Clinical Trial Details
— Status: Recruiting
Administrative data
| NCT number |
NCT06403800 |
| Other study ID # |
22IC7870 |
| Secondary ID |
|
| Status |
Recruiting |
| Phase |
|
| First received |
|
| Last updated |
|
| Start date |
March 11, 2024 |
| Est. completion date |
December 1, 2025 |
Study information
| Verified date |
May 2024 |
| Source |
National Heart and Lung Institute |
| Contact |
Patrick J Howlett, MB ChB |
| Phone |
+447793198119 |
| Email |
patrick.howlett[@]gmail.com |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Observational
|
Clinical Trial Summary
Artisanal, small-scale mining (ASM) is a large and essential component of the world's
economy. Despite attendant risks, there is little research into risks to the health of
artisanal miners. The tanzanite gemstone is mined exclusively in Northern Tanzania, in deep
shafts using ASM techniques. There is concerning evidence that the burden of silicosis and
tuberculosis (TB) amongst miners is high. In addition to miners' personal risks, there is
concern that a high rate of silicotuberculosis may hamper community control of TB.
Our primary aim is to measure the rate of silicosis progression among tanzanite miners. Our
secondary aims include measuring the prevalence of TB among miners, describing TB
transmission patterns in miners and the community, and assessing rates of 'catastrophic'
economic loss amongst miners.
To do this, the investigators propose two studies. First, the investigators will establish a
prospective cohort of 410 small scale tanzanite miners and record symptoms, respiratory
function including spirometry, chest radiography, and prevalence of TB and Human
Immunodeficiency Virus (HIV) infection over an 18-month period. Second, the investigators
will utilize an ongoing community-based TB screening program to perform a cross-sectional
survey of TB prevalence among miners and community members. To assess TB transmission, the
investigators will collect epidemiological data and perform whole genome sequencing (WGS) on
positive Mycobacterium tuberculosis (MTb) culture samples.
Given the lack of research and large global ASM workforce, 1 million of whom are in Tanzania,
the results of this study will assist in the development and introduction of interventions to
reduce the risks to respiratory health of artisanal mining in Tanzania and elsewhere; and
provide ample scope for future work.
Description:
Background Artisanal and small-scale mining (ASM) produces a quarter of the global supply of
key metals for the electronics industry and provides direct employment for an estimated 45
million people. Approximately 10 million are in sub-Saharan Africa (SSA), of whom over 1
million work in Tanzania. ASM is characterized by occupational insecurity and low levels of
safety and environmental protection, but there is little research into its risks,
particularly respiratory and communicable diseases.
Silicosis is an occupational respiratory disease caused by inhalation of respirable
crystalline silica (RCS). It usually presents irreversibly after decades of exposure,
although accelerated disease associated with high initial exposures can lead to respiratory
failure within 1-2 years. To date, silicosis has been examined in only two ASM populations:
in Brazil, where radiographic evidence was reported in 37% of 348 current and ex-miners, and
in Zimbabwe, where a prevalence of 11% was reported among 514 current miners.
Silicosis and RCS exposure increase the risk of pulmonary tuberculosis (PTB). In miners with
silicosis, human immunodeficiency virus (HIV) is also known to multiplicatively increase the
risk of TB. Correspondingly, a high PTB prevalence of between 3% to 14% has been reported in
several studies of sub-Saharan African ASM workers. The role of miners in community PTB
transmission is of considerable public health importance but remains unclear; whole genome
sequencing (WGS) is the most accurate available method for assessing this. HIV prevalence
across small-scale mining populations ranges from 1.8-18%. The role of HIV in the development
and progression of silicosis is unclear and requires further study, with conflicting evidence
on whether it reduces or increases the risk of silicosis.
The World Health Organization (WHO) provides a strong recommendation for screening among
silica-exposed populations. This recommendation is based on an estimated number needed to
screen of 36 in high incidence settings and an increased mortality from TB amongst miners
with silicosis, with a corresponding 82% reduction in mortality in screened compared to
unscreened miners with TB. Despite this recommendation, there is limited evidence,
particularly from Sub-Saharan Africa and in the last two decades, of optimized methods for
doing this. Beyond screening, differentiating silicosis, tuberculosis, and silicotuberculosis
is clinically challenging, leading to misclassification across all diagnoses. Symptoms are
common among miners; for example, in ASM TB screening studies, between 23-39% meet
symptomatic criteria for presumptive TB. There is also a growing appreciation that
subclinical TB is common and plays an important role in transmission. A screening tool that,
either alone or in tandem with current approaches, improves the sensitivity and specificity
for TB would be useful diagnostically and programmatically, potentially allowing allocation
of resources towards higher risk individuals. One recently investigated method which has
shown promise in meeting the WHO target product profile of 90% sensitivity and 70%
specificity for a triage tool is C-reactive protein (CRP). CRP testing can be performed at
the point of care for less than $2-3. Most recently, WHO guidance has recommended CRP (with a
threshold of >5mg/L) may be used in screening for TB disease among adults and adolescents
living with HIV.
