Conditions: COPD COPD Exacerbation COPD Exacerbation Acute Pollution Related Respiratory Disorder Pollution; Exposure
Keywords: Biomass Associated COPD Low-dose Theophylline
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 100
Healthy volunteers: no

Brief summary:
Chronic obstructive pulmonary disease (COPD) is the fourth leading cause of death worldwide, and over 90% of COPD-related deaths occurring in low- and middle-income countries (LMICs). Household air pollution (HAP) - from burning solid fuels such as wood, dung, agricultural crop waste, and coal for energy - is the primary risk factor for COPD in these settings. Biomass-related COPD has a distinct histopathology, phenotype and inflammatory profile when compared to tobacco mediated COPD. Despite the high global burden of biomass-related disease, little is known about the effectiveness of pharmacotherapies for biomass-related COPD; to date, no clinical trials have focused specifically on treatment of biomass-related COPD. This study proposes to assess the health impact of biomass-related COPD and test the effectiveness of low dose theophylline compared to standard therapy among adults with biomass-related COPD in Uganda with the aim to assess whether low-dose theophylline improves respiratory symptoms, decreases the inflammatory profile of serum biomarkers and whether administration attenuates the effect of HAP on lung function. The study additionally aims to assess whether low-dose theophylline is a cost-effective intervention based on the incremental cost-effectiveness ratio and a range of willingness to pay thresholds.

Detailed description:

Arms:
arm 1: Participant in this group will receive low-dose theophylline in addition to standard care, per World Health Organization (WHO) guidelines for management of Chronic Obstructive Pulmonary Disease (COPD) treatment, over a one year period. arm 2: Participant in this group will receive a placebo in addition to standard care, per World Health Organization (WHO) guidelines for management of Chronic Obstructive Pulmonary Disease (COPD) treatment.

Interventions: intervention 1: Theophylline ER intervention 2: Placebo oral tablet intervention 3: Standard of Care Treatment
Intervention descriptions: intervention 1: 200 mg extended release (ER) low-dose theophylline taken orally daily intervention 2: Manufactured methylcellulose placebo tablet taken orally daily intervention 3: Per World Health Organization (WHO) guidelines for management of Chronic Obstructive Pulmonary Disease (COPD) treatment

Protocol document:
ICF_002.pdf: 
 
Effectiveness of Low-Dose Theophylline for the Management of Biomass-
Associated COPD 
 
 
NCT03984188 
 
 
Document Date: 7/27/2021 


Page 1 of 9
MAKERERE UNIVERSITY COLLEGE OF HEALTH SCIENCES
SCHOOL OF MEDICINE RESEARCH AND ETHICS COMMITTEE 
(SOM-REC)
INFORMED CONSENT TEMPLATE FOR INTENDING RESEARCHERS 
Title of the proposed study: “Effectiveness of Low-dose Theophylline for the 
Management of Biomass-associated COPD”
Investigators :
1.Trishul Siddharthan MD; tsiddhar@miami.edu
University of Miami 
2.William Checkley, MD, PhD; wcheckl1@jhmi.edu, 
Johns Hopkins University  
3.Bruce Kirenga, MMED; bruce.kirenga@yahoo.com
Makerere University College of Health Sciences
4.Patricia Alupo, MMED; patricia.alupo@gmail.com
Makerere College of Health Sciences
5. Peter Jackson, MD; peter.jackson@vcuhealth.org 
Virginia Commonwealth University 
Background and rationale for the study:
Chronic lung disease affects people like yourself around the world but there 
are few options for treatment. We are conducting a study to identify 
-       Study #: 20201523        Effective Date: 7/27/2021


Page 2 of 9
potential treatments that may improve your breathing, be accessible and 
low-cost. 
A description of sponsors of the research project and the organizational 
affiliation of the researchers: National Heart, Lung, Blood Institute, National 
Institutes of Health, University of Miami, Makerere University 
 
Purpose:
The purpose of this research study is to identify treatments for people in 
your community who have chronic lung problems and experience symptoms 
such as shortness of breath and tightness in their chest. If you are identified 
as having any of these respiratory problems, you will be asked if you would 
like to participate in a study that will try to find out if your condition can be 
managed with daily pills. This study is being conducted with support from 
the National Institutes of Health in the United States. 
The estimated duration the research participant will need to commit to take 
part in the research project:
100 participants will participate for a total of 12 months. Each participant 
will have 5 visits. The first set of testing will be completed in no more than 
two visits. In total, the procedures will take no more than 45 minutes. If you 
qualify for the study, fieldworkers will follow up every month to provide 
additional medications and perform additional tests. These follow up tests 
should take no more than 30 minutes. 
Procedures:
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Page 3 of 9
If you agree to participate, we will ask you to complete a questionnaire 
about your current health and health history and perform breathing tests. 
We will also measure your blood pressure, weight, and height. If you are a 
woman capable of having a child, you will have a pregnancy test done and it 
must be negative. If you qualify for the study you will be provided with pills 
for a one-year period. Half of the people that participate in this study will 
receive a placebo pill (a pill that looks like the study medication but contains 
no medication.) The other half will receive the medication. The purpose is 
to determine whether the study drug works. 
Neither the field workers nor the study investigators will know which group 
receives the placebo until the end of the study. We will additionally take 
blood tests up to three times during the study. You will be provided with a 
diary to record your symptoms and with a monitor to test air pollution levels 
in your household during the course of the study.
Who will participate in the study:
We are asking you to be a volunteer in a research study. You are being asked 
to participate because you are 40 years of age or older, have full-time 
residence in Nakaseke or Kampala for more than 6 months, and do not 
intend to move away from the community in the next 6 months. You do not 
have to participate if you do not want to. Pregnant women are not allowed 
to participate.
Study Procedures and Risks/Discomforts:
Spirometry 
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Page 4 of 9
The breathing test (“spirometry”) is a special test for assessing how the 
lungs work. We will ask you to breathe deeply into a small machine. This 
process is generally safe; however, in older patients it may cause some 
participants to feel dizzy or lightheaded; some may faint. The 
administration of an inhaled, short-acting bronchodilator is generally safe, 
but may cause some nervousness and tremor and may cause your heart to 
beat fast. To minimize the risk of this test, we will not ask you to perform it 
if you have a high pulse rate or high blood pressure. 
Theophylline 
Theophylline is a once-a-day medication for your breathing. The most 
frequent side-effects are stomach discomfort, headache, insomnia (difficulty 
sleeping) and heart palpitations. You should take the study medication once 
daily, as prescribed. In cases of overdose, (taking too much study drug) the 
side effects include vomiting, cardiac arrhythmias, (irregular heartbeat) and 
seizures that are difficult to treat, which can cause death. If that were to 
happen, you will be provided with a number to call should you have any 
symptoms and you will be referred to Nakaseke Hospital or Makerere Lung 
Institute for further management.
Blood samples
This procedure is quite safe and well tolerated; the risks are of drawing 
blood pain, discomfort, bruising or infection at the puncture site. For each 
blood draw (up to 5 teaspoons), disposable material will be used to avoid the 
risk of infection and will be performed by trained personnel to reduce 
discomfort.
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Page 5 of 9
Benefits:
Being in this study will not help you directly. But your participation in the 
study may benefit other people in the future by helping us learn more about 
treatment for COPD globally. You will receive the results of all health 
testing, including the breathing test results. 
Confidentiality: This research is covered by a Certificate of Confidentiality 
(CoC) from the National Institutes of Health. The researchers with this CoC 
may not disclose or use information, documents, or biospecimens that may 
identify you.
What information is being collected, used, or shared?
To do this research, we will need to collect, use, and share your private 
health information.  By signing this document, you agree that your health 
care providers may release your private health information to us, and that 
we may use any and all of your information that the study team believes it 
needs to conduct the study.  
Who will see, use or share the information? 
The results of this study could be presented in journals or scientific 
conferences, but without your name or any other information that could 
identify you. Your name will not appear in any publication of this study. 
People at the and the University of Miami who work on the study or who need 
to make sure the measurements are being done correctly may see the results 
from the tests, but this information will not include identifying information. 
The final decision to share this data will be taken by the principal 
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Page 6 of 9
investigators. The local Research Ethics Committee (REC) and Uganda 
National Council for Science and Technology (UNCST) are entities which 
may have access to private information that identifies the research 
participants by name. This trial will be registered and may report results on 
www.ClinicalTrials.gov, a publicly available registry of clinical trials
Alternatives:
Participation in the study is not mandatory. You have the alternative to 
continue with the standard of care.
Cost:
There are no anticipated costs associated with this study. All study 
medications will be provided to you free of cost during the trial period. 
Compensation for participation in the study:
We will pay 20,000UsH (~$5) per visit in the form of cash to compensate for 
time requires to complete questionnaires. There will be no reduction in this 
amount or penalties for not completing the study. No compensation is 
available if some injury happens because of your participation in this study. 
The researchers have taken steps to minimize the risks of this study.  Even so, 
you may still have problems or side effects, even when the researchers are 
careful to avoid them. Please tell the researchers listed about any injuries, side 
effects, or other problems that you have during this study.  You should also 
tell your regular doctors.
Reimbursement:
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Page 7 of 9
We will conduct all tests in your home. Should you be required to come for a 
clinic visit for the study, these costs will be reimbursed.
Questions about the study:
If you have any questions or complaints as a result of being in the study, you 
may:
Contact the Local Study Coordinator in Uganda:
Patricia Alupo
Telephone: +256 701124540
Contact the Principal Study Investigator in USA:
Dr. Trishul Siddharthan 
Telephone: +1 305-243-6388
Statement of voluntariness:
Participation in the proposed study is voluntary and participants may join on 
their own free will. Participants also have a right to withdraw from the study 
at any time without penalty.
Dissemination of results: 
Research participants will get feedback on findings and progress of the study. 
Any new information that affects the study or findings that have relevance to 
you will be made available to you and your health care providers.
Ethical approval:
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Page 8 of 9
This study has been reviewed by an Institutional Review Board (IRB), a 
group of people that reviews human research studies in the United States 
and the Human Subjects Review Committee, a group of people that reviews 
human research studies in Uganda. The IRB or Human Subjects Review 
Committee can help you if you have questions about your rights as a 
research participant or if you have other questions, concerns or complaints 
about this research study.  Please call or contact the Human Subjects 
Review Committee of Makerere University School of Medicine (Uganda), 
or the Institutional Review Board of the University of Miami if you have 
questions about your rights as a study participant, feel that you have not 
been treated fairly, or if you have other concerns. 
Contact the Human Subjects Review Committee at:
Secretariat Makerere College of Health Sciences Clinical 
Research Coordination 
Telephone: +256 0414-533541
E-mail: rresearch9@gmail.com or research@chs.mak.ac.ug
Contact the Institutional Review Board (IRB) at:
Telephone: +1- 305-243-3195 Email: hsro@miami.edu 
Consent:
Statement of consent after understanding the study and a signature portion.
-       Study #: 20201523        Effective Date: 7/27/2021


