purdue University Indianapolis, USA
Co-Investigators: Dr. Joseph Rujumba, PhD, Lecturer, Department of Paediatrics and Child Health, Makerere University, Dr. Deogratias Munube, MMed, Hematologist/Oncologist, Department of Paediatrics and Child Health, Mulago National Referral Hospital, Dr. Abner Tagoola, MMed, Senior Consultant Paediatrician, Jinja Regional Referral Hospital, Prof. Chandy John, MD, MS, Ryan White Center for Pediatric Infectious Disease, Indiana University, USA Dr. Russell Ware, Cincinnati Children’s Hospital, Cincinnati, USA
Brief description of the study
This will be an implementation science study which will help develop a toolkit which will enable health workers treat children with sickle cell anemia in Uganda using hydroxyurea. The study will run for a period of two years. The study will be implemented in two sites; that is Atutur district hospital and Jinja Regional Referral hospital. Data about hydroxyurea use will first be collected at national level from bodies like NMS, NDA, MOH, CPHL Mulago hospital sickle cell clinic staff and thereafter, the field team will move to their respective sites and collect data from the patients, caregivers and the sickle cell clinic staff.
The study has three objectives;
- Assess the uptake and proper use of hydroxyurea among SCA patients at Jinja and Atutur Hospitals as a result of the implementation toolkit pilot. Using existing protocols from clinical trials in hydroxyurea therapy, sickle cell clinics, and national clinical guidelines, we will develop a toolkit for hydroxyurea use. The toolkit will include indications, dosing, monitoring schedule, required level of expertise for health workers to prescribe and manage SCA patients with hydroxyurea, information for patients and caregivers, and learning materials to support these practices. After assembling the toolkit, we will assess the uptake and proper implementation of the tool kit in two sites: Jinja - a regional referral hospital in Jinja District and Atutur hospital in Kumi District. We will do this by establishing process and outcomes monitoring systems to support the collection of data to document implementation process. The uptake of hydroxyurea and fidelity to the proper use of hydroxyurea for SCA are the primary quantitative markers of success for this objective.
- Identify key facilitators and barriers for hydroxyurea use in Uganda and use the information to refine the implementation toolkit for use of hydroxyurea. Using a formative evaluation approach following the Consolidated Framework for Implementation Research (CFIR), we will identify key facilitators and barriers for hydroxyurea use in Uganda and use the information to refine the implementation toolkit and overarching implementation strategy. We will interview stakeholders to conceptualize national, regional, and health unit-level implementation factors. At pilot sites, we will employ observation, as well as key informant interviews and focus group discussions with patients, families, health workers, and clinic administrators to better understand hydroxyurea user and provider experiences as well as implementation factors for the intervention.
- Increase health workers’ knowledge and skills to support the implementation and continued advancement of hydroxyurea therapy in Uganda. In this study, we shall train a team of health workers in provision of hydroxyurea therapy and clinical audit techniques. In this way, we shall build capacity to support the continued advancement of hydroxyurea therapy in the country. In addition, we shall assess clinical knowledge, strengths and gaps at pilot sites, establishing ideal characteristics and roles for champions, and identify strategic support structures to guide future implementation of hydroxyurea.
The US National Institute of Health.
Organizational affiliation of researchers
- Indiana University
- Makerere University
Implementation science study
TITLE: Malarial Impact on Neurobehavioral Development (MIND) Study
Principal Investigators: Chandy C John, MD, MS, Indiana University and Paul Bangirana, PhD, Makerere University
Co-Investigators: Andrea Conroy, PhD, Indiana University, Dibyadyuti Datta, MS, PhD, Indiana University, Wanzhu Tu, MS, PhD, Indiana University, Robert O. Opoka, MBChB, M.Med, MPH, MHPE, Makerere University, Richard Idro, MBChB, M.Med, PhD, Makerere University, Ruth Namazzi, MBChB, MMED, Makerere University, Bjarne Robberstad, Msc, PhD, University of Bergen, Margaret Semrud-Clikeman, PhD University of Minnesota, USA, Noeline Nakasujja, MBChB, M.Med, PhD, Makerere University
Brief description of the study
This will be a longitudinal cohort study with a 5 year follow up where caregivers and children with the five most common forms of severe malaria that is cerebral malaria(CM), severe malarial anemia(SMA), malaria with repeated seizures(M/S), respiratory distress(RD), prostration(PR) and healthy community children(CC) from the same neighborhood or household as the children with malaria will be assessed for;
1) To establish the duration and age specific manifestations of neurobehavioral sequelae of severe malaria from childhood to adulthood;
2) Determine the functional and economic costs of neurobehavioral sequelae of severe malaria; and
3) Identify the metabolic, immunologic and parasitic factors predictive of long-term neurobehavioral and functional impairment after severe malaria.
The US National Institutes of Health.
Organizational affiliation of the researchers
1. Indiana University
2. Makerere University
3. University of Bergen
4. University of Minnesota
Longitudinal cohort analysis
Optimizing Benefits While Reducing Risks of Iron in Malaria Endemic Areas.
1. Dr. Ezekiel Mupere, MBChB, MMED, MS, PhD, Department of Paediatrics and Child Health, Makerere University. College of Health Sciences, School of Medicine.
2. Dr. Sarah Cusick, PhD Assistant Professor, Department of Pediatrics, University of Minnesota, School of Medicine.
-Robert O. Opoka, MBChB, MMED Makerere University
-Paul Bangirana, PhD Makerere University
-Deogratius Munube, MBChB, MMed Mulago Hospital
-Michael Georgieff, MD University of Minnesota
-Troy Lund, MD, PhD University of Minnesota
-Maria Kroupina, PhD University of Minnesota
-Michael Sadowsky, PhD University of Minnesota
-James Hodges, PhD University of Minnesota
SPONSOR: National Institutes of Health (NIH).
BRIEF DESCRIPTION OF THE STUDY:
Study design: Randomized, placebo controlled trial of daily oral therapy started concurrently (immediate iron ) or 28 days after (delayed iron) with antimalarial treatment in Ugandan children with uncomplicated malaria and iron deficiency.
1. Establish the effect of immediate Vs delayed iron treatment on long -term iron status.
2. Determine the effect of delayed iron treatment on the incidence of infectious illnesses.
3. Establish the effect of delayed iron treatment on neurobehavioral development.
To determine the effect of immediate vs. delayed iron on the intestinal microbiome profile.
Ugandan children 6-48 months with uncomplicated malaria, anemia, and iron deficiency and healthy, non-anemic community children.
Total of 600 participants (480 Primary children with uncomplicated malaria and iron deficiency and 120 Healthy Community controls).
Daily iron (ferrous sulfate, 2mg/kg/day) or placebo syrup for the first four months, (112 days) of the 12-months (336-days) study.
Study Duration for Individual Participants:
12 months (336) days
Name of the project.
