Lay Title: Checking doses, long-term risks, and benefits of Hydroxyurea in treating children and young adults with Sickle Cell Anaemia in four countries in Africa.

What is the problem/background?

Sickle cell anaemia is common in Kenya, where more than 4000 children are born with the condition each year. Based on positive data from clinical trials, an increasing number of patients in resource rich countries are now being treated with hydroxyurea. In the first phase of REACH, we conducted a clinical trial to investigate the safety of hydroxyurea as a supportive treatment in children with sickle cell anaemia in Kenya, Angola, Uganda and the DRC. In total, 600 children (150 in each site) aged 12 months - 10 years were enrolled into the study. The Protocol number for the Kilifi trial was SSC Protocol # 2752.  All participants were placed on hydroxyurea and monitored closely to investigate both safety and efficacy of the drug. Though our initial results are encouraging, the first phase of the REACH trial did not include a group who were not taking hydroxyurea for comparison with those who take it with regard to a range of specific parameters. For this reason, we now propose to end the current REACH clinical trial and start a larger trial that will investigate long term exposure to hydroxyurea in both these same patients and in a new group of 75 children with confirmed SCA between 3.0 and 10.0 years at each site. Young adults who completed the first phase of this trial will also be asked to rejoin this second phase of the trial.

What questions are we trying to answer?

In the first phase of this trial, we conducted a multi-center phase I/II clinical trial to investigate the safety of hydroxyurea as a supportive treatment in children with sickle cell anaemia in Kenya, Angola, Uganda, and the DRC. We now propose a larger trial that will investigate long term risks and benefits to hydroxyurea in both these same and a second set of cohorts.

Where is the study taking place, how many people does it involve and how are they selected?

The study will take place at four sites throughout Africa. At the Kilifi site, participants will be recruited following written informed consent, from among children diagnosed with SCD at Kilifi County Referral Hospital. There will be a total of 225 participants in the Kilifi study - 150 from the original cohort and 75 new participants. The participants currently range in age from 10 to 18 years, with the exception of a few young adults who exited the study upon turning 18 years old in accordance with the previous protocol schedule. The latter will be invited to rejoin the current phase of the trial. All participants will be followed for four years.

What does the study involve for those who are in it?

All existing participants (original cohort) will undergo a reconsent process to confirm their willingness to continue to participate in the current phase of the trial. Participants from this cohort who choose not to participate in the current phase of the REACH trial will exit the study and will receive the standard of care available at the Kilifi County referral hospital instead. The standard care of sickle cell disease at Kilifi County Hospital includes the prevention of bacterial infections using penicillin among children <5 years, malaria prevention using proguanil, and folic acid supplementation to maintain good health. Hydroxyurea is also available through KCH and will be made available to former members of the REACH Trial.  

For the new cohort, after obtaining consent, each participant will undergo monthly Eligibility Screening (ES) visits for three months, followed by Baseline Evaluation (BE) and hydroxyurea initiation that occur together at Month 0. 

During screening, a medical history, physical examination, and laboratory blood counts at the specified monthly study visits will be performed. Initially, they will attend follow-up visits once a month for 6 months before moving to three monthly visits.

During each screening visit, three after starting hydroxyurea and annually approximately 5 to 10 mls of blood will be drawn at each visit.  Thereafter, at each monthly and quarterly visit less than 5 mls of blood will be drawn for safety laboratory tests. Every 6 months an additional 5 mls will be collected.  The maximum volume of blood collected at any visit will be 10mls.  Each child enrolled in the second cohort will undergo a special drug absorption blood test called PK to determine the starting dose of hydroxyurea at the 2^nd month of the screening visits.  For this PK study, each study participant will first receive a single 500mg capsule of hydroxyurea to swallow and then have 4 blood samples collected at approximately 15, 30, 60, and 180 minutes after the dose. These timed blood collections will be used to measure the hydroxyurea in blood to generate the optimal dose. These blood samples will be collected through separate finger-pricks (like when taking samples for malaria) using tinny tubes, with a total blood volume of <1mL (few drops) for the PK studies.

