Pharmacokinetics of oral hydroxyurea solution
Research type
Research Study
Full title
A prospective open label, pharmacokinetic study of an oral hydroxyurea solution in children with sickle cell anemia
IRAS ID
248582
Contact name
Russell Keenan
Contact email
Sponsor organisation
Nova Laboratories Limited
Eudract number
2017-004568-37
Duration of Study in the UK
2 years, 5 months, 1 days
Research summary
Summary of Research
This is an open label, observational, safety and pharmacokinetic study of oral hydroxycarbamide solution administered to children aged from 6 months – 17.99 years (i.e. to the day before 18th birthday), both male and female, who have a diagnosis of sickle cell anaemia (SCA). Hydroxycarbamide is also known as Hydroxyurea. Hydroxycarbamide is used to treat some children with sickle cell anaemia. Hydroxycarbamide is available in tablets and capsules, which may require the need to halve or quarter them to meet specific daily doses. Intermediate doses can only be delivered accurately with an oral liquid formulation. Moreover, some young children find it difficult to swallow tablets and capsules.
Children are often administered unlicensed (compounded) liquid formulations of hydroxycarbamide prepared either in hospital pharmacies or by commercial compounders. Although these unlicensed oral solutions are currently meeting a paediatric need, it potentially exposes children to medication errors and the higher risk of unfavourable reactions or inadequate effectiveness. Nova Laboratories have been supplying a compounded, unlicensed hydroxycarbamide oral solution to the UK market for almost 10 years. There is a clear need for an approved child-appropriate, oral solution formulation of hydroxycarbamide.
This study aims to investigate the safety and the levels of hydroxycarbamide in the blood (pharmacokinetics) of a new oral hydroxycarbamide 100mg/ml solution formulation in children with SCA.Blood samples for pharmacokinetics analysis will be taken over a six hour period at the ‘Day 1’ and ‘Month 6’ visit. Further single PK samples will be obtained at regular visits if feasible. Children will be assessed in clinic every two weeks for the first two months and then monthly until month 15 (dose escalation will be every eight weeks where feasible until maximum tolerated dose is reached). Children will be followed up one month after study completion.
Up to 25 children will be recruited.
Summary of Results
PARTICIPANT CLINICAL STUDY RESULTS SUMMARY
1. STUDY INFORMATION
Title of Study: A Prospective Open Label, Pharmacokinetic Study of an Oral Hydroxyurea Solution in Children with Sickle Cell AnemiaShort Title and Acronym: Pharmacokinetics of Oral Hydroxyurea Solution (INV543 HUPK)
This is a summary of the main results of a clinical study for the new liquid version of the drug hydroxyurea.
Study Sponsor:
Nova Laboratories Limited (UK) sponsored this study and would like to share the results with the participants and the public.Chief Investigator:
1. Dr Angela Rankine Mullings
Investigators:
2. Dr Russell Keenan (UK Co-ordinating Investigator) 3. Dr Paul Telfer 4. Dr Mark Velangi 5. Dr Baba Inusa 6. Dr Subarna ChakravortyParticipating Site(s):
1. Sickle Cell Unit, University of West Indies, Kingston, Jamaica 2. Alder Hey Children's NHS Foundation Trust, Liverpool, UK 3. Barts, The Royal London Hospital, London, UK 4. Birmingham Children’s Hospital, Birmingham, UK 5. Evelina London Children’s Hospital, London, UK 6. Kings College Hospital, London, UKDate: DECEMBER 2022
2. THANK YOU
Nova Laboratories would like to thank all the children who participated, their parents, families, guardians and their caregivers for taking part in the HUPK clinical trial, and particularly for continuing on during the significant challenges posed during the COVID-19 pandemic. By being part of this study you have helped the researchers learn more about using a liquid form of hydroxyurea to treat children with sickle cell disease.
We hope this summary helps those involved and who participated understand and feel proud of the important role they played in this medical research.
This summary is for information purposes only. If you need further medical advice, please contact your doctor. If you participated in this study and you have further questions about the results, please contact the doctor and study teams at the site using the details provided to you during the study.
