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
Devereux et al. Trials
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
Graham Devereux 0
Seonaidh Cotton 2
Peter Barnes 1
Andrew Briggs 7
Graham Burns 6
Rekha Chaudhuri 5
Henry Chrystyn 4
Lisa Davies 9
Anthony De Soyza 8
Shona Fielding 3
Simon Gompertz 12
John Haughney 13
Amanda J. Lee 3
Kirsty McCormack 2
Gladys McPherson 2
Alyn Morice 10
John Norrie 2
Anita Sullivan 12
Andrew Wilson 11
David Price 13
0 Respiratory Medicine, Chest Clinic C, Aberdeen Royal Infirmary, University of Aberdeen , Aberdeen AB25 2ZN , UK
1 Imperial College, National Heart & Lung Institute , Dovehouse Street, London SW3 6LY , UK
2 Centre for Healthcare Randomised Trials (CHaRT), University of Aberdeen , Aberdeen AB25 2ZN , UK
3 Medical Statistics Team, Division of Applied Health Sciences, University of Aberdeen , Aberdeen AB25 2ZD , UK
4 Division of Pharmacy & Pharmaceutical Sciences, University of Huddersfield , Huddersfield HD1 3DH , UK
5 Gartnavel General Hospital, University of Glasgow , Glasgow G12 0YN , UK
6 Department of Respiratory Medicine, Royal Victoria Infirmary , Newcastle Upon Tyne NE1 4LP , UK
7 Institute of Health & Wellbeing, University of Glasgow , 1 Lilybank Gardens, Glasgow G12 8RZ , UK
8 Medical School, University of Newcastle , Newcastle Upon Tyne NE2 4HH , UK
9 Aintree Chest Centre, University Hospital Aintree , Liverpool L9 7AL , UK
10 Cardiovascular and Respiratory Studies, Castle Hill Hospital , Hull HU16 5JQ , UK
11 Department of Medicine, Norwich Medical School, University of East Anglia , Norwich NR4 7TJ , UK
12 Queen Elizabeth Hospital Birmingham , Birmingham B15 2WB , UK
13 Centre of Academic Primary Care, University of Aberdeen , Aberdeen AB25 2ZD , UK
Background: Chronic obstructive pulmonary disease (COPD) is associated with high morbidity, mortality, and health-care costs. An incomplete response to the anti-inflammatory effects of inhaled corticosteroids is present in COPD. Preclinical work indicates that 'low dose' theophylline improves steroid responsiveness. The Theophylline With Inhaled Corticosteroids (TWICS) trial investigates whether the addition of 'low dose' theophylline to inhaled corticosteroids has clinical and cost-effective benefits in COPD. Method/Design: TWICS is a randomised double-blind placebo-controlled trial conducted in primary and secondary care sites in the UK. The inclusion criteria are the following: an established predominant respiratory diagnosis of COPD (post-bronchodilator forced expiratory volume in first second/forced vital capacity [FEV1/FVC] of less than 0.7), age of at least 40 years, smoking history of at least 10 pack-years, current inhaled corticosteroid use, and history of at least two exacerbations requiring treatment with antibiotics or oral corticosteroids in the previous year. A computerised randomisation system will stratify 1424 participants by region and recruitment setting (primary and secondary) and then randomly assign with equal probability to intervention or control arms. Participants will receive either 'low dose' theophylline (Uniphyllin MR 200 mg tablets) or placebo for 52 weeks. Dosing is based on pharmacokinetic modelling to achieve a steady-state serum theophylline of 1-5 mg/l. A dose of theophylline MR 200 mg once daily (or placebo once daily) will be taken by participants who do not smoke or participants who smoke but have an ideal body weight (IBW) of not more than 60 kg. A dose of theophylline MR 200 mg twice daily (or placebo twice daily) will be taken by participants who smoke and have an IBW of more than 60 kg. Participants will be reviewed at recruitment and after 6 and 12 months. The primary outcome is the total number of participant-reported COPD exacerbations requiring oral corticosteroids or antibiotics during the 52-week treatment period. (Continued on next page)
(Continued from previous page)
Discussion: The demonstration that ‘low dose’ theophylline increases the efficacy of inhaled corticosteroids in COPD
by reducing the incidence of exacerbations is relevant not only to patients and clinicians but also to health-care
providers, both in the UK and globally.
Trial registration: Current Controlled Trials ISRCTN27066620 was registered on Sept. 19, 2013, and the first subject was
randomly assigned on Feb. 6, 2014.
Chronic obstructive pulmonary disease (COPD) is a lung
disease characterised by progressive airflow obstruction
that is not fully reversible and does not change markedly
over several months . COPD is common, is caused
predominantly by cigarette smoking, and is usually
diagnosed from the age of 50 years onwards. In the UK,
there arenearly one million diagnosed cases, and COPD
accounts for 5–6 % of all deaths (about 28,000 deaths
in 2012) . COPD is typically associated with
increasing breathlessness on exertion, disability, work
absence, premature retirement, morbidity, psychological
co-morbidities, reduced quality of life, and premature
mortality [1, 3, 4]. COPD is associated with high
healthcare expenditure: in the UK, National Health Service
(NHS) expenditure is about £1 billion per year; for each
patient with COPD, the average annual NHS direct costs
are £819 (more than £1,300 in severe COPD) .
Exacerbations are an important clinical feature of COPD.
These are usually precipitated by viral infection or air
pollution and are characterised by increasing dyspnoea, cough,
sputum expectoration, and malaise. Exacerbations are
associated with accelerated lung function decline, reduced
physical activity, reduced quality of life, and increased mortality
[6–9]. Approximately 15 % of patients with COPD are
hospitalised with exacerbations each year. Exacerbations are the
second leading cause for emergency hospital admission and
account for 60 % of the total direct costs of COPD to the
NHS [1, 5]. Typically, 12 % of patients with COPD die in
the year following hospitalisation with an exacerbation .
