RATIONALE AND DESIGN OF THE COMPARISON OF THREE COMBINATION THERAPIES IN LOWERING BLOOD PRESSURE IN BLACK AFRICANS (CREOLE STUDY): 2 x 3 FACTORIAL RANDOMIZED SINGLE-BLIND MULTICENTRE TRIAL

Dike B. Ojji, PhD,a Neil Poulter, FMedSci,b Albertino Damasceno,PhD,c Karen Sliwa, MD, PhD,d Wynand Smythe,PhD,e Nicky Kramer, B.Pharm,e Motasim Badri,PhD f,g Veronica Francis,BA,e Akinyemi Aje, FMCP,h Felix Barasa, MMed,i Anastase Dzudie,PhD,j Erika Jones, PhD,g Abubakar Kana, FWACP,k Mntla Pindile,FCP(SA),l Charles Mondo, PhD,m Okechukwu Ogah, PhD,h Elijah N. Ogola, MMed,n Gboyega Ogunbanjo,FCFP(SA),o Ikechi Okpechi, PhD,g Gabriel Shedul, FMCFM,p Mahmoud Sani, PhD,q Grace Shedul,B.Pharm,r and Bongani Mayosi, DPhil,g

Abuja, Nigeria; London; United Kingdom; Maputo, Mozambique; Cape Town, South Africa; Riyadh, Saudi Arabia; Ibadan, Nigeria; Eldoret, Kenya; Douala, Cameroon; Kano, Nigeria; Pretoria, South Africa; Kampala, Uganda; Nairobi, Kenya

Corresponding Author:

Prof Bongani Mayosi,

University of Cape Town, Faculty of Health Sciences,

Barnard Fuller Building, Anzio Road, Observatory, Cape Town

Rondebosch 7700

Cape Town, South Africa

Tel: +27 (0) 21 406-6101/6

Email: bongani.mayosi@uct.ac.za

a. Department of Medicine, Faculty of Clinical Sciences, University of

Abuja/University of Abuja Teaching Hospital, Gwagwalada, Abuja, Nigeria,

b. Imperial Clinical Trials Unit, School of Public Health, Imperial College London, United Kingdom

c. Eduardo Mondlane University Hospital, Maputo, Mozambique

d. Hatter Institute of Cardiovascular Research in Africa, Cape Town, South Africa,

e. Clinical Research Centre, Faculty of Clinical Sciences, University of Cape Town, South Africa

f. Department of Basic Sciences, College of Sciences & Health Professions King Saud Bin Abdul-Aziz University for Health Sciences NGHA, Riyadh, Saudi Arabia

g. Department of Medicine, Faculty of Clinical Sciences, University of Cape Town

h. University College Hospital, Ibadan, Nigeria

i. MOI University Hospital, Eldoret, Kenya,

j. Douala General Hospital, Douala, Cameroon

k. Department of Medicine, Aminu Kano Teaching Hospital, Kano, Nigeria

l. Department of Cardiology, Sefako Makgatho Health Sciences University, Pretoria, South Africa

m. St Francis Hospital, Nsambya, Kampala, Uganda

n. Department of Clinical Medicine and Therapeutics, University of Nairobi, Kenya

o. Department of Family Medicine & Primary Health Care, Sefako Makgatho Health Sciences University, Pretoria, South Africa

p. Department of Family Medicine, University of Abuja Teaching Hospital, Gwagwalada, Abuja,

q. Aminu Kano Teaching Hospital, Kano Nigeria

r. Department of Pharmacy, University of Abuja Teaching Hospital, Gwagwalada, Abuja, Nigeria

ABSTRACT

Background: Current hypertension guidelines recommend the use of combination therapy as first-line treatment or early in the management of hypertensive patients. Although there are many possible combinations of blood pressure(BP)-lowering therapies, the best combination for the black population is still a subject of debate as no large randomized controlled trials (RCTs) have been conducted in this group to compare the efficacy of different combination therapies to address this issue.