Dihydroartemisinin-Piperaquine or Sulphadoxine Pyrimethamine for the Chemoprevention of Malaria in Children with Sickle Cell Anaemia in eastern and southern Africa: a double-blind randomized trial (the CHEMCHA trial).
- Dr Richard Idro, PhD, Makerere University College of Health Sciences.
- Prof Kamija Phiri, PhD, College of Medicine, University of Malawi Faculty of Medicine.
- Dr Thandile Gondwe, College of Medicine, Malawi, Site-PI Malawi.
- Dr Kondwani Kawazi, College of Medicine, Malawi, Co-Investigator, Malawi.
- Dr Robert O. Opoka, Makerere University, Uganda, Site-PI, Uganda.
- Joseph Rujumba, Makerere University, Uganda, Co-Investigator.
- Joseph Ssenkusu, Makerere University, Uganda, Statistician
- Prof Chandy C. John, Indiana University USA, Co-investigator.
- Prof Bjarne Robberstad, University of Bergen, Norway, Co-investigator
- Prof Feiko ter Kuile, Liverpool School of Tropical Medicine, Uk, Co-investigator.
Overview of the project and objectives.
Background and rationale:
An estimated 300,000 babies are born with Sickle Cell Anaemia (SCA) annually. Affected children have chronic ill health and many suffer premature death. Ill health is commonly precipitated by febrile illnesses including malaria. Antimalarial chemoprophylaxis is an important strategy, but current regimes are either sub-optimally effective (e.g. monthly sulphadoxine-pyrimethamine, SP) or difficult to adhere to (e.g. daily proguanil). We propose Dihydroartemisinin-Piperaquine (DP) as the agent with most potential to be used across Africa.
Aim of the study:
The study is aimed to produce the necessary evidence to assess whether weekly DP should be recommended as a strategy for malaria chemoprevention in children with Sickle Cell Anemia.
Our objective is to determine the efficacy, safety, uptake, acceptability and cost effectiveness of malaria chemoprevention with weekly single day courses of DP vs monthly single day courses of SP in children with SCA in eastern and southern Africa.
- To assess the feasibility and stakeholder perspectives on the uptake (acceptability) and the potential for future roll-out of weekly DP versus monthly SP.
- Determine the safety and cumulative dosing of DP, especially on cardiac function.
- Monitor the development of malaria parasite resistance to DP in clinical isolates over time.
- Assess patients’ health-related quality of life, cost-effectiveness, equity and economic implications of using weekly courses of DP versus monthly courses of SP as chemoprevention in SCA.
- Assess acceptability of weekly courses of DP for malaria chemoprevention in SCA versus monthly courses of SP as chemoprevention in SCA.
- Conduct policy advocacy to engage key stakeholders on policy decisions on using weekly courses of DP or monthly courses of SP for the chemoprevention for the chemoprevention of malaria in SCA.
Funder: The Research Council of Norway, Global Health and Vaccination Research (GLOBVAC)
Sponsor: Liverpool School of Tropical Medicine (LSTM)
- University of Bergen
- Makerere University
- Global Health Uganda.
- The University of Malawi.
- Training and Research Unit of Excellence (Malawi).
Randomized, double-blind, parallel-group superiority trial
Title: Hydroxyurea therapy for Neurological and Cognitive Protection in Pediatric Sickle
Cell Anemia in Uganda: a single arm open label trial.
|Background and rationale:|
Annually, an estimated 200,000 babies are born with Sickle Cell Anemia (SCA)
worldwide. Affected children often suffer repeated acute illnesses and chronic ill health
from vascular occlusive phenomenon. In particular, they are at a high risk of stroke due
to the development of sickle cell cerebral vascular (SCV) injury. SCV can also cause
neurocognitive impairment. Stroke risk may be predicted by abnormal cerebral arterial
flow detected by transcutaneous Doppler ultrasound (TCD). We propose a trial to test
the impact of daily hydroxyurea treatment over 3 years in children with sickle cell
anemia on the frequency and severity of SCV.
The specific aims are:
Determine the impact of hydroxyurea therapy on the frequency and severity of SCV in a
cohort of children treated for three years, as measured by 3 distinct outcomes: abnormal TCD,
neurocognitive impairment and primary stroke, compared with baseline.
In aim 1: we will enroll a new longitudinal cohort of 270 children ages 3-9 years selected
randomly from among eligible patients attending Mulago hospital SCA clinic (MHSCC) roster,
without evidence of prior stroke by examination. The hypothesis is that hydroxyurea therapy will
prevent, stabilize or improve SCV and its effects. Eligible subjects will be evaluated by TCD,
stroke-focused neurological examination and neurocognitive testing at baseline. Following initial
assessments, study subjects will begin standardized hydroxyurea therapy. Overtime, we shall
compare changes in the frequency and severity of each distinct measure of SCV with baseline by
repeating these three tests at 18 and 36 months and against the age specific prevalence of SCV in
children who did not receive any intervention in the earlier BRAIN SAFE I observational study.
Evaluate the impact of hydroxyurea on structural SCV using MRI and MRA in a
randomly selected subset of this cohort.
In Aim 2, a subset of the study subjects, a randomly selected subset of 90 subjects, will undergo
brain imaging at baseline and at 36 months to assess structural findings over time. The
hypothesis is that prospective brain imaging by MRI and MRA provides critical structural
definitions of SCV changes or stabilization over three years compared to baseline, while on
hydroxyurea. Results of brain imaging and biomarkers will be correlated with these outcomes
Assess changes to anemia, malnutrition status, C-reactive protein and other inflammatory
markers during hydroxyurea therapy, over time, compared with baseline levels.
In aim 3, we shall prospectively examine for risk factors for SCV overtime. Biomarkers for risk
of SCV may include severe anemia, the inflammatory marker C-reactive protein (CRP) and
malnutrition status. The hypothesis is that a higher burden of anemia, inflammation and
malnutrition predispose African children with SCA to greater burden of SCV than in the West.
Changes in the values of these biomarkers will be assessed over time while on hydroxyurea.
This will be an open label, single arm trial of hydroxyurea to test the three-year impact
of hydroxyurea treatment in children with SCA on each of three clinically important outcomes:
abnormal cerebral arterial flow, neurocognitive impairment and primary stroke
Site: Participants will be recruited from Mulago hospital SCA Clinic in Kampala, Uganda.
|1. Dr Richard Idro, MMED, PhD, Makerere University College of Health Sciences.|
2. Prof Nancy S. Green, MD, Department of Pediatrics, Columbia University.
Research Training in Infection and Neurodevelopment in Uganda.
Aim 1. Expand research expertise in Uganda in the areas of:
1.Neurodevelopmental and cognitive assessment,through training of a doctoral student and post-doctoral fellow in neuropsychology at Makerere University.
2. Nutrition-related risk of infection and neurocognitive impairment, through training of a post-doctoral fellow in nutritional epidemiology at Makerere University.