Page 9 of 9
STATEMENT OF CONSENT/ASSENT 
........................................................................... has described to me what is 
going to be done, the risks, the benefits involved and my rights regarding this 
study. I understand that my decision to participate in this study will not alter 
my usual medical care. In the use of this information, my identity will be 
concealed. I am aware that I may withdraw at anytime. I understand that by 
signing this form, I do not waive any of my legal rights but merely indicate 
that I have been informed about the research study in which I am voluntarily 
agreeing to participate. A copy of this form will be provided to me.
Name ……………………… 
Signature/thumb print of participant ………………… Date ……
Name………………………
Signature of witness (if applicable)……………Date…………….
Name ……………………
Signature of interviewer/Person obtaining informed consent 
…………………… Date ………………….
-       Study #: 20201523        Effective Date: 7/27/2021

Prot_000.pdf: 
 
Effectiveness of Low-Dose Theophylline for the Management of Biomass-
Associated COPD 
 
 
NCT03984188 
 
Document Date: 12/22/2020 


IRB Study Number: 20201523 
Version 1, Date: 12/22/2020 
 
 
Page 1 of 15 
Revised: October 3, 2024 
INSTRUCTIONS: 
Protocol Title 
Effectiveness of Low-dose Theophylline for the Management of Biomass-associated 
COPD 
 
IRB Review History 
NA 
 
Objective 
Conduct a pilot trial to assess the efficacy of low-dose theophylline intervention 
among adults with biomass-related COPD. We will conduct a pilot randomized 
placebo-controlled trial among 100 adults with biomass-related COPD, randomized to 
either low-dose theophylline or placebo in Nakaseke and Kampala, Uganda. Both arms 
will have access to salbutamol as needed (standard care). The primary outcome will be 
one-year change in St. George Respiratory Questionnaire score, an instrument 
previously validated in this setting. We will collect lung function measurements (forced 
expiratory volumes) and serum fibrinogen/hs-CRP, as well as 48-hour personal 
exposure assessments to HAP and demographic questionnaires during one year follow 
up. 
 
Evaluate incremental cost-effectiveness of theophylline, and explore differences 
across settings. We will administer the SF-36 quarterly for one year and calculate the 
incremental cost-effectiveness ratio (ICER) of low-dose theophylline plus salbutamol 
relative to salbutamol alone, measured as the incremental cost per incremental QALY 
gained. We will compare the estimated cost-effectiveness of theophylline to traditional 
benchmarks (e.g. per-capita GDP) as well as revealed willingness-to-pay for other health 
interventions in Uganda. We will additionally develop a Markov model using lung 
function decline models to extend cost-effectiveness estimates to other resource-limited 
settings 
 
Background 
Household air pollution (HAP) is the key risk factor for chronic obstructive pulmonary 
disease (COPD) in LMICs.[1] COPD is a leading cause of morbidity and mortality 
globally, with over 90% of COPD-related deaths occurring in low- and middle-income 
countries (LMICs). Household air pollution (HAP) – from burning solid fuels such as 
wood, dung, agricultural crop waste, and coal for energy – is the primary risk factor for 
COPD in these settings.[1] Globally, nearly 3 billion people rely on solid fuels (biomass, 
which includes wood, dung, and agricultural crop waste, or coal) for cooking and 
heating.[2] Biomass fuel is the main domestic energy source for ~40% of all households 
and ~90% or rural households in LMICs. Individuals exposed to HAP in LMICs are 41% 
more likely to have COPD than those without the exposure.[1]  
 
Biomass-related COPD has a distinct histopathology, phenotype and inflammatory 
profile when compared to tobacco mediated COPD.[3] Individuals with biomass-related 
COPD demonstrate a different mechanism of injury with increased anthracosis, small 
airway thickening and peripheral fibrosis on lung biopsy compared to individuals with 
tobacco smoke mediated COPD.[4, 5] Individuals with biomass-related COPD 
additionally present with different phenotypes compared to tobacco-related COPD 
marked by increased cough, phlegm, airway thickening and air trapping, as well as 


IRB Study Number: 20201523 
Version 1, Date: 12/22/2020 
 
 
Page 2 of 15 
Revised: October 3, 2024 
higher rates of bronchodilator reversibility and hyper responsiveness, signifying an 
elevated degree of airway inflammation.[1, 5] Biomass-related COPD has a different 
inflammatory profile with higher circulating levels of CD4 inflammatory mediators (TH2, 
IL-4 and IL-10) than individuals with tobacco related disease and therefore represent a 
different endotype.[3] These findings suggest a different response to treatment and 
disease prognosis compared to tobacco-mediated disease.[3] Despite the high global 
burden of biomass-associated disease, little is known about the effectiveness of 
pharmacotherapies for biomass-related COPD; to date, no clinical trials have focused 
specifically on treatment of biomass-related COPD.[3]  
 
No clinical trials exist related to cost-effectiveness of interventions related to chronic 
management of COPD in LMICs.[6] Current management guidelines for COPD in LMICs 
recommend inhaler delivered therapy which is either unavailable or unaffordable in low- 
and middle-income settings.[6, 7] Effective use of inhaled therapies requires device-
specific education, which would not be required with and oral therapy such as 
theophylline.[8] In one study of eight LMICs, there was no availability of ipratropium 
inhalers, a key recommended treatment for chronic management of COPD in LMICs.[9] 
A study among 52 countries found that among 40% of individuals the cost of medication 
would amount to 1 day of work to purchase a monthly course of salbutamol, above cost-
effectiveness benchmarks in LMICs.[10] In several of the countries studied the monthly 
cost of medications accounted for 4.5 days’ wage.[10] A similar study in India found 
inhaled salbutamol was unaffordable for 80% of the population based on drug pricing 
and wages.[11] Although no trials have been designed to evaluate the cost-effectiveness 
of treatment for COPD in LMICs, economic modeling demonstrates that annual per-
capita costs for managing COPD with inhaler-based therapy would amount to USD 
13,000-14,000 per disability adjusted life year (DALY) averted, well above cost 
effectiveness benchmarks.[12] An effective, and low cost therapy for the management of 
COPD is desperately needed to address the growing burden of disease in LMICs.    
 
