Conducting clinical trials in sub-Saharan Africa: challenges and lessons learned from the Malawi Cryptosporidium study

Background An effective drug to treat cryptosporidial diarrhea in HIV-infected individuals is a global health priority. Promising drugs need to be evaluated in endemic areas which may be challenged by both lack of resources and experience to conduct International Committee of Harmonisation-Good Clinical Practice (ICH-GCP)-compliant clinical trials. Methods We present the challenges and lessons learned in implementing a phase 2A, randomized, double-blind, placebo-controlled trial of clofazimine, in treatment of cryptosporidiosis among HIV-infected adults at a single site in Malawi. Results Primary challenges are grouped under study initiation, study population, study implementation, and cultural issues. The lessons learned primarily deal with regulatory system and operational barriers, and recommendations can be applied to other human experimental trials in low- and middle-income countries, specifically in sub-Saharan Africa. Conclusion This study demonstrated that initiating and implementing human experimental trials in sub-Saharan Africa can be challenging. However, solutions exist and successful execution requires careful planning, ongoing evaluation, responsiveness to new developments, and oversight of all trial operations

Recruitment strategies used to enrol healthy volunteers in the first pneumococcal human infection study in Africa: Lessons from Blantyre, Malawi

Background Human infection studies (HIS) also known as Controlled Human Infection Models (CHIM) are a relatively new concept in African countries to clinicians, scientists, and communities alike. We have introduced HIS/CHIM studies to Malawi during the last four years by developing an experimental human pneumococcal carriage model. This CHIM was used to test the efficacy of a licensed 13-valent Pneumococcal Conjugate Vaccine (PCV13) against experimental nasal pneumococcal carriage. Traditional and digital recruitment strategies into this novel trial were explored. Objectives To describe various methods of recruitment in this first CHIM study in Malawi. Methods The clinical trial within the context of which these data were recorded was registered with the Pan African Clinical Trials Registry (REF: PACTR202008503507113) on 03 August 2020. The project was conducted at the Malawi Liverpool Wellcome Programme (MLW) in Blantyre, Malawi between April 2021, and September 2022. Source populations were college students and community members within Blantyre. Recruitment strategies included sharing study information in written or visual form, community sensitization meetings, snowball contacts (word of mouth from previous volunteers), branded clothing and participating in radio and television programs. Results 299 volunteers attended screening clinic, of whom 278 were recruited. Sixty-six recruited volunteers (23.7%) were college students and 212 (76.3%) were from the community. Snowball word-of-mouth contacting was the most successful recruitment strategy, with 201 (72.3%) participants recruited using this method. 195 (70.1%) were men of whom 149 (76.4%) joined the study through snowballing. Conclusion or recommendation Using a variety of recruitment strategies led to successful recruitment in this novel controlled human infection study. Most participants were recruited through snowballing

Experimental pneumococcal carriage in people living with HIV in Malawi: the first controlled human infection model in a key at-risk population

Background: As well as suffering a high burden of pneumococcal disease people living with HIV (PLHIV) may contribute to community transmission in sub-Saharan African (sSA) settings. Pneumococcal vaccination is not currently offered to PLHIV in sSA but may prevent disease and reduce transmission. More evidence of vaccine effectiveness against carriage in PLHIV is needed. An Experimental Human Pneumococcal Carriage model (EHPC) has been safely and acceptably used in healthy adults in Malawi to evaluate pneumococcal vaccines against carriage and to identify immune correlates of protection from carriage. This study will establish the same model in PLHIV and will be the first controlled human infection model (CHIM) in this key population. Methods: Healthy participants with and without HIV will be inoculated intranasally with Streptococcus pneumoniae serotype 6B. Sequential cohorts will be challenged with increasing doses to determine the optimal safe challenge dose to establish experimental carriage. Nasal fluid, nasal mucosal, and blood samples will be taken before inoculation and on days 2, 7, 14, and 21 following inoculation to measure pneumococcal carriage density and identify immune correlates of protection from carriage. The vast majority of natural pneumococcal carriage events in PLHIV do not result in invasive disease and no invasive disease is expected in this study. However, robust participant safety monitoring is designed to identify signs of invasive disease early should they develop, and to implement treatment immediately. Participants will complete a Likert-style questionnaire at study-end to establish acceptability. Interpretations: We expect the EHPC model to be safely and acceptably implemented in PLHIV. The CHIM can then be used to accelerate pneumococcal vaccine evaluations in this population, and an evidence-based pneumococcal vaccination policy for PLHIV in sSA

Piloting electronic informed consenting in a pneumococcal human infection study in Blantyre, Malawi