3. Epidemiology and pathogenesis of infection-related brain injury, through training of a doctoral student and post-doctoral fellow in infectious disease epidemiology at Makerere University, and training of a doctoral student in immunology at Indiana University.
Students will conduct their research within ongoing malaria, HIV and micronutrient deficiency research projects and will participate in integrated core training designed to foster interdisciplinary collaboration. Epidemiology trainees will complement their on-site training with Masters of Infectious Disease Epidemiology online training from the London School of Tropical Medicine and Hygiene. At completion of training, graduates will be ready for positions as university faculty or in the Ministry of Health, working on research and/or interventions to understand, prevent and treat infection-related neurocognitive impairment.
Aim 2. Build research capacity in Uganda through development of a core laboratory and data management center, and workshop and short-term training of clinical and laboratory personnel.
The core lab and data management centers established in the prior period will be enhanced, with additional lab capacity for molecular biology studies, and additional data center database and statistical capability. Focused workshop and short-term training will be provided to medical, neuropsychology, and laboratory personnel involved in research studies at Makerere University, to build on-site research capacity in the areas of infectious disease, nutrition and neurodevelopment research. At the project completion, quantifiable improvement in research capacity will lead to an improved research environment that supports further independent work in infectious disease, nutrition and neurodevelopment.
Aim 3. Advance research capacity in Uganda through research administration training.
Independent research capacity requires expertise in research administration. The renewal application will build on the strengths of administration training provided by the original grant by providing training for Masters Degrees in Management Studies and in Business Administration, with a focus on research study administration
Principal Investigator: Dr. Idro Richard
Renewed for another 5 years till 2023
An observational follow up extension study of the cohort of children who participated in the randomized, double-blinded clinical trial of hydroxyurea at fixed dose (20 mg/kg/day) compared to maximum tolerated dose (MTD) hydroxyurea in Ugandan children living in a malaria endemic area. The aim of this follow up extension study is to obtain long-term follow-up data to assess laboratory and clinical effects, as well as organ function (liver, kidneys, spleen, brain), growth and development.
Status: Active/ Ongoing
Location: Both studies are conducted at Mulago National referral Hospital Kampala
Principal Investigator: Dr. Opoka Robert
R25 Global Health Fellowships
1. Dr. Damalie Nalwanga
2. Dr. Theresa Piloya
3. Dr. Ahmed Ddungu
4. Mr. Tom Ngabirano
Sickle Cell Disease in a Low Resource Area: Benefits of Hydroxyurea in Mitigating Early Onset Lung Disease.
Principal Investigator: Dr. Aanyu Hellen.
Title: The Role of Iron Deficiency in the Neurodevelopment of Children Perinatally Exposed to HIV (ID-ND study)
1. Sarah Cusick, Ph.D. Assistant Professor, Department of Pediatrics, University of Minnesota, Minneapolis, Minnesota, USA
2. Victor Musiime, MBChB, MMed, PhD, Senior Lecturer, Makerere University College of Health Sciences; Investigator, Joint Clinical Research Centre, Kampala, Uganda
1. Paul Bangirana, PhD Makerere University
2. Michael Georgieff, MD University of Minnesota
3. Maria Kroupina, PhD University of Minnesota
ID-ND study will examine how iron deficiency is related to brain function in children perinatally exposed to HIV. It is being conducted by Dr. Sarah Cusick – University of Minnesota, Minneapolis, USA, and Dr. Victor Musiime from Joint Clinical Research Centre, Kampala, Uganda.
Our major aim is to establish the iron status of perinatally exposed children 6-59 months and to determine whether iron status is associated with neurobehavioral test scores. The cross-sectional study will enroll a total of 210 children between the ages of 6 and 59 months: 70 infected with HIV, 70 exposed to HIV during gestation but uninfected themselves, and 70 unexposed, uninfected children identified in the community.
HI children will be consecutively recruited from the Pediatric Clinic at JCRC. Potential HEU children will be identified at the Prevention of Maternal to Child Transmission (PMTCT) clinic in the adult clinic at JCRC, HUU children will be identified in the community by community liaison volunteers affiliated with JCRC, but all interested caregivers and their children will be led to the Pediatric clinic to determine study eligibility so that informed consent can be obtained and eligibility criteria verified.
We will administer neurobehavioral tests [Behavioral Rating Scales, Mullen Scales of Early Learning, Early Childhood Vigilance Test (ECVT), Behavioral Rating Inventory of Executive Function (BRIEF) and the Child Behavior Checklist (CBCL)] and compare outcomes in each group of children by iron status. We shall also have a single venous blood draw of 5-7 mL. per child.
The study will evaluate the relationship between measures of body iron and scores of learning, memory, and behavior in children exposed to HIV as compared to children not exposed to HIV.
The aim of the project is to establish a Center Of Excellence For Patient-Centered Care And Non-Communicable Disease Management In Uganda.
1. Dr. Robert Kalyesubula
2. Dr. Kayongo Alex
Project wrapping up.
Implementing a digital Child mental Health screening, literacy and Management Tool in Faith based settings.
Principal Investigator: Dr. Janet Nakigudde.
Oral Antihyoertensive Therapy: Apathway to efficient reduction of Maternal Complications from Severe Hypertension in Low Resource Environments.
Principal Investigator: Dr. Ononge.
Project is winding up.
Title: Malaria Associated Pathogenesis of Chronic Kidney Disease (MAP-CKD) Study
Sponsor: The US National Institutes of Health, National Institute of Allergy and Infectious Diseases (NIAID), Kidney Disease Obesity and Nutritional Disorders
Principal Investigator: Dr Andrea L. Conroy, PhD, Indiana University
Site Principal Investigator: Dr Anthony Batte, MBChB, MMED, Pediatric Nephrology, Makerere University/ Global Health Uganda.
Study sites: Mulago national referral and teaching hospital, Jinja and Lira regional referral hospitals
Study design: Prospective multi-site cohort study.
Sample size:939 children
Duration: 5 years
The objective of this study is to prospectively define the impact of severe malaria in childhood on kidney injury and recovery and to define pathways of maladaptive repair that may represent modifiable targets to improve long-term outcomes following Acute Kidney Injury (AKI). This study will provide the first prospective data to comprehensively evaluate kidney recovery following severe malaria associated AKI.
- To determine risk factors for short-term and long-term kidney disease following severe malaria
- To define host pathways associated with maladaptive kidney repair following severe malaria associated AKI.
- To define the impact of AKI and persistent kidney disease on morbidity, mortality, and health-related quality of life.
Primary outcome measures:
Chronic kidney disease (CKD) defined as an eGFR<90mL/min/1.73m2 or age-specific albuminuria
Title: Blood-Biomarkers and Risk Factors of Acute Brain Injury associated with Neurodisability in Ugandan Children (BRAIN-Child) Study
Sponsor: The US National Institutes of Health, The National Institute of Neurological Disorders and Stroke (NINDS)
Principal Investigator: Dibyadyuti Datta, MS PhD, Indiana University School of Medicine
Site Principal Investigator: Paul Bangirana, PhD, Makerere University
University/ Global Health Uganda.
