Smart et al. Trials (2023) 24:603 Trials https://doi.org/10.1186/s13063-023-07649-7 STUDY PROTOCOL Open Access Prospective identification of variables as outcomes for treatment (PIVOT): study protocol for a randomised, placebo-controlled trial of hydroxyurea for Ghanaian children and adults with haemoglobin SC disease Luke R. Smart1,2,3* , Catherine I. Segbefia4,5, Teresa S. Latham1, Susan E. Stuber1,3, Kwesi N. Amissah‑Arthur6,7, Klenam Dzefi‑Tettey8, Adam C. Lane1,2, Yvonne A. Dei‑Adomakoh9,10,11 and Russell E. Ware1,2,3 Abstract Background Haemoglobin SC (HbSC) is a common form of sickle cell disease (SCD), especially among individuals of West African ancestry. Persons with HbSC disease suffer from the same clinical complications and reduced quality of life that affect those with sickle cell anaemia (HbSS/Sβ0). Retrospective anecdotal data suggest short‑term safety and benefits of hydroxyurea for treating HbSC, yet rigorous prospective data are lacking regarding optimal dosing, clinical and laboratory effects, long‑term safety and benefits, and appropriate endpoints to monitor. Prospective Investigation of Variables as Outcomes for Treatment (PIVOT) was designed with three aims: (1) to measure the toxici‑ ties of hydroxyurea treatment on laboratory parameters, (2) to assess the effects of hydroxyurea treatment on sickle‑ related clinical and laboratory parameters, and (3) to identify study endpoints suitable for a future definitive phase III trial of hydroxyurea treatment of HbSC disease. Methods PIVOT is a randomised, placebo‑controlled, double blind clinical trial of hydroxyurea. Approximately 120 children and 120 adults ages 5–50 years with HbSC disease will be enrolled, screened for 2 months, and then ran‑ domised 1:1 to once‑daily oral hydroxyurea or placebo. Study treatment will be prescribed initially at 20 ± 5 mg/kg/ day with an opportunity to escalate the dose twice over the first 6 months. After 12 months of blinded study treat‑ ment, all participants will be offered open‑label hydroxyurea for up to 4 years. Safety outcomes include treatment‑ related cytopenias, whole blood viscosity, and adverse events. Efficacy outcomes include a variety of laboratory and clinical parameters over the first 12 months of randomised treatment, including changes in haemoglobin and fetal haemoglobin, intracranial arterial velocities measured by transcranial Doppler ultrasound, cerebral oxygena‑ tion using near infrared spectrometry, spleen volume and kidney size by ultrasound, proteinuria, and retinal imaging. Exploratory outcomes include functional erythrocyte analyses with ektacytometry for red blood cell deformability and point‑of‑sickling, patient‑reported outcomes using the PROMIS questionnaire, and 6‑min walk test. *Correspondence: Luke R. Smart luke.smart@cchmc.org Full list of author information is available at the end of the article © The Author(s) 2023. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecom‑ mons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Smart et al. Trials (2023) 24:603 Page 2 of 14 Discussion For children and adults with HbSC disease, PIVOT will determine the safety of hydroxyurea and identify measurable changes in laboratory and clinical parameters, suitable for future prospective testing in a definitive multi‑ centre phase III clinical trial. Trial registration PACTR, PACTR202108893981080. Registered 24 August 2021, https:// pactr. samrc. ac. za Keywords Sickle cell disease, Haemoglobin SC disease, Hydroxyurea, Adults, Children Administrative information Name and contact informa‑ Russell E. Ware, MD PhD Note: the numbers in curly brackets in this protocol refer tion for the trial sponsor {5b} Division of Hematology to SPIRIT checklist item numbers. The order of the items 3333 Burnet AvenueCincinnati Children’s Hospital Medical has been modified to group similar items (see http:// Center www. equat or- netwo rk. org/ repor ting- guide lines/ spirit- Cincinnati, OH 45229 2013- state ment- defin ing- stand ard- proto col- items- for- Russell.Ware@cchmc.orgPhone: 513–803‑4597 clinic al- trials/). Role of sponsor {5c} Cincinnati Children’s Hospital Medical Center (CCHMC) is the sponsor of PIVOT, Title {1} Prospective Identification of Variables responsible for the conduct of the study as Outcomes for Treatment (PIVOT): in accordance with all applicable local Study Protocol for a Randomised, and international laws and regulations, Placebo‑controlled Trial of Hydroxyu‑ including without limitation ICHE6 rea for Ghanaian Children and Adults guidelines for Good Clinical Practices. with Haemoglobin SC Disease Trial registration {2a and 2b}. PACTR, PACTR202108893981080. Registered 24 August 2021, https:// pactr. samrc. ac.z a/. Introduction Protocol version {3} October 20, 2021; Version 1.2 Background and rationale {6a} Funding {4} PIVOT receives financial support includ‑ ing drug donation by Addmedica, Inc., Sickle cell disease (SCD) is among the world’s most com- (Paris, France). Addmedica has no role monly inherited haemoglobin (Hb) disorders. SCD is in the design of the study, data col‑ highly prevalent in sub-Saharan Africa, with more than lection, results analysis, or manuscript submission. 300,000 babies born annually, affecting an estimated Author details {5a} 1Division of Hematology, Cincinnati 1–2% of newborns in some countries [1, 2]. SCD is Children’s Hospital Medical Center, caused by structural variation in the beta globin com- Cincinnati, USA 2 ponent of Hb, and the two most common variants are Department of Pediatrics, University of Cincinnati College of Medicine, haemoglobin S (HbS) and haemoglobin C (HbC). Both Cincinnati, USA HbS and HbC result from point mutations affecting the 3Global Health Center, Cincinnati sixth amino acid of beta globin, changing glutamic acid Children’s Hospital Medical Center, Cincinnati, USA to valine or lysine, respectively. Co-inheritance of two 4Department of Child Health, University HbS alleles (HbSS) or one HbS allele and one HbC allele of Ghana Medical School, Accra, Ghana 5 (HbSC) results in erythrocytes that are prone to intravas-Department of Child Health, Korle Bu Teaching Hospital, Accra, Ghana cular sickling and cellular dehydration, with a proportion 6Ophthalmology Unit, Department becoming hyperdense cells that promote HbS polymeri- of Surgery, University of Ghana Medical sation and increase blood viscosity [3]. School, Accra, Ghana 7Ophthalmology Unit, Department Individuals with SCD suffer from a wide variety of of Surgery, Korle Bu Teaching Hospital, acute and chronic medical complications that lead to Accra, Ghana 8 substantial morbidity, poor quality of life, and early mor-Department of Radiology, Korle Bu Teaching Hospital, Accra, Ghana tality [4]. Compared with HbSS, persons with HbSC 9Department of Haematology, University typically have a less severe form of SCD, yet still suffer of Ghana Medical School, Accra, Ghana 10 from acute and chronic disease complications, includ-Department of Haematology, Korle Bu Teaching Hospital, Accra, Ghana ing chronic haemolytic