Theophylline Effects in the Fontan Circulation (THIEF Pilot Study)
Phase: PHASE2
Conditions: Congenital Heart Disease
Sponsor: Oslo University Hospital

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Title Page  
Protocol Title:  
THeophyllIne Effects in the Fontan circulation 
A single group treatment phase 2 single-arm no-masking study to assess safety and efficacy of a 
short-term oral treatment with theophylline (ATC-no. R03D A04) in terms of improvements in 
cardiorespiratory fitness, health-related quality of life, cardiac performance and respiratory 
function in male and female adolescents aged 16 to 25 years with a Fontan-type surgical 
palliation of univentricular congenital heart disease. 
Protocol Number: 5.1 (May 5, 2023) 
Amendment Number: 02 
Compound: Theophylline (ATC R03D A04) 
Brief Title:  
THeophyllIne EFfects in the Fontan circulation - potential improvements in cardiorespiratory 
fitness, health-related quality of life, cardiac performance and respiratory function from oral 
treatment with theophylline in adolescent males and females with Fontan-type palliation of 
univentricular congenital heart disease 
Study Phase: phase 2 / pilot 
Acronym: THIEF pilot study 
Sponsor Name: Oslo University Hospital 
Legal Registered Address: Postboks 4950 Nydalen, 0424 Oslo, Norway 
Regulatory Agency Identifier Number(s) 
EU CT:  2022-500301-41-00 
ClinicalTrials.gov ID: NCT05717049 
Approval Date: May 16, 2023 
 
 
 
 
 
 
 

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Sponsor Signatory: 
 
 
 
 
Gaute Døhlen MD PhD,  
Department head, Department of Paediatric Cardiology, 
Oslo University Hospital Rikshospitalet 
 
Date    
 
 
 
Medical Monitor Name (= Executive committee) and Contact Information 
Pediatric cardiology medical monitor (and PI) 
Thomas Möller MD PhD (head of the executive committee) 
Department of Paediatric Cardiology, Oslo University Hospital Rikshospitalet 
Address: Postboks 4950 Nydalen, 0424 Oslo, Norway 
Tel: 90737865(trial cell phone)  
E-mail: thomas.moller@ous-hf.no 
 
 
 
 
 
Date:  
 
Adult cardiology medical monitor 
Ola Gjesdal MD PhD (member of the executive committee) 
GUCH unit, Department of Cardiology, Oslo University Hospital Rikshospitalet 
Address: Postboks 4950 Nydalen, 0424 Oslo, Norway 
Tel: 90714472 (trial cell phone)  
E-mail: olgjes@ous-hf.no 
 
 
 

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Contact Details:  
Sponsor (Oslo University Hospital): 
Name and title Gaute Døhlen MD PhD, department 
head,  
Department of Paediatric Cardiology, Oslo University 
Hospital Rikshospitalet 
Address: Postboks 4950 Nydalen, 0424 Oslo, Norway 
Tel: +47 23070000  
E-mail: gdohlen@ous-hf.no 
Coordinating Investigator  
Name and title not applicable 
Principal Investigator 
Name and title  
Thomas Möller MD PhD, senior consultant / 
researcher, head of the executive committee 
Department of Paediatric Cardiology, Oslo University 
Hospital Rikshospitalet 
Address: Postboks 4950 Nydalen, 0424 Oslo, Norway 
Tel: +47 90737865 (trial cell phone) 
E-mail: thomas.moller@ous-hf.no 
Participating Sites: 
Name and title 
Thomas Möller MD PhD, senior consultant / 
researcher, head of the executive committee 
Department of Paediatric Cardiology, Oslo University 
Hospital Rikshospitalet 
Address: Postboks 4950 Nydalen, 0424 Oslo, Norway 
Tel: +47 90737865 (trial cell phone)  
E-mail: thomas.moller@ous-hf.no 
  
Participating Sites: 
Name and title 
Ola Gjesdal MD PhD, senior consultant, member of 
the executive committee 
GUCH unit, Department of Cardiology, Oslo 
University Hospital Rikshospitalet 
Address: Postboks 4950 Nydalen, 0424 Oslo, Norway 
Tel: +47 90714472 (trial cell phone) 
E-mail: olgjes@ous-hf.no 
 
 
 

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Protocol Amendment Summary of Changes Table 
 
DOCUMENT HISTORY 
Document 
Date 
Original Protocol 
29-08-2022 
Amendment 01, protocol version 4 
04-11-2022 
Amendment 02, protocol version 5 
28-03-2023 
Amendment 02, protocol version 5.1 in response 
to evaluation of substantial modifications from 28-
03-2023 
05-05-2023 
 