3. WHY WAS THE RESEARCH NEEDED?
Before a treatment is made available to all patients, researchers carry out clinical studies to get information about how well a treatment works, and how safe it is.
Sickle cell disease (SCD) is a genetic condition, meaning that children inherit it from their parents and are born with the condition. People with SCD have a problem with the protein produced inside red blood cells called haemoglobin (Hb), which is responsible for carrying oxygen through the body. Whereas normal red blood cells are a round, disc shape and flexible, in people with SCD the haemoglobin clumps together and causes the red blood cells to change into a sickle (crescent) shape, which are stiff and sticky. These sickle red blood cells can block blood vessels resulting in extreme pain (pain crisis) and organ damage. They also break down faster than normal red blood cells resulting in too few red blood cells, a condition known as anemia.
SCD is a serious and lifelong health condition, however there are currently treatments available to manage the symptoms. One such treatment that has been used for several decades is a drug called hydroxyurea (“hi-drox-ee-ur-EE-a”), also known as hydroxycarbamide (“hi-drox-ee-CAR-ba-myde”). Previous research studies and use in clinical practice over many years has shown it to be very effective at reducing the incidence of pain crisis and complications of this disease. Hydroxyurea is usually taken in a tablet or capsule form once daily and has been shown to be safe, with most people tolerating the medicine very well with no or few mild side effects.
A new, child-friendly, strawberry-flavoured, liquid version of this medicine has been developed. This liquid version allows doctors to prescribe the dose of hydroxyurea more accurately for children, based on each child’s weight. The researchers in this study wanted to learn how the new liquid version works in children with SCD, particularly children as young as 6 months of age.
4. WHAT WERE THE MAIN QUESTIONS STUDIED?
The main questions the researchers wanted to answer in this study were:
• How does the body handle the new liquid hydroxyurea solution (how well it gets into the body, travels through, is used by and then removed from the body)? This is a process known as ‘Pharmacokinetics’.
• How safe is the new liquid formulation?
• How effective is the new liquid formulation?
• Do children find the new liquid palatable (taste and smell) and is the product itself user-friendly for children and parents?
5. WHO PARTICIPATED IN THIS STUDY?
The study included 32 children with sickle cell anemia, males and females, aged from 8 months up to 18 years of age. The participants were recruited from Jamaica (12 children) and the UK (20 children). The average age of a child was 5 years.
All except two children identified their race as Black or African American.
The study started in January 2019 and ended in December 2021.
6. WHAT HAPPENED DURING THIS STUDY?
Children were consented to the trial and began treatment with the new liquid hydroxyurea. All children started on the same dose of hydroxyurea, 15 mg per kg bodyweight once a day. Children were asked to participate and attend in-clinic visits every 2-4 weeks for the first 8 weeks and then monthly after that, with a 12 week maximum between in-clinic visits for blood samples for assessing safety. Telephone calls replaced some in-clinic visits where possible during the height of the COVID-19 pandemic, which impacted the recruitment phase of this trial between March 2020 and September 2021. During the in-clinic visits doctors reviewed the children’s symptoms and blood results and if it was safe to do so, slowly (every 4-8 weeks) increased the dose until the best dose for each child was found, up to a maximum of 35 mg per kg bodyweight once a day. Children were allowed to remain on the study drug for a maximum of 15 months.
During the trial, children took part in 2 longer in-clinic days to assess ‘pharmacokinetics’. The first was at the beginning of the study when the very first dose of the liquid hydroxyurea was given in the clinic, and the second 6 months later. On these ‘pharmacokinetic’ days, children gave a series of blood samples for measuring the levels of hydroxyurea present in the blood. A single blood sample for measuring the hydroxyurea level was also given at any visit during the study if it was convenient and appropriate.
On average, during the course of the trial, children attended 13 in-clinic visits and received 3 telephone visits, as well as one final safety follow up call after completing the study.
After the study completed, children were continued on hydroxyurea, either on the liquid where available or capsules/tablets where appropriate.
7. WHAT WERE THE RESULTS OF THIS STUDY?
This is a summary of the main results from this study for all participants combined. The individual results of each participant may be different and are not included in this summary.