anaemia, vaso-occlusive pain, 11Ghana Institute of Clinical Genetics, acute chest syndrome, infections, splenomegaly, splenic Korle Bu, Accra, Ghana infarction, gallstones, nephropathy, priapism, and leg ulcers [5, 6]. In HbSC, stroke is relatively less common than in HbSS, presumably due to a higher Hb concentra- tion, while avascular necrosis and retinopathy are more S mart et al. Trials (2023) 24:603 Page 3 of 14 common, due to increased blood viscosity and impaired and laboratory parameters, and which study endpoints rheology [7, 8]. might be suitable for a definitive phase III trial of patients In many high-income countries, early identification of with HbSC disease receiving hydroxyurea therapy. The SCD through newborn screening and aggressive early proposed study will be critical for collecting high-quality interventions, including hydroxyurea therapy have led to evidence that could change practice and potentially help marked improvements in both morbidity and mortality millions of patients with HbSC worldwide. [9, 10]. Most efforts to diagnose and manage SCD have focused on HbSS, the most common and severe form [4]. Objectives {7} However, HbSC accounts for ~ 25–30% of all diagnoses in the USA [11] and almost 50% of all diagnoses in Ghana. 1) To measure the toxicities of hydroxyurea treatment Research studies funded by the National Heart Lung on laboratory parameters in a large cohort of chil- and Blood Institute (NHLBI) within the National Insti- dren and adults with HbSC disease tutes of Health (NIH) in the USA have collectively doc- 2) To assess the effects of hydroxyurea treatment on umented the safety and efficacy of hydroxyurea therapy a variety of sickle-related clinical and laboratory for both adults and children with HbSS [12–15]. Labora- parameters in a large cohort of children and adults tory benefits include increased Hb and fetal haemoglo- with HbSC disease bin (HbF) as well as decreased white blood cells (WBC), 3) To identify which study endpoints are suitable for a absolute neutrophil count (ANC), and absolute reticu- phase III trial of patients with HbSC disease receiving locyte count (ARC). Clinical benefits include reduced hydroxyurea therapy painful vaso-occlusive events, acute chest syndrome, transfusions, and hospitalisations; these effects are con- sistent and sustainable and optimised when hydroxyu- rea is titrated to the maximum tolerated dose (MTD) Trial design {8} [16–18]. Hydroxyurea therapy is also associated with PIVOT is a prospective randomised double-blind pla- reduced mortality in HbSS [10, 19–22]. Based on decades cebo-controlled Phase II clinical trial of hydroxyurea of clinical trial evidence, the NHLBI, the American and treatment for children and adults with HbSC disease. The British Societies of Haematology, and others recommend trial uses a non-inferiority design framework. An equal hydroxyurea treatment for both adults and children with number of children (< 18 years old) and adults (≥ 18 years HbSS, beginning at 9 months of age [23–25]. Hydroxyu- old) as well as male and female participants will be rea has now been approved for the treatment of HbSS by enrolled. Treatment randomisation between hydroxyu- the US Food and Drug Administration (FDA) for adults rea and placebo will occur 1:1. After 12 months of ran- (in 1997) and children above 2  years (in 2017) as well domised study treatment, haematological toxicity rates as the European Medicines Agency (EMA) for all ages will be compared between arms. If there is no evidence (in 2007), but it is not yet approved for the treatment of of harmful toxicities related to hydroxyurea treatment, all HbSC disease. study participants will then be offered open-label hydrox- In the NHLBI Evidence-Based Report on Manage- yurea, which will continue until 4 years from the date of ment of SCD, few recommendations refer to HbSC dis- first treatment. ease, due to lack of high-quality evidence in this large but under-investigated patient population [23]. After Methods: participants, interventions, the NHLBI evidence-based guidelines were published, a and outcomes summary of evidence gaps included the “most pressing Study setting {9} clinical research needs for disease-modifying therapies” PIVOT will be conducted at Korle Bu Teaching Hospi- and listed the need to determine the efficacy of hydrox- tal (KBTH), which is a premier referral, consultancy, and yurea in non-HbSS genotypes, especially HbSC disease tertiary care hospital in Accra, Ghana. Currently, KBTH, [26]. To date, hydroxyurea has not been investigated pro- which is the third biggest referral centre in Africa, has spectively as a disease-modifying treatment for HbSC, 2000 beds, 21 clinical and diagnostic departments, and and it is unknown whether it will have the same salu- four Centres of Excellence. It has both a Paediatric and tary effects as for HbSS. Currently, there is only sporadic an Adult Sickle Cell Clinic (Ghana Institute of Clinical and anecdotal use of hydroxyurea for HbSC, primarily Genetics). “clinical drift” from experience with HbSS. For children and adults with HbSC disease, there is a striking lack of Eligibility criteria {10} evidence about the safety of hydroxyurea treatment, the Potential participants who meet all of the following crite- effects of treatment on a variety of sickle-related clinical ria are eligible for enrolment into the study: Smart et al. Trials (2023) 24:603 Page 4 of 14 1. Documented HbSC disease informed consent document (and assent when appropri- 2. Age: ≥ 5.0 and ≤ 50.0  years of age, at the time of ate) for review and times for questions provided before enrolment any forms are signed. 3. Steady-state laboratory values in the following ranges: Additional consent provisions for collection and use a. Hb 6.0–12 g/dL of participant data and biological specimens {26b} b. ARC > 50 × 109/L Two additional questions will allow participants/guard- c. WBC count > 2.0 × 109/L ians to permit or decline: (1) the storage of research spec- d. ANC > 1.0 × 109/L imens for future research and (2) the sharing of research e. Platelet count > 75 × 1 09/L specimens with future collaborators. 4. Participant, parent, or guardian willing and able to provide informed consent Interventions 5. Ability to comply with all study related treatments, Explanation for the choice of comparators {6b} evaluations, and follow-up There is no current standard therapy recommended for all patients with HbSC disease; therefore, placebo was Potential participants who meet any of the following chosen as the optimal comparison. Two therapies are criteria are disqualified from enrolment in the study: currently approved by the US FDA and the EMA for treatment of HbSC disease (crizanlizumab and voxelo- 1. Hydroxyurea treatment currently or within the tor), but the trials that led to their approval enrolled very past 6 months few individuals with HbSC [27, 28], the benefits for HbSC 2. ≥ 6 blood transfusions within the past 12 months were less certain, and they were approved for treatment 3. > 10 hospitalisations in the past 12 months of those ≥ 16 years old (crizanlizumab) or ≥ 12 years (vox- 4. Serum creatinine more than twice the upper limit elotor) at the time this trial was designed. Therefore, nei- for age AND ≥ 176.8 μmol/L ther treatment was deemed an appropriate comparator. 