Guardians and research staff experiences and views about the consent process in hospital-based paediatric research studies in urban Malawi: A qualitative study.

BACKGROUND: Obtaining consent has become a standard way of respecting the patient's rights and autonomy in clinical research. Ethical guidelines recommend that the child's parent/s or authorised legal guardian provides informed consent for their child's participation. However, obtaining informed consent in paediatric research is challenging. Parents become vulnerable because of stress related to their child's illness. Understanding the views held by guardians and researchers about the consent process in Malawi, where there are limitations in health care access and research literacy will assist in developing appropriate consent guidelines. METHODS: We conducted 20 in-depth interviews with guardians of children and research staff who had participated in paediatric clinical trial and observational studies in acute and non-acute settings in the Southern Region of Malawi. Interviews were audio-recorded, transcribed verbatim, and thematically analysed. Interviews were compared across studies and settings to identify differences and similarities in participants' views about informed consent processes. Data analysis was facilitated by NVIVO 11 software. RESULTS: All participants across study types and settings reported that they associated participating in research with therapeutic benefits. Substantial differences were noted in the decision-making process across study settings. Guardians from acute studies felt that the role of their spouses was neglected during consenting, while staff reported that they had problems obtaining consent from guardians when their partners were not present. Across all study types and settings, research staff reported that they emphasised the benefits more than the risks of the study to participants, due to pressure to recruit. Participants from non-acute settings were more likely to recall information shared during the consent process than participants in the acute setting. CONCLUSION: The health care context, culture and research process influenced participants' understanding of study information across study types and settings. We advise research managers or principal investigators to define minimum requirements that would not compromise the consent process and conduct study specific training for staff. The use of one size fits all consent process may not be ideal. More guidance is needed on how these differences can be incorporated during the consent process to improve understanding and delivery of consent. Trial registration Not applicable.

A clinical trial of enteral Levetiracetam for acute seizures in pediatric cerebral malaria.

BACKGROUND: Acute seizures are common in pediatric cerebral malaria (CM), but usual care with phenobarbital risks respiratory suppression. We undertook studies of enteral levetiracetam (eLVT) to evaluate pharmacokinetics (PK), safety and efficacy including an open-label, randomized controlled trial (RCT) comparing eLVT to phenobarbital. METHODS: Children 24-83 months old with CM were enrolled in an eLVT dose-finding study starting with standard dose (40 mg/kg load, then 30 mg/kg Q12 hours) titrated upward until seizure freedom was attained in 75% of subjects. The RCT that followed randomized children to eLVT vs. phenobarbital for acute seizures and compared the groups on minutes with seizures based upon continuous electroencephalogram. Due to safety concerns, midway through the study children allocated to phenobarbital received the drug only if they continued to have seizures (either clinically or electrographically) after benzodiazepine treatment. Secondary outcomes were treatment failure requiring cross over, coma duration and neurologic sequelae at discharge. PK and safety assessments were also undertaken. RESULTS: Among 30 comatose CM children, eLVT was rapidly absorbed and well-tolerated. eLVT clearance was lower in patients with higher admission serum creatinine (SCr), but overall PK parameters were similar to prior pediatric PK studies. Within 4 h of the first dose, 90% reached therapeutic levels (> 20 µg/mL) and all were above 6 µg/mL. 7/7 children achieved seizure freedom on the initial eLVT dose. Comparing 23 eLVT to 21 phenobarbital patients among whom 15/21 received phenobarbital, no differences were seen for minutes with seizure, seizure freedom, coma duration, neurologic sequelae or death, but eLVT was safer (p = 0.019). Phenobarbital was discontinued in 3/15 due to respiratory side effects. CONCLUSION: Enteral LVT offers an affordable option for seizure control in pediatric CM and is safer than phenobarbital. TRIAL REGISTRATION: NCT01660672 . NCT01982812 .

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.

Clofazimine pharmacokinetics in HIV-infected adults with diarrhea: Implications of diarrheal disease on absorption of orally administered therapeutics.