Most COPD management guidelines recommend the
use of inhaled corticosteroids usually in combination
with inhaled long-acting β2 agonists to reduce COPD
exacerbation rates [1, 10]. However, the responses observed
in COPD are not as marked as in asthma; inhaled
corticosteroids do not fully suppress airway inflammation in
COPD, and patients continue to have exacerbations
despite high inhaled corticosteroid doses . Although
inhaled corticosteroids are beneficial in COPD, the airway
inflammation in COPD is relatively insensitive to their
anti-inflammatory effects even at high doses [12–14].
Oral theophylline has been used conventionally as a
bronchodilator in COPD for over 70 years; however, to
achieve modest clinical effects, relatively high blood
levels (10–20 mg/l) with clinical monitoring are
required. Unfortunately, the therapeutic index of ‘high
dose’ theophylline is narrow. Prior use at ‘high dose’ as a
bronchodilator frequently resulted in drug
concentrations close to those where side effects were encountered,
namely nausea, gastrointestinal upset, cardiac
arrhythmias, and malaise. Not surprisingly, use of ‘high dose’
theophylline has declined in recent years and is being
replaced by better-tolerated inhaled bronchodilator
therapies. Recently, however, preclinical studies have
demonstrated that theophylline at ‘low dose’ (plasma
concentration of 1–5 mg/l) increases the sensitivity of
COPD airway inflammation to the anti-inflammatory
effects of inhaled corticosteroids [15–22]. The concept
that ‘low dose’ theophylline may produce a beneficial
synergistic effect by increasing the corticosteroid sensitivity
in COPD is supported by two small randomised controlled
trials with inflammatory indices as primary outcomes and
a Canadian health administration database study [23–25].
The potential benefit of using ‘low dose’ theophylline to
increase corticosteroid responsiveness in COPD is that,
when used in combination with inhaled corticosteroids,
it should reduce exacerbation rates. Moreover, ‘low dose’
theophylline is inexpensive and is anticipated to avoid
the side effects encountered with conventional ‘high
dose’ theophylline, making blood monitoring unnecessary.
Here, we describe the Theophylline With Inhaled
Corticosteroids (TWICS) study, a randomised double-blind
placebo-controlled trial that will test the hypothesis that
in patients with COPD established on a treatment
regimen including an inhaled corticosteroid, the addition of
oral ‘low dose’ theophylline will reduce the rate of
exacerbation. The full protocol is available as Additional file 1.
TWICS is a double-blind randomised, placebo-controlled,
UK multicentre clinical trial comparing the addition of
‘low dose’ theophylline or placebo for 52 weeks with
current COPD therapy that includes inhaled
corticosteroids in COPD patients who in the previous year have
had two or more exacerbations of COPD treated with
oral corticosteroids or antibiotics. Fig. 1 provides a
schematic representation of study design and schedule.
Fig. 1 Flow diagram of study design and schedule. bd, Twice a day (Bis in die); CATest, COPD (Chronic Obstructive Pulmonary Disease)
Assessment Test; EQ-5D, EuroQOL five-dimension questionnaire; MRC, Medical Research Council; od, Once a day (Omne in die)
The trial is set in primary and secondary care sites in
the UK. In primary care, some general practices act as
recruitment sites, whereas others act as Participant
Identification Centres with identified participants being
evaluated in other primary or secondary care recruitment
sites. The first subject was randomly assigned on Feb. 6,
2014. In total, 1424 eligible people with COPD will be
randomly assigned to receive visually identical ‘low dose’
theophylline (Uniphyllin MR 200 mg once or twice
daily) or placebo for 52 weeks. The trial is approved by
Scotland A Research Ethics Committee (#13/SS/0081,
June 28, 2013) and the Medicines and Healthcare
Products Regulatory Agency (EudraCT 2013-001490-25,
CTA 21583/0218/001, Aug. 8, 2013). All participants are
required to give written informed consent.
Inclusion criteria comprise an established predominant
respiratory diagnosis of COPD (Global Initiative on
Obstructive Lung Disease [GOLD]/National Institute for
Health and Care Excellence [NICE] Guideline definition:
post-bronchodilator forced expiratory volume in first
second/forced vital capacity [FEV1/FVC] of less than
0.7), age of at least 40 years, a smoking history of at least
10 pack-years, current use of inhaled corticosteroid
therapy, a history of at least two exacerbations requiring
treatment with antibiotics or oral corticosteroids in the
previous year (based on patient report). In addition,
participants must be clinically stable at the time of
recruitment (no COPD exacerbation for at least 4 weeks).
The main exclusion criteria are current use of
theophylline, hypersensitivity to theophylline, or use of drugs
known to interact with theophylline or increase serum
theophylline  (for full list, see Additional file 1).
Further exclusion criteria are a predominant respiratory
disease other than COPD, unstable ischaemic heart
disease, or any other clinically important disease/disorder
which, in the investigator’s opinion, either puts the
participant at risk because of study participation or may
influence the results of the study or the participant’s
ability to take part in the study. For women, current
pregnancy or breast-feeding and planned pregnancy
during the study are exclusion criteria.
Identification, recruitment, and randomisation
Potential participants are recruited from both primary
and secondary care across the UK with the aim of
recruiting the majority of participants (more than 50 %)
from primary care. Recruitment strategies differ between
centres, depending on local geographic and NHS
In primary care, potential participants are identified
from searches of general-practice databases. In some
centres, COPD community matrons and other
community-based intermediate care services for
patients with COPD are available and are used to identify
potential participants. In secondary care, potential
participants are identified from those patients who are attending
hospital respiratory out-patient clinics, spirometry
services, or smoking cessation services. Some trial centres
also have access to volunteer databases/registries.
Potential participants are sent an invitation letter and a patient
information leaflet informing them of the trial aims and
level of involvement required. The letter provides a variety
of methods for interested potential participants to contact
the local trial team.