Methods: The comparison of three combination therapies in lowering blood pressure in Black Africans (CREOLE) study is a randomized single-blind trial that will compare the efficacy of amlodipine plus hydrochlorothiazide, versus amlodipine plus perindopril, and versus perindopril plus hydrochlorothiazide in Blacks residing in sub Saharan Africa (SSA). 702 patients aged 30-79 years with a sitting systolic BP of 140mmHg and above, and less than 160 mmHg on antihypertensive monotherapy, or sitting systolic BP of 150 mmHg and above, and less than 180 mmHg on no treatment, will be centrally randomised into any of the three arms (234 into each arm). The CREOLE study is taking place in ten sites in sub-Saharan Africa, and the primary outcome measure is change in ambulatory systolic BP (ASBP) from baseline to 6 months. The first patient was randomized in June 2017 and the trial will be concluded in 2020.

Conclusion: The CREOLE trial will provide unique information as to the most efficacious two-drug combination in blacks residing in SSA, and thereby inform the development of clinical guidelines for the treatment of hypertension in this sub region.

INTRODUCTION

Hypertension is a common and independent risk factor for cardiovascular mortality worldwide and therefore the importance of effective treatment cannot be overemphasized.1,2 It has been shown in many different randomised controlled trials that BP reduction is associated with reduced cardiovascular morbidity and mortality.3,4 Furthermore, a meta-analysis of 61 prospective observational studies covering 1 million adults and 12.7 million person-years at risk has substantiated that for every 2 mmHg difference in mean systolic blood pressure (SBP), there is a 7% difference in the risk of ischaemic heart disease mortality and 10% difference in the risk of cerebrovascular accident.5

Reducing blood pressure to target levels is therefore a major priority in preventing clinical events in hypertension, and typically this requires more than one medication in the majority of patients. For example, in the large Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack (ALLHAT) trial, less than 30% of the subjects achieved BP goal on mono-therapy.6

Randomised controlled trials (RCTs) in hypertension as early as the 1950s showed that patients with malignant hypertension were markedly transformed by the introduction of anti-hypertensive therapy.7 Over the following decades (during the 1970s, 1980s and early 1990s), trials of severe and moderate hypertension confirmed the cardio protective, reno protective and neuro protective benefits of lowering BP, with a series of placebo-controlled trials of milder levels of hypertension also taking place.7 By the end of 1980s, the results of a number of these placebo-controlled trials in hypertension showed in meta-analysis that a reduction in SBP of 10-12 mmHg and DBP reduction of 6-7 mmHg reduced the incidence of cerebrovascular accident by about 40%,4 which was comparable with the risk reduction reported from prospective observational studies.8 However, the risk of non-fatal myocardial infarction and coronary heart disease death was reduced by about 14% which is less than what was expected from prospective observational data.4,5

Following these placebo-controlled trials and the resultant meta-analyses, a series of trials set out to compare the benefits of contemporary drugs over standard therapy. In 2000, the Blood Pressure Lowering Treatment Trialists Collaboration published a meta-analysis of these trials that included data from approximately 75,000 patients. This demonstrated that angiotensin receptor blockers were effective in reducing total cardiovascular events, angiotensin converting enzyme inhibitors and diuretic plus beta-blocker based regimens are more effective than calcium channel blockers in preventing heart failure, and that calcium channel blockers may be more effective in preventing stroke.9

Results from various RCTs showed that the majority of patients with hypertension require at least two BP-lowering agents if recommended targets are to be reached.10-16 Consequently, there has been a lot of emphasis by the various guidelines on the use of combinations of two or three agents on the management of hypertension.17-21

Guidelines differ regarding which combination of two BP-lowering agents they recommend, and none has been able to recommend with certainty optimal combinations for black populations.19-23 This is because there are no large RCTs that have compared the efficacy of contemporary combination therapies among any black populations, 24 despite the high burden of hypertension and its complications in this group.25-27

RATIONALE FOR THE STUDY

Although it might be argued that findings in African-Americans can be extrapolated to Black Africans since they have the same ancestral origin, the differences in selection in previous generations, ethnic admixture and differences in lifestyle suggest that such an extrapolation may be inappropriate.28-30 In addition, among African-American patients with hypertension, no large RCTs trials have evaluated optimal combinations of antihypertensive medications.