5. Any known underlying condition or illness, includ- ing chronic pain, co-morbid chronic disease (e.g. tuberculosis, retroviral infection, etc.) which makes Intervention description {11a} study participation ill-advised Oral hydroxyurea and placebo will be prescribed once 6. Use of other therapeutic agents for SCD such as daily with instructions to self-administer ideally at a L-glutamine, arginine, crizanlizumab, rivipansel, regular time either in the morning or before bedtime. If voxelotor, decitabine, or magnesium currently or the time of a scheduled dose is missed, the dose may be within the past 6 months (temporary exclusion) administered at any time during the same calendar day. 7. Previous stem cell transplant or other myelosup- For children incapable of swallowing tablets, the tab- pressive therapy lets can be chewed or crushed for mixing with water or 8. Inability to take or tolerate daily oral hydroxyurea, juice. Dosing will occur with 1000  mg tablets (scored including known allergy to hydroxyurea therapy or in 250 mg) and 100 mg tablets (scored in 50 mg). Study known malignancy treatment will be started at a dose of 20.0 ± 5.0  mg/kg/ 9. Pregnancy (for post-menarchal females only) day. 10. Participation in a therapeutic clinical trial or prior The dose will be escalated up to twice in the first disease-modifying treatments currently or in the 6 months if all of the following are true: ANC > 3.0 × 1 09/L, past 6 months Hb > 7.0  g/dL, ARC > 80 × 109/L, platelets > 100 × 109/L. 1 1. Blood transfusion within the past 2 months (tem- Dosing flexibility is permitted to allow for rounding to porary exclusion) available tablet strengths. A dosing calculator will pro- vide a recommended dose. The maximum daily dose of study treatment will not exceed 2000 mg or 35 mg/kg/day Who will take informed consent? {26a} without prior discussion and approval from the PIVOT Study nurses and doctors are delegated to obtain Medical Coordinating Centre (MCC). Minor dose adjust- informed consent from adults and parents or guardians ments will be made as necessary to accommodate any of children < 18 years old, as well as assent from children changes in a participant’s weight. In the event of sple- 10–17 years old. After detailed discussion of the protocol nomegaly and hypersplenism, dose adjustments may be and the risks and benefits of participation, a copy of the modified after consultation with the MCC. S mart et al. Trials (2023) 24:603 Page 5 of 14 Criteria for discontinuing or modifying allocated After the initial 12 months of randomised treatment, all interventions {11b} participants will be invited to continue open label treat- Study treatment will be temporarily discontinued ment until 4 years from the first treatment initiation. Any for haematological toxicity defined as any of the fol- incidental findings will be shared with their clinical team. lowing: ANC < 1.0 × 109/L; Hb < 4.0  g/dL regard- Post-trial care will be provided by the local clinical team. less of ARC; Hb < 6.0  g/dL with an ARC < 100 × 109/L; Clinical trial insurance will provide compensation to ARC < 80 × 109/L with an Hb < 7.0  g/dL, or platelet those who suffer harm from trial participation. count < 80 × 1 09/L. If recovery occurs after 1 week, study treatment may resume at the previous dose. If toxicity Outcomes {12} persists for > 2  weeks or occurs twice within a 3-month The following outcomes will be measured after period in the absence of another potential cause, study 12 months of therapy: treatment will be held until recovery and then reduced by 2.5  mg/kg/day. In certain limited clinical circum- 1. Cumulative incidence of haematological toxicities stances, laboratory parameters below these haematologi- (primary outcome) cal thresholds do not represent true marrow suppression 2. Cumulative incidence of laboratory and clinical and dose-limiting toxicity, and the investigators and adverse events ≥ grade 2 and serious adverse events MCC after discussion will have discretion whether or not (SAEs), graded according to the Common Terminol- to reduce the daily treatment dose. ogy Criteria for Adverse Events (CTCAE) version 4.0, In addition, if the Hb exceeds 12  g/dL (with ≥ 1.0  g/ except for minor adjustments to laboratory grading dL increase from the baseline value); then, this will be due to the underlying nature of SCD as described in recorded as a laboratory toxicity. If the study partici- the “Adverse event reporting and harms {22}” section pant has symptoms of hyperviscosity such as dizziness 3. Change from baseline in a variety of laboratory and or headache, then a phlebotomy of 5–10  mL/kg can be clinical parameters performed, with full-volume replacement of IV normal saline to prevent hypovolaemia, and study treatment will a. Cerebral Hb oxygen saturation continue. b. Three-dimensional splenic volume If a female becomes pregnant, treatment will be dis- c. Intracerebral arterial blood flow velocity continued for the duration of the pregnancy, but the d. Grade of retinopathy participant will remain in the trial. Investigators may dis- e. Whole blood viscosity continue treatment for any participant at their discretion f. Erythrocyte deformability if, in their professional opinion, the participant’s health, g. Quality of life safety, and/or well-being is threatened by continued par- ticipation in the study. 4. Cumulative incidence of pain, acute chest syndrome, acute splenic sequestration, sepsis, malaria, stroke, Strategies to improve adherence to interventions {11c} and death over 12 months of therapy Participants will be reminded about the importance of 5. Cumulative incidence of blood transfusions and hos- consistent once daily dosing at each study visit. Partici- pitalisations pants will be instructed to return unused medication at each study visit, and the number of unused tablets will be counted and recorded. Counselling will be provided to Participant timeline {13} those who report low adherence. After written informed consent is obtained, participants will complete at least 2 months of screening visits before Relevant concomitant care permitted or prohibited randomisation. After randomisation, participants will during the trial {11d} receive either oral hydroxyurea or placebo for 12 months, All care is permissible, except for the medications men- followed by an opportunity for subsequent open label tioned in the exclusion criteria. treatment that will continue up to 48  months from the time of first participant randomisation. See Fig.  1 for Provisions for post‑trial care {30} schedule of events. Participants will be enrolled from the sickle cell clinics where they usually attend. Their care throughout the trial Sample size {14} will be overseen by their usual clinical team in accordance The primary study hypothesis is that