Clinical Trial Details
— Status: Completed
Administrative data
| NCT number |
NCT04476758 |
| Other study ID # |
20-0099 |
| Secondary ID |
|
| Status |
Completed |
| Phase |
|
| First received |
|
| Last updated |
|
| Start date |
February 10, 2021 |
| Est. completion date |
October 30, 2023 |
Study information
| Verified date |
October 2023 |
| Source |
University of Alabama at Birmingham |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Observational
|
Clinical Trial Summary
This study is investigating the role of allergic (Th2) inflammation in patients with Cystic
Fibrosis (CF) and history of fungal infection and/or Allergic Bronchopulmonary Aspergillosis.
Little is known about fungal infection in CF and conflicting results exist on whether this
results in worse lung function over time. There is concern that persistent fungal infection
can result in worse clinical outcome measures in patients with CF. Also, it is unclear how
ABPA develops, but may be related to the amount of fungus a patient with CF is infected with.
This study looks at inflammatory patterns and allergic responses to fungal elements to help
identify biomarkers and signs of allergic disease in fungally infected patients with CF.
Description:
While bacteria are predominant agents in CF lung disease, fungi are often isolated in both
sputum and bronchoalveolar lavage fluid (BAL), yet their role in CF is not fully understood.
Fungal infection in CF has a wide spectrum of presentations, varying from transient detection
to persistent infection, acute fungal bronchitis with resulting pulmonary exacerbation,
sensitization to fungal allergens, and allergic bronchopulmonary aspergillosis (ABPA). While
there are clinical guidelines for the diagnosis and treatment of ABPA in patients with CF,
there are few guidelines and recommendations regarding monitoring, clinical care, and
antifungal treatment in the various presentations of CF fungal disease; further, the clinical
impact of fungi without ABPA is poorly understood. While inflammation in CF is classically
considered a neutrophil and macrophage driven process (Th1), eosinophils and allergic
cytokines (Th2) have been shown to be elevated in the presence of fungal disease in both
clinical and animal CF studies. Studies have also shown decreased lung function (e.g. percent
predicted forced expiratory volume in one second, ppFEV1) in individuals with frequent fungal
detection in their sputum, and associations with Pseudomonas infection and use of
antimicrobials. Adults with CF are also more prone to fungal sensitization when compared to
non-CF patients as well as having higher rates of allergic rhinitis and atopy. In a
retrospective study performed at our center, we found that children with intermittent or
chronic fungal infections experienced more rapid decline in lung function compared to those
without fungal infections regardless of ABPA status (see preliminary data). Understanding
whether fungal infections are driven by an allergic (Th2) inflammatory process may alter
treatment approaches by utilizing steroids and antifungal therapies more readily in patients
with fungal infection to combat lung function decline. Limited studies have investigated the
frequency of allergic sensitization to fungal pathogens in individuals with CF, the frequency
of allergic sensitization in the pediatric CF population in general, and the unique
inflammatory profiles and phenotypes of CF fungal infections, both in the sputum and the
serum.
Hypothesis: We hypothesize that children with CF and fungal infections without ABPA will have
elevated allergic inflammatory profiles and increased sensitization to fungal elements
compared to those without fungal infection.
Specific Aim 1: Compare Th2 inflammation in patients with and without fungal infections in
patients with CF and to those with ABPA.
- Approach: We will obtain serum and sputum samples from 25 patients with either (1)
fungal infection without ABPA, n=10 (defined as ≥ two positive fungal cultures in prior
18 months), (2) no fungal infection, n=10, and (3) ABPA, n=5, and measure specific
sputum and serum cytokine measurements to evaluate Th2 and Th1 inflammatory pathways.
- Biomarkers measured: Eosinophilic cationic protein (ECP), Interleukin-4 (IL4),
Interleukin-5 (IL5), Interleukin-10 (IL10), Interleukin-13 (IL13), and eosinophil count
in both serum and sputum.
- Expected outcome: Individuals with fungal infection without APBA will have elevated Th2
markers of inflammation compared to those with no fungal infection. We will also compare
to those with ABPA as a separate control group. We will also measure Th1 markers to be
used as a reference to previously established inflammatory profiles seen in CF, seeing
if those with fungal disease deviate towards a more Th2 driven process.
Specific Aim 2: Investigate allergic sensitization to fungal elements in patients with CF
fungal infection without ABPA compared to those without fungal infection and to those with
ABPA.
- Approach: We will measure total IgE and serum ImmunoCAP testing of specific IgE levels
to fungal proteins of various species (Aspergillus, Candida, etc). to determine fungal
sensitization. We will also survey patients regarding environmental exposures to explore
relationships with allergic sensitization.
- Expected outcome: Individuals with fungal infection without ABPA will be more likely to
show allergic sensitization to fungal elements when compared to those with no fungal
infection.
The results of this study will help characterize the inflammatory profile associated with CF
fungal infections contributing to the understanding of both the infectious and allergic
nature of disease in the CF population. From this, the contribution to both the
pathophysiology and clinical characteristics of CF fungal infections will serve as a step
towards understanding management options, care guidelines, and disease progression for this
unique set of hard to treat organisms.
Recruitment: We propose to recruit 25 patients with CF aged between 8 and 25 years who agree
to participate in this cross-sectional study looking at the immune system characteristics of
fungal infection and ABPA. We plan to screen individuals coming to their routine CF clinic
and approach them regarding their interest in participating in this study. From this, we will
explain the concept, hypothesis, and procedures involved with intent to schedule them for a
research visit.