Always talk to your doctor before making any treatment decisions.
7.1 Hydroxyurea Effects:
• The way the body handles the new liquid form of hydroxyurea was found to be the same in infants, older children and adolescents. Therefore, in all children, the dose only needs to be adjusted for bodyweight and not age.
• The effectiveness of the liquid hydroxyurea (laboratory markers and symptoms) was as expected and the same as previously reported with capsules and tablets.
7.2 Hydroxyurea Safety:
The safety of the new liquid hydroxyurea was found to be in line with the known safety information already available outside of the study for capsules and tablet forms of hydroxyurea (i.e. there were no unexpected safety signals or information produced by the study).
• There were no deaths reported in this study.
• There were no serious adverse reactions due to the drug.
• There were 9 participants (28%) who had a total of 28 adverse drug reactions.
• The most common adverse reaction was a decrease in blood platelets or neutrophils, which were short lived and recovered quickly on dose reduction or temporary halt in the drug.
• These adverse reactions in the blood were more common in infants under the age of 2 years and were linked with recent or concurrent illnesses such as viral and upper respiratory tract infections.
• There were 9 participants who left the study early.
• None of the participants left the study due to an adverse reaction to the drug.
7.3 Hydroxyurea Palatability:
The taste and smell (palatability and acceptability) of liquid hydroxyurea was found to be positive.
• With 83% of children liking the taste and smell.
• A total of 85% of children preferred the liquid over a tablet or capsule.
• Overall 81% of parents/caregivers found that it was very easy to administer the new liquid hydroxyurea to children under 6 years of age.8. HOW HAS THIS STUDY HELPED?
The results of this study have helped researchers learn about the best way to dose and the safety of liquid hydroxyurea in infants, children and adolescents.
The results are based only on the participants included in this one study. Deciding what is the best way to dose and what works best for patients almost always takes results from several studies. Other studies may provide new information or different results.
This summary is provided for informational purposes only. If you need medical advice about your own health or situation, please contact your doctor.
No further studies with liquid hydroxyurea are presently planned by the Sponsor.9. WHERE CAN I LEARN MORE ABOUT THIS STUDY?
You can find more information about this study at the website listed below:
https://eur03.safelinks.protection.outlook.com/?url=https%3A%2F%2Fu2790089.ct.sendgrid.net%2Fls%2Fclick%3Fupn%3DXv3JSvJ-2B3M71ppf7N9agbRehJ-2Fi4xyo44sEgJVCl5BcbW9wgc64X2JjNxW-2BqMpAMROqk0V-2FLWSI-2B-2FMhX0MEiqw-3D-3DNkgW_E1aO2-2BZlVOSJJV-2FajQqskegTd6IRomHYTi-2Fbt8SH3YKc-2BIMdBMCiqCt1OlS1w-2FGI6IJJjShmYIwyu0Z-2B1J4LDyZHIMjzchjWvDk5zWJHUNU-2FRTI18U-2FitfPZNbEdlBqSsESI1ar7LudZvw8jXj9z7mviZIBNv540X-2BXbpNkPWQ0NZDs380-2FQ4v1r5HJOqC6PIZY-2BNpBzygJ25KTeseX7ig-3D-3D&data=05%7C01%7Capprovals%40hra.nhs.uk%7C946a38d88395474dc21c08dae3702ce7%7C8e1f0acad87d4f20939e36243d574267%7C0%7C0%7C638072368168441867%7CUnknown%7CTWFpbGZsb3d8eyJWIjoiMC4wLjAwMDAiLCJQIjoiV2luMzIiLCJBTiI6Ik1haWwiLCJXVCI6Mn0%3D%7C3000%7C%7C%7C&sdata=57XgCIhRMWec3d1YUgZxdBJs6%2FpnHcaKHQ%2BCUZba0ec%3D&reserved=0REC name
North West - Liverpool Central Research Ethics Committee
REC reference
18/NW/0644
Date of REC Opinion
30 Nov 2018
REC opinion
Further Information Favourable Opinion