Study site: Mulago national referral and teaching hospital
Study design: A longitudinal cohort study.
Sample size: 300 children
Duration: 2 years
Persistent neurocognitive impairments (NCI) are common complications of two seemingly unrelated neural system disorders that cause brain injury in children. I.e.. cerebral malaria(CM)and traumatic brain injury(TBI).
Pediatric cerebral malaria, continues to be a high burden in most African nations.
Hence the global need for reliable, non-invasive diagnostic stools that can predict the risk future NCI as soon as possible after ABI.
Children in particular would benefit from the new research that could lead to early therapeutic interventions
This study would address the critical need in Uganda , where there is an increasing burden of noninfectious diseases such as TBI in the already malaria affected setting adding to the risk of future NCI.
- Determine if biomarkers and risk factors of brain injury elevated in pediatric cerebral malaria (CM) are elevated in pediatric traumatic brain injury (TBI)
- Determine if elevated brain injury biomarkers in pediatric TBI correlate with post-discharge mortality, neurocognitive impairment (NCI), or health-related quality of life outcomes at 6-month follow-up
- Expand capacity for interdisciplinary NCI research in Uganda by supporting training in neuropsychological methods that apply to NCI after pediatric TBI.
Primary outcome measures:
- Admission/enrollment biomarker levels.
- Neurocognitive outcomes outcomes (age-adjusted z-scored) at follow-up (1-2 weeks and 6 months)
Title: Dihydroartemisinin-piperaquine and azithromycin for the post-discharge management of children with severe anaemia in Malawi, Kenya and Uganda; A multicentre, parallel-group, two-arm, randomised, double-blind superiority trial
Funder: European & Developing Countries Clinical Trials Partnership (EDCTP)
Sponsor: Training and Research Unit of Excellence (TRUE), P.O. Box 30538, Blantyre, Malawi.
Partners institutions: Training and Research Unit of Excellence; University of Bergen; Makerere University; Global Health, Uganda; KEMRI-CDC, Kenya; Indiana University; Liverpool School of Tropical Medicine; University of Amsterdam; US Centers for Disease Control and Prevention, Kenya.
Chief Investigator: Prof Kamija S. Phiri, TRUE and KUHes, Malawi
Country Co-Principal Investigators:
- Dr Richard Idro, Department of Paediatrics and Child Health, Makerere University
- Dr Robert Opoka, Department of Paediatrics and Child Health, Makerere University/Global Health Uganda
- Dr Simon Kariuki, KEMRI Centre for Global Health Research (CGHR) and CDC Collaboration
- Prof Feiko ter Kuile, KEMRI/CDC and LSTM, Pembroke Place, L3 5QA Liverpool, United Kingdom
- Dr Thandile Gondwe, Training and Research Unit of Excellence, Malawi
Background: Severe anaemia is associated with significant post-discharge morbidity and mortality in children in malaria-endemic Africa. A recent trial in Kenya and Uganda showed that three months of post-discharge malaria chemoprevention (PDMC) with monthly dihydroartemisinin-piperaquine (DP) in recently transfused children with severe anaemia prevented 35% of deaths or all-cause readmissions by six months post-discharge. The protective effect was restricted to the 3-month PDMC intervention period. PDMC-DP did not affect non-malarial causes of readmissions; 45% and 80% of the remaining readmissions and sick-child clinic visits (SCCV) were due to other causes. We hypothesise that the beneficial effect of PDMC can be boosted further by combining DP with azithromycin (AZ), a potent broad-spectrum antibiotic known to reduce all-cause mortality in African children.
Primary efficacy objective: To determine if PDMC with 4 courses of monthly AZ treatment in combination with 4 months of weekly DP is superior to PDMC with weekly DP-alone in reducing non-malaria SCCV by six months post-discharge in children aged <5 years admitted with severe anaemia (Hb<5g/dl) who are ready to be discharged and are clinically stable and able to switch to oral medication.
Study Type: A multi-centre, 2-arm, placebo-controlled, randomized-controlled superiority trial.
Sample size: 958 participants (479 per arm).
Sites: 6 hospitals, 2 in Malawi, 2 in western Kenya and 2 in Uganda, in areas with moderate to intense malaria transmission. The number of hospitals will be expanded during recruitment if so required
Follow-up procedures: Children will be followed for 6 months by passive case detection in 3 phases: Pre-intervention (1 week between discharge and randomisation); Intervention (1-17 weeks post-discharge); post-intervention (extended follow-up period from 18 to 26 weeks post-discharge)
Capacity building: Two post-doctoral fellows and four PhD fellows will be trained through the PDMC II project
Tittle: The Relationship Between Mean Glucose And Hba1c In Ugandan Youth With T1d: An Observational Study
Principle Investigator: 1. Antoinette Moran, MD. University of Minnesota 2. Thereza Piloya-Were, MD. Makerere University, Kampala Uganda
Co-Investigator: Dr Catherine Nyangabyaki MD, St Francis Hospital Nsambya, Kampala Uganda
Brief Description of the study
This is a multicenter observational study among African youth living with T1D. The one-year study targeting 60 participants works on a cohort of 20 participants for 6 weeks aged between 4-26years. Glucose sensors are inserted in each participant for 10-14 days to continuously monitor their blood glucose.
At baseline there will be a screening point-of-care (POC) HbA1c level.
Once eligibility is confirmed, a one-time blood draw will be done for complete blood count (CBC), peripheral smear, reticulocyte count, Lactate Dehydrogenase levels (LDH), hemoglobin electrophoresis (Hb electrophoresis), Glucose 6-Phosphate Dehydrogenase (G6PD) levels, ferritin levels, and total iron binding capacity. Repeat tests at each 2 week period include laboratory and POC HbA1c at period beginning and end, and Continuous glucose monitor (CGM) upload at period end, data is then compared to the subsequent labatory and POC HbA1Cs to study the relationship.
- To determine the relation between laboratory measured HbA1c and mean glucose as measured by continuous glucose monitoring (assessed over 10-14 days per sensor period)
- To determine the consistency of the relation between laboratory measured HbA1c and the mean glucose using multiple measurements in Ugandan Children and Youth
- To determine relation between laboratory measured HbA1c and factors known to impact red blood cell survival
- To determine the relation between point of care HbA1c and mean glucose in this population
Study location: The study will take place at the pediatric diabetes clinics at Mulago hospital and St. Francis Nsambya Hospital, both in kampala and in near proximity each other.
Study sponsor: This is an investigator Initiated Study. Abbott Diabetes Care is supplying both the Freestyle Libre Pro CGM sensor device and the Freestyle Libre2 CGM sensor Device. They are providing travel funds to the Minnesota team to train Ugandans, also covering local investigator time, laboratory and patient costs.