Amendment 01 (substantial modification: (Nov 04, 2022) 
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of 
Directive 2001/20/EC of the European Parliament and the Council of the European Union. 
Overall Rationale for the Amendment 
 A decision in the study team was made to use an electronic log book solution for better 
monitoring of participant compliance and AE’s. This decision was made after initial trial 
application authorization. 
Section # and Name 
Description of Change 
Brief Rationale 
Signature page 
Filled in correct contact 
details 
Preliminary placeholders from 
protocol version 1 are replaced 
Protocol Amendment 
Summary of Changes 
Table 
A table and overview of 
amendment history has 
been added 
Necessary change together with 
amendment no.1 
1.1 Synopsis, Brief 
summary 
Added information about 
electronic participant log 
book in ViedocMe (part of 
the eCRF database) 
A decision in the study team was 
made to use an electronic log book 
solution. This decision was made 
after trial authorization. 
4.1 Overall design 
Added information about 
electronic participant log 
book in ViedocMe (part of 
the eCRF database) 
A decision in the study team was 
made to use an electronic log book 
solution. This decision was made 
after trial authorization. 
Whole document 
Typographic and semantic 
errors and flaws including 
institutional name changes 
were corrected 
(Non-substantial changes) 
 
 
 

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Amendment 02 (substantial modification: March 28, 2023) 
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of 
Directive 2001/20/EC of the European Parliament and the Council of the European Union. 
Overall Rationale for the Amendment 
Initial screening visits of potential participants revealed frequent screening failure (6 out of 10 
visits) due to biochemical exclusion criteria, namely elevated ammonia and/or mildly elevated 
INR in the absence of signs of moderate/severe liver disease by other biochemical (bilirubin, 
ALT) or imaging findings (MRI or ultrasound). The intention behind liver-related exclusion 
criteria was to exclude participants with either potential hepato-cellular carcinoma or with severe 
Fontan-associated liver disease with significantly impaired synthesis or significantly increased 
theophylline toxicity.  
Experiences with repeated screening failure, experiences with the initial three enrolled 
participants, and a focused review of available scientific literature resulted in the following 
considerations: 
− Porto-systemic shunting of enteral venous blood to the systemic venous system leads to 
elevated ammonia and should probably be expected frequently late (> 10 years) after the 
Fontan operation (Takefuta 2021) (1). Hence ammonia is not suited to discriminate 
different degrees of hepatic involvement in Fontan patients. 
− In a previous study of hepatic and cardiac function in Fontan patients, spontaneous INR 
had a median of 1.2 equivalent to the upper normal range (Camposilvan 2008) (2). A 
spontaneous INR above the upper normal limit (>1.2) is probably a too restrictive 
exclusion criteria in a Fontan population. In addition, the use of direct oral anti-coagulant 
drugs may cause slightly elevated INR in the absence of warfarin treatment (Ofek 2017) 
(3). 
− Bilirubin has been shown to correlate with slow theophylline clearance in cirrhotic 
patients (Mangione 1978) (4). Even in the absence of elevated ammonia and severe liver 
disease, a theophylline concentration within therapeutic range was achieved by 2/3 
participants on a low starting dose (200 mg BID) or even after dose reduction from initial 
dosage (100mg BID)  
Other practical protocol, recruitment and consent issues that became obvious during the first 
screening visits and inclusions (see table). 
 
Section # and Name 
Description of Change 
Brief Rationale 
1.1 (Synopsis) 
4.1 (Overall design) 
6.5 (Dose 
modification)  
Reduced starting dose of 
study drug depending on 
bilirubin level, and option 
to further reduce to OD 
depending on study drug 
concentration 
Theophylline clearance has been 
demonstrated to correlate with 
bilirubin level, and 2/3 participants 
have achieved therapeutic 
theophylline concentrations on study 
drug dosage below recommended 
staring dose in adults 