Inclusion and Exclusion Criteria 
Inclusion criteria for the parent study are: 1. Age ≥ 40 years; 2. Full-time resident of 
Nakaseke or Kampala; 3. Currently using a traditional stove only. Inclusion criteria for 
this trial include: 1. post-bronchodilator FEV1/FVC < the lower limit of normal of the 
Global Lung Initiative Mixed Ethnic reference population [13, 14]; 2. Grade B-D COPD 
[15] 3. Daily biomass exposure  
 
Exclusion criteria include: 1. Plans to move within one year; 2. Uncontrolled 
hypertension, 3. Pregnancy (assessed by urine pregnancy test among women of child-
bearing age/menstrual history), 4. Current use of chronic respiratory medications (LABA, 
LAMA, ICS), 5. History of post-treatment pulmonary tuberculosis, 6. ≥10 pack year 
tobacco smoking history, 7. Known intolerance or contraindication to theophylline. 
 
Number of Subjects 
100 Subjects recruited in Uganda 
 
Study-Wide Recruitment Methods 
We will enroll participants previously identified with COPD from either the LiNK Cohort 
Study (Johns Hopkins University IRB00077312) or GeCO Study (Johns Hopkins  
University IRB00111874). Trained field workers will visit households to contact eligible 
participants, invite them to the study, and obtain informed consent. Those that agree to 


IRB Study Number: 20201523 
Version 1, Date: 12/22/2020 
 
 
Page 3 of 15 
Revised: October 3, 2024 
participate will be asked to complete questionnaires and screened for COPD using 
spirometry for confirmatory testing. 
 
The primary design will be a randomized placebo-controlled trial, for which we will 
randomize 100 adults into two groups of 50 to receive either daily 200 mg ER low-dose 
theophylline (“intervention”) versus placebo (“control”). Each group will additionally 
receive standard care per WHO guidelines for management of COPD in LMICs. We will 
block randomize with a block size of four to each of the two groups using sealed 
envelopes. We will enroll adults either identified with COPD from the LINK and GeCO 
study previously conducted in Nakaseke and Kampala, Uganda.  
 
Participants will be enrolled and followed in their homes. Demographic questionnaires 
will be applied to obtain socioeconomic information, exposure history to cigarettes and 
household air pollution, occupational exposure, medical history and family history of 
respiratory illness. Data will be collected by field trained field workers at each site and 
will be electronically entered into REDCap using tablets computers.[16] 
 
Low-dose theophylline (200 mg ER) will be provided in childproof bottles once a month 
to participants enrolled in the intervention arm by trained field workers. Medications will 
be refilled monthly by fieldworkers. Placebo pills will be manufactured in identical 
packaging and will be provided for individuals with COPD randomized to the control arm. 
Standard care for COPD per WHO guidelines (salbutamol inhalers as needed) will be 
provided to both arms prescribed by study clinicians. 
 
Spirometry: Spirometry will be performed on participants at baseline, 6 months, 12 
months post-randomization. We have an experienced team of fieldworkers who have 
conducted previous population-based studies using spirometry.[17] Spirometry will be 
conducted on all participants before and after bronchodilator therapy (400 mcg of 
salbutamol using a spacer) following standardized guidelines.[18] We will use the Easy 
on-PC handheld spirometer (ndd, Zurich, Switzerland), a device that has been validated 
and used in several large population-based studies.[19, 20] We will record post-
bronchodilator PEF, FEV1, and FVC. 
 
Health-related Quality of Life Measures – The primary outcome of the study will be 
change in respiratory symptoms (SGRQ) at 12 months. We will additionally measure 
physical health and mental health domains through the SF-36. We will administer these 
surveys at baseline, six months and twelve months.   
 
 
Table 1.  Proposed exposure and outcome assessment time table  
Study Time Point 
(baseline) 
 3 months  
 6 months  
9 
months 
 12 
months  
Primary outcomes 
 
 
 
 
 
  SGRQ 
X 
 
X 
 
X 
Personal exposure  
 
 
 
 
 
  48-h PM2.5, BC, CO 
X 
X 
X 
X 
X 
Secondary outcomes 
 
 
 
 
 
  SF-36 
X 
 
X 
 
X 
  PEF 
X 
 
X 
 
X 
  FEV1 
X 
 
X 
 
X 
  FVC 
X 
 
X 
 
X 
  Biomarkers 
X 
 
X 
 
X 
Covariates 
 
 
 
 
 


IRB Study Number: 20201523 
Version 1, Date: 12/22/2020 
 
 
Page 4 of 15 
Revised: October 3, 2024 
 
 
 
 
 
 
 
Biomarkers: We will validate fibrinogen, an FDA approved biomarker for all-cause 
mortality and exacerbations among those with COPD, to lung function and COPD 
exacerbations in our setting.[21-23] We will additionally collect hs-CRP and serum 
eosinophils. We will conduct blood draws at baseline, six months and twelve months 
with the aim of assessing response to theophylline as well as identifying sub-groups 
which may have a differential response to therapy. We will store blood samples in 
Uganda for future analysis.  
 
HAP Measurements: We will measure personal PM2.5 concentrations using the 
Ultrasonic Personal Air Sampler (UPAS, Access Sensor Technologies, Fort Collins, CO, 
USA), a gravimetric sampler, and CO using the EL-USB-CO (Lascar Electronics Inc., 
Eire, PA). PM2.5  and CO monitors for personal exposure will be worn near the breathing 
zones of the index participants. Participants will be encouraged to wear the monitors 
continuously during the 48-hour period, and to keep close while sleeping. Black carbon 
content of each personal filter will be determined using a validated optical attenuation 
measure.[24, 25] 
 
CT Imaging: We will conduct inspiratory and expiratory computerized tomography (CT) 
scans among study participants at baseline and assess central airway wall thickness 
(percentage wall area, thickness-to-diameter ratio) if additional funding is obtained. We 
will aim to assess whether there is a differential response to treatment among those with 
unique phenotypes of central airway disease. We will only conduct CT scans with 
amendment to the IRB and informed consent. 
 
Study Timelines 
We will follow participants monthly for a one-year period, and enrollment will be 
staggered over a one-year period. 
 
Study Endpoints 
The primary outcomes for this pilot trial at one year include a) difference in SGRQ score 
between groups;  
 
Secondary outcome variables. 
a) difference in lung function decline and airway reversibility; b) differences in health-
related quality of life as determined by the SF-36. We will additionally take detailed 
clinical history to evaluate for frequency and duration of COPD exacerbations, frequency 
and duration of hospitalization, exacerbation severity and use of additional medications 
for respiratory illness (i.e. antibiotics or steroids). Patients will keep diary cards to record 
and symptoms, adverse events, rescue medication, sick days and loss of workdays 
because of exacerbation.  
  Socio-demographics 
X 
 
 
 
 
  Clinical history 
X 
X 
X 
X 
X 
  Weight/height/BMI 
X  
 
 
 
 
  Diet/food security 
X 
 
 
 
 
Abbreviations: BC, black carbon; BMI, body mass index CO, carbon monoxide PM2.5, fine 
particulate matter; SF-36, Short Form 36 survey; SGRQ, St. George Respiratory Questionnaire; 
PEF, peak expiratory flow; FEV1, forced expiratory volume in 1 second; FVC, forced vital capacity 


IRB Study Number: 20201523 
Version 1, Date: 12/22/2020 
 
 
Page 5 of 15 
Revised: October 3, 2024 
Procedures Involved 
Spirometry 
We will use the EasyOne Pro (ndd, Zurich Switzerland)8,9. We will follow standard criteria 
from the ATS for the measurement of DLCO (40), and adjust values of DLCO by altitude 
and carboxyhemoglobin levels. The device is easy to use and training will be provided 
for all health workers involved in the study to comply with the 2005 joint European 
Respiratory Society and American Thoracic Society measurement standards. In addition 
we will have a centralized quality control system in which we will grade all tests 
according to published standards.10 Regular supervision will take place and feedback will 
be provided to all field workers. We will record forced vital capacity (FVC), forced 
expiratory volume in one second (FEV1), as well as store individual flow-volume curves 
for quality control assessment and further analysis.  
 