TITLE: Diabetes in African Youth; Improving Glucose Time-In-Range (DAY Time).
The United States National Institute of Health.
(NIH NATL INST OF DIABETES/DIG/KIDNEY DIS)
SITE PI; 1. Dr Thereza Piloya-Were; Pediatric endocrinologist, Principal investigator (Mulago National Referral and Teaching Hospital.
- Dr, Catherine Nyangabyaki; Pediatrician; Co- Principal Investigator (St. Francis Hospital Nsambya).
- Dr, Antoinette Moran, Principal Investigator, University of Minnesota.
- Mulago National Referral and Teaching Hospital
- Francis Hospital Nsambya.
University of Minnesota – Data monitoring and coordinating center.
STUDY DESIGN: Randomized Clinical Trial
SAMPLE SIZE: 180 participants
DURATION: 5 years (August 1, 2022 – July 31 2027) with individual participant follow up for 12 months.
This Randomized Clinical Trial aims to improve Type 1 Diabetes care in East African children and Young adults by testing the hypothesis that enabling patients to continuously monitor glucose levels, with flash Continuous Glucose Monitor (CGM) technology will improve glucose-time-range (glucose level 70-180mg/dl); compared to the existing standard of care of self-monitoring of blood glucose with finger pokes.
- To determine if patient ability to continuously observe plasma glucose levels for 6 months using flash intermittently scanned CGM improves glucose time in range compared to baseline. The change in glucose time in range while wearing the unblinded CGM will be compared to change in time in range in patients performing 3x/day Self-monitoring of blood glucose (wearing a blinded CGM for end point measurement).
- To perform a cost analysis on flash glucose monitoring compared to 3x day self-monitoring of blood glucose, to determine whether this technology is cost effective in the setting of a low resource nation.
Novel use Of Hydroxyurea in an African Region with Malaria (NOHARM): A trial for children with sickle cell anemia
1. Compared to placebo, hydroxyurea did not increase the incidence or severity of malaria events in Ugandan children with sickle cell anemia.
2. Hydroxyurea provided significant clinical and laboratory benefits, suggesting it will be safe and effective across sub-Saharan Africa.
Novel use Of Hydroxyurea in an African Region with Malaria (NOHARM): A trial for children with sickle cell anemia
1. Compared to placebo, hydroxyurea did not increase the incidence or severity of malaria events in Ugandan children with sickle cell anemia.
2. Hydroxyurea provided significant clinical and laboratory benefits, suggesting it will be safe and effective across sub-Saharan Africa.
Hydroxyurea treatment is recommended for children with sickle cell anemia (SCA) living in high-resource malaria-free regions, but its safety and efficacy in malaria-endemic sub-Saharan Africa, where the greatest sickle cell burden exists, remain unknown.
In vitro studies suggest hydroxyurea could increase malaria severity, and hydroxyurea-associated neutropenia could worsen infections. NOHARM was a randomized, double-blinded, placebo-controlled trial conducted in malaria-endemic Uganda, comparing hydroxyurea to placebo at 20 ± 2.5 mg/kg/day for 12 months.
The primary outcome was incidence of clinical malaria. Secondary outcomes included SCA-related adverse events, clinical and laboratory effects, and hematological toxicities. Children received either hydroxyurea (N=104) or placebo (N=103).
Malaria incidence did not differ between children on hydroxyurea [0.05 episodes/child/year, 95% CI (0.02, 0.13)] versus placebo [0.07 episodes/child/year (0.03, 0.16)]; the hydroxyurea/placebo malaria incidence rate ratio was 0.7 [(0.2, 2.7), p=0.61].
Time to infection also did not differ significantly between treatment arms. A composite SCA-related clinical outcome (vaso-occlusive painful crisis, dactylitis, acute chest syndrome, splenic sequestration, or blood transfusion) was less frequent with hydroxyurea (45%) than placebo (69%, p=0.001).
Children receiving hydroxyurea had significantly increased hemoglobin concentration and fetal hemoglobin, with decreased leukocytes and reticulocytes. Serious adverse events, sepsis episodes, and dose-limiting toxicities were similar between treatment arms.
Three deaths occurred (two hydroxyurea, one placebo, none from malaria). Hydroxyurea treatment appears safe for children with SCA living in malaria-endemic sub-Saharan Africa, without increased severe malaria, infections, or adverse events. Hydroxyurea provides SCA-related laboratory and clinical efficacy, but optimal dosing and monitoring regimens for Africa remain undefined.
Aim 1. Establish needed research expertise in Uganda in the areas of:
1.Neurodevelopmental and cognitive assessment, through training of two doctoral students and a post-doctoral fellow in neuropsychology at Makerere
2. Epidemiology and pathogenesis of infection-related brain injury, through doctoral training for epidemiology, microbiology and immunology at Makerere University, and biostatistics at the University of Minnesota; and Masters of Medicine training for two residents at Makerere University in translational infectious disease and neurology
All students will conduct their research within the University of Minnesota-Makerere University cerebral malaria and meningitis research projects and will participate in integrated core training. This training is designed to foster interdisciplinary collaboration. At completion of training, graduates will be ready for positions as university faculty or in the Ministry of Health, working on research and/or interventions to understand, prevent and treat infection-related neurocognitive impairment.
Aim 2. Identify and implement best practices in faculty mentorship at Makerere University. A mentorship committee will be set up with faculty from Makerere University and the University of Minnesota (UMN). This committee will review guidelines and best practices information from other universities, conduct a survey of faculty at Makerere University and peer universities, and develop best practices guidelines for mentorship at Makerere University. These practices will then be implemented in the departments involved in this training grant, and feedback obtained after one year that will allow for revision of guidelines. By the grant’s completion, a document for mentorship training will be generated and provided to Makerere University leadership for consideration of University-wide implementation.
Aim 3. Build research capacity in Uganda through workshop and short-term training for medical, laboratory, and database personnel.
Focused workshop and short-term training will be provided to medical, neuropsychology, laboratory, and database personnel involved with the study and other research studies at Makerere University, to build on-site research capacity in the areas of infectious disease and neurodevelopment research. At the project completion, quantifiable improvement in research capacity will lead to an improved research environment that supports further independent work in infectious disease and neurodevelopment.
The excellent teaching and training facilities at Makerere University, including the Makerere University Microbiology and Immunology laboratories and the clinical and data offices allow for most training and course work to be performed in Uganda. Supplemental course work and laboratory training will be provided at the UMN for PhD students and post-doctoral fellows, and distance learning capabilities and visiting lecturers from UMN will provide important UMN resources to trainees who remain in Uganda. The Center for Infectious Diseases and Microbiology Translational Research (CIDMTR) at UMN provides a particularly excellent site for higher-level laboratory and epidemiology and biostatistics training. The combination of course work and integrated core training, including clinical, lab, and neuropsychology rotations for all trainees, and the interdisciplinary nature of the research grants in which trainees will conduct research, provide an excellent basis for development of well-rounded researchers willing to explore complex research questions. The training focus of this proposal, bringing together basic science, clinical, epidemiologic and statistical researchers to better understand and prevent infection-relate neurocognitive impairment, addresses a major gap in translational infectious disease research training in Uganda. The novel training proposed will create a new generation of interdisciplinary researchers who can work together to understand, prevent, and treat infection-related neurocognitive morbidity in Uganda.