HYPOTHESIS

Previous studies in black Africans showed that calcium channel blockers and diuretics to be more efficacious as monotherapy when compared with angiotensin converting enzyme inhibitors.31,32 Based on these, we aim to test the hypothesis that therapy with a combination of amlodipine plus hydrochlorothiazide is more efficacious than the combinations of perindopril plus amlodipine, and perindopril plus hydrochlorothiazide in reducing mean 24-hour ambulatory systolic blood pressure (ASBP) levels in black Africans.

OBJECTIVES

Primary Objectives

The primary objective of the CREOLE study is to determine which of the three ‘two-drug’ anti-hypertensive combinations of amlodipine plus perindopril versus amlodipine plus hydrochlorothiazide versus perindopril plus hydrochlorothiazide) is most effective in reducing 24 hour ASBP in black African patients with hypertension.

Secondary Objectives

The secondary objectives of the study are:

1. To determine which of these combinations is most effective in reducing other measures of blood pressure which include:

i. 24-hour ambulatory diastolic BP (ADBP)

ii. Clinic BP

iii. Day time and nighttime BP

iv. 24-hour ASBP variability measured by ambulatory blood pressure monitoring (ABPM).

2. To determine which of the three combinations of two -antihypertensive agents is most effective in increasing the proportion of patients who achieve BP control (BP control is defined as SBP < 140mmHg and DBP< 90mmHg), and proportion of patients classified as “responders” (responders are defined as those with a reduction of SBP > 20mmHg and DBP> 10mmHg during the trial).

3. To determine the effect of these three combinations on:

i. Micro- and macro-albuminuria,

ii. Fasting blood glucose,

iii. Fasting lipid profile,

iv. Serum sodium, potassium, urea, creatinine and estimated glomerular filtration rate,

v. Adverse events causing permanent discontinuation of therapy.

STUDY DESIGN

The CREOLE trial is a randomized single-blind trial comparing the efficacy of amlodipine plus hydrochlorothiazide with a combination of amlodipine plus perindopril, and a combination of perindopril plus hydrochlorothiazide (Figure1).

Although the study is strictly classified as single-blinded since the commercial products to be used do not match each other, measures will be taken to mask the identity of dispensed medications in order to minimise bias. Such measures include: re-packaging the products into identical blister packs with identical labels such that patients, pharmacists administering the medications and physicians assessing the outcomes are not aware of the group assignments. In addition, physicians and investigators do not have any access to the medications as during follow up visits the patient reports first to the site Pharmacist who collects any remaining packs before sending the patient to the Physician. And after follow up review by the physicians, the patient goes to the study pharmacist to collect fresh medications and does not return to the physician. Furthermore, the Pharmacist educates the patient not to reveal the colour or shapes of the tablets he or she is taking. And lastly during site initiation visits and training, investigators were trained never to ask of the shape or colour of patients’ medications as this is completely blinded to them.

Allocation to study groups is performed using randomization in a 1:1:1 allocation ratio, with stratification by age (less than 55 years or 55 years and above) and blocked by site. A randomisation list is drawn up centrally for each site and includes enrolment numbers randomly allocated to one of the three trial combinations of amlodipine plus perindopril or amlodipine plus hydrochlorothiazide or perindopril plus hydrochlorothiazide. Enrolled patients take their allocated enrolment numbers to the pharmacy where the corresponding study medications are dispensed to them in medication blister packs labelled with unique patient identification numbers consisting of the centre and randomization numbers.

The label contain dosing instructions and temperature storage requirements. All labelling is in English. After the two-month clinic visit, patients receive a higher dose of the same medication they were randomized to and instructed to complete the treatment.

Patients commence treatment at a starting dose of amlodipine/hydrochlorothiazide 5/12.5 mg or amlodipine/perindopril 5/4 mg or perindopril/hydrochlorothiazide 4/12.5 mg. These doses will be increased at the two months visit, to amlodipine/hydrochlorothiazide 10/25 mg or amlodipine/perindopril 10/8mg or perindopril/hydrochlorothiazide 8/25 mg unless patients cannot tolerate higher doses as judged by the physician or have a systolic blood pressure of less than 100mmHg.

If after four months of treatment, clinic SBP is greater than160 mm Hg or DBP is greater than100 mm Hg, atenolol 50 mg once daily will be added to the trial therapy unless contraindicated, in which case an alternative agent that is not a thiazide diuretic, ACE inhibitor or calcium channel blocker such as 12.5mg of spironolactone or 2mg of doxazosin will be added at the investigator’s discretion. Whilst the intention to treat (ITT) principal will be maintained, there will be sensitivity analyses excluding BP values from this group of patients on non-trial agents by carrying forward their 4 month BP data to 6 months.