We will administer 4 puffs from a salbutamol inhaler (100 mcg / puff) via a spacer and 
repeat spirometry 10-15 minutes later. We will define reversibility as an improvement of 
> 12% or > 0.2 L in baseline FEV1 or FVC. In order to minimize the risks associated with 
administration of bronchodilator, we will administer only two puffs of salbutamol, rather 
than the four-puff dose that is more routinely recommended in a clinical setting. In 
extremely rare cases, a person can have a reaction to salbutamol in the form of a 
hypersensitivity reaction or cardiac arrhythmia. A trained physician will be available to 
the research team in the event of an adverse reaction. The study team will monitor heart 
rate/rhythm, blood pressure and SpO2. For a cardiac event, patients will be located at 
the care center. It is important to emphasize that a reaction to salbutamol is extremely 
rare, and for this reason salbutamol is standard in the treatment and diagnosis of 
restrictive lung disease. To minimize risks, exclusion criteria for salbutamol use include a 
pulse greater than 120 beats/minute and BP > 180 (systolic)/100(diastolic). 
 
Low-dose theophylline 
Low-dose theophylline has been proposed as a treatment for biomass-related COPD in 
LMICs.[26] Theophylline has been used in the treatment of chronic obstructive airway 
diseases, including COPD, for more than 70 years and remains widely prescribed 
worldwide, largely due to its low expense.[26] In many high-income countries, the 
frequency of side effects and the drug’s narrow therapeutic index has led to reduced 
usage for management of COPD. However, a number of studies have demonstrated that 
theophylline at lower doses (1-5mg/L) results in improved respiratory symptoms via 
transcriptional downregulation of inflammatory genes.[27-29] Therapeutic monitoring is 
not necessary at such doses. Previous studies among individuals with tobacco-related 
COPD have demonstrated low-dose theophylline monotherapy results in improved lung 
function (FEV1), respiratory symptoms and decreased the frequency and duration of 
exacerbations.[30] Theophylline may prove to be an effective therapy for biomass-
related COPD given availability, low cost, and anti-inflammatory mechanism of 
action.[26, 31]  
 
Computerized tomography Scans (CT)  
Participants will undergo CT scans of the chest as follows. Inspiratory Views: 1–1.5 mm 
collimation at 2 cm intervals in full inspiration. High spatial frequency reconstruction 


IRB Study Number: 20201523 
Version 1, Date: 12/22/2020 
 
 
Page 6 of 15 
Revised: October 3, 2024 
algorithm (can use bone algorithm on GE machine) with window levels at mediastinum 
440 width, level 40 and lung 1000 width, level –700.  
Prone Images: Performed with 1–1.5 mm collimation at 2 cm intervals in full inspiration 
as noted above 
Expiratory Views: 3 post expiratory views with 1–1.5 mm collimation at end expiration 
following a forced vital capacity maneuver. Expiratory views are performed at the level of 
the aortic arch, the tracheal carina, and above the diaphragm. The scanner will be 
subjected to a monthly quality assessment with a phantom check including uniformity, 
linearity, and noise. In addition, we will ensure engineering check of spatial and contrast 
resolution and an annual medical physics check every 6 months.  
 
Data and Specimen Banking 
Serum samples will be stored in Uganda for future analysis and will be accessible by 
members of the study staff.  
 
Data Management 
We will determine whether low-dose theophylline intervention results in improved self-
reported respiratory symptoms (SGRQ) compared to standard care. For repeated 
outcome measurements (e.g., SGRQ, PEF, FEV1, FVC), linear mixed effects models will 
be used to account for within-subject correlation. The main analysis will be by intention 
to treat (ITT), based on cases where the primary outcome is available and will therefore 
rely on an assumption that data is missing at random. We will describe the number (%) 
with missing primary outcome, look at reasons for missingness and consider 
characteristics of the patients excluded from the ITT analysis at 12 months. Multiple 
imputation for the primary analysis will be used if the missing data exceeds 10% of 
randomized patients. Exposures will be aggregated to represent chronic exposure as 
determined by the health outcomes. We will utilize regression analysis for longitudinal 
outcomes. We will use generalized estimated equations for repeated measurements.  
 
We will examine repeated measurements of SGRQ by treatment group and carry out 
exploratory analyses to consider effects of the intervention over time. The SGRQ has 
previously been shown to have a standard deviation of 20 points in a similar population 
and a minimal clinical important difference of 4 points (a previous study involving low-
dose theophylline resulted in a 7.8 point difference between intervention and 
control).[30] A sample of 80 participants with COPD total will be needed to produce an 
80% one-sided confidence interval that excludes a 4-point difference in SGRQ under the 
scenario of a 7.8 point difference in means.[32] Of the 150 individuals we will contact 
with COPD from our existing cohort and trial, I expect 75% to have Grade B-D COPD 
based on our previous studies. Of those we can expect 10% to decline to participate and 
an additional 10% who will drop out of the trial over a year based on our previous 
experience. With conservative estimates I expect to have 90 participants (45 per arm) 
who will complete the pilot trial.  
 
We will additionally compare exposure-response relationship between HAP and FEV1 
between groups to assess whether theophylline attenuates exposure-response 
associations. For the exposure-response associations, analyses will be conducted within 
the intervention and the control groups separately, as well as in a combined analysis. 
Non-linear associations between exposure and health outcomes will be examined using 
generalized additive models and other spline-based approaches.[33]  
. 


IRB Study Number: 20201523 
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Page 7 of 15 
Revised: October 3, 2024 
Provisions to Monitor the Data to Ensure the Safety of Subjects 
We will collect data on safety and tolerability of theophylline and placebo. We will utilize 
study clinicians for reporting and evaluation. Study participants will be educated on 
detecting arrhythmias (i.e. persistent supraventricular tachycardia) and will be instructed 
to call the on-call study clinician with any event. We will maintain a data safety and 
monitoring board with reporting of all serious adverse events (including seizure) within 
24 hours by a study clinician. We will utilize health monitoring infrastructure of ongoing 
studies (GeCO) to adjudicate adverse events. Health centers will be identified based on 
participants’ residence and patients will be referred and transported for health-related 
events. 
 
Plan for reporting unanticipated problems or study deviations. 
In addition to the protection of human subjects and minimization of risks detailed above, 
we will convene a Data Safety Monitoring Board (DSMB) for this study. Investigators will 
record pertinent data on all reportable adverse events using an adverse event report 
form. These forms will include the following information: 1) an estimation of event 
severity (mild, moderate, serious), 2) if a therapeutic intervention was necessary to 
prevent permanent impairment or damage, 3) if there was an immediate threat of death 
due to the event, 4) if the event was unexpected or more severe than expected, 5) if 
there was a causal relationship to study procedures, 6) if the patient was withdrawn from 
study procedures because of the event, 7) status of the adverse event at the time of 
initial adverse event report, and 8) final outcome of the adverse event. Reportable 
adverse event forms will be submitted to the Johns Hopkins Institutional Review Board 
and to the DSMB. Serious adverse events will be reported to the IRB and DSMB by 
telephone or e-mail within 7 days of discovery of the event. 
 
There will be no interim analysis conducted and no early stopping rules for the trial  
 
Withdrawal of Subjects 
There is no definition for treatment failure. Participants will be removed from the study if 
they chose to no longer participate or there is loss to follow up on two subsequent visits.  
 
