Novel use Of Hydroxyurea in an African Region with Malaria (NOHARM): A trial for children with sickle cell anemia

Key Points:

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

Key Points:

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.

A2. Rationale

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.

Study Site:
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.

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.

Study site:
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.

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.

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

Introduction of a Condom Uterine Balloon Tamponade Device for Postpartum Hemorrhage

Sites: Kiryandongo, Masindi, Lyantonde, Gombe, Itojho, Kitagata.


1. Dr. Sam Ononge

2. Gynuity