A3. Infection and neurocognitive impairment in sub-Saharan Africa
A3a. Infection and neurocognitive impairment in children in sub-Saharan Africa
Studies by our research team in Uganda have documented that one in four children with cerebral malaria will have long-term cognitive impairment. Given the frequency of cerebral malaria in sub-Saharan Africa, these findings suggest that up to 200,000 children annually may develop long-term cognitive impairment from cerebral malaria. Other studies have demonstrated that even repeated episodes of uncomplicated malaria are associated with impaired cognition and worse school performance. Additional studies in children in developing countries have demonstrated cognitive or neurodevelopmental impairment associated with repeat episodes of diarrheal disease schistosomiasis and various intestinal helminth infections.
PI: Professor Sarah Kiguli.
Transfusion and Treatment of severe anaemia in African children (TRACT): A study protocol for a randomized controlled trial.
In sub-Saharan Africa, where infectious diseases and nutritional deficiencies are common, severe anaemia is a common cause of paediatric hospital admission, yet the evidence to support current treatment recommendations is limited.
To avert overuse of blood products, the World Health Organisation advocates a conservative transfusion policy and recommends iron, folate and anti-helminthics at discharge. Outcomes are unsatisfactory with high rates of in-hospital mortality (9-10%), 6-month mortality and relapse (6%).
A definitive trial to establish best transfusion and treatment strategies to prevent both early and delayed mortality and relapse is warranted.
TRACT is a multicentre randomized controlled trial of 3954 children aged 2 months to 12 years admitted to hospital with severe anaemia (haemoglobin < 6 g/dl). Children will be enrolled over 2 years in 4 centres in Uganda and Malawi and followed for 6 months.
The trial will simultaneously evaluate (in a factorial trial with a 3 x 2 x 2 design) 3 ways to reduce short-term and longer-term mortality and morbidity following admission to hospital with severe anaemia in African children.
The trial will compare:
(i) R1: liberal transfusion (30 ml/kg whole blood) versus conservative transfusion (20 ml/kg) versus no transfusion (control). The control is only for children with uncomplicated severe anaemia (haemoglobin 4-6 g/dl);
(ii) R2: post-discharge multi-vitamin multi-mineral supplementation (including folate and iron) versus routine care (folate and iron) for 3 months;
(iii) R3: post-discharge cotrimoxazole prophylaxis for 3 months versus no prophylaxis. All randomisations are open.
Enrolment to the trial started September 2014 and is currently ongoing. Primary outcome is cumulative mortality to 4 weeks for the transfusion strategy comparisons, and to 6 months for the nutritional support/antibiotic prophylaxis comparisons. Secondary outcomes include mortality, morbidity (haematological correction, nutritional and infectious), safety and cost-effectiveness.
If confirmed by the trial, a cheap and widely available ‘bundle’ of effective interventions, directed at immediate and downstream consequences of severe anaemia, could lead to substantial reductions in mortality in a substantial number of African children hospitalized with severe anaemia every year, if widely implemented.
Completed (Dec 2018)
Principal Investigator (Uganda):
Noeline Nakasujja, MB ChB., MMed., PhD. Department of Psychiatry, Makerere University College of Health Sciences.
Principal Investigator (USA):
Michael J. Boivin, Ph.D., MPH. International Neurologic & Psychiatric Epidemiology Program, Michigan State University.
1. Bruno Giordani – Ph. D. Neuropsychology Section, Department of Psychiatry, University of Michigan.
2. Robert Opika Opoka – MB ChB., MMed. MPH. Department of Pediatrics & Child Health, Makerere University College of Health Sciences.
3. Paul Bangirana -PhD. Department of Psychiatry, Makerere University College of Health Sciences.
4. Connie Page – PhD. Department of Statistics and Probability, Michigan State University.
5. Chandy C. John – MD., M.S. Department of Pediatrics, University of Minnesota.
6. Richard Idro – MB ChB., MMed., PhD. Department of Pediatrics & Child Health, Mulago Hospital.
7. Jed Magen, DO, MS. Department of Psychiatry, Michigan State University.
Mulago Hospital, Kampala.
1. To evaluate the effectiveness of Computerized Cognitive Rehabilitation Training (CCRT) in improving neuropsychological performance and psychiatric outcomes in Ugandan children who survive severe malaria.
2. To evaluate whether severity of malaria illness (e.g., immunological brain inflammation, EEG abnormalities) is predictive of neuropsychological benefit from CCRT.
Inhaled Nitric Oxide as Adjunctive Therapy for Malaria : A Randomized Controlled Trial
Principal investigator (Uganda):
Robert Opika Opoka, MB ChB., MMed., MPH. Department of Pediatrics & Child Health, Makerere University College of Health Sciences.
Principal investigator (Canada):
Kevin Kain – MD, FRCPC Professor of Medicine, Canada Research Chair in Molecular Parasitology,
Director of Global Health – McLaughlin Center for Molecular Medicine, University of Toronto, Director,
Sandra A. Rotman Laboratories – McLaughlin-Rotman Centre for Global Health, Director, Center for Travel and Tropical Medicine, Toronto General Hospital
1. Dr. AbnerTagoola – MBChB, MMED, MPH, Jinja Regional Referral Hospital
2. Dr. Sophie Namasopo – MBChB, MMED, Jinja Regional Referral Hospital
3. Dr. Chandy C. John – M.D., M.S., Department of Pediatrics, University of Minnesota.
4. Dr. W. Conrad Liles – MD, PhD, Department of Medicine, University of Toronto.
5. Dr. Michael Hawkes – MD, FRCPC, Institute of Medical Sciences, University of Toronto Dr. Christopher Miller, PhD, University of British Columbia.
Jinja Regional Referral Hospital, Jinja District.
To determine the efficacy of inhaled nitric oxide for the adjunctive treatment of P. falciparum malaria.
Our specific aim is:
To determine whether supplemental low flow inhaled nitric oxide gas (80 ppm) in addition to Ugandan Standard of Care treatment reduces levels of angiopoeitin-(Ang-2) from baseline in children with moderately severe and severe malaria compared to Standard of Care treatment alone.
Uterine Balloon Tamponade for Postpartum Hemorrhage in Three Low Income Countries.
Postpartum hemorrhage (PPH) is one of the main contributors to maternal morbidity and mortality globally.