Patient Selection: Patients will be recruited from the CF Center at CHCO by study
investigators or qualified research coordinators at the time of a routine clinic visit.
Study Visit: We plan to prospectively recruit 25 subjects with CF during a period of clinical
stability. Subjects will have one research clinic visit that will coincide with their clinic
visit at CHCO Pulmonary Clinic facilities. The following diagnostic information will be
entered onto Case Report Forms: demographic information, diagnostic history and mutations,
CF-related co-morbidities, historic microbiology results including fungal culture results,
medications including modulator therapy and long-term antibiotic regimens, previous allergy
testing, diagnostic criteria for ABPA (if applicable). We will also utilize historical
clinical data from the medical record to establish other co-morbidities, lung function trends
and baseline, history of other bacterial infections, history of allergy diagnoses, and other
pertinent medical history and diagnostic testing (ie previous CT scan results, previous blood
work, etc.). The following evaluations will be performed :
- Historical data in the medical record. Examples include Co-morbid diagnoses related to
CF (such as but not limited to CF related diabetes, CF liver disease, asthma, etc),
previous blood work (such as but not limited to serum IgE levels, previous allergy
testing, bronchoscopy data and lavage studies, routine and urgent/admission CF labs,
etc), previous spirometery and lung function data, previous nutritional and growth data
(BMI, vitamin levels, etc), previous microbiology and culture data, etc.
- BMI measurements obtained from regular CF clinic visit
- Height and weight to be obtained and subsequently calculated.
- Pulmonary function testing obtained from regular CF clinic visit. Spirometry will be
performed according to American Thoracic Society criteria, while absolute values will be
converted to percent predicted using the Global Lung Function initiative reference
equations34.
- Sputum collection. Spontaneously expectorated sputum will be used as possible.This will
be collected at home by the patient following a routine respiratory airway clearance
regimen within 12 hours of clinic visit. The sample will be placed in a mailed specimen
cup and placed on ice and brought to the clinic visit. If sputum is not able to be
expectorated prior to visit, we will attempt to utilize remaining sputum expectorated
that is not used for clinical needs for further analysis and storage. Sputum may be
collected by sputum induction according to the current CFF Therapeutics Development
Network standard operating procedure if 1) unable to expectorate, (2) patient meets
clinical criteria for sputum induction and (3) clinic is able to perform research
induced sputum based on current COVID-19 guidelines to ensure safety of team member and
adequate PPE supply.
For safety reasons, the induction procedures will only be performed for subjects who meet the
following criteria on the day of the induction: FEV1 ≥ 30% predicted, No history of > 5 mL
hemoptysis within 48 hours prior to the visit, Able to tolerate the sputum induction
procedure. Of note, there is little significant difference in specimen quality for analysis
between expectorated and induced sputum. Markers to be tested as previously described above.
- Environmental fungal exposure questionnaire. Will be performed prior to finish of clinic
visit. This questionnaire in entirety is a validated questionnaire used by Dr. Andy Liu.
Given time constraints for study participants, we are using a modified questionnaire
focused on questions of interested to this study (e.g. pertaining to fungal exposure).
This has not been validated but may provide important information in this pilot study
for future research
- Serum collection. Peripheral venous blood draw will be performed by certified individual
using appropriate sterile technique by the CTRC. Samples will be labeled per research
protocol standards. Markers to be tested described above.
- All sputum samples to be banked and saved for potential microbiome, mycobiome and
transcriptome analysis, assessing gene expressions unique to various inflammatory
pathways.
Sample Size Estimates: Power and sample size for the study proposal is fixed due to the
expected number of eligible patients to be recruited into this pilot study during the study
window. Based on preliminary data and the described definitions of types of infection,
investigators anticipate that over a 1-year recruitment window they will be able to enroll
approximately 10 individuals with no fungal infection, 10 patients with a fungal infection
but not ABPA and 5 with ABPA. The primary analysis plan focuses on the description and
comparison of key plasma and sputum measures described in Table 3. Power analysis provides
the detectable effect sizes when comparing the control arm (no fungal infection) to either
the non-ABPA group or the ABPA group. Calculations are based on a power of 80% and Type I
error rate of 0.05 for two-sided two-sample equal-variance t-test conducted in PASS version
15 statistical software (2). Group sample sizes of 10 and 5 in the fungal infection groups
achieve 80% power to reject the null hypothesis of zero effect size when the population
effect size is 1.36 and 1.66 respectively. Thus, the study is powered at 80% to detect a
difference in the mean markers to be measured greater than 1.66 and 1.32 standard deviations.
Given limited data in the literature regarding Th2 markers in CF, we are basing these
calculations off of deviations from a mean for the multiple Th2 markers we are testing.
Data Collection and Storage: All subjects will be de-identified upon study sample collection
and stored with a master key. There will be limited access to this information with the PI
and only essential research staff able to monitor and view the data. All hardcopy source
documents will be kept in a locked file cabinet in the CF research team's storage facilities.
Additionally, to further ensure data integrity, data for this study will be stored in
Research Electronic Data Capture system (REDCap), which will allow limited access to only
essential personal. REDCap enables in-line validation to minimize transcription errors and
provides real-time notifications of data submission and allows immediate central monitoring
and feedback. Access to data requires an encrypted secure socket layer (SSL) connection and
changes are logged by user ID, time stamp and project. Databases are backed up frequently.
