Protocol for a feasibility randomized controlled trial to evaluate the efficacy, safety and tolerability of N-acetylcysteine in reducing adverse drug reactions among adults treated for multidrug-resistant tuberculosis in Tanzania

Funding: This study receives financial supports from the European and Developed Countries Clinical Trials Partnership (EDCTP2) program supported by the European Union project through the Senior Fellowship Scheme TMA1463 awarded to Stellah G Mpagama.Background Adverse drug reactions (ADRs) frequently occur in patients using second-line anti-tuberculosis medicine for treatment of multidrug resistant tuberculosis (MDR-TB). ADRs contribute to treatment interruptions which can compromise treatment response and risk acquired drug resistance to critical newer drugs such as bedaquiline, while severe ADRs carry considerable morbidity and mortality. N-acetylcysteine (NAC) has shown promise in reducing ADRs for medications related to TB in case series or randomized controlled trials in other medical conditions, yet evidence is lacking in MDR-TB patients. TB endemic settings have limited capacity to conduct clinical trials. We designed a proof-of-concept clinical trial primarily to explore the preliminary evidence on the protective effect of NAC among people treated for MDR-TB with second-line anti-TB medications. Methods This is a proof-of-concept randomized open label clinical trial with 3 treatment arms including a control arm, an interventional arm of NAC 900 mg daily, and an interventional arm of NAC 900 mg twice-daily administered during the intensive phase of MDR-TB treatment. Patients initiating MDR-TB treatment will be enrolled at Kibong’oto National Center of Excellence for MDR-TB in the Kilimanjaro region of Tanzania. The minimum anticipated sample size is 66; with 22 participants in each arm. ADR monitoring will be performed at baseline and daily follow-up over 24 weeks including blood and urine specimen collection for hepatic and renal function and electrolyte abnormalities, and electrocardiogram. Sputum will be collected at baseline and monthly thereafter and cultured for mycobacteria as well as assayed for other molecular targets of Mycobacterium tuberculosis. Adverse drug events will be analysed over time using mixed effect models. Mean differences between arms in change of the ADRs from baseline (with 95% confidence intervals) will be derived from the fitted model. Discussion Given that NAC promotes synthesis of glutathione, an intracellular antioxidant that combats the impact of oxidative stress, it may protect against medication induced oxidative damage in organs such as liver, pancreas, kidney, and cells of the immune system. This randomized controlled trial will determine if NAC leads to fewer ADRs, and if this protection is dose dependent. Fewer ADRs among patients treated with MDR-TB may significantly improve treatment outcomes for multidrug regimens that necessitate prolonged treatment durations. Conduct of this trial will set the needed infrastructure for clinical trials.Publisher PDFPeer reviewe

Causal Pathways from Enteropathogens to Environmental Enteropathy: Findings from the MAL-ED Birth Cohort Study

Background Environmental enteropathy (EE), the adverse impact of frequent and numerous enteric infections on the gut resulting in a state of persistent immune activation and altered permeability, has been proposed as a key determinant of growth failure in children in low- and middle-income populations. A theory-driven systems model to critically evaluate pathways through which enteropathogens, gut permeability, and intestinal and systemic inflammation affect child growth was conducted within the framework of the Etiology, Risk Factors and Interactions of Enteric Infections and Malnutrition and the Consequences for Child Health and Development (MAL-ED) birth cohort study that included children from eight countries. Methods Non-diarrheal stool samples (N = 22,846) from 1253 children from multiple sites were evaluated for a panel of 40 enteropathogens and fecal concentrations of myeloperoxidase, alpha-1-antitrypsin, and neopterin. Among these same children, urinary lactulose:mannitol (L:M) (N = 6363) and plasma alpha-1-acid glycoprotein (AGP) (N = 2797) were also measured. The temporal sampling design was used to create a directed acyclic graph of proposed mechanistic pathways between enteropathogen detection in non-diarrheal stools, biomarkers of intestinal permeability and inflammation, systemic inflammation and change in length- and weight- for age in children 0–2 years of age. Findings Children in these populations had frequent enteric infections and high levels of both intestinal and systemic inflammation. Higher burdens of enteropathogens, especially those categorized as being enteroinvasive or causing mucosal disruption, were associated with elevated biomarker concentrations of gut and systemic inflammation and, via these associations, indirectly associated with both reduced linear and ponderal growth. Evidence for the association with reduced linear growth was stronger for systemic inflammation than for gut inflammation; the opposite was true of reduced ponderal growth. Although Giardia was associated with reduced growth, the association was not mediated by any of the biomarkers evaluated. Interpretation The large quantity of empirical evidence contributing to this analysis supports the conceptual model of EE. The effects of EE on growth faltering in young children were small, but multiple mechanistic pathways underlying the attribution of growth failure to asymptomatic enteric infections had statistical support in the analysis. The strongest evidence for EE was the association between enteropathogens and linear growth mediated through systemic inflammation

Epidemiology of traumatic brain injury patients at Kilimanjaro Christian medical centre, Moshi, Tanzania