At the recruitment/baseline visit at the local trial
centre, eligibility is established, the trial explained,
questions addressed, and informed written consent provided
by the participant.
Participants are randomly assigned by using a
computerised randomisation system available as both an interactive
voice response telephone system and an internet-based
application. The randomisation service is administered by the
Centre for Healthcare Randomised Trials (CHaRT),
University of Aberdeen. Consenting patients will be stratified by
region of trial centre and recruitment setting (primary and
secondary) and then randomly assigned with equal
probability to the intervention and control arms.
The active intervention is Uniphyllin MR 200 mg tablets
and a visually identical control placebo. The packaging
and labelling of active and placebo interventions are
identical. Intervention is for 52 weeks of therapy.
‘Low dose’ theophylline dosing is based on
pharmacokinetic modelling of theophylline and incorporates the
major determinants of theophylline steady-state
concentration (i.e., weight, smoking status, and theophylline
clearance [27, 28]) and is designed to achieve a
steadystate serum theophylline level of 1–5 mg/l and certainly
less than 10 mg/l (more than 10 mg is the level associated
with ‘high dose’ theophylline, possible side effects, and
augmentation of corticosteroid insensitivity) (Appendix 1
of the Additional file 1). Dosing is determined by the
participant’s ideal body weight (IBW) and self-reported
smoking status. IBW is computed by using the Devine
formulae: IBWfemale = 45 + 0.9 (height in cm – 152) kg,
and IBWmale = 50 + 0.9 (height in cm – 152) kg .
A dose of theophylline MR 200 mg once daily (one
placebo once daily) is taken by participants who do not
smoke or participants who smoke but have an IBW of not
more than 60 kg. A dose of theophylline MR 200 mg twice
daily (one placebo twice daily) is taken by participants
who smoke and have an IBW of more than 60 kg.
To be classed as a “non-smoker”, a participant must
have abstained from smoking for at least 12 weeks. If
less than the IBW, the actual body weight is used to
determine dose. When informed of their patient’s
participation in the trial, general practitioners are advised to
manage their patient for exacerbations as in normal
clinical practice but to assume that the participant is taking
low-dose theophylline, and the prescription of
interacting drugs that increase serum theophylline levels should
be avoided. In the event that drugs that interact to
increase theophylline concentration have to be prescribed
for 3 weeks or less, patients are asked to suspend taking
study medication and recommence their study
medication after the course of interacting drug has been
completed. If the interacting drug is prescribed for more
than 3 weeks, participants discontinue the study
medication but remain in the study and are followed up in
accordance with the trial protocol.
In secondary care trial sites, the first pack of 4-week
study medication is dispensed from the local Clinical
Trials Pharmacy. In primary care trial sites, the first pack
of study medication is couriered to the participant’s
home from the lead Clinical Trials Pharmacy in Aberdeen.
Subsequent packs containing a 24-week drug supply are
delivered to the participants’ homes at around weeks 3
and 27 via a signed-for delivery service operated by a third
party. Receipt of trial medication is confirmed by signature
on delivery. Written informed consent to pass on a
participant’s name and address to the third-party distributer is
obtained at recruitment.
Primary outcome variables
The primary outcome measure is the total number of
exacerbations of COPD necessitating changes in
management (minimum management change—use of oral
corticosteroids or antibiotics) during the 52-week treatment
period, as reported by the participant. The primary
economic outcome measure is cost per quality-adjusted life
year (QALY) gained during the 52-week treatment period.
Secondary outcome variables
During the 52-week treatment period, the secondary
outcomes are the following: number of
participantreported COPD exacerbations requiring hospital
admission, number of episodes of pneumonia, number of
emergency hospital admissions (all causes),
postbronchodilator lung function (FEV1FVC), all-cause and
respiratory mortality, serious adverse events, adverse
reactions, total dose of inhaled corticosteroid,
utilisation of primary or secondary health care for respiratory
events, disease-specific health status (COPD
Assessment Test, or CAT) , Medical Research Council
(MRC) dyspnoea scale , generic health-related
quality of life (EQ-5D) , and modelled lifetime
incremental cost per QALY.
Follow-up and data collection
Participants are reviewed at face-to-face assessments at
recruitment and after 6 and 12 months of treatment.
Approximately 2 weeks after enrolment, participants are
contacted by telephone to ascertain whether they are
tolerating the study intervention.
In the event that a participant is unable to attend a
scheduled follow-up assessment visit because of an acute
illness (e.g., exacerbation of COPD) or other reasons, the
visit can be postponed, ideally within 4 weeks of the
scheduled assessment visit. Participants unable to attend
a face-to-face assessment at 6 and 12 months are followed
up by telephone or a home visit or sent the questionnaire
to complete at home. The schedule for data collection
within the study is outlined in Table 1.
The following data are collected:
Regular use of prescription drugs is recorded at
recruitment as free text and at the 6- and 12-month assessments.
Smoking history (age commenced, age ceased, and
average cigarettes smoked per day) is recorded at
recruitment and at the 6- and 12-month assessments.
Packyear consumption is computed at recruitment.
Height and weight
Height and weight are measured at recruitment, and
weight is measured at the 6- and 12-month assessments.
Number of chronic obstructive pulmonary disease
The primary outcome measure of the total number of
COPD exacerbations requiring antibiotics/oral
corticosteroids whilst on study medication is ascertained at
the 6- and 12-month assessments. The total number of
participant-reported COPD exacerbations will be validated
for approximately 20 % of randomly identified participants
by examination of primary care records after the study.
Concordance between participant-recorded and primary
care records will be computed by using percentage
agreement, and more than 80 % will be deemed acceptable .