All Patients will be randomised and followed up for 6 months. Last patient follow up visit will occur 18 months after first patient randomized. (Figure2).

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Figure 2: CREOLE Timelines of the study

Study Population

The enrolled patients are those referred to primary and secondary care in the study sites for the management of primary hypertension (figure 3).

Figure 3: Study sites in Sub Saharan Africa

Inclusion Criteria

Eligible patients will be aged 30-79 years with a sitting SBP ≥140 mm Hg and < 160 mmHg on antihypertensive monotherapy, or sitting SBP ≥ 150 mm Hg and < 180 mm Hg on no antihypertensive treatment.

Exclusion Criteria

The following patients will be excluded from the study:

1. Those with clinically defined congestive heart failure

2. Those with estimated glomerular filtration rate (eGFR) less than 30 ml/min

3. Those with history of coronary heart disease including chronic stable angina, myocardial infarction or acute coronary syndrome

4. Patients with a history of a stroke or transient ischaemic attack

5. Patients with known or suspected secondary hypertension

6. Those with any other concomitant illness, physical or mental impairment that could interfere with the effective conduct of the study

7. Those who are pregnant or those of child-bearing age who are not taking reliable contraception.

8. Patients with gout and serum potassium < 3.5mmol/L

Primary Endpoint

The primary outcome measure is change in ASBP from baseline to 6 months. This will be calculated as the difference between the mean ASBP at randomization and that at the end of follow up. ABPM will be used as it is a better reflection of true overall BP and therefore a stronger predictor of adverse CV events than routine clinic readings. 30,31

Ambulatory blood pressure will be performed with MEDITECH ABPM monitors (ABPM- 05 model). Patients will wear the ABPM device for a minimum of 24 hours with automatic readings every 30 minutes both in the daytime and at night.30, 31 Daytime will be defined as 9 AM through 9 PM, and night-time as 12 midnight through 6 AM.30 Small, medium or large blood pressure cuffs will be utilized as appropriate on the non-dominant arm.

Secondary Endpoint

The secondary endpoints include:

1. Change in ADBP from baseline to 6 months

2. Change in clinic BP from baseline to 2, 4 and 6 months

3. Change in daytime and night time BP measured using ABPM from baseline to 6 months

4. BP variability also measured using ABPM

5. Proportion of patients who achieve BP control at 2, 4 and 6 months (with BP control defined as less than140 mmHg SBP and less than 90 mmHg DBP)

6. Proportion of “responders” (defined as clinic BP reduction greater than 20mmHg SBP and greater than 10 mmHg DBP) at two, four and six months

7. Change in micro- and macro-albuminuria measured using spot urine at baseline and 6 months

8. Changes in fasting blood glucose concentration, fasting lipid profile, serum sodium, potassium urea, creatinine and eGFR from baseline to 6 months

9. Adverse events causing permanent discontinuation of trial therapy

STATISTICAL CONSIDERATIONS AND STUDY SIZE

Power of the study

The sample size calculation is based on detecting a 3.0mmHg difference in the 24-hour mean ASBP assuming a standard deviation in 24-hour ASBP of 9 mmHg. By recruiting a total of 702 participants (234 participants per group), in order to achieve a total of 210 evaluable participants per group (assuming a 10% dropout rate). This will provide the trial with a power of 84% at a significance level of 5%.

Statistical Analysis

Mean differences among the three randomised groups will be analysed using the analysis of variance (ANOVA) test, and if required, the Turkey post-hoc test, and differences in proportions using the 2test, or Fisher exact test, as appropriate. These analyses will include comparison of absolute 24-hour ASBP values, 24-hour blood pressure variability, mean night-time and day-time ambulatory BP, rates of BP control and BP response, clinic systolic and diastolic BPs, and other variables. Analyses at two and six months will also be conducted using the Mixed Model Repeated Measures (MMRM). A sensitivity analysis will be conducted excluding blood pressure values from those on non-trial agents a six months with a carry forward of four month blood pressures. Multiple linear regression analysis and logistic regression analysis will be conducted to determine variables associated with continuous or binary outcomes respectively. Analysis will be further stratified by presence or absence of diabetes mellitus, and age less than < 55 years versus 55 years and above. The Stata (TX, USA) statistical software will be used for data analysis.