hydroxyurea treat- with the national guidelines and local clinical practices. ment for children and adults with HbSC disease will not cause excess haematological toxicities. We shall use Smart et al. Trials (2023) 24:603 Page 6 of 14 Fig. 1 Schedule of enrolment, interventions, and assessments for PIVOT. Superscript digit one (.1) indicates the following: visits may occur within a window of+/‑ 7 days during months 0‑24 and +/‑14 days during months 24‑48 a non-inferiority study design to compare toxicity rates two sites (adult and paediatric) to achieve approximate between the treatment arms. In the US experience, [29] balance with respect to age at enrolment. Participants laboratory toxicities were identified in ~ 20% of the HbSC will be randomly assigned to a blinded treatment arm patients receiving hydroxyurea, but these were retro- using the randomisation module in REDCap Cloud, a spective data and the dose was not escalated to MTD. In secure, web-based, 21 CRF Part 11-compliant electronic the PIVOT trial, we estimate a cumulative haematologi- data capture system. The data coordinating centre pro- cal toxicity rate of ~ 20% in the placebo arm and allow a grammed REDCap to randomise in blocks of 8 partici- 15% margin for non-inferiority in the hydroxyurea arm. pants and to stratify by age (above or below 18 years at Based on these assumptions, we calculate that 176 study time of consent), and the allocation sequence is gener- participants are needed with an overall 80% power. The ated by the randomisation software in REDCap. enrolment target will be 240 patients (50% children, 50% adults). This sample size will allow 10% screen fail and Concealment mechanism {16b} 8% drop out in year 1, leaving 100 evaluable participants The study pharmacist will know whether the partici- in each age cohort who will receive placebo-controlled pant is randomised to group A or group B but will also study treatment for 12 months. We estimate ≤ 25% drop- be blinded and not know which group is active drug or out rate over the 4-year span of the study. We will not placebo. The tablets for group A and group B will have an enrol additional patients if the dropout rate exceeds the identical appearance. estimated rate. Implementation {16c} Recruitment {15} After completion of screening visits, participants’ clini- The study will be discussed with patients at their regu- cal history and laboratory results will be reviewed by the larly scheduled visits to the adult and paediatric sickle MCC at CCHMC. The MCC will inform the data coor- cell clinics, and printed informational fliers will be dis- dinating centre (DCC) about appropriateness for ran- tributed to patients and their families to sensitise them domisation and the DCC will then notify the clinical site to the trial. regarding readiness to randomise. The clinical site will schedule a study visit at which randomisation will occur. Assignment of interventions: allocation At the randomisation visit, updated labs will be col- Sequence generation {16a} lected and reviewed by the study physician. If the labs are Study participants will be randomised to one of two treat- appropriate for treatment initiation, the study physician ment categories (hydroxyurea or placebo) at an approxi- will inform the pharmacy that the participant is ready for mately 1 to 1 ratio. Randomisation will be stratified at the randomisation. The clinical pharmacist will access the S mart et al. Trials (2023) 24:603 Page 7 of 14 secure interactive web randomisation system, randomise be assessed using an RR Mechantronics Lorrca MaxSis. the participant to either group A or group B using the Hb types will be distinguished and quantitated using REDCap Cloud randomisation module, and dispense the high-performance liquid chromatography (HPLC). The correct treatment. 6-min walk test will be assessed by study clinicians after completion of training and demonstration of compe- Assignment of interventions: blinding tency. Cerebral regional tissue Hb oxygen saturation will Who will be blinded {17a} be assessed using near infrared spectroscopy bilaterally. All investigators, the site study team, the participants, Spleen volume and kidney length will be assessed using the parents, outcome assessors, and data analysts will be ultrasound performed by a consultant radiologist. Intrac- blinded to the study treatment assignment. The partici- erebral arterial velocities will be assessed using transcra- pant’s study ID and treatment allocation will be recorded nial Doppler (TCD) ultrasound performed by certified in a blinded list, to which only the CCHMC DCC direc- examiners who have completed a training course and tor and lead database administrator will have access until submitted an adequate number of high-quality exams. the study is completed or stopping rules are reached. Retinopathy will be assessed using retinal photography Since hydroxyurea at MTD causes predictable changes and optical coherence tomography, with angiography for to the complete blood count (CBC) such as increased positive cases, performed by experienced ophthalmology mean corpuscular volume (MCV) and lower WBC and technicians and interpreted by a consultant ophthalmol- ANC, all investigators will agree to not view the routine ogist. Quality of life will be assessed using the PROMIS clinic CBC results or assess laboratory trends; instead, questionnaire. another designated healthcare provider will examine the local lab results for possible toxicities and communicate Plans to promote participant retention and complete with the local study pharmacist about appropriate dosing follow‑up {18b} including escalation. Participants will be reimbursed a small amount for trans- portation and time spent at study visits. To enhance par- Procedure for unblinding if needed {17b} ticipant retention, more than one mobile phone number If an acute safety concern arises that requires a study will be obtained for each patient and family. Permission participant’s randomised treatment assignment to be will be obtained to contact a close friend or neighbour in unblinded, the site will immediately generate an email the event that their mobile phone is out of service. They to the principal investigators (PIs) and the DCC direc- will be sent SMS text reminders prior to their follow-up tor with complete details of the situation. If the decision visits. to unblind is made, the DCC director and lead database administrator will determine the allocation code accord- Data management {19} ing to the randomisation file and disclose the partici- Study data will be collected and managed using the RED- pant’s treatment assignment to the site PI or designee. Cap Cloud™ electronic data capture system. REDCap The allocation will not be disclosed to other study per- Cloud™ is a secure 21 CFR Part 11-compliant web-based sonnel, monitors, nor the study participant’s family. application designed to support data capture for research There will not be verbal disclosure of the code at any studies, providing (1) an intuitive interface for validated time. Details