The American Thoracic Society/European Respiratory
Society guideline definition of COPD exacerbation is used:
a worsening of patient’s dyspnoea, cough, or sputum
beyond day-to-day variability sufficient to warrant a change in
Table 1 Schedule of study assessments
Written informed consent
Total number COPD exacerbations
requiring oral corticosteroids/antibiotics
Health-related quality of life (EQ-5D)
Disease-related health status
(CAT, MRC dyspnoea)
Post-bronchodilator lung function
Adverse events/drug reactions
X boxes represent which aspect of the assessment is conducted. CAT COPD (Chronic Obstructive Pulmonary Disease) Assessment Test, COPD Chronic obstructive
pulmonary disease, EQ-5D EuroQOL five-dimension questionnaire, GP General practitioner, MRC Medical Research Council
management . The minimum management change will
be treatment with antibiotics or oral corticosteroids. A
minimum of 2 weeks between consecutive hospitalisations/
start of new therapy is necessary to consider events as
separate. A modified American Thoracic Society/European
Respiratory Society operational classification of exacerbation
severity will be used for each exacerbation: level I, increased
use of their short-acting β2 agonist; level II, use of oral
corticosteroids or antibiotics; level III, care by services to
prevent hospitalisation; level IV, admitted to hospital .
The number of emergency hospital admissions whilst on
study medication is ascertained at the 6- and 12-month
assessments. COPD-associated emergency admissions
are also identified. The number of participant-reported
hospital admissions will be validated for a randomly
identified sample of 20 % of participants by examination
of primary and secondary care records after the study.
Concordance between participant-recorded and
primary/secondary care records will be computed by using
percentage agreement, and more than 80 % will be
deemed acceptable .
Health-related quality of life
Health-related quality of life data are captured at
recruitment and at the 6- and 12-month assessments by
questionnaire using the EuroQoL 5D (EQ-5D 3-level version)
Index , which has been used widely in COPD. The
completed instrument can be translated into
quality-oflife utilities suitable for calculation of QALYs through
the published UK tariffs .
Disease-related health status
Disease-related health status is ascertained at
recruitment and at the 6- and 12-month assessments by
questionnaire using the CAT . The CAT is an eight-item
unidimensional measure of health status impairment in
COPD and is completed by the subject. The CAT has a
scoring interval of 0–40; 0–5 is the norm for healthy
non-smokers, and more than 30 is indicative of a very
high impact of COPD on quality of life . The CAT is
reliable and responsive, correlates very closely with the
St George Respiratory Questionnaire, and is preferred
because it provides a more comprehensive assessment of
the symptomatic impact of COPD [30, 36, 37].
The MRC dyspnoea scale is included in the
recruitment and the 6- and 12-month assessments . The
MRC dyspnoea scale has been in use for many years to
grade the effect of breathlessness on daily activities. The
MRC dyspnoea scale is a single question which assesses
breathlessness related to activities. The scoring interval
is 1–5; 1 refers to ‘Not troubled by breathlessness except
on strenuous exercise’, and 5 indicates ‘Too breathless to
leave the house or breathless when dressing or
undressing’. The MRC score has been validated against walking
test performance and other metrics of COPD health
status (e.g., St George Respiratory Questionnaire ).
Post-bronchodilator lung function
Post-bronchodilator lung function is measured at
recruitment and 6 and 12 months by using spirometry performed
to American Thoracic Society/European Respiratory
Society standards .
In keeping with the NHS perspective adopted for the
economic analysis, health-care utilisation is the focus of
the costing for the study. This includes the study drug,
concomitant medications, general practitioner visits, and
any-cause hospitalisations during the previous 6 months
and is ascertained at the 6- and 12-month assessments.
Adverse reactions and serious adverse events
The trial complies with the UK NHS National Research
Ethics Service guidelines for reporting adverse events
. Adverse reactions and serious adverse events whilst
on study medication are ascertained at the 2-week
telephone call and the 6- and 12-month assessments.
Participants are notified of recognised adverse reactions and
encouraged to contact the local study centre if they
Compliance with study medication is assessed at the
6and 12-month assessments. Participants will be asked to
return empty drug bottles and unused medication;
compliance will be calculated by pill counting .
The sample size of 1424 was estimated on the basis of
the ECLIPSE (Evaluation of COPD Longitudinally to
Identify Predictive Surrogate Endpoints) study reporting
the frequency of COPD exacerbation in 2138 patients
. For patients identical to our target population (who
in a 1-year period have at least two self-reported COPD
exacerbations requiring antibiotics or oral
corticosteroids), the mean (standard deviation) number of COPD
exacerbations within 1 year was 2.22 (1.86) . Given a
similar rate in the placebo arm, 669 subjects are needed
in each arm of the trial to detect a clinically important
reduction in COPD exacerbations of 15 % (i.e., from a
mean of 2.22 to 1.89) with 90 % power at the two-sided
5 % significance level. With an estimated 6 % loss to
follow-up, 712 participants are required in each study
arm (i.e., 1424 in total).
All analyses will be governed by a comprehensive
statistical analysis plan that is in place and will be in accordance
with the intention-to-treat principle with a per-protocol
analysis performed as a sensitivity. The per-protocol
analysis will exclude participants who were not
compliant (at less than 75 %) with their study medication.
Primary clinical outcome
The number of COPD exacerbations requiring
antibiotics or oral corticosteroids in the 52-week treatment
period will be compared between randomised groups by
using a generalised linear model with log-link function,
an appropriate dispersion parameter, and length of time
in the study as an offset. Estimates will be adjusted for
centre and other baseline covariates that are known to
be strongly related to outcome (e.g., age, smoking, and
COPD hospitalisations in the year prior to study). An
over-dispersion parameter will be used to adjust for
An NHS perspective will be adopted in keeping with the
NICE reference case for health technology assessments
. The health economic evaluation will be conducted
in two stages. First, the cost-effectiveness of treatment
will be calculated for the within-trial period on the
basis of observed data. Second, the results of the trial
will be extrapolated to patient lifetimes by using
The within-trial analysis will make use of the
healthcare resource use data (translated to a cost per patient
by using unit cost standard reference sources), the
exacerbation rate associated with the treatment arms, and
the quality-of-life effects estimated from the EQ-5D
combined with utility data to calculate QALYs.