Traumatic brain injury (TBI) affects 10 million people annually. Clinical epidemiology can inform prevention initiatives to curb this burden. Kilimanjaro Christian Medical Centre (KCMC) is a referral hospital for 11 million people with neurosurgical capacity located in Moshi, Tanzania. Methods: Secondary analysis of a prospective observational TBI Acute Care Registry at the KCMC Casualty Department (CD) included all patients presenting between May 5 and July 27th, 2013. Means with standard deviations (SD), Fisher’s exact or Chi-squared with a binomial logistic regression reporting Odds Ratios (OR) with 95% confidence intervals (CI) was calculated using Stata IC (College Station, TX). Results: 171 total patients were enrolled in the TBI Registry. The mean age was 32.1 years (range 1–99, SD 16.6), with 71% between 15 and 45 years of age. 82% were male and 28% cases involved alcohol. Causes of TBI were road traffic injuries (RTI) (74%), assaults (13%) or falls (8%). 52% of RTI’s involved motorcycle users. The mean Glasgow Coma Score (GCS) was 12.6 (range 3-15, SD 4.04) with 19% of patients having severe TBI (GCS of <9). The overall mortality rate was 13% for all CD patients, 14% for admitted patients and 80% for patients admitted to the ICU. Death was associated with hypoxia (OR 16.0 (95% CI 5.4, 47.5), hypotension (OR 7.3 (95% CI 1.4, 38.4) and low GCS (GCS <9, OR 29.7 (95% CI 9.6, 92.0). Severe TBI had a 53% mortality rate, while moderate and mild TBI 12% and 3% fatality rates respectively. Of severe TBI patients, 63.6% suffered disability from their injury compared to 27% of moderate and 3% of mild TBI. Conclusion: Most TBI patients were young males involved in road traffic collisions, predominantly involving motorcycles. Over a quarter of them involve alcohol. Our data support that TBI causes significant death and disability

Protocol for a feasibility randomized controlled trial to evaluate the efficacy, safety and tolerability of N-acetylcysteine in reducing adverse drug reactions among adults treated for multidrug-resistant tuberculosis in Tanzania

BackgroundAdverse drug reactions (ADRs) frequently occur in patients using second-line anti-tuberculosis medicine for treatment of multidrug resistant tuberculosis (MDR-TB). ADRs contribute to treatment interruptions which can compromise treatment response and risk acquired drug resistance to critical newer drugs such as bedaquiline, while severe ADRs carry considerable morbidity and mortality. N-acetylcysteine (NAC) has shown promise in reducing ADRs for medications related to TB in case series or randomized controlled trials in other medical conditions, yet evidence is lacking in MDR-TB patients. TB endemic settings have limited capacity to conduct clinical trials. We designed a proof-of-concept clinical trial primarily to explore the preliminary evidence on the protective effect of NAC among people treated for MDR-TB with second-line anti-TB medications.MethodsThis is a proof-of-concept randomized open label clinical trial with 3 treatment arms including a control arm, an interventional arm of NAC 900&nbsp;mg daily, and an interventional arm of NAC 900&nbsp;mg twice-daily administered during the intensive phase of MDR-TB treatment. Patients initiating MDR-TB treatment will be enrolled at Kibong'oto National Center of Excellence for MDR-TB in the Kilimanjaro region of Tanzania. The minimum anticipated sample size is 66; with 22 participants in each arm. ADR monitoring will be performed at baseline and daily follow-up over 24&nbsp;weeks including blood and urine specimen collection for hepatic and renal function and electrolyte abnormalities, and electrocardiogram. Sputum will be collected at baseline and monthly thereafter and cultured for mycobacteria as well as assayed for other molecular targets of Mycobacterium tuberculosis. Adverse drug events will be analysed over time using mixed effect models. Mean differences between arms in change of the ADRs from baseline (with 95% confidence intervals) will be derived from the fitted model.DiscussionGiven that NAC promotes synthesis of glutathione, an intracellular antioxidant that combats the impact of oxidative stress, it may protect against medication induced oxidative damage in organs such as liver, pancreas, kidney, and cells of the immune system. This randomized controlled trial will determine if NAC leads to fewer ADRs, and if this protection is dose dependent. Fewer ADRs among patients treated with MDR-TB may significantly improve treatment outcomes for multidrug regimens that necessitate prolonged treatment durations. Conduct of this trial will set the needed infrastructure for clinical trials.Trial registrationPACTR202007736854169 Registered 03 July 2020

The impact of alcohol among injury patients in Moshi, Tanzania: a nested case-crossover study

Abstract Background Globally, alcohol is responsible for 3.3 million deaths annually and contributes to 5.9% of the overall global burden of disease. In Sub-Saharan Africa, alcohol is the leading avoidable risk factor accounting for a substantial portion of death and disability. This project aimed to determine the proportion of injuries related to alcohol and the increased risk of injury due to alcohol among injury patients seeking care at the emergency department (ED) of Kilimanjaro Christian Medical Centre (KCMC) in Moshi, Tanzania. Methods A representative cross-sectional sample of adult patients presenting to the KCMC ED with acute injury were enrolled in this study with a nested case-crossover design. Patient demographics, injury characteristics, and severity as well as alcohol use behaviors were collected. Alcohol breathalyzers were administered to the enrolled patients. Data on activities and alcohol use were collected for the time period 6 h prior to injury and two control periods: 24–30 h prior to injury and 1 week prior to injury. Results During 47 weeks of data collection, 24,070 patients were screened, of which 2164 suffered injuries, and 516 met the inclusion and exclusion criteria, consented to participate, and had complete data. Of the study participants, 76% were male, and 30% tested positive for alcohol on arrival to the ED. Alcohol use was associated with being male and being employed. Alcohol use was associated with an increased risk of injury (OR 5.71; 95% CI 3.84–8.50), and specifically road traffic injuries were associated with the highest odds of injury with alcohol use (OR 6.53, 95% CI 3.98–10.71). For all injuries and road traffic injuries specifically, we found an increase in the odds of injury with an incremental increase in the dose of alcohol. Conclusions At KCMC in Moshi, Tanzania, 3 of 10 injury patients tested positive for alcohol on presentation for care. Similarly, alcohol use conveys an increased risk for injury in this setting. Evidence-based prevention strategies for alcohol-related injuries need to be implemented to reduce alcohol misuse and alcohol-related injuries