of the time, circumstances, and reason for data entry, (2) audit trails for tracking data manipulation emergency unblinding are to be documented in the par- and export procedures, (3) automated export procedures ticipant’s medical records and any relevant case report for seamless data downloads to common statistical pack- forms (CRFs). ages, and (4) validated electronic signatures. The RED- Cap Cloud™ system supports a secure web application Data collection and management designed exclusively to support data capture for research Plans for assessment and collection of outcomes {18a} studies, with a secure internet-based connection that Sickle-related clinical events will be collected during uses low bandwidth, suitable for research in low- and interval study visits through both patient and family middle-income countries. reports and review of medical records. Physical exami- Data will be entered into the electronic data record nation will be performed by study clinicians experienced directly from the clinical site. Electronic data will be with SCD. A CBC will be performed using a haematol- reviewed for accuracy and completion by research staff. ogy analyser with a five-part leukocyte differential and Programmes will be created to run logical and missing automated reticulocyte count. Whole blood viscosity value error checks on the data files. Audit reports will will be performed using a Brookfield Ametek rheom- result from these programmes and will be used to clean eter. Erythrocyte deformability and point-of-sickling will the data. Quality control analyses are performed on the Smart et al. Trials (2023) 24:603 Page 8 of 14 data at standard time intervals. Outliers will be reviewed, PCR, Sanger sequencing, and next generation sequenc- resolved, and the database updated as necessary. ing to identify genetic variations that could influence the The DCC will remotely monitor data accuracy and clinical phenotype in HbSC disease or to modify hydrox- completeness and also be responsible for on-site moni- yurea response. If participants agree during the informed toring. The DCC will be responsible for maintaining the consent, specimens will be stored for future research. data centrally, randomisation, maintaining the blind, monitoring enrolment and completeness of data, and Statistical methods generating queries to notify sites of incomplete data. In Statistical methods for primary and secondary outcomes addition, the DCC will be responsible for statistical anal- {20a} ysis, including summary reports for MCC review and The lab and clinical parameters will be analysed either as performing on-site monitoring visits to compare submit- continuous or categorical variables. Event rates for toxici- ted data with source documents. The DCC will also pre- ties and clinical complications will be compared to base- pare a semi-annual report for the independent data safety line after 6 and 12  months of blinded study treatment, monitoring board (DSMB). The study site is responsible using non-inferiority methods. for reporting AEs centrally to the DCC via electronic data entry. Interim analyses {21b} Clinical site monitoring is conducted to ensure that A formal interim analysis is not planned, but the DSMB the rights and well-being of trial participants are pro- will receive a summary of accrued data every 6 months. tected, that the reported trial data are accurate, com- The DSMB will recommend either continuation or termi- plete, and verifiable, and that the conduct of the trial is nation of the study at each meeting. Termination may be in compliance with the currently approved protocol/ suggested at any time and reasons for early termination amendment(s), with International Conference on Har- include, but are not limited to, SAEs affecting more than monisation Good Clinical Practice (ICH GCP), and with one third of the study participants enrolled. applicable regulatory requirement(s). A local monitor will be employed for on-site trial monitoring following the Methods for additional analyses (e.g. subgroup analyses) data safety monitoring plan (DSMP). Additional remote {20b} database and on-site monitoring will be conducted by the Subgroup analysis will be performed to analyse the ben- MCC and DCC as assigned by the international PI. efit of hydroxyurea in participants with high versus low incidence of pain episodes and by baseline clinical and Confidentiality {27} laboratory factors that indicate more and less severe Each participant will be given a study ID number, which disease. will allow de-identified information to be collected with- out the participant’s name, including clinical informa- Methods in analysis to handle protocol non‑adherence tion and laboratory results. No information concerning and any statistical methods to handle missing data {20c} the study or the data will be released to any unauthorised All study data collected from eligible participants will be third party without prior written approval of the sponsor. used in the analysis of primary and secondary outcomes. All research activities will be conducted in as private a For participants who withdraw prior to study comple- setting as possible. Study participant contact information tion, all data points will be included in analysis up to will be securely stored at each clinical site for internal and including the time of study withdrawal. Missing data use during the study. At the end of the study, all records related to primary endpoints will not be imputed. will be securely maintained for as long a period as dic- tated by the reviewing institutional review board (IRB), Plans to give access to the full protocol, participant‑level institutional policies, regulatory authority, or sponsor data, and statistical code {31c} requirements. De-identified data will be made available to all investiga- tors whose proposed use of data has been approved by an Plans for collection, laboratory evaluation, and storage internal review committee identified for this purpose and of biological specimens for genetic or molecular analysis with a signed data-sharing agreement between all parties. in this trial/future use {33} Peripheral blood will be collected and placed onto a Oversight and monitoring Whatman FTA card and into a PaxGene tube for DNA Composition of the coordinating centre and trial steering preservation, and genomic DNA will be purified later committee {5d} using standard laboratory techniques. These samples will The primary PIVOT clinical site will be led by be analysed using a variety of laboratory methods such two local PIs specialised in adult haematology and S mart et al. Trials (2023) 24:603 Page 9 of 14 paediatric haematology respectively. Both of these Adverse event reporting and harms {22} local PI’s have investigative research teams at KBTH. To document medication safety, AEs and SAEs will be The PIVOT study team in KBTH will also include a collected and reported to the MCC and DCC using data study coordinator, study physicians, nurses, pharma- collection forms. AE reporting will utilise the CTCAE