The tanzanite gemstone is mined exclusively in a 5x2 km strip of land in Mererani, Northern
Tanzania. Miners use deep shafts and basic techniques. Three sources of evidence raise
concern that the burden of silicosis and PTB among the estimated 9,000-12,000 ASM tanzanite
miners is high. First, a recent cross-sectional survey of 330 miners estimated a silicosis
prevalence of 30% on chest radiograph and a microbiologically confirmed PTB prevalence of 6%
among miners and 8% in the surrounding community. Miners had a median age of 35 years and
just 5 years of employment. Second, a case series from the local tertiary referral hospital
found a primary diagnosis of silicosis or silicotuberculosis made up 22% of respiratory
admissions; over half were under 45 years old and 63% required oxygen therapy. Third, in an
occupational clinic for miners and their families, 22% of 315 miners had silicosis on chest
X-ray (CXR) and 18% of 243 tested had confirmed PTB.
Study Rationale
There is clear evidence of significant occupational risks resulting in a high burden of
aggressive silicosis in young tanzanite miners and a high burden of tuberculosis among miners
and the community. By using a prospective cohort study design, the investigators will be able
to describe the rate of change of silicosis, which is important for understanding the disease
burden. Importantly, for the case of occupational research, prospective study reduces the
risk of healthy worker bias.
Cross-sectional evidence is highly suggestive of a high burden of aggressive silicosis in
young tanzanite miners. To understand and ultimately to prevent the risks, prospective study
is required. PTB prevalence is also high among miners and the local community.
This study aims to characterize the progression of silicosis among a cohort of tanzanite
miners and measure PTB prevalence and transmission patterns in a cross-sectional, screened
population of miners and community members. Given a high PTB prevalence amongst miners,
improved triage methods are needed, and utilizing CRP represents a feasible, cost-effective
approach to this.
Importantly, cost-effective prevention strategies for silicosis and TB are available. A
better knowledge of the extent of the silicosis burden in the Tanzanite communities and
improved understanding of potential barriers and opportunities for implementation will inform
targeted and appropriate preventive strategies.
This study is part of a long-running partnership between Kibong'oto Infectious Diseases
Hospital (KIDH) and the mining community that provides clinical care and performs clinical
research. Through the identification of occupational respiratory diseases, silicosis and
tuberculosis, miners will have access to care and treatment. In the longer term, this study,
dependent upon its findings, and collaboration with Imperial College, provides a platform for
interventional studies potentially aimed at reducing RCS exposure and silicosis and
tuberculosis disease. By identifying groups of miners or characteristics of miners who face
higher risks of disease - for example, those miners who are drillers - the investigators may
be able to intervene effectively and prevent the risks associated with these groups.
Importantly, in the case of tuberculosis, preventing disease among a group of miners may also
reduce the risk of transmission within the community - understanding this dynamic is also an
aspect of the study.
More broadly, the ASM community is a vital part of the global economy. By promoting a safe
and secure working environment, the study directly informs the United Nations Sustainable
Development Goals (SDG 8.8). Given the large global artisanal mining population - 1 million
of whom are based in Tanzania - the study would be of global importance and applicability.
Objectives
Primary Objectives
- Broad: To test the hypothesis that small-scale tanzanite miners have a high rate of
rapidly progressive silicosis, characterized by changes in chest radiology and markers
of respiratory impairment over an 18-month period. Furthermore, the investigators
hypothesize that the rate is directly related to high RCS exposure and is modified by
the presence of PTB and HIV.
- Specific: The investigators shall measure change in the International Labour
Organization (ILO) classification of pneumoconioses over an 18 month in a cohort of 410
small-scale tanzanite miners and test whether this is related to cumulative RCS
exposure.
Secondary Objectives
1. Broad: To test the hypothesis that small-scale tanzanite miners have a high prevalence
of PTB which is related directly to high exposures to RCS during mining activity and is
modified by the presence of silicosis and HIV.
• Specific: The investigators shall measure the prevalence of microbiologically
confirmed PTB and test whether this is related to cumulative RCS exposure in a
cross-sectional study by the end of quarter 1 of the study period.