After the 3-month screening procedures, all participants in the second cohort will then commence hydroxyurea at this PK-determined dose and will remain in the study for up to four years of hydroxyurea treatment. 

For the existing cohort, hydroxyurea will be maintained at a maximum tolerated dose until the end of study participation. We will monitor this through blood counts taken every three months, with each visit requiring less than 1 ml of blood.

For all participants, the following additional non-invasive study procedures will be done at screening and annually thereafter: 

• A brain examination using an ultrasound machine (TCD) to determine the risk of having a stroke.
• An abdominal ultrasound scan to measure both the spleen and kidney sizes.
• An exam that uses light to measure how oxygen is supplied to the brain. This exam is called Near Infra-Red Spectroscopy (NIRS).
• X-rays of the wrist will be performed at the beginning and at end of the study to measure the growth and bone age.
• A urine sample for special tests to measure kidney function.
• A blood sample for DNA tests.
• Malaria blood tests.

Sperm counts/motility will be an optional collection in adult males. Self-examination of growth and development parameters (tanner staging) such as the size of breasts, presence of pubic hair and size of testicles will be done. After 6 months, the first cohort will undergo regular monitoring, which includes medical history reviews, physical examinations, and blood count assessments (less than 1 ml of blood) during every scheduled visit, every three months. A urine sample will be collected for kidney function tests and checking for body chemicals in the urine once a year. For all female participants who have reached menarche, a urine pregnancy test will be done at every visit.

Young adults who attain/attained 18 years, will also be reconsented to resume study participation.

What are the benefits and risks/costs of the study for those involved?

We anticipate that, as has been the case in studies conducted in the USA and Europe, and in the first phase of the REACH trial, hydroxyurea will make a major positive impact on the lives of study participants. The drug and the monitoring for the drug will be made available free of charge throughout the course of the study. Children and their parents will be informed of the experimental nature of this study such that there should be no prior expectation that it would be safe or appropriate for hydroxyurea to be used long term before we can assess its impact through this trial. Although hydroxyurea is a very well tolerated medication with few significant risks the most significant side effect is mild bone marrow suppression. These are reversible by temporary discontinuation of the medication or dose adjustments.  Given the burden of traveling to the clinic, we will provide an out-of-pocket allowance of 500 Kenyan shillings and reimburse travel expenses during follow-up visits, to help cover the costs of travel  and  out of pocket expenses. The amounts will be based on the most current standard ‘KEMRI-Wellcome Trust Research Programme Guidelines for Study Benefits and Out of Pocket Allowances. If the participant falls sick, we will only reimburse the cost of transport incurred.

How will the study benefit society?

We anticipate that this study will provide key information regarding the use of hydroxyurea in children with SCA in Africa and will provide data to feed into the design of further trials that may affect policy.

When does the study start and finish?

The study will start once ethical approval is obtained and is expected to end in about four years.      At that point, all patients will go back to the standard of care and treatment options provided by the Kilifi County and Referral Hospital.

Sickle cell anaemia is common in Kenya where more than 4000 children are born with the condition each year. Based on positive data from clinical trials, an increasing number of patients in resource rich countries are now being treated with hydroxyurea. In the first phase of this trial, we conducted a multi-center phase I/II clinical trial to investigate the safety of hydroxyurea as a supportive treatment in children with sickle cell anaemia in Kenya, Angola, Uganda and the DRC. In total, 600 children aged 12 months - 10 years (150 in each site) were enrolled into the study. All were placed on hydroxyurea and monitored closely to investigate both safety and efficacy of the drug. We now propose a larger trial that will investigate long term exposure to hydroxyurea in both these same and a second set of cohorts with the aim of shaping national management policies for all children born with sickle cell anaemia in Africa.