Though administration of a uterotonic effectively controls bleeding for most women who have PPH, about 5-10% of diagnosed PPH cases will require additional interventions beyond uterotonics to stop bleeding.
In many low resource settings, these second- and third-line therapies, including blood transfusion and surgical procedures, are not immediately available or feasible outside of tertiary care centers.
Additional low-tech definitive treatments are urgently needed to fill the gap in care.
Use of the Uterine Balloon Tamponade (UBT) is recognized by several agencies, including World Health Organization (WHO), International Federation of Gynecologist & Obstetricians (FIGO), and International Confederation of Midwives (ICM), as an effective means of limiting blood loss in refractory PPH. The UBT is a medical technique that uses a balloon to apply pressure to the inside of the uterus to stop bleeding after delivery. It is used when primary interventions fail.
The UBT used in this study consists of a urinary catheter, a condom, cotton string ties, a large syringe, and a one-way valve. The condom attached to the catheter is inserted into the uterus and inflated with water.
The balloon can stay in place for up to 24 hours.
This research is taking place in Egypt, Senegal and Uganda and will include 18 secondary level and district referral hospitals with an average of 160 vaginal deliveries a month.
In Uganda, it will take place in 6 district hospitals namely; Gombe Hospital, Masindi Hospital, Kiryandongo Hospital, Itojo Hospital, Lyantonde Hospital and Kitagata Hospital.
It will run over a period of 15 months from November 2016 to March 2018.
This research is a joint collaboration of Gynuity Health Projects, Massachusetts General Hospital and local partners in each country which in Uganda are Makerere University and Global Health Uganda.
Sites: Kiryandongo, Masindi, Lyantonde, Gombe, Itojho, Kitagata.
1. Dr. Sam Ononge
Acute vs. Delayed Iron: Effect on Red Cell Iron incorporation in Severe Malaria
Acute vs. delayed iron therapy : Effect on iron status, anemia and cognition
Predictive biomarkers of mortality and morbidity in children hospitalized with acute febrile illness
Non-Invasive Assessment of Maternal Endothelial Function to Predict Fetal Growth Restriction in a malaria Endemic Area (EndoPAT Study).
PI: Dr. Andrea Conroy
Enhancing Ugandan HIV-affected Child Development With Caregiver Training . (Tororo).
PI: Dr. Noeline Nakasujja
Completed (August 2018)
Enhancing Ugandan HIV-affected Child Development With Caregiver Training (Tororo).
PI: Dr. Noeline Nakasujja
Completed (August 2018)
Cellular and Plasma Markers of Vertical HIV_1 Infection.
PI: Dr. Opoka Robert
Completed (Jan 2019)
The aim of the project was to evaluate the predictive validity of the modified Fagan and the Early Childhood Vigilance test in Ugandan Children at risk from HIV disease.
PI: Dr. Noeline Nakasujja
Completed (May 2019)
Sensitivity of Lung Ultrasound in Ugandan Children with Radiographic Pneumonia.
PI: Dr. Robert Opoka
Implementing School based Child Mental Health Prevention Program In Uganda.
PI: Dr. Janet Nakigudde
Prospective Analysis of the Pharmacokinetics and Pharmacodynamics of Hydroxyurea Treatment In Ugandan Children with Sickle Cell Anemia.
PI: Dr. Opoka Robert
SICKLE CELL ANAEMIA IN LOW RESOURCE AREA: BENEFITS OF HYDROXYUREA IN MITIGATING EARLY ONSET LUNG DISEASE
Principal Investigator: Evans Machogu, MD
1. Hellen Aanyu-Tukamuhebwa, MD
2. Robert O Opoka, MD
3. Chandy C. John, MD
4. Stephanie D. Davis, MD
Mulago Hospital Sickle Cell Clinic Kampala, Uganda.
BRIEF DESCRIPTION OF THE STUDY
It is prospective cohort study with one year follow up comparing baseline lung function among children with sickle cell anaemia (SCA) age >5 years currently on hydroxyurea for at least a year and enrolled in the Novel Use of Hydroxyurea in an African Region with Malaria (NOHARM) study follow up cohort (cases) compared to SCA controls not on Hydroxyurea followed in Mulago Hospital Sickle Cell Clinic. Subjects will be followed for repeat functions after a year.
Sample size approximately 80 children in the continuation phase of the NOHARM Study and 80 SCA control patients.
STUDY OBJECTIVES AND AIMS
Since it is still unclear whether the use of hydroxyurea in the NOHARM clinical trial may slow the onset or even prevent the development of lung disease in children with SCA , our study seeks to evaluate this younger cohort of patients started on hydroxyurea and followed prospectively. Our objective is to determine whether early initiation of hydroxyurea is protective against early onset of obstructive or restrictive lung disese.
Specific aim 1:
To evaluate pulmonary function indices (FVC ,FEV1 and FEF25-75 %) in children >5 years with SCA in low resource areas currently enrolled in the NOHARM Study, and who have been on hydroxyurea for atleast one year and compare these lung function values to age and gender and matched children not taking hydroxyurea . We hypothesize that children on hydroxyurea will have slower progression to developing notable lung disease on Pulmonary Function Test (PFTs) and slower decline in lung function.
PRIMARY END POINTS: The difference between pulmonary Function indices (FVC, FEV1, FEF 25-75%) between the two groups subjects at the beginning of the study.
SECONDARY END POINTS: Correlation of pulmonary function indices with routine clinical and laboratory data including nutritional status.
Title: Effect of Solar Powered Oxygen Delivery on Childhood Mortality in Uganda: a cluster-randomized trial.
Principal investigator (Uganda): Dr. Robert Opika Opoka, MBChB, MMED, MPH
Department of Pediatrics & Child Health, Mulago Hospital
Principal investigator (Canada): Michael Hawkes, MD, PhD, FRCPC, University of Alberta
The objective of this proposal is demonstrate the efficacy of solar powered oxygen delivery systems in children hospitalized with acute hypoxemic respiratory illness in Uganda.
Our primary aim is to:
1. Compare the 48-hour mortality among children < 5 years, admitted with hypoxemia before and after implementation of solar powered oxygen delivery at 20 hospitals in Uganda, adjusting for confounding effects of calendar time and site using a cluster-randomized stepped wedge design.
Secondary aims are to:
1. Compare secondary safety and efficacy outcomes among trial participants.
2. Monitor the functioning, service requirements, and installation and maintenance costs of solar powered oxygen delivery systems at 20 resource-constrained pediatric hospitals
3. Build capacity by training and monitoring performance of pediatric nurses for oxygen delivery at these 20 hospitals
The working hypothesis is that solar powered oxygen delivery systems, previously shown to be an effective and safe method of oxygen delivery at low-resource hospitals, can decrease the mortality of children admitted with hypoxemia.