2. Broad: To test the hypothesis that the proportion of clustered PTB cases among tanzanite
miners and the community is high and that the proportion of community cases transmitted
from miners is higher than the proportion transmitted within the community.
• Specific: The investigators shall use whole genome sequencing (WGS) methods to observe
whether cases of PTB from a cross-sectional and 18-month cohort study are clustered and
if a community member is more likely to have contracted TB from a miner or a community
member.
3. Broad: To test the hypothesis that occupational disease-related morbidity amongst
tanzanite miners results in 'catastrophic' economic loss.
• Specific: Using standardized tools, the investigators shall measure the costs of TB
and silicosis treatment in an 18-month cohort of miners and compare these costs to a
standard definition of catastrophic costs for TB treatment.
4. Broad: To test if adding C-reactive protein (CRP) measurement to standard PTB screening
algorithms in tanzanite miners improves its sensitivity and specificity.
• Specific: The investigators shall test the sensitivity, specificity, and area under
the receiver operating curve of CRP compared to a culture reference standard for the
diagnosis of TB in a cross-sectional study by the end of quarter 1 of the study period.
5. Broad: To use whole genome sequencing (WGS) to determine rates of Mycobacterium
tuberculosis (Mtb) drug resistance in the mining community and examine what proportion
of drug-resistant cases are associated with silicosis and clustering over an 18-month
period.
• Specific: The investigators shall describe the proportion and characteristics of
drug-resistant tuberculosis isolates from an 18-month cohort study as identified by
whole genome sequencing.
6. Broad: To elicit stakeholder understanding of the causes of occupational respiratory
disease and the acceptability of interventions designed to reduce their risks.
• Specific: The investigators shall use qualitative methods, including interviews and
focus groups, to explore stakeholder understanding of occupational respiratory disease
and possible interventions by the end of quarter 2 of the study.
Methodology
To achieve the primary objective, the investigators will establish a representative
prospective cohort study of 410 small-scale tanzanite miners and measure their baseline
prevalence of silicosis, PTB, and HIV infection using validated methods. The primary
outcome measure will be change in chest radiograph using the International Labour
Organization (ILO) scale over the 18-month study period, starting from Q1 2023 and
ending in Q3 2024. The investigators will also measure respiratory symptoms and lung
function through spirometry. The questionnaire is designed to take 20 to 25 minutes.
To measure PTB prevalence amongst miners (secondary objective 1), the investigators will
screen miners in the cohort for PTB at enrolment and at 18 months using a comprehensive
screening approach of symptoms and chest radiography, followed by a molecular test
called GeneXpert (Xpert) and sputum culture. PTB will be defined as a positive result on
culture or Xpert.
During the study follow-up, miners will be invited to attend the occupational health
clinic at Kibong'oto Infectious Diseases Hospital (KIDH) if they are concerned they have
PTB; TB and HIV testing and treatment is free at the clinic.
To investigate clustering of PTB within the mines (secondary objective 2), the
investigators will undertake WGS on culture-positive Mycobacterium tuberculosis (Mtb)
samples from the mining cohort and their contacts (>18 years of age). The investigators
will determine the proportion of cases arising from transmission within mines by
identifying clustered cases compared to non-clustered cases. The WGS pipeline will also
ascertain the proportion of miners with anti-TB drug resistance (secondary objective 5)
and speciate the TB isolates.
In a linked cross-sectional survey, the investigators will enroll approximately 2400
miners and community members from an ongoing community-based screening program led by
KIDH, and from incident TB cases from the local Mererani health center and KIDH clinic.
Amongst symptomatic individuals, the investigators will perform Xpert testing and Mtb
culture, with positive cultures proceeding to WGS. The investigators will collect
demographic and PTB risk factor data on enrolled participants and combine this dataset
with the miner's cohort to create a combined dataset of Mtb WGS samples. By performing
WGS on all positive cultures, the investigators can determine the proportion of
community cases arising from miners based on their phylogenetic association. The
investigators will then investigate risk factors amongst clustered vs non-clustered
cases and whether this is modified by being a miner/non-miner. The cross-sectional
questionnaire is designed to take less than 5 minutes.
To investigate change in economic status (secondary objective 3), the investigators will
use questionnaire methods to measure changes in occupational status, monthly estimated
income, and healthcare expenditure of miners in the cohort over an 18-month period. The
investigators will then determine if catastrophic economic loss has occurred using a
standard definition. The addition of CRP and phone screen testing (PoST) to triage
testing amongst miners will allow testing of whether the diagnostic accuracy of
screening for the presence of PTB amongst miners can be improved (secondary objective
4).