Analysis of Missing Outcome Data

The analysis will be conducted according to the intention-to-treat principle, meaning that participants will be analysed in the groups to which they will have been randomised regardless of compliance with the protocol. Patients who have discontinued study drug will be invited to attend scheduled clinic visits. If the subject does not attend study visits, follow up will be attempted by telephone or email to obtain information regarding study outcomes and adverse events. Imputation of some missing data will be carried out subsequently for sensitivity analyses of ABPM values, height, weight and laboratory values using the multiple imputation technique.

ETHICAL PRINCIPLES

The study is conducted in accordance with the guidelines laid down by the International Conference on Harmonisation for Good Clinical Practice. All investigators obtained ethical approval from their local institutional review boards which are affiliates of their national review boards. Eligible patients are approached regarding potential participation in the study, and the study purpose, procedures, risks, and potential benefits explained by the study coordinator and/or principal investigators. Potential patients are given the opportunity to ask questions. Patients who voluntarily agree to participate in the study are asked to document their informed consent.

MANAGEMENT OF THE STUDY

Study personnel at the participating sites are responsible for completing case report forms (CRFs) through accessing a computerised programme (Electronic Clinical Data Management System) via the internet and entering the required trial information for electronic submission to the server located at the Data Management and Monitoring Centre at University of Cape Town. This includes all relevant BP variables uploaded directly from the MEDITECH machines into the Electronic Clinical Data Management System database.

The University of Abuja serves as the Project Coordinating Centre. Both the Universities of Abuja and Cape Town have access to all the study data. Individual sites will have access to their own centres’ data and are provided site-specific data summaries periodically by the Data Management and Monitoring Centre in Cape Town. Source documentation supporting the trial information are stored at the investigator site and made available for trial related monitoring, audits, IRB/IEC review and regulatory inspections when required. The Investigator retains all study records files in accordance with applicable regulatory requirements. The data management plan outlines the procedures and guidelines to ensure data quality is adhered to.

Patient information will be stored in a high security computer system and kept strictly confidential. Subject confidentiality will further be ensured by utilizing a subject identification code number to correspond to treatment data on the computerized files. Only the Data Management and Monitoring Centre will be aware of the unblinded data until the trial is completed or a recommendation is made to terminate the trial.

A Trial Operations Committee consisting of members of the Abuja and Cape Town Project Coordinating Offices meets via telephone conference on a weekly basis to address the operational matters of the study, and to implement the decisions of the Trial Steering Committee.

The Trial Steering Committee consists of the Principal Investigator, the Co-Principal Investigators, and the national co-ordinator for each country, the statistician, the study pharmacist and the trial monitor. The Principal Investigator chairs this committee and the trial steering committee meets monthly.

An external and independent Data Safety and Monitoring Committee (DSMC) monitors the trial for safety and efficacy. The DSMC reviews the data for safety when all 2-month data, 4-month data and 6-month data are ready, and then as determined by the DSMC.

SOURCES OF FUNDING

Funding for the trial was provided by the GlaxoSmithKline Africa Non-Communicable Disease Open Lab Grant (Project Number: 8264). The investigational medicinal products were donated by Aspen Pharmacare as part of their educational grant.

Although, the medications were donated by ASPEN pharmaceutical (since it is the only pharmaceutical company in sub-Saharan Africa found to manufacture all the three classes of generic medications used in this study), they are not in any way involved in sponsoring this study. Aspen is an approved manufacturer by the South African regulator, the Medicines Control Council (MCC), and have a licence to manufacture. They are audited and checked to regularly to ensure they comply with Good Manufacturing Practices in order to have this licence. The MCC of South Africa is part of the Pharmaceutical Inspection Co-operation Scheme (PIC/S) which is an international agreement between regulatory authorities to harmonise inspection procedures worldwide by developing common standards in the field of GMP.