Risks to Subjects 
Medical risks, listing all procedures, their major and minor risks and expected 
frequency. 
Low-dose theophylline at therapeutic levels of <10 mg/L is well tolerated with minimal 
adverse side effects compared to standard therapeutic levels (10-20 mg/L).[34] In 
previous trials there were no significant differences between low-dose theophylline and 
placebo group. The most frequent drug-related adverse effects were stomach 
discomfort, headache, insomnia and palpitations. Other serious side effects include 
potential seizure. Blood draws are generally safe and well tolerated; the risk include 
bruising, infection at puncture site and pain or discomfort. 
 
Steps taken to minimize the risks.  
For spirometry to minimize the risk of injury associated with fainting, the maneuver is 
performed with participants seated in a stationary chair.  Technicians administering the 
test will be trained to watch for signs of faintness and to stop the test if the participant 
appears unusually breathless or uncomfortable. There is no risk of cross-contamination or 
infection as disposable mouthpieces will be used. Questions are also asked to screen out 
those people who have or recently had conditions that place them at risk when doing 


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Page 8 of 15 
Revised: October 3, 2024 
spirometry (including recent myocardial infarction; eye, chest, or abdominal surgery; and 
tachycardia). Participants with current respiratory symptoms will be asked to re-schedule 
their appointment.  
 
To minimize the risks associated with administration of bronchodilator, we will administer 
only two puffs of salbutamol, rather than the four-puff dose that is more routinely 
recommended in a clinical setting. In extremely rare cases, a person can have a reaction 
to salbutamol in the form of a hypersensitivity reaction or cardiac arrhythmia. The study 
team will monitor heart rate/rhythm, blood pressure and SpO2. For a cardiac event, we will 
transport any patient to the nearest capable care center. It is important to emphasize that 
a reaction to salbutamol is extremely rare, and for this reason salbutamol is standard in 
the treatment and diagnosis of restrictive lung disease. To minimize risks, exclusion 
criteria for salbutamol use include a pulse greater than 120 beats/minute and BP > 180 
mmHg (systolic)/100 mmHg (diastolic). To minimize the risk associated with blood draw, 
we will use disposable materials for each procedure, which significantly reduces the risk 
of disease transmission. In addition, the study staff is trained in sampling, reducing the 
risks and complications. Also, established standard procedures in the art of venipuncture 
and antisepsis and biosecurity measures will be followed.  
 
Financial risks to the participants. 
There are no anticipated financial risks to participants. LD-theophylline has been well 
studied in both high- and low-income settings with minimal side effects.[30, 35] Among 
these previous studies there have been no reported serious adverse events related to 
the medication.  
 
Potential Benefits to Subjects 
This will be one of the first studies to evaluate the effectiveness and cost-effectiveness 
of chronic pharmacotherapy for biomass-related COPD. The high prevalence (~40%) of 
biomass fuel use globally and association between HAP and COPD make the potential 
impact of this intervention of high importance. Additionally, this study will provide a 
framework and tools for designing and adapting RCTs to evaluate the effectiveness of 
chronic medical therapy for other respiratory diseases. Our relationships with Ugandan 
government stakeholders and international organizations increase the potential impact 
and reach of our research.  
 
Vulnerable Populations 
Vulnerable populations will not be included in this study 
 
Multi-Site Research 
Study activities will occur in Nakaseke and Kampala, Uganda. All study activities have 
been approved by the Makerere College of Health Sciences School of Medicine IRB and 
the Uganda Council of Science and Technology. Data analysis will occur in Uganda and 
at the University of Miami. All IRBs will be updated with changes in the protocol. All sites 
will safeguard data using encrypted cloud software. All data will remain deidentified 


IRB Study Number: 20201523 
Version 1, Date: 12/22/2020 
 
 
Page 9 of 15 
Revised: October 3, 2024 
unless required by the DSMB. There will be no interim analysis unless specified by the 
DSMB.     
 
Community-Based Participatory Research 
Study design and approach was conducted in collaboration with the African Center for 
Social Sustainability (https://accessuganda.org), a community-based health organization 
which aims to empower the local rural community through education, healthcare and 
economic programs. Results will be disseminated in coordination with ACCESS Uganda 
to the community and Ugandan Ministry of Health.  
 
Sharing of Results with Subjects 
Study participants will have results shared at the conclusion of the trial. Study staff will 
be available to answer any questions.  
 
Setting 
The study will take place in Nakaseke and Kampala, Uganda. Recruitment and follow up 
will occur at Nakaseke General Hospital and Makerere Lung Institute for all medical 
testing and follow up. Air pollution measurements will be taken at prespecified time 
points in participant’s houses.  
 
Resources Available 
Recruitment will be undertaken by two Ugandan physicians (Drs. Patricia Alupo and 
Esther Namazzi). Additionally, and independent study clinician (Dr. Richard Munana) will 
oversee theophylline levels and independently report adverse events.  Theophylline and 
salbutamol will be dispensed by the Makerere Lung Institute with a trained pharmacist. 
Phlebotomy will be conducted by qualified nurses and spirometry and air pollution 
monitoring will be conducted by qualified research personnel. All staff will be hired 
through the Makerere Lung Institute that will oversee recruitment, good clinical practices, 
and data quality and control.  
 
Prior Approvals 
Approval for the following protocol has been obtained by the Makerere College of Health 
Sciences School of Medicine IRB (REF 2020-093) as well as the Johns Hopkins School 
of Medicine IRB (IRB 00209008). 
 
Recruitment Methods 
We will enroll participants previously identified with COPD from either the LiNK Cohort 
Study (Johns Hopkins University IRB00077312) or GeCO Study (Johns Hopkins  
University IRB00111874). Trained field workers will visit households to contact eligible 
participants, invite them to the study, and obtain informed consent. Those that agree to 
participate will be asked to complete questionnaires and screened for COPD using 
spirometry for confirmatory testing. Participants will be paid $5 at baseline, 6 months and 
12 months visit to compensate for time required to complete questionnaires and obtain 


IRB Study Number: 20201523 
Version 1, Date: 12/22/2020 
 
 
Page 10 of 15 
Revised: October 3, 2024 
additional studies ($15 total per participant). There will be no reduction or penalties for 
not completing the study 
 
Local Number of Subjects 
No subjects will be recruited at the University of Miami 
 
Confidentiality 
We do not anticipate legal risks related to breach of confidentiality for participants in 
Uganda. We will set up several mechanisms to ensure the confidentiality of data 
collected from the participants. Confidentiality of all responses will be the highest priority 
for the research team. The site coordinator will assign a unique identification code to the 
participant once enrolled in the study. This number will be used to identify the case on all 
hard and electronic copy documents and will be part of the survey data that is entered. 
Name of and telephone numbers to contact participants and caregivers will not appear 
on the questionnaires or questionnaire data files. 
Choose the statements below that are applicable to this research:  
 
26(a).  Will the research collect protected health information or personally identifiable 
information from the EMR or from subjects at UHealth and/or JHS? 
☐  Yes (If checked go to 26(b)) 
☒  No (If checked, go to  Section 27) 
 
26(b).  Check the box next to the correct statement below  
☐   Research Subjects will sign a HIPAA Authorization before the research will collect 
this data.  
☒   Research Subjects will not sign a HIPAA Authorization for this data collection and 
the research is requesting a waiver of HIPAA authorization from the IRB.   
 
26(c).  How will the research store the data?  
☐  On a University of Miami electronic device (e.g. encrypted, password-protected 
computer) 
☒  On a cloud-based storage system that is approved by the University of Miami  
☐  On the secured JHS SharePoint environment  
☐  Other, specify:  Click here to enter text. 
 