cists, and research assistants. Version 4.0, where all AE are categorised by organ sys- The PIVOT trial will be guided by both the MCC tem and graded by severity. Only AE grade 2 and above and DCC located at CCHMC. The MCC will be led including all SAE will be reported. Table  1 lists excep- by the international PI and a co-investigator. The co- tions to the CTCAE version 4.0 guidelines that will be investigator will be the primary clinical coordinator used for AE grading of selected laboratory parameters in to assist the site with clinical questions, dosing issues, the PIVOT study. AEs, and other questions related to interpretation of Several complications are expected to occur in PIVOT the protocol. The DCC is led by the international PI because of the underlying disease process of HbSC (e.g. and assisted by a team of experienced personnel who haemolytic anaemia, acute painful episodes, etc.) and the have substantial expertise in multicentre clinical trials, known side effect profile of hydroxyurea. A list of many online electronic data capture, and hybrid monitor- expected and potentially serious AE, as well as exceptions ing of data quality and completeness. The whole team to the CTCAE, is included in Tables 2 and 3. A PIVOT (KBTH and CCHMC) will meet monthly via video unexpected AE is defined as any AE or SAE that is not conference, and the local site coordinators will meet usually associated with either the underlying disease pro- with the CCHMC coordinators on a separate monthly cess of HbSC or treatment with hydroxyurea. The PI will call. An annual in-person meeting will occur along use clinical judgement along with consensus knowledge with an on-site sponsor monitoring visit conducted by about SCD in determining event expectedness. Hydrox- MCC and DCC leadership. yurea-related complications will be reviewed by the PIVOT PI or MCC representative to determine the abil- ity to continue therapy. Composition of the data monitoring committee, its role An SAE is an AE occurring during any study phase and reporting structure {21a} (screening, treatment or follow-up) that fulfils one or An independent DSMB has been formed to provide more of the following criteria: safety and oversight for the study. The DSMB is com- posed of international experts in SCD, both paediatric 1. Results in death and adult, as well as clinical trial design and patient 2. Is immediately life-threatening advocacy. The DSMB will convene every 6  months to 3. Requires in-patient hospitalisation > 7  days or pro- review accrued data summaries prepared by the DCC. longs an existing hospitalisation The DSMB will make recommendations to the MCC 4. Results in persistent or significant disability/incapac- for either continuation or termination of the study at ity each meeting. Termination may be suggested at any 5. Is a congenital abnormality or birth defect time and reasons for early termination include, but are 6. Is an important medical event that may jeopardise not limited to, SAEs affecting more than one third of the subject or may require medical intervention to the study participants enrolled. prevent one of the outcomes listed above Table 1 List of laboratory exceptions to the CTCAE, version 4.0, grading guidelines Parameter Grade 2 Grade 3 Grade 4 Hb (g/dL) 5.0–6.0 4.0–4.9 < 4.0 WBC (× 109/L) 1.0–1.999 0.5–0.999 < 0.5 ANC (× 1 09/L) 0.5–0.999 0.2–0.499 < 0.2 Platelets (× 109/L) 50–79 20–49 < 20 Total bilirubin (μmol/L) 85.5–171 171.1–342 > 342 AST (IU/L) 150–300 301–1000 > 1000 ALT (IU/L) 150–300 301–1000 > 1000 Creatinine (μmol/L) Doubling of baseline serum creatinine 141.44–176.8 > 176.8 and value ≥ 88.4 μmol/L ARC (× 109/L) with Hb < 7.0 g/dL 50–80 10–49 < 10 Smart et al. Trials (2023) 24:603 Page 10 of 14 Table 2 List of expected and potentially serious adverse events in all PIVOT participants with HbSC related to sickle cell disease • Abnormal TCD velocities • Fever without source • Pain, non‑specific • Acute chest syndrome • Haematuria • Pain, severe abdominal • Adenotonsillar disease • Haemolysis • Pain, sternal or rib • Albuminuria • Haemorrhagic Stroke • Pneumonia • Amenorrhea • Hand‑foot syndrome/dactylitis • Priapism • Anaemia (severe) • Headache • Proteinuria • Aplastic crisis • Hemiplegia • Pulmonary embolism • Arthralgia • Hepatic sequestration • Pulmonary hypertension • Avascular necrosis of hip/shoulder • Hepatomegaly • Pulmonary infiltrate on chest x‑ray • Bacteraemia • Hospitalisation > 24 h • Pyelonephritis • Bone infarction • Hyperbilirubinemia • Recurrent wheezing episodes • Cardiac arrhythmia • Hypersplenism • Renal failure • Cardiomegaly • Hypertension • Renal insufficiency • Cerebrovascular accident • Hypocalcaemia • Renal papillary necrosis • Cholecystitis • Hyposthenuria • Reticulocytopenia • Cholelithiasis • Hypotension • Reticulocytosis • Cognitive dysfunction • Hypoxemia (PO2 < 65 mm Hg) • Retinal haemorrhage • Constipation • Ileus • Retinopathy • Cranial nerve palsy • Infection, line • Rhabdomyolysis • Death • Infection, other bacterial • Seizure • Decreased lung function • Infection, pneumococcal • Septicaemia • Decreased renal function • Infection, viral • Silent infarct • Delayed growth/puberty • Jaundice • Skin ulcer • Depression • Leukocytosis • Sleep apnoea • Dizziness • Meningitis • Splenic sequestration • Electrolyte imbalance • Nephropathy • Splenomegaly • Elevated serum transaminases • Osteomyelitis • Stroke • Elevated TCD velocities • Pain, back • TIA • Elevated urinary urobilinogen • Pain, chest • Tonsillar hypertrophy • Empyema • Pain, joint • Transfusion, unanticipated • Fever with infection • Pain, long bone • Vaso‑occlusive pain Table 3 List of expected and potentially serious adverse events in PIVOT associated with hydroxyurea therapy • Allergic reaction • Hypersplenism • Pancytopenia • Anaemia • Increased ALT • Rash • Anorexia • Increased creatinine • Reticulocytopenia • Constipation • Leukopenia • Skin ulcers/gangrene • Diarrhoea • Nail/skin hyperpigmentation • Splenomegaly • Gastritis • Nausea • Thrombocytopenia • Hair loss • Neutropenia • Vomiting • Increase in at least one of the following laboratory parameters: MCV, MCH, MCHC, nucleated RBC, Hb electrophoresis (%S and %F) • Decrease in at least one of the following laboratory parameters: ARC, % reticulocytes, RBC, WBC, ANC, platelet count, haematocrit, Hb electrophoresis %A, total bilirubin, LDH, and ferritin All SAEs will be reported to the KBTH IRB and Ghana or relationship to the investigational product, a follow-up FDA, per their reporting requirements. Additionally, SAE report will be sent to the KBTH IRB, Ghana FDA, SAEs will be promptly reported to the MCC and DCC and MCC. All SAEs will be followed until resolution or safety officer. If an ongoing SAE changes in its intensity S mart et al. Trials (2023) 24:603 Page 11 of 14 stabilisation. SAE reporting will be completed using the prolonged follow-up to describe the long-term safety and PIVOT SAE CRF available in the study database. effectiveness of hydroxyurea. Hydroxyurea is a logical and intuitive treatment for Frequency and