AUTHORS’ DISCLOSURE

DO and NP conceived the study and together with BMM who also gave conceptual advice, and edited the manuscript; DO, NP, BMM and VF wrote the protocol and designed the study. NK and WS contributed to the pharmaceutical design of the study. All authors read and approved the final draft of the manuscript. The authors are solely responsible for the design and conduct of this study, all study analyses, the drafting and editing of the paper and its final contents. The authors declare no conflict of interest.

ACKNOWLEDGEMENTS

Our sincere appreciation goes to GlaxoSmithKline Africa Non-Communicable Disease Open Lab Team.

DISCUSSION

The CREOLE trial is the first randomized controlled trial to compare the efficacy of three front-line combination therapies in the treatment of hypertensive black patients living in sub-Saharan Africa. This study is timely as the most efficacious two-drug combination in hypertensive black patients living in sub-Saharan Africa is still a matter of debate as there are no large RCT data in this population group which has compared contemporary front-line combinations, despite the high burden of hypertension and its complications in this group.25-27 Although it could be argued that findings in African-Americans can be extrapolated to Black Africans since they have the same ancestral origin, the differences in selection in previous generations, ethnic admixture and differences in lifestyle between these two populations suggest that such an extrapolation may be inappropriate. 28-30

Calcium channel blockers and diuretics have been found to more efficacious as monotherapy in the black Africans than Caucasians when compared with angiotensin converting enzyme inhibitors.33,34 What is not known however is whether therapy with a combination of calcium channel blocker plus hydrochlorothiazide may be more efficacious than the combinations of calcium channel blocker plus ACE inhibitor or ACE inhibitor plus hydrochlorothiazide in reducing mean 24 hour ASBP levels in black Africans.

The three combination therapies will be force-titrated to the highest doses after two months which will allow for proper comparison amongst the three study arms. To ensure optimal BP control, if at the four-month visit, clinic SBP is greater than160 mmHg and/or DBP is greater than 100 mmHg, atenolol 50 mg once daily will be added to the trial therapy. Atenolol is chosen because of easy access to it at the various studies sites. However, if atenolol is contraindicated, an alternative agent, which is not a thiazide diuretic, calcium channel blocker or ACE inhibitor such 12.5mg of spironolactone or 2mg of doxazosin will be added at the physicians’ or investigators’ discretion.

In conclusion, even though current guidelines recommend the use of combination therapy as first-line treatment or early in the management of hypertensive patients, the best combination in blacks living in sub-Saharan Africa is still a matter of debate as there are no large RCTs comparing different combination therapies in this population. The CREOLE trial will therefore provide unique information as to the most efficacious two-drug combination in black patients in sub-Saharan Africa and ultimately inform the development of clinical guidelines for the treatment of hypertension for this region.35

STUDY STATUS

The first patient was randomised in June 2017. The total number of patients randomised as of the end of 2 October 2017 is 404 (Figures 4 & 5).

Figure 4: Study sites recruitment progress per site

Figure 4 The graphs compares the number of patients enrolled to the number of patients screened (as at 13 September 2017) to projected recruitment expected for the individual site.

Figure 5: CREOLE Recruitment weekly Projections and study status

SUMMARY

The CREOLE study when completed will be the first RCT to prospectively compare the efficacy of three front-line anti- hypertensive combinations therapy in blacks residing in sub Saharan Africa. The results of this trial will provide unique data for evidence-based treatment of hypertension in the sub region.

DISCLOSURE

CREOLE study is registered with ClinicalTrials.gov (NCT02742467). The authors are solely responsible for the design and conduct of the study. They are also responsible for all the study analysis, the drafting and editing of manuscript and its final content. The authors have no conflicts of interest. NP has however received speaker and advisory board honoraria from several companies producing blood pressure lowering agents.

FUNDING/ CONTRIBUTIONS / ACKNOWLEDGEMENTS

Funding for the trial was provided by the GlaxoSmithKline Africa Non-Communicable Disease Open Lab Grant (Project Number: 8264). The investigational medicinal products were donated by Aspen Pharmacare as part of their educational grant. DO and NP conceived the study and together with BMM who also gave conceptual advice, and edited the manuscript; DO, NP, BMM and VF wrote the protocol and designed the study. NK and WS contributed to the pharmaceutical design of the study. All authors read and approved the final draft of the manuscript.