26(d)  Select one of the following:  
☐  The Principal Investigator (and/or Study Team members) will record (e.g. write 
down, abstract) data acquired in a manner that does not include any indirect or direct 
identifiers (listed in the instructions for Section 26 of this protocol), and the recorded data 
will not be linked to the individual’s’ identity.   
   OR 
☒  The Principal investigator (and/or Study Team members) will record (e.g. write 
down, abstract) the data collected in a manner that does not include any direct identifiers 
(see list in the instructions for Section 26 of this protocol) of any subject. Instead, the 


IRB Study Number: 20201523 
Version 1, Date: 12/22/2020 
 
 
Page 11 of 15 
Revised: October 3, 2024 
Principal Investigator and/or Study Team members shall will assign a code (that is not 
derived in whole or in part from any direct or indirect identifiers of the individual) to 
each study subject and link the code to the study subject’s identity. The link to each 
subject’s identity and/ or other identifiable information will be maintained on a document 
separate from the research data.  
 
26(e)  Additional requirement for Jackson Health System Data: 
 
  Not-applicable, no data will be acquired from JHS under a waiver of authorization.  
 
  JHS data, including Protected Health Information (PHI) and/or Personally Identifiable 
Information (PII), acquired from JHS for this research under a waiver of authorization shall 
only be stored on the secured JHS SharePoint environment made available by JHS. I and 
the Study Team members shall not copy or store the JHS sourced personally identifiable 
information (PII), including protected health information (PHI) data to any other system, 
including any systems maintained or provided by the University of Miami. I and the Study 
Team shall only copy or transfer JHS-sourced data that has been properly de-identified in 
accordance with all requirements contained in the HIPAA Rules by removing all of the 
identifiers listed in the instructions for Section 26 of this protocol. 
 
 
27. Biospecimens 
 
  Not applicable.  No biospecimens will be collected 
 
  Bio-Specimens obtained for this research will be stored without any   
direct or indirect identifiers.   
 
 
 Bio-Specimens obtained for this research will be stored in a de-identified 
coded manner.    
 
  When required to transport data or bio-specimens for this research, the research 
team will transport the data and bio-specimens in a de-identified (or anonymous) 
manner with a link to the individual subject’s identity maintain separately from the 
data and/or bio-specimen. 
 
Provisions to Protect the Privacy Interests of Subjects 
All data will be deidentified and blinded to study investigators other than independent 
study clinician and study pharmacist for the purposes of adverse event reporting. We will 
set up several mechanisms to ensure the confidentiality of data collected from the 
participants. Confidentiality of all responses will be the highest priority for the research 
team. The site coordinator will assign a unique identification code to the participant once 
enrolled in the study. This number will be used to identify the case on all hard and 
electronic copy documents and will be part of the survey data that is entered. Name of 
and telephone numbers to contact participants and caregivers will not appear on the 
questionnaires or questionnaire data files. 


IRB Study Number: 20201523 
Version 1, Date: 12/22/2020 
 
 
Page 12 of 15 
Revised: October 3, 2024 
 
 
Compensation for Research-Related Injury 
Trial insurance will be provided by Goldstar Insurance Co Ltd. 
(CTI/GSI/KA/100002/2020) for 36 months with a 12 mo extended reporting 
period. The liability of the underwriters shall not exceed USD 100,000 per loss 
and in the aggregate for any one period of insurance.  
Economic Burden to Subjects 
Participants will not incur costs related to study drugs or procedures. All costs will be 
accounted for through the parent grant mechanism (1K23HL146946; PI: Siddharthan).  
 
Consent Process 
We will enroll participants previously identified with COPD from either the LiNK Cohort 
Study (JHU IRB00077312) or GeCO Study (JHU IRB00111874). Trained field workers 
will visit households to contact eligible participants, invite them to the study, and obtain 
informed consent in either English or Luganda. Those that agree to participate will be 
asked to complete questionnaires and screened for COPD using spirometry for 
confirmatory testing. 
 
Not applicable.  This research will not collect data from JHS record under a waiver of 
authorization  
 
Notwithstanding the preceding “I confirm” statements above, I agree that neither I nor 
any member of the study team listed on the IRB submission for this Protocol shall ever 
re-use or re-disclose any of the information acquired from Jackson Health System in any 
format, whether identifiable or de-identified, to any individual or entity without first 
obtaining written permission from Jackson Health System, even if such re-use or re-
disclosure is permissible by law (e.g., HIPAA). 
   
  
                       12/18/2020 
______________________________________________ 
PI Signature                                                               Date 
 
Drugs or Devices 
Study drugs will be delivered to Makerere Lung Institute. Low-dose theophylline 
(Unicontin 400mg) and salbutamol inhalers will be provided by SurgiPharm in Kampala. 
Identical placebo tablets will be manufactured and delivered by Kampala Pharmaceutical 
Industries. Study drugs will be stored in locked cabinets. Medications will be allocated to 
pill containers monthly, labeled with participant names and date. Allocation will be based 
on a master list of participants and allocation group that will be only accessible to trial 
pharmacist (Ivan Segawa) and local safety clinician (Richard Munana).  
 
 


IRB Study Number: 20201523 
Version 1, Date: 12/22/2020 
 
 
Page 13 of 15 
Revised: October 3, 2024 
1. 
Siddharthan, T., et al., Association Between Household Air Pollution Exposure 
and Chronic Obstructive Pulmonary Disease Outcomes in 13 Low-and Middle-
income Country Settings. American journal of respiratory and critical care 
medicine, 2018(ja). 
2. 
Bonjour, S., et al., Solid fuel use for household cooking: country and regional 
estimates for 1980-2010. Environmental Health Perspectives, 2013. 121(7): p. 
784-90. 
3. 
Pérez-Padilla, R., A. Ramirez-Venegas, and R. Sansores-Martinez, Clinical 
characteristics of patients with biomass smoke-associated COPD and chronic 
bronchitis, 2004-2014. Chronic Obstructive Pulmonary Diseases: Journal of the 
COPD Foundation, 2014. 1(1): p. 23. 
4. 
Rivera, R., et al., Comparison of lung morphology in COPD secondary to 
cigarette and biomass smoke. The International Journal of Tuberculosis and Lung 
Disease, 2008. 12(8): p. 972-977. 
5. 
Moran-Mendoza, O., et al., Wood smoke-associated lung disease: a clinical, 
functional, radiological and pathological description. The International Journal of 
Tuberculosis and Lung Disease, 2008. 12(9): p. 1092-1098. 
6. 
Beran, D., et al., Burden of asthma and chronic obstructive pulmonary disease 
and access to essential medicines in low-income and middle-income countries. 
The Lancet Respiratory Medicine, 2015. 3(2): p. 159-170. 
7. 
Mendis, S., et al., The availability and affordability of selected essential 
medicines for chronic diseases in six low-and middle-income countries. Bulletin 
of the world health organization, 2007. 85(4): p. 279-288. 
8. 
Fink, J.B. and B.K. Rubin, Problems with inhaler use: a call for improved 
clinician and patient education. Respiratory care, 2005. 50(10): p. 1360-1375. 
9. 
Mendis, S., et al., Gaps in capacity in primary care in low-resource settings for 
implementation of essential noncommunicable disease interventions. International 
journal of hypertension, 2012. 2012. 
10. 
Lessing, C., C. Mace, and K. Bissell, The availability, pricing and affordability of 
three essential asthma medicines in 52 low-and middle-income countries. 
Pharmacoeconomics, 2013. 31(11): p. 1063-1082. 
11. 
Kotwani, A., Availability, price and affordability of asthma medicines in five 
Indian states. The International Journal of Tuberculosis and Lung Disease, 2009. 
13(5): p. 574-579. 
12. 
Stanciole, A.E., et al., Cost effectiveness of strategies to combat chronic 
obstructive pulmonary disease and asthma in sub-Saharan Africa and South East 
Asia: mathematical modelling study. Bmj, 2012. 344: p. e608. 
13. 
Miller, M.R., et al., Standardisation of spirometry. Eur respir J, 2005. 26(2): p. 
319-38. 
14. 
Quanjer, P.H., et al., Multi-ethnic reference values for spirometry for the 3–95-yr 
age range: the global lung function 2012 equations. European Respiratory 
Journal, 2012. 40(6): p. 1324-1343. 
15. 
Vogelmeier, C.F., et al., Global strategy for the diagnosis, management and 
prevention of chronic obstructive lung disease 2017 report. Respirology, 2017. 
22(3): p. 575-601. 