Nonparametric bootstrapping will be used to capture
sampling uncertainty in the observed data, and results will
be presented as cost per exacerbation avoided and cost
per QALY gained within the trial period with
accompanying confidence intervals (or cost-effectiveness acceptability
curves if more appropriate). The extrapolation analysis
will make use of regression estimates of exacerbation on
cost and quality of life from the trial, as well as
previously published models of COPD, to guide the
extrapolation to patient lifetimes. In addition to sampling
uncertainty, extensive sensitivity analysis will be
performed to understand the importance of alternative
modelling assumptions for the extrapolated results.
COPD is a common disease associated with high
morbidity, mortality, and health-care costs despite the
widespread use of inhaled corticosteroids. Although inhaled
corticosteroids are beneficial in COPD, a relative
insensitivity of COPD airway inflammation to the
antiinflammatory effects of high-dose inhaled corticosteroids
has been demonstrated [12–14]. TWICS is a randomised
double-blind placebo-controlled trial that tests the
hypothesis: Does the addition of oral ‘low dose’
theophylline reduce the rate of exacerbation in patients with
COPD established on a treatment regimen including an
The primary outcome of COPD exacerbations is
clinically important for patients, their carers, and health
services; exacerbations of COPD are associated with
many adverse outcomes, including mortality, and their
management comprises 60 % of NHS expenditure for
COPD . To be eligible in TWICS, participants must
have an established diagnosis of COPD on the basis of
the spirometric finding of FEV1/FVC of less than 0.7
and of at least two exacerbations in the previous year.
These criteria reflect the findings of the ECLIPSE study
that the single best predictor of exacerbations is a
history of exacerbations . Moreover, patients of the
frequent-exacerbation phenotype (of at least two
exacerbations in a year) are present at all severities of COPD
(22 % of GOLD stage 2, 33 % of stage 3, and 47 % of
stage 4), and the frequent-exacerbation phenotype is
relatively stable over a 3-year period and can be
identified on the basis of patient recall.
It is almost certain that a substantial proportion of the
participants in TWICS will have severe lung disease and
will have limited exercise tolerance. Allowances have
been made in the trial design to facilitate participation
by this group of patients: at site discretion, participants
can be recruited at home, and those unable to attend
follow-up assessment visits will be assessed by telephone
review and postal collection of quality-of-life
questionnaires; the majority (at least 48 of 52 weeks) of study
medication will be couriered directly to the homes of
participants, thus avoiding travel to study centres to
Oral theophylline has conventionally been used
primarily as a bronchodilator in COPD for over 70 years;
however, to achieve modest clinical effects, relatively
high blood levels (10–20 mg/l) are required. The
bronchodilator effect of this ‘high dose’ theophylline is the
consequence of inhibition of phosphodiesterase and
consequent relaxation of airway smooth muscle; however,
phosphodiesterase inhibition is also associated with the
side effects of theophylline, namely nausea,
gastrointestinal upset, cardiac arrhythmias, and malaise. The use of
high-dose theophylline has declined in recent years, and
current COPD guidelines have relegated high-dose
theophylline to third-line therapy because of its narrow
therapeutic index, modest clinical effect, side effect
profile, drug interactions, the need for monitoring and the
development of inhaled long-acting β2 agonists,
antimuscarinics, and the widespread use of inhaled
corticosteroids [1, 10]. The use of ‘low dose’ theophylline
derives from the demonstration by preclinical studies and
two small randomised controlled trials that theophylline
at ‘low dose’ (plasma concentration of 1–5 mg/l)
increases the sensitivity of COPD airway inflammation to
the anti-inflammatory effects of inhaled corticosteroids
[15–22]. Previous studies have investigated the potential
anti-inflammatory effects of ‘low dose’ theophylline in
COPD and asthma (not in conjunction with inhaled
corticosteroids). However, they have used a ‘one size fits all’
dosing approach (e.g., all participants received 100 mg
twice daily or 200 mg twice daily) [20, 23, 24, 44–46]. In
contrast, in TWICS, theophylline dosing is stratified, as
determined by IBW and smoking status. Population
studies have demonstrated that theophylline
pharmacokinetics are influenced by weight, COPD disease status
(reduced clearance), and smoking (increased clearance)
[28, 47–56]. Smoking induces theophylline clearance by
approximately 60 %, which gradually returns to normal
levels upon smoking cessation, and this has been
incorporated into the definition of a non-smoker in TWICS.
The use of IBW in preference to actual weight avoids
the potential for giving an inappropriately high dose of
theophylline to obese participants; furthermore, use of
IBW is good clinical practice. In TWICS, theophylline
dosing is based on pharmacokinetic modelling
incorporating the major determinants of theophylline
steadystate concentration, i.e., weight, smoking status, and
clearance of theophylline (low, normal, or high), and is
designed to achieve a steady-state serum theophylline
level of 1–5 mg/l and certainly less than 10 mg/l.
Theophylline is metabolised in the liver by the enzyme
CYP1A2, which is induced by smoking and inhibited by
a number of medications with a consequent increase in
serum theophylline levels . For this reason, the
exclusion criteria include long-term use of drugs known to
increase serum theophylline.
Theophylline in the form of intravenous aminophylline
has been used in the treatment of severe acute
exacerbations of COPD in hospital settings. However, research
does not support this modality of treatment and this is
reflected in guideline recommendations [1, 10], and the
use of intravenous aminophylline has rapidly declined.
When used, intravenous aminophylline is usually
administered as a loading dose followed by a maintenance
infusion in patients not established on theophylline, and
for patients established on theophylline, only the
maintenance infusion is given because of toxicity concerns.