plans for auditing trial conduct {23} HbSC, due to its known potency to induce HbF and Clinical site monitoring will be conducted to ensure that inhibit sickle polymerisation, as well as its low cost and the rights and well-being of trial participants are pro- ease of oral administration. The importance of HbF in tected, that the reported trial data are accurate, com- HbSC disease remains undefined, though HbF is known plete, and verifiable, and that the conduct of the trial to delay both HbS polymerisation and HbC crystallisa- is compliant with the currently approved protocol/ tion [3]. PIVOT will simultaneously evaluate the labora- amendment(s), with ICH GCP, and with applicable regu- tory and clinical responses to hydroxyurea among both latory requirement(s). A local monitor will be employed paediatric and adult populations. Despite the plethora of for on-site trial monitoring following the DSMP and data regarding hydroxyurea treatment for HbSS, there are Ghanaian regulatory requirements. Remote database relatively few published studies for patients with HbSC, monitoring will occur at least monthly by the DCC, and and much less is known about its benefits and risks for annual on-site sponsor monitoring will occur in addition this population, especially in adults. to visits performed by the locally-assigned monitor. The first descriptions of haematological response to hydroxyurea in HbSC disease were published 25  years ago [30] when it was noted in a small case series (6 Plans for communicating important protocol amendments patients) that low dose hydroxyurea (10–20  mg/kg/day) to relevant parties (e.g. trial participants, ethical increased the Hb, MCV, and HbF while decreasing neu- committees) {25} trophils and reticulocytes. This was soon followed by Any protocol amendments will be agreed upon by the several other small case series that confirmed haemato- investigators and submitted for approval to the IRB and logical changes with low dose [31] and both haemato- Ghana FDA for approval before implementation. The logical and clinical improvement with escalated dosing trial registry will be updated after ethical/regulatory [32, 33]. The largest retrospective analysis was a multi- approval has been obtained. Trial participants will be centre survey of US-based academic haematologists informed of any changes that affect their involvement or that described hydroxyurea effects on HbSC among 133 treatment, and if necessary, they will be re-consented for children, teens, and young adults treated at 23 academic ongoing participation. centres across the USA. Approximately 5% of the patients with HbSC were receiving hydroxyurea; the median age Dissemination plans {31a} at treatment initiation was 15 years; and the most com- At the end of the trial, a main outcome manuscript will mon clinical indication was vaso-occlusive pain and/ be submitted to a peer reviewed medical journal and the or acute chest syndrome. The number of pain episodes trial results will be presented at an international meeting. decreased significantly after 12  months of treatment. Other results generated from the trial that are not pub- The reduction in vaso-occlusive pain was 38%, similar to lished in the main outcome manuscript will be submit- adults with HbSS (44%) or children with HbSS (52%) [13, ted for publication in peer-reviewed medical journals and 15], but the retrospective and open-label nature of the presented at local, national, regional, and international data left several questions unanswered. The hydroxyurea scientific meetings. Addmedica has no role in the analy- dosing was highly variable, with 20% of treated patients sis of results or decision to publish results and will not receiving < 15  mg/kg/day while another 20% was tak- write, review, or comment on manuscripts. ing > 25 mg/kg/day. There appeared to be a greater reduc- tion in painful episodes in those who started on ≥ 20 mg/ Discussion kg/day in children ≥ 15  years old, but no difference in PIVOT is the first randomised controlled phase 2 trial those < 15 years old. Lab toxicities requiring a dose hold of hydroxyurea for the treatment of HbSC disease. Pro- or adjustment occurred in 20% of treated patients, usu- spective therapeutic trials for treatment of HbSC dis- ally due to neutropenia and/or thrombocytopenia. Only ease are sorely needed, and hydroxyurea is a natural one patient reported increased pain in association with candidate given the extensive experience success in a higher Hb level. There were no statistically significant treatment for HbSS. This will be the largest prospec- changes in the Hb level after 12 months of treatment, and tive description of children or adults with HbSC disease treatment was associated with modest increases in MCV treated with hydroxyurea, enrolling 120 children and 120 (+ 11 fL) and HbF (+ 3%), and mild decreases in WBC adults who will be randomised to active drug or placebo and ANC [29]. In contrast, PIVOT will initiate blinded for 12  months before an open-enrolment phase with study treatment at 20 mg/kg/day in all participants with Smart et al. Trials (2023) 24:603 Page 12 of 14 two opportunities to escalate the dose during the first pain from AVN) may not respond quickly enough or be 6 months of treatment. Dosing toxicities in previous clin- reversible enough to demonstrate efficacy in 12 months. ical trials of hydroxyurea for HbSS disease in Africa have In summary, PIVOT is the first randomised placebo- not revealed a significant increase in cytopenias with controlled blinded trial to provide prospective data fixed or escalated dosing [34–36]. regarding the safety of hydroxyurea, the appropriate dose Hydroxyurea is a prime candidate for treatment of range, and the clinical effects in HbSC. PIVOT will pro- HbSC disease because it is relatively inexpensive, widely vide invaluable details regarding a wide range of clinical available, and already used extensively for treatment of and laboratory outcomes that will not only be essential HbSS disease in both high-income countries and sub- for the design a future definitive phase 3 clinical trial Saharan Africa. This trial will be conducted in Ghana but will also have immediate clinical implications for where the burden of HbSC disease is arguably the high- the large number of people living with HbSC in Ghana est in the world, and effective long-term treatment is and around the world. Instead of anecdotal usage offered especially needed. Ghana is an ideal location for several only to patients with severe symptoms or potentially irre- reasons: (1) there is a large amount of HbS and HbC versible organ damage, hydroxyurea could emerge as an in the population, so HbSC is a common form of SCD; important treatment option before the onset of acute (2) the KBTH programmes are established and have and chronic clinical complications. If effective and safe well-known leaders in the field; (3) hydroxyurea is now as disease modifier, hydroxyurea could be an inexpensive becoming a more common treatment for HbSS in Ghana. and accessible option