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16. 
Harris, P.A., et al., Research electronic data capture (REDCap)—a metadata-
driven methodology and workflow process for providing translational research 
informatics support. Journal of biomedical informatics, 2009. 42(2): p. 377-381. 
17. 
Jaganath, D., et al., Prevalence of chronic obstructive pulmonary disease and 
variation in risk factors across four geographically diverse resource-limited 
settings in Peru. Respiratory research, 2015. 16(1): p. 40. 
18. 
Miller, M.R., et al., Standardisation of spirometry. European respiratory journal, 
2005. 26(2): p. 319-338. 
19. 
Jaganath, D., et al., Prevalence of chronic obstructive pulmonary disease and 
variation in risk factors across four geographically diverse resource-limited 
settings in Peru. Respiratory research, 2015. 16(1): p. 40. 
20. 
Buist, A.S., et al., International variation in the prevalence of COPD (the BOLD 
Study): a population-based prevalence study. The Lancet, 2007. 370(9589): p. 
741-750. 
21. 
Duvoix, A., et al., Blood fibrinogen as a biomarker of chronic obstructive 
pulmonary disease. Thorax, 2013. 68(7): p. 670-676. 
22. 
Mannino, D.M., et al., Plasma fibrinogen as a biomarker for mortality and 
hospitalized exacerbations in people with COPD. Chronic obstructive pulmonary 
diseases (Miami, Fla.), 2015. 2(1): p. 23. 
23. 
Mannino, D.M., et al., Fibrinogen, COPD and mortality in a nationally 
representative US cohort. COPD: Journal of Chronic Obstructive Pulmonary 
Disease, 2012. 9(4): p. 359-366. 
24. 
Ahmed, T., et al., Measurement of black carbon (BC) by an optical method and a 
thermal-optical method: Intercomparison for four sites. Atmospheric 
Environment, 2009. 43(40): p. 6305-6311. 
25. 
Baumgartner, J., et al., Highway proximity and black carbon from cookstoves as a 
risk factor for higher blood pressure in rural China. Proc Natl Acad Sci U S A, 
2014. 111(36): p. 13229-34. 
26. 
Barnes, P.J., Theophylline in chronic obstructive pulmonary disease: new 
horizons. Proceedings of the American Thoracic Society, 2005. 2(4): p. 334-339. 
27. 
Cosio, B.G., et al., Low-dose theophylline enhances the anti-inflammatory effects 
of steroids during exacerbations of COPD. Thorax, 2009. 64(5): p. 424-429. 
28. 
Ford, P.A., et al., Treatment effects of low-dose theophylline combined with an 
inhaled corticosteroid in COPD. Chest, 2010. 137(6): p. 1338-1344. 
29. 
Barnes, P.J., Theophylline. American journal of respiratory and critical care 
medicine, 2013. 188(8): p. 901-906. 
30. 
Zhou, Y., et al., Positive benefits of theophylline in a randomized, double‐blind, 
parallel‐group, placebo‐controlled study of low‐dose, slow‐release theophylline 
in the treatment of COPD for 1 year. Respirology, 2006. 11(5): p. 603-610. 
31. 
Checkley, W., et al., Management of NCD in low-and middle-income countries. 
Global heart, 2014. 9(4): p. 431-443. 
32. 
Cocks, K. and D.J. Torgerson, Sample size calculations for pilot randomized 
trials: a confidence interval approach. Journal of clinical epidemiology, 2013. 
66(2): p. 197-201. 
33. 
Hastie, T. and R. Tibshirani, Generalized additive models for medical research. 
Stat Methods Med Res, 1995. 4(3): p. 187-96. 


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34. 
Devereux, G., et al., Use of low-dose oral theophylline as an adjunct to inhaled 
corticosteroids in preventing exacerbations of chronic obstructive pulmonary 
disease: study protocol for a randomised controlled trial. Trials, 2015. 16(1): p. 
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35. 
Singh, M., et al., Effect of low dose theophylline as adjunct in treatment of COPD. 
2016, Eur Respiratory Soc. 
 

SAP_001.pdf: 
 
Effectiveness of Low-Dose Theophylline for the Management of Biomass-
Associated COPD 
 
 
NCT03984188 
 
 
Document Date: 10/19/2023 


 
 
 
 
Low-dose Theophylline for the Management of Biomass Associated COPD  
 
Introduction 
 
The majority of morbidity and mortality related to COPD occurs in low- and middle-income 
countries (LMICs). Despite the growing burden of biomass smoke-related COPD, few studies 
have been conducted to assess the effectiveness of respiratory medications in this setting. 
Low-dose theophylline, an oral once-daily medication, has been recommended for the 
treatment of COPD in LMICs without the use of inhaled steroids or bronchodilators. The Low-
dose Theophylline for the Management of Biomass-Associated COPD (LODO-BCOPD) study 
aims to explore the drug's clinical efficacy and cost-effectiveness in the treatment of biomass-
related COPD in low-income populations. 
 
Research Hypothesis 
 
The study hypotheses are:  
• Low dose theophylline results in improved quality of life among those with BCOPD 
compared to placebo. 
• Low dose theophylline is cost-effectiveness for the management of biomass-
associated COPD in a low-income setting. 
 
Study design and participants. 
 
This was a parallel arm placebo-controlled randomized trial. 100 participants were 
randomized a 1:1 allocation ratio to receive either the Intervention or the placebo. The trial 
design is fully described in the protocol paper (Siddharthan et al. Trials 2021) 
 
Selection of clinic and participants. 
This trial was conducted in Nakaseke district, at Nakaseke hospital.  
Participants were eligibility criteria included: 
• Age 30 years and above. 
• Full time residents of the study area (Nakaseke district),  
• Current use of traditional stoves only for cooking,  


 
 
• Post-bronchodilator FEV1/FVC < the lower limit of normal of the Global Lung Initiative 
Mixed Ethnic reference population.  
• Grade B-D COPD 
• Daily biomass exposure.  
 
Participants were excluded from the study for the following reasons: 
 
• Planning to move within one year of study commencement. 
• Having uncontrolled hypertension 
• Pregnancy.  
• Use of chronic respiratory medication. 
• History of post-treatment pulmonary tuberculosis. 
• Greater than 10 pack year tobacco smoking history. 
• Known intolerance or contraindication to theophylline. 
 
Interventions. 
 
Participants both on the intervention and control arm received the standard of care as per the 
WHO guidelines for the management of COPD in LMICs i.e. (COPD specific education and 
salbutamol inhalers).  In addition to the standard of care, those randomised to the intervention 
arm received 200 mg ER low-dose theophylline daily. Drugs were dispensed monthly for each 
of the participants for a period of 12 months by the research assistants. 
 
Trial procedures. 
Patients were screened from the community at Nakaseke hospital and those who were eligible 
were then enrolled into the study. Participants were then randomised to receive either the 
placebo or investigational product by the research pharmacist. Spirometry and baseline data 
was collected by trained research assistants from each of the study participants and a 
participant visit schedule was then created for each of the participants.  Spirometry and 
Demographic data were then collected at the different timepoints (3 months, 6 months, and 
12 months) by the trial research nurses. 
 
 


 
 
Outcomes. 
The primary outcome measure of the trial was change in the mean St. George’s Respiratory 
Questionnaire (SGRQ) scores at 12 months.  The key exposures and secondary outcomes 
are summarized in the table below. Secondary outcome include change in SGRQ at 3 months 
with 95% CI provided.  
 
 
Sample Sizes. 
A sample of 99 participants with COPD total were required to have an 80% two-sided 
confidence interval that excludes a 4-point difference in SGRQ under the scenario of a 7.8-
point difference in means. Adjusting for a 10% loss to follow up rate we planned to recruit 110 
participants.  
 
Duration of intervention  
The intervention was implemented for 12 months, with endpoint data collected after 3 and 
12 months.  
 