Inevitably, during TWICS, some participants will be
admitted to hospital with very severe life-threatening
exacerbations of COPD, and the attending physician may
wish to use intravenous aminophylline. Pharmacokinetic
modelling demonstrates that patients receiving ‘low
dose’ theophylline will not achieve toxic levels of
theophylline following the usual loading dose of aminophylline,
because their baseline serum theophylline concentrations
will vary between 1 and 5 mg/l; and after the loading dose
of aminophylline, serum theophylline will remain within
the conventional bronchodilating interval of 10–20 mg/l.
This is clinically important as the attending physician
will not be aware whether a TWICS participant is on
theophylline or placebo, and the modelling confirms
that an aminophylline infusion can be safely
administered if thought by the attending physician to be clinically
indicated. Study medication will be suspended whilst the
participant receives intravenous aminophylline and
restarted when the aminophylline discontinued. In
keeping with guideline recommendations, serum
theophylline will be measured 24 h after commencing
intravenous aminophylline (allocation status will not
be discernible from such a level) [1, 10]. All
participants are given (and advised to carry) a credit
cardsized alert card giving brief information about the trial
with advice for clinicians, contact details for the local
investigator, and the contact details for emergency
unblinding. The participant’s primary care physician is
informed of participation and provided with
appropriate clinical advice.
Theophylline has been used for decades, and many
clinicians are familiar with its use; moreover, ‘low dose’
theophylline is considerably less expensive than inhaled
therapies and does not incur the costs of monitoring of
blood levels. The demonstration that low-dose
theophylline increases the efficacy of inhaled corticosteroids in
COPD by reducing the incidence of exacerbations will
be relevant not only to patients and clinicians but also
to health-care providers, both in the UK and globally.
The first subject was recruited on February 6, 2014, and
the trial is currently recruiting patients. The anticipated
date of last participant assessment is October 2016.
CAT: COPD (Chronic Obstructive Pulmonary Disease) Assessment Test;
COPD: Chronic obstructive pulmonary disease; ECLIPSE: Evaluation of COPD
Longitudinally to Identify Predictive Surrogate Endpoints; EQ-5D: EuroQOL
five-dimension questionnaire; FEV1: Forced expiratory volume in first second;
FVC: Forced vital capacity; GOLD: Global Initiative on Obstructive Lung
Disease; IBW: Ideal body weight; MR: modified release; MRC: Medical
Research Council; NHS: National Health Service; NICE: National Institute for
Health and Care Excellence; QALY: Quality-adjusted life year;
TWICS: Theophylline With Inhaled Corticosteroids.
PB is a co-founder of RespiVert (now part of Johnson & Johnson, New
Brunswick, NJ, USA), which has developed new treatments of asthma and
COPD on the basis of the mechanism of action of theophylline. He is on the
Scientific Advisory Board of Napp Pharmaceuticals Limited (Cambridge, UK).
The other authors declare that they have no competing interests.
GD and DP helped to conceptualize and design the study and to obtain the
funding and are co-chief investigators. SC helped to obtain the funding and
is the senior trial manager. PB conceived of low-dose theophylline augmenting
inhaled corticosteroids in COPD and helped to conceptualize and design the
study and to obtain the funding. AB helped to conceptualize and design the
study and to obtain the funding and is responsible for the health economics
aspects. GB and SG helped to conceptualize and design the study. RC, LD, ADS,
JH, AM, JN, AS, and AW helped to conceptualize and design the study and to
obtain the funding. HC helped to conceptualize and design the study and to
obtain the funding and conducted the pharmacokinetic modelling. SF shares
responsibility for the statistical analysis. AJL helped to conceptualize and design
the study and to obtain the funding and shares responsibility for the statistical
analysis. KMcC and GMcP helped to obtain the funding. All authors read and
approved the final manuscript.
This project is funded by the National Institute for Health Research Health
Technology Assessment Programme (project number 11/58/15). The
Uniphyllin MR tablets have been provided gratis by Napp Pharmaceuticals
Limited. As a courtesy, Napp Pharmaceuticals Limited will be provided with a
copy of any manuscript prior to submission. We would like to acknowledge
Nicholas Locantore for providing us with detailed data from the ECLIPSE study.
Department of Health disclaimer
The views and opinions expressed therein are those of the authors and do
not necessarily reflect those of the Health Technology Assessment
Programme, the National Institute for Health Research, the NHS, or the
Department of Health.
1. National Institute for Health and Care Excellence . Chronic obstructive pulmonary disease: management of chronic obstructive pulmonary disease in adults in primary and secondary care . Clin Guidel CG101 . http:// guidance.nice.org.uk/CG101/Guidance/pdf/English. Accessed 20 Jan 2015 .
2. Office for National Statistics. Leading causes of deaths registered in England and Wales . 2012 . http://www.ons.gov.uk/ons/search/index.html? newquery= mortality+by+cause+and+age . Accessed 20 Jan 2015 .
3. Ferrer M , Alonso J , Morera J , Marrades RM , Khalaf A , Aguar MC , et al. Chronic obstructive pulmonary disease stage and health-related quality of life. The quality of life of chronic obstructive pulmonary disease study group . Ann Intern Med . 1997 ; 127 : 1072 - 9 .
4. Stahl E , Lindberg A , Jansson SA , Rönmark E , Svensson K , Andersson F , et al. Health-related quality of life is related to COPD disease severity . Health Qual Life Outcomes . 2005 ; 3 : 56 .
5. Britton M. The burden of COPD in the U .K. : results from the confronting COPD survey . Respir Med . 2003 ; 97 : S71 - 9 .
6. Donaldson GC , Seemungal TA , Bhowmik A , Wedzicha JA . Relationship between exacerbation frequency and lung function decline in chronic obstructive pulmonary disease . Thorax . 2002 ; 57 : 847 - 52 .
7. Donaldson GC , Wilkinson TM , Hurst JR , Perera WR , Wedzicha JA . Exacerbations and time spent outdoors in chronic obstructive pulmonary disease . Am J Resp Crit Care Med . 2005 ; 171 : 446 - 52 .