A subgroup of stakeholders will be invited to take part in semi-structured qualitative
interviews and focus groups (secondary objective 6). The number of participants will be
determined by saturation of data; however, theoretically is expected to be approximately
20 individuals and, similarly, 4-5 focus group sessions of 4-8 individuals. Interviews
and focus groups will be expected to last approximately 20 and 60 minutes respectively.
These stakeholders will be asked for their understanding of the causes and etiology of
respiratory diseases amongst themselves and their work colleagues and regarding the
potential acceptability of interventions designed to reduce their risk of occupationally
acquired disease. The investigators will use the capability, opportunity, motivation,
behavior (COM-B) model to understand from a theoretically informed perspective,
opportunities and barriers to interventions. Interviews (conducted in Swahili) will be
audio recorded, transcribed, anonymized, and analyzed using thematic analysis.
Finally, in participants who provide specific consent, sputa and Mtb culture isolates
from both studies and serum from the cohort study will be retained in -20 C freezers at
KIDH for future studies. Separate ethical approval will be required for future studies
on these retained samples.
Study Procedure
Persons attending the TB screening program who meet the eligibility criteria for either
the cross-sectional survey alone or both cross-sectional and cohort studies will be
identified by study staff involved in the screening program and offered the opportunity
to take part in the studies. Should they express interest, an informed consent process
and subsequent study enrollment will be undertaken by different staff members. The
consent process will include the provision of a participant information sheet to the
potential participant. The participant will be provided time to read this document or,
should they be illiterate, it will be read to them by the study staff member.
Both the cohort study and cross-sectional survey will utilize routine data collected as
part of standard TB screening. This will include demographic data, symptom data, chest
X-ray (CXR), HIV screening, and (where applicable) a GeneXpert (Xpert) result. Informed
consent will be captured on paper forms. All results will be made available to the
participant as they are completed, for example, CXR reports (by the onsite radiographer)
and Xpert results will become available on the day and will be provided to the
participant.
In addition to participants identified during the TB screening program, contacts within
the mines and the homes of persons identified to have TB will be contact traced for TB
and invited for testing. For the miners, the investigators will do this by contacting
the mine managers and asking them to invite fellow teammates or other close contacts of
the identified case. For home contacts, if they are able to attend the screening
program, the investigators will ask the case to encourage their family contacts to
attend. If they are more distant, the investigators will offer two options: either
labeled sputum samples can be taken home and brought to the screening program, or the
investigators will contact local TB control officers in the case household's area, who
will arrange for testing. Identified cases will be linked to local treatment programs.
Furthermore, Xpert-positive incident TB attending Mererani health center/KIDH during a
three-month period around the time of the study will be offered the opportunity to
enroll in the cross-sectional survey, should they meet its eligibility criteria.
For cohort participants, face-to-face study visits will take place at month 0 and 18
months, to coincide with TB screening program visits. These dates are currently
estimated at Q1 2023 and Q3 2024. Additional 6 and 12-month telephone visits will be
arranged. These and the 18-month visit are detailed in the study protocol.
Routine data collection for screening participants in the cross-sectional survey
includes:
- A questionnaire from the National TB and Leprosy program asking about demographic
data and TB symptoms, administered by study staff and transcribed electronically
using REDCap software
- A digital CXR (all miners and community members who are WHO symptom screen
positive) with initial reports provided by the onsite radiographer
- Voluntary counseling and testing for HIV with linkage to care
- For those with a positive symptom screen for TB, sputum testing for TB with
GeneXpert (Xpert)
Additional testing and data collection as part of the cross-sectional survey will
include:
- For miners, finger prick testing for CRP using the point of care iChroma™ M3 device
- For participants screening positive for TB (estimated approximately 20-30% based on
previous studies), a series of two sputum samples will be requested which will be
pooled and then split with 1ml taken forward for Xpert testing (as noted in routine
testing) and the remaining half retained.
- For community participants in the cross-sectional study, if the Xpert sample is
positive, the second retained sample will be taken for Mtb culture.
- For miners in the cross-sectional or cohort study participants, all retained sputum
samples will undergo Mtb culture.
- All positive Mtb culture results from either study will proceed to WGS.
- Simple techniques to enhance sample production will be taught to all staff.
Procedures for obtaining, handling, and processing sputum samples will follow
standardized KIDH laboratory guidelines.
- All positive Mtb culture samples will be stored at -20 C according to standard KIDH
lab protocols.
- Swab samples from participants' mobile phone screens will be collected. Real-time
PCR will be used to identify Mtb in the PoST sample similar to methods described in
recent studies. This will be performed at a later date and results will not be used
clinically as this is experimental.