that changes the lives of millions of This growing familiarity with hydroxyurea makes Ghana individuals with HbSC disease. an attractive place to conduct additional research studies on hydroxyurea, since the Ghana FDA has approved the Trial status medication for HbSS and investigators and families are The current PIVOT protocol at the time of manuscript more aware of the treatment benefits. submission is Version 1.2, written on October 20, 2021. The study will be conducted across a large medical Recruitment for the study began on 13 April 2022, and it campus and involves two separate clinics and a separate is estimated that recruitment will finish on or around 30 research laboratory that will allow collection of a variety June 2023. of exploratory outcomes. The effect of treatment-related changes in the Hb on the whole blood viscosity will be measured on location with fresh blood and will be corre- Abbreviations AE A dverse event lated to any clinical complications, meeting an important ALT A lanine aminotransferase safety aim. Retinopathy is a particularly common com- ANC Absolute neutrophil count plication of HbSC disease possibly because of the den- ARC A bsolute reticulocyte count AST A spartate aminotransferase sity and increased viscosity of the erythrocyte containing CBC Complete blood count both HbS and HbC. We have the first opportunity to test CCHMC Cincinnati Children’s Hospital Medical Center the effect of hydroxyurea on retinopathy in a randomised CTCAE Common Terminology Criteria for Adverse Events CRF Case report form fashion across age spans and with advanced ophthal- DCC Data coordinating centre mological evaluation. RBC deformability may be a more DSMB Data safety monitoring board immediate target that demonstrates clinical improve- DSMP D ata safety monitoring plan EMA European Medicines Agency ment over the short term, and the site has been equipped FDA Food and Drug Administration with an ektacytometer and viscometer to capture func- Hb H aemoglobin tional aspects of the RBC before and after hydroxyurea HbC H aemoglobin C HbF Haemoglobin F, fetal haemoglobin treatment. HbS H aemoglobin S Our trial has some potential limitations. The size of the HbSβ0 H aemoglobin S‑beta thalassemia zero trial may not provide the power needed to demonstrate HbSC Haemoglobin SC HbSS Haemoglobin SS efficacy if the clinical gains are less prominent over the HPLC High‑performance liquid chromatography first year of randomised treatment. We have attempted ICH GCP International conference on harmonization good clinical practice to provide optimal benefit by starting at a moderate IRB Institutional review board KBTH Korle Bu Teaching Hospital weight-based dose (20 mg/kg/day) and allowing for dose LDH L actate dehydrogenase escalation if haematological parameters permit. The MCC Medical coordinating centre optimal clinical outcomes for a trial of HbSC disease are MCV Mean corpuscular volume MTD Maximum tolerated dose unknown. Many of the clinical morbidities occur later in NHLBI National Heart Lung and Blood Institute life and more slowly than in HbSS disease. Some of the NIH National Institutes of Health most prominent components of disease (e.g. chronic PI Principal investigator PIVOT Prospective Identification of Variables as Outcomes for Treatment S mart et al. Trials (2023) 24:603 Page 13 of 14 SAE S erious adverse event KNA receives grant funding from Optos Inc. (RIS 1065442) and NIH—H3 Eyes SCD Sickle cell disease of Africa (5U54HG009826). SPIRIT S tandard protocol items: recommendations for interventional LRS has no competing interests. trials REW is consultant for Nova Laboratories; receives research donations from TCD Transcranial Doppler ultrasound Bristol Myers‑Squibb, Addmedica, and Hemex Health; and chairs Data and WBC W hite blood cell Safety Monitoring Boards for Novartis and Editas. SES is a consultant for the American Society of Hematology Research Acknowledgements Collaboration. We thank the clinical teams and trial participants at the paediatric and adult TSL has no competing interests. clinical trial sites at Korle Bu Teaching Hospital, Dr. Kwaku Ohene‑Frempong for YAD has no competing interests. discussions at early stages of the trial, members of the DSMB, and Addmedica for donation of the study treatment. Author details 1 Division of Hematology, Cincinnati Children’s Hospital Medical Center, Authors’ contributions{31b} Cincinnati, USA. 2 Department of Pediatrics, University of Cincinnati College ACL is the statistician. He contributed to the design, to development of the of Medicine, Cincinnati, USA. 3 Global Health Center, Cincinnati Children’s Hos‑ proposal, and to development of the statistical analysis plan. CIS is the local pital Medical Center, Cincinnati, USA. 4 Department of Child Health, University PI and consultant haematologist for paediatrics. She contributed to the study of Ghana Medical School, Accra, Ghana. 5 Department of Child Health, Korle Bu design and to development of the proposal. KDT is the consultant radiologist. Teaching Hospital, Accra, Ghana. 6 Ophthalmology Unit, Department of Sur‑ She contributed to the study design, to the development of the protocol, and gery, University of Ghana Medical School, Accra, Ghana. 7 Ophthalmology Unit, to establishing radiological assessments. KNA is the consultant ophthalmolo‑ Department of Surgery, Korle Bu Teaching Hospital, Accra, Ghana. 8 Depart‑ gist. He contributed to the study design, to the development of the proposal, ment of Radiology, Korle Bu Teaching Hospital, Accra, Ghana. 9 Department and to establishing the ophthalmological assessments. LRS is the international of Haematology, University of Ghana Medical School, Accra, Ghana. 10 Depart‑ co‑investigator and the head of the MCC. He contributed to the study design, ment of Haematology, Korle Bu Teaching Hospital, Accra, Ghana. 11 Ghana to the development of the proposal, and to establishing the laboratory and Institute of Clinical Genetics, Korle Bu, Accra, Ghana. clinical evaluations. REW is the international PI. He conceived the study and led the proposal and protocol development. SES contributed to the study Received: 30 March 2023 Accepted: 13 September 2023 design and to development of the proposal and wrote the first draft of the protocol. TSL is the head of the DCC. She contributed to the study design and to development of the proposal and the creation of the study database. YAD is the local PI and consultant haematologist for adults. She contributed to the study design and to development of the proposal. All authors read and References approved the final manuscript. 1. World Health Organization. Regional Office for Africa. Sickle‑cell disease: a strategy for the WHO African Region. 2010. Authors’ information 2. Piel RB, Patil AP, Howes RE, et al. Global epidemiology of sickle haemoglo‑ N/a. bin in neonates: a contemporary geostatistical model‑based map and population estimates. Lancet. 2013;381(9681):142–51. Funding {4} 3. Nagel RL, Fabry ME, Steinberg MH. 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