8. Seemungal TA , Donaldson GC , Paul EA , Bestall JC , Jeffries DJ , Wedzicha JA . Effect of exacerbation on quality of life in patients with chronic obstructive pulmonary disease . Am J Resp Crit Care Med . 1998 ; 157 : 1418 - 22 .
9. Soler-Cataluna JJ , Martinez-Garcia MA , Roman Sanchez P , Salcedo E , Navarro M , Ochando R. Severe acute exacerbations and mortality in patients with chronic obstructive pulmonary disease . Thorax . 2005 ; 60 : 925 - 31 .
10. Global Initiative on Obstructive Lung Disease, Inc. Global strategy for the diagnosis, management and prevention of chronic obstructive pulmonary disease . 2014 . http://www.goldcopd.org/uploads/users/files/ GOLD_ Report2014_Feb07 .pdf. Accessed 20 Jan 2015 .
11. Barnes PJ , Ito K , Adcock IM . Corticosteroid resistance in chronic obstructive pulmonary disease: inactivation of histone deacetylase . Lancet . 2004 ; 363 : 731 - 3 .
12. Culpitt SV , Maziak W , Loukidis S , Nightingale JA , Matthews JL , Barnes PJ . Effect of high dose inhaled steroid on cells, cytokines, and proteases in induced sputum in chronic obstructive pulmonary disease . Am J Resp Crit Care Med . 1999 ; 160 : 1635 - 9 .
13. Culpitt SV , Rogers DF , Shah P , De Matos C , Russell RE , Donnelly LE , et al. Impaired inhibition by dexamethasone of cytokine release by alveolar macrophages from patients with chronic obstructive pulmonary disease . Am J Resp Crit Care Med . 2003 ; 167 : 24 - 31 .
14. Hattotuwa KL , Gizycki MJ , Ansari TW , Jeffery PK , Barnes NC . The effects of inhaled fluticasone on airway inflammation in chronic obstructive pulmonary disease: a double-blind, placebo-controlled biopsy study . Am J Resp Crit Care Med . 2002 ; 165 : 1592 - 6 .
15. Ito K , Barnes PJ , Adcock IM . Glucocorticoid receptor recruitment of histone deacetylase 2 inhibits interleukin-1beta-induced histone H4 acetylation on lysines 8 and 12 . Mol Cell Biol . 2000 ; 20 : 6891 - 903 .
16. Ito K , Ito M , Elliott WM , Cosio B , Caramori G , Kon OM , et al. Decreased histone deacetylase activity in chronic obstructive pulmonary disease . N Engl J Med . 2005 ; 352 : 1967 - 76 .
17. Ito K , Yamamura S , Essilfie-Quaye S , Cosio B , Ito M , Barnes PJ , et al. Histone deacetylase 2-mediated deacetylation of the glucocorticoid receptor enables NF-kappaB suppression . J Exp Med . 2006 ; 203 : 7 - 13 .
18. Barnes PJ . Targeting the epigenome in the treatment of asthma and chronic obstructive pulmonary disease . Proc Am Thorac Soc . 2009 ; 6 : 693 - 6 .
19. Marwick JA , Caramori G , Stevenson CS , Casolari P , Jazrawi E , Barnes PJ , et al. Inhibition of PI3Kdelta restores glucocorticoid function in smoking-induced airway inflammation in mice . Am J Resp Crit Care Med . 2009 ; 179 : 542 - 8 .
20. Ito K , Lim S , Caramori G , Cosio B , Chung KF , Adcock IM , et al. A molecular mechanism of action of theophylline: Induction of histone deacetylase activity to decrease inflammatory gene expression . Proc Natl Acad Sci U S A . 2002 ; 99 : 8921 - 6 .
21. Cosio BG , Tsaprouni L , Ito K , Jazrawi E , Adcock IM , Barnes PJ . Theophylline restores histone deacetylase activity and steroid responses in COPD macrophages . J Exp Med . 2004 ; 200 : 689 - 95 .
22. To Y , Ito K , Kizawa Y , Failla M , Ito M , Kusama T , et al. Targeting phosphoinositide-3-kinase-delta with theophylline reverses corticosteroid insensitivity in chronic obstructive pulmonary disease . Am J Resp Crit Care Med . 2010 ; 182 : 897 - 904 .
23. Cosio BG , Iglesias A , Rios A , Noguera A , Sala E , Ito K , et al. Low-dose theophylline enhances the anti-inflammatory effects of steroids during exacerbations of COPD . Thorax. 2009 ; 64 : 424 - 9 .
24. Ford PA , Durham AL , Russell RE , Gordon F , Adcock IM , Barnes PJ . Treatment effects of low-dose theophylline combined with an inhaled corticosteroid in COPD . Chest. 2010 ; 137 : 1338 - 44 .
25. Cyr MC , Beauchesne MF , Lemiere C , Blais L. Effect of theophylline on the rate of moderate to severe exacerbations among patients with chronic obstructive pulmonary disease . Br J Clin Pharmacol . 2008 ; 65 : 40 - 50 .
26. Medicines Complete . Pharmaceutical Press,, London. 2015 . https:// www.medicinescomplete.com/about/subscribe.htm. Accessed 20 Jan 2015 .
27. Barr RG , Rowe BH , Camargo Jr CA. Methylxanthines for exacerbations of chronic obstructive pulmonary disease: meta-analysis of randomised trials . Br Med J . 2003 ; 327 : 643 .
28. Powell JR , Vozeh S , Hopewell P , Costello J , Sheiner LB , Riegelman S. Theophylline disposition in acutely ill hospitalized patients . The effect of smoking, heart failure, severe airway obstruction, and pneumonia . Am Rev Respir Dis . 1978 ; 118 : 229 - 38 .
29. Shah B , Sucher K , Hollenbeck CB . Comparison of ideal body weight equations and published height-weight tables with body mass index tables for healthy adults in the United States . Nutrition Clin Pract . 2006 ; 21 : 312 - 9 .