Study design: The study is a multi-centre prospective evaluation of SPO2 and we shall use a stepped-wedge cluster-randomized design to allow for robust scientific conclusions about the efficacy of SPO2. We enroll patients under 5 years of age admitted to selected Ugandan health facilities with hypoxemia and we will include 20 hospitals, and a total of 2400 hospitalized patients
Study sites: We will enroll 20 sites namely Lyantonde Hospital, Kitagata Hospital, Kagadi Hospital, Kyenjojo Hospital, Bundibugyo Hospital, Karisizo Hospital, Sembabule HC IV, Gombe Hospital, Kayunga Hospital, Adumi HC IV, Atiak HC IV, Kitgum Hospital, Apac Hospital, Lalogi HC IV, Bukedde HC IV, Muyembe HC IV, Bugobero HC IV, Bumanya HC IV, Kamuli Hospital, Kidera HC IV.
Research procedures and/or interventions:
1. Children presenting to selected study hospitals and meeting the inclusion criteria, the parent or legal guardian will be approached for consent to participate in the study. If granted, the patient will be admitted to the pediatric ward, where there will be a SPO2 system installed or not, according to random timing of installation at each site.
2. All patients will receive standard care for their underlying disease, including antibiotics for pneumonia, intravenous fluids as necessary, blood transfusion as necessary, antipyretics, oxygen if available and any other medical therapy required.
3. Basic demographic and clinical data will be collected from the case admission record, and patients will be followed during their hospital admission. The primary outcome is death at 48 hours after admission. Possible alternative outcomes include: death after 48 hours, discharge, and transfer to another facility.
4. During hospitalization, secondary outcomes will be recorded, including vital signs at after admission, and daily thereafter until hospital discharge. Oxygen utilization (flow rate, duration) will be recorded throughout hospitalization. The need for oxygen therapy will be assessed daily, using standardized criteria for weaning oxygen. The length of stay among survivors will be recorded, as well as the final patient disposition (discharged without disability, discharged with disability, transferred to another facility, or death).
Duration of study: 2 years.
TITTLE: Zinc for Infection Prevention in Sickle Cell Anemia (ZIPS)
1. Chandy C. John, MD, MS Indiana University
2. Robert O. Opoka, MBChB, MMED, MPH Makerere University
1. Russell E. Ware, MD, PhD Cincinnati Children’s Hospital
2. Ruth Namazzi, MBChB, MMED, Makerere University
3. Abner Tagoola, MBChB, MMED, Jinja Regional Referral Hospital
4. Dibyadyuti Datta, PhD , Indiana University
5. Andrea Conroy, PhD, Indiana University
Thrasher Research Fund
Clinical Performance Site: Sickle Cell Clinic, Nalufenya, Jinja Regional Referral Hospital, Uganda
A randomized double-blinded placebo-controlled trial of zinc to reduce the incidence of severe or invasive infections in Ugandan children with sickle cell anemia (SCA) aged between 1.00 and 4.99 years of age, living in the malaria endemic area of mid-eastern Uganda, who attend the Nalufenya Sickle Cell Clinic, Jinja Regional Referral Hospital whose caretakers consent to study participation.
Study treatment is zinc (10 mg zinc sulphate) or placebo, administered once a day in a tablet form.
The specific aim of the study is to determine if zinc supplementation reduces severe or invasive infections in Ugandan children 1.00-4.99 years of age with SCA.
The study is also assessing five secondary outcomes that may be affected by zinc supplementation in children:
1) incidence of all clinically diagnosed infections;
2) incidence of culture or PCR-confirmed bacterial infections,
3) incidence of vaso-occlusive crises (VOC),
4) incidence of hospitalizations,
5) change in height-for-age z-score. We hypothesize that children with SCA who receive zinc supplementation will have less clinical infections, less culture or PCR-confirmed bacterial infections, less VOC, less hospitalizations, and better growth than children who receive placebo.
Study is ongoing.
Neurodevelopmental outcomes in children with severe malaria.
The research proposed in this study is innovative in several aspects, including the choice of study population, the multi-factorial assessment of potential risk factors, and the methods proposed to test for risk factors. This study will be, to our knowledge, the first prospective study to assess NDI in the five most common types of severe malaria and also the first prospective study of NDI in children with severe malaria treated with artesunate. All prior studies of NDI in severe malaria in African children to date, including our studies, have assessed these sequelae in children treated with quinine or chloroquine. Comparison of AS to quinine treatment will give insight into the ways in which AS may increase or decrease NDI, and inform consideration on adjunctive therapy to prevent NDI in children receiving AS.
The goal of this proposal is to determine the risk factors for and the pathogenesis of neurodevelopmental impairment in children with the five types of severe malaria treated with artesunate.
1. Objective AIM 1
To establish the functional areas and degree of neurodevelopmental function affected by the five major forms of severe malaria in children treated with artesunate.
The working hypotheses for this objective are that: 1) children with all forms of severe malaria will have developmental impairment; 2) areas and degree of impairment will differ according to form of malaria; 3) artesunate therapy will be associated with lower levels of developmental impairment than quinine.
We will test these hypotheses by comparing areas and age-adjusted levels of neurologic, developmental, and behavioral impairment in children with 5 types of severe malaria (CM, RD, M/S, SMA, and prostration) treated with artesunate compared to healthy children 12 months after enrollment. The level of impairment in children with CM or SMA will be compared in children in the present (artesunate) and past (quinine) studies.
Primary outcome measures:
1) Mullen Early Learning Scales Composite (measure of overall cognition)
2) Early Childhood Vigilance Test (measure of attention)
3) Color Object Association Test (measure of declarative memory) at 12 months after enrollment/discharge
Secondary outcome measures:
1) Behavioral Rating Inventory of Executive Functions (BRIEF)
2) Z-scores on individual Mullen Early Learning Scales
3) Presence of neurologic deficits at discharge or 12 months follow-up
2. Objective AIM 2
To identify the immunologic, metabolic, and nutritional risk factors associated with neurodevelopmental impairment in children with severe malaria treated with artesunate.
The working hypotheses for this objective are that: 1) specific factors are associated with developmental impairment in severe malaria, and 2) these factors differ according to the type of severe malaria. We will test these hypotheses by comparing the presence/level of risk factors in children with severe malaria to level of neurologic, developmental, and behavioral impairment in these children 12 months after enrollment.
Risk factors assessed:
1) Markers of endovascular inflammation (NO and ADMA, specific cytokines, endothelial activation markers, oxidative stress markers)
2) Markers of central nervous system inflammation or injury (cerebrospinal fluid NO and ADMA, cytokines, oxidative stress markers)
3) Metabolic changes (carboxyhemoglobin, hypoglycemia, lactic acidosis)
4) Micronutrients affected by inflammation and associated with developmental impairment (iron, vitamin A, vitamin E).
Principal Investigator: Dr. Opoka Robert.
Ended Dec 2018, Renewed as MIND
Optimising Iron Status while minimizing morbidity in HIV- infected Ugandan Children.
Principal Investigator: Dr. Musiime Victor.