Oral drug absorption kinetics are usually established in populations with a properly functioning gastrointestinal tract. However, many diseases and therapeutics can alter gastrointestinal physiology and cause diarrhea. The extent of diarrhea-associated impact on drug pharmacokinetics has not been quantitatively described. To address this knowledge gap, we used a population pharmacokinetic modeling approach with data collected in a phase IIa study of matched human immunodeficiency virus (HIV)-infected adults with/without cryptosporidiosis and diarrhea to examine diarrhea-associated impact on oral clofazimine pharmacokinetics. A population pharmacokinetic model was developed with 428 plasma samples from 23 HIV-infected adults with/without Cryptosporidium infection using nonlinear mixed-effects modeling. Covariates describing cryptosporidiosis-associated diarrhea severity (e.g., number of diarrhea episodes, diarrhea grade) or HIV infection (e.g., viral load, CD4+ T cell count) were evaluated. A two-compartment model with lag time and first-order absorption and elimination best fit the data. Maximum diarrhea grade over the study duration was found to be associated with a more than sixfold reduction in clofazimine bioavailability. Apparent clofazimine clearance, intercompartmental clearance, central volume of distribution, and peripheral volume of distribution were 3.71 L/h, 18.2 L/h (interindividual variability [IIV] 45.0%), 473 L (IIV 3.46%), and 3434 L, respectively. The absorption rate constant was 0.625 h-1 (IIV 149%) and absorption lag time was 1.83 h. In conclusion, the maximum diarrhea grade observed for the duration of oral clofazimine administration was associated with a significant reduction in clofazimine bioavailability. Our results highlight the importance of studying disease impacts on oral therapeutic pharmacokinetics to inform dose optimization and maximize the chance of treatment success.

Examination of ELISA against PCR for assessing treatment efficacy against Cryptosporidium in a clinical trial context.

BACKGROUND: Cryptosporidium is a gastrointestinal pathogen that presents a serious opportunistic infection in immunocompromised individuals including those living with human immunodeficiency syndrome. The CRYPTOFAZ trial, previously published, was conducted in Malawi to evaluate the efficacy of clofazimine in response to an unmet need for drugs to treat cryptosporidiosis in HIV populations. A combination of rapid diagnostic tests, ELISA, qPCR, and conventional sequencing were employed to detect Cryptosporidium in 586 individuals during pre-screening and monitor oocyst shedding and identify enteric co-pathogens in 22 enrolled/randomized participants during the in-patient period and follow-up visits. METHODOLOGY: Oocyst shedding as measured by qPCR was used to determine primary trial outcomes, however pathogen was detected even at trial days 41-55 in individuals randomized to either clofazimine or placebo arms of the study. Therefore, in this work we re-examine the trial outcomes and conclusions in light of data from the other diagnostics, particularly ELISA. ELISA data was normalized between experiments prior to comparison to qPCR. The amount of all identified enteric pathogens was examined to determine if co-pathogens other than Cryptosporidium were major causative agents to a participant's diarrhea. CONCLUSION: ELISA had higher sample-to-sample variability and proved to be equally or less sensitive than qPCR in detecting Cryptosporidium positive samples. Compared to qPCR, ELISA had equal or greater specificity in detecting Cryptosporidium negative samples. Sequencing identified several Cryptosporidium species including viatorum which has never been identified in Malawi and Southern Africa. In addition to Cryptosporidium, enterotoxigenic E. coli was also identified as a pathogen in diarrheagenic amounts in 4 out of 22 participants.

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. FUNDING: Wellcome Trust.

"At first, I was very afraid"-a qualitative description of participants' views and experiences in the first Human Infection Study in Malawi.

Background: Human infection studies (HIS) involve deliberately infecting healthy volunteers with a pathogen in a controlled environment to understand infection and support the development of effective vaccines or treatments. HIS research is expanding to many low and middle-income settings to accelerate vaccine development. Given the implementation of the first HIS research to establish the experimental human pneumococcal carriage model's feasibility, we sought to understand the participant's opinions and experiences. Methods: We used a qualitative, descriptive approach to understand participants perceptions and experiences on HIS participation. Sixteen healthy adult participants were invited to participate in in-depth exit interviews to discuss their experiences, motivations and concerns. Results: Our findings showed that the likelihood of participation in HIS research rests on three essential conditions: motivation to participate, compensation and advocacy. The motivation and decision to participate was based on reasons including altruism, patriotism, monetary and material incentives, and while compensation was deemed appropriate, concerns about unanticipated research-related risks were raised. Participant advocate groups were recommended for increasing awareness and educating others in the broader community about HIS research. Conclusions: Participants' experiences of HIS in Malawi provide the basis of what can be acceptable in HIS research in lower-income countries and areas where study procedures could be adjusted.

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.