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APPENDIX

Steering Committee Members

Dike Ojji, Chair, University of Abuja, Abuja/University of Abuja Teaching Hospital, Nigeria,

Neil Poulter, Imperial College, London

Bongani Mayosi, University of Cape Town, South Africa

Karen Sliwa, University of Cape Town, South Africa

Motasim Badri, University of Cape Town, South Africa

Albertino Damasceno, Eduardo Mondlane University, Maputo, Mozambique

Anastase Dzudie, Douala General Hospital/Faculty of Health Sciences, Cameroon

Elijah Ogola, University of Nairobi/Kenyatta National Hospital, Nairobi, Kenya

Charles Mondo, St Francis Hospital, Nsambya, Kampala, Uganda

Okechukwu Ogah, University College Hospital, Ibadan, Nigeria

Veronica Francis, University of Cape Town, South Africa

Nicky Kramer, University of Cape Town, South Africa

Wynand Smythe, University of Cape Town, South Africa

Site Principal Investigators

Anastase Dzudie, Douala General Hospital/Faculty of Health Sciences, Douala, Cameroon

Elijah Ogola, University of Nairobi/Kenyatta National Hospital, Nairobi, Kenya

Felix Barasa, MOI University Teaching Hospital, Eldoret, Kenya

Albertino Damasceno, Eduardo Mondlane University, Maputo, Mozambique

Gabriel Shedul, University of Abuja Teaching Hospital, Gwagwalada, Abuja, Nigeria,

Sani Mahmoud, Aminu Kano Teaching Hospital, Kano, Nigeria

Dr Okechukwu Ogah University College Hospital, Ibadan Nigeria

Ikechi Okpechi, University of Cape Town, South Africa,

Erika Jones, University of Cape Town, South Africa

Charles Mondo, St Francis Hospital, Nsambya, Kampala, Uganda

Prof Pindile Mntla Sefako Makgatho Health Sciences University (Medunsa Campus), Pretoria, South Africa

Prof Gboyega Ogunbanjo Department of Family Medicine & Primary Health Care, Sefako Makgatho Health Sciences University (Medunsa Campus) South Africa

Data Safety Monitoring Committee

Ayodele Falase, University of Ibadan/University College Hospital, Ibadan, Nigeria

Davies Adeloye, Covenant University, Otta, Ogun State, Nigeria

Michael Adikwu, University of Abuja, Abuja, Nigeria

Felicia Anumah, University of Abuja, Abuja, Nigeria

Brian Rayner, University of Cape, Cape Town, South Africa

Creole: Recruitment at Week 17

Projected vs Screened vs Enrolled 02 October 2017

Week 17 (02 October 2017)Projected Recruitment (Cumulative)

TotalAbujaKanoIbadanDoualaCape TownKampalaMaputoEldoretNairobiPretoria74111478787878787877.80000000000001177.80000000000001178Week 17 (02 October 2017)Screened (Cumulative)

TotalAbujaKanoIbadanDoualaCape TownKampalaMaputoEldoretNairobiPretoria551140101109444139472460Week 17 (02 October 2017)Enrolled (Cumulative)

TotalAbujaKanoIbadanDoualaCape TownKampalaMaputoEldoretNairobiPretoria4041167052403633312150

Recruits

Creole Recruitment Week 17

Actual Weekly Recruitment vs Projected Weekly Recruitment

02 October 2017

Actual Weekly Recruitment (cumulative)

Week 1Week 2 Week 3 Week4Week 5Week 6Week 7Week 8Week 9 Week 10Week 11Week 12Week 13Week 14Week 15Week 16Week 17June July AugustSeptemberOctober 412243137546888122155179219245277314362404Projected Weekly Recruitment (cumulative)

Week 1Week 2 Week 3 Week4Week 5Week 6Week 7Week 8Week 9 Week 10Week 11Week 12Week 13Week 14Week 15Week 16Week 17June July AugustSeptemberOctober 4080120160200240280320360400440480520560600640680Total Projected Recruitment

Week 1Week 2 Week 3 Week4Week 5Week 6Week 7Week 8Week 9 Week 10Week 11Week 12Week 13Week 14Week 15Week 16Week 17June July AugustSeptemberOctober 741741741741741741741741741741741741741741741741741

Recruits

1