Additional testing and data collection as part of the cohort study will include:
- A questionnaire asking about respiratory symptoms and past respiratory medical
history, occupational related dust exposures, and economic status. This will also
be administered by study staff.
- Venepuncture with samples sent for full blood count (FBC), renal function and
electrolytes (U+E), and CD4 count and viral load (if HIV positive and no result
available in the last 12 months, or clinically indicated) and a single (5 ml) EDTA
and serum sample retained for storage. If CD4 count is <350 cells/mm3 or HIV viral
load is >1000 copies/mL, then participants will be linked to their local HIV clinic
for further management as per national guidelines.
- Pre- and post-bronchodilator spirometry will be undertaken by a trained member of
the study team with data recorded electronically
For all participants who identify as smokers, a brief smoking cessation intervention
will be provided.
Participants for the qualitative element of the study will be recruited from the miners'
cohort and relevant stakeholders based on purposive sampling and participant willingness
to be involved. A separate patient information leaflet and informed consent process will
be undertaken for this group. To attempt to reduce sampling bias, stakeholders will be
invited through a consensus decision by the research team. Individuals and groups of
miners will be invited from attendees to screening on multiple different days evenly
distributed through the recruitment period.
Follow Up During follow-up, cohort participants will receive two telephone follow-up
appointments at approximately 6 and 12 months. These appointments are designed to
ascertain their current location, brief health status, and occupational status.
A second and final face-to-face study visit at month 18 will involve:
- A questionnaire asking about change in occupational role and status, respiratory
symptoms and new respiratory conditions, and change in economic status
- Repeat sputum and testing using the same procedures as outlined in the month zero
visit
- A digital CXR
- Spirometry with reversibility testing
- Voluntary counseling and testing for HIV with linkage to care
- Venepuncture with samples sent for full blood count (FBC), renal function and
electrolytes (U+E), C-reactive protein (CRP), and a single (5 ml) EDTA and serum
sample retained for storage.
During the follow-up period, the mining cohort participants will be encouraged to attend
the occupational clinic at Kibong'oto Infectious Diseases Hospital (KIDH) if they have
any new respiratory symptoms that require investigation. They will be reimbursed for
their travel expenses. TB and HIV testing and treatment at the clinic are free. As per
standard TB diagnosis protocols at KIDH, sputum samples will be tested with GeneXpert
(Xpert) and sent for TB culture. Positive culture results will be sent for whole genome
sequencing (WGS). Outcomes for all participants who test positive for TB will be
followed up using the Tanzanian National TB program electronic records system and
contacted to encourage attendance if a loss to follow-up is noted. Follow-up will be
limited to the duration of TB treatment (6 months for drug-sensitive TB, 9 months for
multidrug-resistant TB (MDR-TB)).
Sample Size
The best estimate of the prevalence of silicosis in tanzanite miners is 30% following a
median of 5 years employment in the mines. Local measurements of respirable silica
indicate very high average exposure levels (up to 10.6 mg/m3). There are no local data
on which to base sample size calculation for a study of disease progression; hence, the
investigators have used information from longitudinal studies of workforces with
comparably high silica exposures. In a study of slate pencil workers in India, with a
baseline prevalence of 55%, 32% of 279 workers had progressive silicosis (defined as,
using the International Labour Organization (ILO) classification, an increase in ≥2
steps in profusion of small opacities, or a ≥1 step increase in the size of small or
large opacities, or the presence of new large opacities) over 16 months follow-up. This
figure is close to that among the Hawk's Nest tunnellers in the US, many of whom died
over a period of 18 months; and to those in populations of sandblasters in Turkey (82%
progression over 4 years) and the Gulf of Mexico (52% over 2 years).
On this basis, the investigators have conservatively estimated that 20% of a sample of
tanzanite miners will show progression over 18 months; the total includes 1 in 3 workers
with silicosis at baseline and an additional 10% with incident disease.
Using a normal approximation of a binomial model, a confidence interval of +/-5%, and a
significance level α=0.05 with power 95%, provides a sample size of 246 (estimated
number of outcomes=49). To account for mine clustering, and using an intra-cluster
correlation coefficient (ICC) of 0.01 (higher than the usual workplace ICC of <0.003),
the investigators applied a design factor of 1.49 (1 + ICC(n'-1) where n' = average
cluster size), increasing the required sample size to 367 or 410 assuming a 10% loss to
follow-up. Based on an estimated tuberculosis prevalence of 6%, and using the same
approach, this study will be able to estimate prevalence to a 95% confidence interval of
+/-2.3%. Likewise, assuming 1200 community members and a PTB prevalence of 8%, the
investigators will be able to detect if 60% of community cases originate from miners
(α=0.05, power 95%).