Background Electronic consent can potentially improve accuracy, workflow, and overall patient experience in clinical research but has not been used in Malawi, owing to uncertainty about data security and technical support. Objectives We explored the feasibility of using electronic consent (e-consent) in an ongoing human infection study in Blantyre Malawi. We dual-consented participants by both electronic and paper methods to assess the feasibility of electronic consent, and then compared benefits and challenges of the two methods. Methods The approved paper consent forms were digitized using Open Data Kit (ODK). Following participant information giving by the research staff, healthy literate adult participants with no audio-visual impairments completed a self-administered e-consent and provided an electronic signature. Signed e-consent forms were uploaded to a secure study server. While the participants were in clinic, the signed electronic consent form was printed as a copy for the participant. The feasibility, advantages and disadvantages including data safety consideration for e-consenting were evaluated by exploring issues surrounding use of e-consenting versus paper-based consenting. Consent forms were analysed by research staff for errors such as overwriting and legibility. Results We piloted 109 participants to e-consenting. It was found to be user friendly, had 0% (n 0/109) errors compared to 43.1% (n 47/109) in paper based methods along with enhanced data safety. The challenges included difficult digitization of ethics stamped documents, volunteer unfamiliarity with tablet user interface and its requirement for a working internet and printer. Conclusion E-consenting was feasible but required additional resource investment. Benefits included error minimization and data security

Effect of 13-valent pneumococcal conjugate vaccine on experimental carriage of Streptococcus pneumoniae serotype 6B in Blantyre, Malawi: a randomised controlled trial and controlled human infection study

Background The effect of childhood pneumococcal conjugate vaccine implementation in Malawi is threatened by absence of herd effect. There is persistent vaccine-type pneumococcal carriage in both vaccinated children and the wider community. We aimed to use a human infection study to measure 13-valent pneumococcal conjugate vaccine (PCV13) efficacy against pneumococcal carriage. Methods We did a double-blind, parallel-arm, randomised controlled trial investigating the efficacy of PCV13 or placebo against experimental pneumococcal carriage of Streptococcus pneumoniae serotype 6B (strain BHN418) among healthy adults (aged 18–40 years) from Blantyre, Malawi. We randomly assigned participants (1:1) to receive PCV13 or placebo. PCV13 and placebo doses were prepared by an unmasked pharmacist to maintain research team and participant masking with identification only by a randomisation identification number and barcode. 4 weeks after receiving either PCV13 or placebo, participants were challenged with 20 000 colony forming units (CFUs) per naris, 80 000 CFUs per naris, or 160 000 CFUs per naris by intranasal inoculation. The primary endpoint was experimental pneumococcal carriage, established by culture of nasal wash at 2, 7, and 14 days. Vaccine efficacy was estimated per protocol by means of a log-binomial model adjusting for inoculation dose. The trial is registered with the Pan African Clinical Trials Registry, PACTR202008503507113, and is now closed. Findings Recruitment commenced on April 27, 2021 and the final visit was completed on Sept 12, 2022. 204 participants completed the study protocol (98 PCV13, 106 placebo). There were lower carriage rates in the vaccine group at all three inoculation doses (0 of 21 vs two [11%] of 19 at 20 000 CFUs per naris; six [18%] of 33 vs 12 [29%] of 41 at 80 000 CFUs per naris, and four [9%] of 44 vs 16 [35%] of 46 at 160 000 CFUs per naris). The overall carriage rate was lower in the vaccine group compared with the placebo group (ten [10%] of 98 vs 30 [28%] of 106; Fisher's p value=0·0013) and the vaccine efficacy against carriage was estimated at 62·4% (95% CI 27·7–80·4). There were no severe adverse events related to vaccination or inoculation of pneumococci. Interpretation This is, to our knowledge, the first human challenge study to test the efficacy of a pneumococcal vaccine against pneumococcal carriage in Africa, which can now be used to establish vaccine-induced correlates of protection and compare alternative strategies to prevent pneumococcal carriage. This powerful tool could lead to new means to enhance reduction in pneumococcal carriage after vaccination

MARVELS Recruitment Strategies - audio and video files

The objective of the study was to describe various methods of recruitment in first CHIM study in Malawi. Human Infection studies (HIS) also known as Controlled Human Infection Model (CHIM) are relatively a new concept in African countries to clinicians, scientists and communities. Human infection studies were introduced in the last four years in Malawi and was used to test efficacy of a licensed 13-valent Pneumococcal Conjugate Vaccine (PCV13) against experimental nasal pneumococcal carriage. Traditional and digital recruitment strategies into novel trial were explored.The published items are radio segments and television programs which were used as recruitment strategies in both our local language (Chichewa) and English.</p