30. COPD Assessment Test . http://www.catestonline.co.uk/. Accessed 20 Jan 2015 .
31. Fletcher CM . Standardised questionnaire on respiratory symptoms: a statement prepared and approved by the MRC Committee on the Aetiology of Chronic Bronchitis (MRC breathlessness score) . Br Med J . 1960 ; 2 : 1665 .
32. The EuroQol Group. EuroQol-a new facility for the measurement of health-related quality of life . Health Policy . 1990 ; 16 : 199 - 208 .
33. Quint JK , Donaldson GC , Hurst JR , Goldring JJP , Seemungal TR , Wedzicha JA . Predictive accuracy of patient-reported exacerbation frequency in COPD . Eur Resp J . 2011 ; 37 : 501 - 7 .
34. Celli BR , MacNee W. ATS /ERS Task Force. Standards for the diagnosis and treatment of patients with COPD: a summary of the ATS/ERS position paper . Eur Resp J . 2004 ; 23 : 932 - 46 .
35. Dolan P. Modelling valuations for health states . Med Care . 1997 ; 11 : 1095 - 108 .
36. Dodd JW , Hogg L , Nolan J , Jefford H , Grant A , Lord VM , et al. The COPD assessment test (CAT): response to pulmonary rehabilitation . A multicentre , prospective study. Thorax . 2011 ; 66 : 425 - 9 .
37. Jones PW , Harding G , Berry P , Wiklund I , Chen WH , Kline LN . Development and first validation of the COPD assessment test . Eur Resp J . 2009 ; 34 : 648 - 54 .
38. Bestall JC , Paul EA , Garrod R , Garnham R , Jones PW , Wedzicha JA . Usefulness of the Medical Research Council (MRC) dyspnoea scale as a measure of disability in patients with chronic obstructive pulmonary disease . Thorax . 1999 ; 54 : 581 - 6 .
39. Miller MR , Hankinson J , Brusasco V , Burgos F , Casaburi R , Coates A , et al. ATS/ ERS task force . Standardisation of spirometry. Eur Resp J . 2005 ; 26 : 319 - 38 .
40. National Research Ethics Service. Safety and progress reports (CTIMPs) . http://www.hra. nhs.uk/research-community/during-your-research-project/ safety-reporting/. Accessed 20 Jan 2015 .
41. Farmer KC . Methods for measuring and monitoring medication regimen adherence in clinical trials and clinical practice . Clin Therap . 1999 ; 21 : 1074 - 90 .
42. Hurst JR , Vestbo J , Anzueto A , Locantore N , Müllerova H , Tal-Singer R , et al. Evaluation of COPD longitudinally to identify predictive, surrogate endpoints. Susceptibility to exacerbation in chronic obstructive pulmonary disease . N Engl J Med . 2010 ; 363 : 1128 - 38 .
43. National Institute for Health and Care Excellence . Guide to the methods of technology appraisal 2013 . http://publications.nice.org.uk/pmg9. Accessed 20 Jan 2015 .
44. Lim S , Tomita K , Caramori G , Jatakanon A , Oliver B , Keller A , et al. Low-dose theophylline reduces eosinophilic inflammation but not exhaled nitric oxide in mild asthma . Am J Respir Crit Care Med . 2001 ; 164 : 273 - 6 .
45. Sullivan P , Bekir S , Jaffar Z , Page C , Jeffery P , Costello J. Anti-inflammatory effects of low-dose oral theophylline in atopic asthma . Lancet . 1994 ; 343 : 1006 - 8 .
46. Ohta K , Fukuchi Y , Grouse L , Mizutani R , Rabe KF , Rennard SI , et al. A prospective clinical study of theophylline safety in 3810 elderly with asthma or COPD . Resp Med . 2004 ; 98 : 1016 - 24 .
47. Hunt SN , Jusko WJ , Yurchak AM . Effect of smoking on theophylline disposition . Clin Pharmac Ther . 1976 ; 19 : 546 - 51 .
48. Powell JR , Thiercelin JF , Vozeh S , Sansom L , Riegelman S. The influence of cigarette smoking and sex on theophylline disposition . Am Rev Resp Dis . 1977 ; 116 : 17 - 23 .
49. Jusko WJ . Role of tobacco smoking in pharmacokinetics . J Pharmacokinet Biopharm . 1978 ; 6 : 7 - 39 .
50. Jusko WJ , Schentag JJ , Clark JH , Gardner M , Yurchak AM . Enhanced biotransformation of theophylline in marihuana and tobacco smokers . Clin Pharmac Ther . 1978 ; 24 : 406 - 10 .
51. Hendeles L , Weinberger M , Bighley L. Disposition of theophylline after a single intravenous infusion of aminophylline . Am Rev Resp Dis . 1978 ; 118 : 97 - 103 .
52. Cusack G , Kelly JG , Lavan J , Noel J , O'Malley K. Theophylline kinetics in relation to age: the importance of smoking . Br J Clin Pharmacol . 1980 ; 10 : 109 - 14 .
53. Chrystyn H , Mulley BA , Peake MD . Dose response relation to oral theophylline in severe chronic obstructive airways disease . Br Med J . 1988 ; 297 : 1506 - 10 .
54. Chrystyn H , Ellis JW , Mulley BA , Peake MD . The accuracy and stability of Bayesian theophylline predictions . Ther Drug Monit . 1988 ; 10 : 299 - 305 .
55. Chrystyn H , Mulley BA , Peake MD . The accuracy of a pharmacokinetic theophylline predictor using once daily dosing . Br J Clin Pharmacol . 1987 ; 24 : 301 - 7 .
56. Chrystyn H , Ellis JW , Mulley BA , Peake MD . Bayesian derived predictions for twice daily theophylline under outpatient conditions and an assessment of optimal sampling times . Br J Clin Pharmacol . 1989 ; 27 : 215 - 21 .