Randomisation. 
The allocation sequence for the random assignment of the intervention was generated using 
STATA version 16.0 and this was then uploaded to the Redcap data management software 
where the random assignment of participants to one of the two arms was done.  We used 
block randomisation with block sizes of 4. The allocation sequence was uploaded directly onto 
Table 1.  Primary and secondary outcomes. 
Outcome 
(baseline) 
 3 months   6 months  
9 
months 
 12 
months  
Primary outcomes 
 
 
 
 
 
  SGRQ 
X 
 
X 
 
X 
Secondary outcomes 
 
 
 
 
 
  SF-36 
X 
 
X 
 
X 
  PEF 
X 
 
X 
 
X 
  FEV1 
X 
 
X 
 
X 
  FVC 
X 
 
X 
 
X 
  Biomarkers 
X 
 
X 
 
X 
Abbreviations: SF-36, Short Form 36 survey; SGRQ, St. George Respiratory Questionnaire; 
PEF, peak expiratory flow; FEV1, forced expiratory volume in 1 second; FVC, forced vital 
capacity 


 
 
the redcap platform by the trial statisticians this enabled us to conceal the sequence up to the 
point of randomisation. 
 
Randomisation Implementation. 
 
The trial statistician developed the allocation sequence, and the research study nurses 
enrolled participants in the study. Following enrolment into the study, the trial pharmacist used 
the Redcap data management tool to assign each participant to a particular arm. 
 
Blinding. 
 
Study participants, research nurses, the principal investigators, and the research study 
coordinator were all blinded to which randomisation arm of the participant. Placebo pills 
manufactured in identical packaging as the active drug dispensed to those on the intervention 
arm were used to maintain the blinding of participants and information about the study arm 
was only known to the research pharmacist to maintain the blinding of the other study staff. 
 
Statistical analysis. 
The baseline characteristics of participants were compared between the two arms using 
medians (IQR) for continuous variables and proportions for categorical variables. Outcomes 
were analyzed by both the intention-to-treat and per-protocol analysis method using linear 
mixed-effects regression methods for the primary and secondary continuous outcomes and 
random effects logistic regression methods for binary outcomes. Baseline imbalances were 
adjusted for in both the primary and secondary analysis, and results both unadjusted and 
adjusted analyses will be presented. All analyses were adjusted for arm, baseline outcome 
scores summarize.  
 
Missing Data. 
Missing data on outcomes and key covariates will be assessed prior to analyses. Where 
missingness is greater than 5% we will implement therefore multiple imputation (MI) methods 
appropriate for random effects models. Data will be assumed to be missing at random (MAR), 
and respondents with missing data will be described by clinic and key sociodemographic 
characteristics.   
 


 
 
 
 
Planned subgroup and secondary analyses. 
Subgroup analyses for the differences in the effectiveness of the intervention in affecting 
primary and selected secondary outcomes will be assessed age (continuous), sex 
(male/female), BMI (categorical), socioeconomic status (categorical), education (categorical), 
tobacco use (yes/no) and medication adherence (>80%).  
 
Analysis of secondary outcomes will include change in COPD Assessment Test (CAT), 
exacerbations and respiratory-related hospitalizations, inflammatory biomarkers (e.g. 
fibrinogen, hs-CRP) and lung function. We will additionally conduct exploratory analysis to 
compare the exposure-response relationship between 2.5µg and FEV1 between study arms 
to assess whether theophylline attenuates the association. For the exposure-response 
associations, analyses will be conducted within the intervention and the control groups 
separately, as well as in a combined analysis. Non-linear associations between exposure and 
health outcomes will be examined using generalized additive models and other spline-based 
approaches.  
 
Lastly, we will utilize measurements of the EQ-5D at baseline and months 3 and 6 to convert 
scores into health utility estimates using validated conversion formula. The incremental 
number of QALYs gained, comparing intervention participants to controls, can then be 
calculated by measuring the longitudinal values of health utility over the intervention period in 
each arm.  
 
Two-sided P values of 0.05 or less will be considered to indicate statistical significance. 
Analysis will be performed with STATA version 18 software. Analysis will be independently 
replicated and reported.  
 
 
 
 
 


 
 
Allocated to intervention (n= ##) 
Allocated to Placebo (n=##) 
Withdrawn (n= ##) 
Lost to follow up (n=##) 
Withdrawn (n=##) 
Lost to follow up (n=##) 
Screened/Assessed for eligibility 
(n=###/###) 
 
Declined to participate (n=##) 
Consented (n=###) 
Ineligible (n=##) 
Declined to participate (n=##) 
Other reasons (n=##) 
Randomized (n=##) 
 
 
Tables. 
Figure 1: Overall Study Status 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Included in analysis (n= ##) 
Included in analysis (n=##) 
ENROLLMENT 
ALLOCATION 
FOLLOW-UP 
Active (n=##) 
Follow up completed (n=##) 
Active (n=##) 
Follow up completed (n=##) 
ANALYSIS 


 
3 
 
 
Table 1. Baseline characteristics of study population 
 
Intervention   N=###) 
Placebo(, N=###) 
Facility-level (N=40) 
 
 
Age (years) 
##.# (##.#) 
##.# (##.#) 
BMI (kg/m2) 
##.# (##.#) 
##.# (##.#) 
Sex 
 
 
Female 
##.# (##.#) 
##.# (##.#) 
Male 
##.# (##.#) 
##.# (##.#) 
Marital status 
 
 
Never married 
##.# (##.#) 
##.# (##.#) 
Married or living as married 
##.# (##.#) 
##.# (##.#) 
Widowed 
##.# (##.#) 
##.# (##.#) 
Separated or divorced 
##.# (##.#) 
##.# (##.#) 
Educational attainment 
 
 
No formal education 
##.# (##.#) 
##.# (##.#) 
Primary education  
##.# (##.#) 
##.# (##.#) 
Secondary or tertiary education 
##.# (##.#) 
##.# (##.#) 
Employment status 
 
 
?? 
##.# (##.#) 
##.# (##.#) 
?? 
##.# (##.#) 
##.# (##.#) 
Wealth index tertile* 
 
 
Lowest 
##.# (##.#) 
##.# (##.#) 
Middle 
##.# (##.#) 
##.# (##.#) 
Highest 
##.# (##.#) 
##.# (##.#) 
Medical History 
 
 
Hypertension 
##.# (##.#) 
##.# (##.#) 
Heart disease 
##.# (##.#) 
##.# (##.#) 
Diabetes 
##.# (##.#) 
##.# (##.#) 
Pulmonary Tuberculosis 
##.# (##.#) 
##.# (##.#) 
Asthma  
##.# (##.#) 
##.# (##.#) 
COPD 
##.# (##.#) 
##.# (##.#) 
Smoking History 
 
 
Current 
##.# (##.#) 
##.# (##.#) 
Former 
##.# (##.#) 
##.# (##.#) 
Never 
##.# (##.#) 
##.# (##.#) 


 
4 
 
Table 2. Impact of intervention on primary and secondary outcomes  
Outcome 
INTERVENTION 
mean (SD) 
 
(N) 
EUC 
mean 
(SD) 
HIV+D 
(N) 
AMD 
95% CI 
p-value 
k 
Primary 
outcome: Mean 
SGRQ score at 3 
months 
## (##) 
## 
## (##) 
## 
### 
(###, 
###) 
#### 
#### 
Secondary 
outcomes  
 
 
 
 
 
 
 
 
Mean SGRQ 
score at 12 
months  
## (##) 
## 
## (##) 
## 
### 
(###, 
###) 
#### 
#### 
 
Table 3. Analysis of primary and selected secondary outcomes by subgroup 
Outcome 
HIV+D 
mean 
(SD) or 
n/N 
EUC 
mean 
(SD) or 
n/N 
AMD/OR 
95% CI 
p-value 
Total 
p-value for 
interaction 
Sex 
 
 
 
 
 
 
 
Primary outcome: Mean 
SGRQ score, after 3 
months after enrolment 
 
 
 
 
 
 
 
Female 
## (##) 
## (##) 
### 
(###, 
###) 
#### 
#### 
#### 
Male 
## (##) 
## (##) 
### 
(###, 
###) 
#### 
#### 
#### 
Secondary outcomes  
 
Mean SGRQ score, 
after 12 months after 
enrolment. 
## (##) 
## (##) 
### 
(###, 
###) 
#### 
#### 
#### 
Female 
## (##) 
## (##) 
### 
(###, 
###) 
#### 
#### 
#### 
Male 
## (##) 
## (##) 
### 
(###, 
###) 
#### 
#### 
####