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1.1 (Synopsis) 
Removed mandatory gender 
ratio of 1:1 
Both genders should be represented 
in study group, but no rationale for 
1:1 existed 
1.3 (Schedule of 
Activities) 
Screening laboratory tests 
(more comprehensive 
compared to baseline and 
follow-up) might be 
collected locally and 
shipped to the study centre 
up to 28 days before 
screening visit and repeated 
on the day of visit if 
informed consent has been 
signed previously. 
Our study design has been shown to 
allow for safe participant monitoring 
independently of travel distance to 
the study center. To avoid futile long-
distance travel due to screening 
failure by laboratory results. 
1.2 (Schedule of 
Activities) 
4.1 (Overall design) 
Home-based ECG-
monitoring device is started 
during baseline visit 
Recording of baseline ECG-readings 
with the monitoring device for 
comparison during treatment 
monitoring 
1.3 (Schedule of 
Activities) 
A time interval of 1-3 days 
for completing baseline 
visit with polygraphy has 
been defined with 
subsequent start of study 
medication 
Practical / logistical difficulties to 
always perform polygraphy during 
first night after baseline visit (device 
shipping and device turnover 
between participants) 
5.1 (Inclusion 
criteria) 
Rephrasing of general liver-
related criteria 
Defining of only severe Fontan-
associated liver disease as safety 
issue during theophylline use 
(corresponding to bilirubin-
dependent study drug start dose) 
5.2 (Exclusion 
criteria) 
The upper limit of 
acceptable INR has been 
altered. 
Some elevation of INR in the absence 
of severe liver disease has been 
described in Fontan patients and in 
patients using direct oral 
anticoagulative drugs 
5.2 (Exclusion 
criteria) 
Liver imaging exclusion 
criteria has been rephrased 
as “Hepato-cellular-
carcinoma (HCC)-suspect 
lesions” by liver imaging. 
The imaging-related exclusion 
criteria of “nodules > 10 mm” by 
MRI or ultrasound images have been 
difficult to apply to imaging reports 
from individual patient files. We 
noted frequent descriptions of lesions 
below/above 10 mm with altered 
perfusion, but without a 
nodular/expansive structure. 

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5.2 (Exclusion 
criteria) 
Ammonia has been 
removed from biochemical 
exclusion criteria 
Disease-specific alterations in liver 
circulation in patients with Fontan 
circulation have led to screening 
failure in an unexpected high 
percentage of potential participants 
due to elevated ammonia levels in the 
absence of severe liver disease. 
5.5 (Screening 
failures) 
Re-screening permitted  
A rescreening option with optimized 
blood work circumstances will 
improve recruitment of participants 
with otherwise no signs of severe 
liver disease. 
10.4.2 (Contraception 
Guidance) 
Absence of opposite gender 
sexual activity during study 
period has been explicitly 
defined as sufficient 
contraception. 
Unnecessary use of oral 
contraception in female Fontan 
patients must be avoided due to risk 
of thromboembolism. 
 
 
 
 
 
Amendment 02 (May 5 2023, changes after evaluation of substantial modification from March 
28, 2023) 
 
Section # and Name 
Description of Change 
Brief Rationale 
 10.1.3. Informed 
Consent Process 
The inclusion details of 
participants who reside at 
long distance from the 
study centre (but within 1 
hour travel distance from 
nearest hospital) is 
described.  
Unplanned study visits for those 
participants will require preparedness 
of local hospitals and health care 
providers of relevant specialty. 
5.4. Screen Failures 
The maximum number of 
rescreening attempts has 
been defined as being two. 
To limit rescreening attempts. 
 
 
 
 
 

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Table of Contents 
1. 
Protocol Summary ........................................................................................................12 
1.1. 
Synopsis ..........................................................................................................................12 
1.2. 
Schema ............................................................................................................................16 
1.3. 
Schedule of Activities (SoA) ..........................................................................................17 
2. 
Introduction ...................................................................................................................20 
2.1. 
Study Rationale ...............................................................................................................21 
2.2. 
Background .....................................................................................................................21 
2.3. 
Benefit/Risk Assessment ................................................................................................22 
2.3.1. 
Risk Assessment .............................................................................................................22 
2.3.2. 
Benefit Assessment .........................................................................................................25 
2.3.3. 
Overall Benefit: Risk Conclusion ...................................................................................26 
3. 
Objectives and [Endpoints and/or Estimands] ..........................................................27 
4. 
Study Design ..................................................................................................................29 
4.1. 
Overall Design ................................................................................................................29 
4.2. 
Scientific Rationale for Study Design ............................................................................31 
4.2.1. 
Participant Input into Design ..........................................................................................32 
4.3. 
Justification for Dose ......................................................................................................32 
4.4. 
End of Study Definition ..................................................................................................33 
5. 
Study Population ...........................................................................................................34 
5.1. 
Inclusion Criteria ............................................................................................................34 
5.2. 
Exclusion Criteria ...........................................................................................................35 
5.3. 
Lifestyle Considerations .................................................................................................36 
5.3.1. 
Meals and Dietary Restrictions .......................................................................................36 
5.3.2. 
Caffeine, Alcohol, and Tobacco .....................................................................................36 
5.3.3. 
Activity ...........................................................................................................................36 
5.4. 
Screen Failures ................................................................................................................36 
5.5. 
Criteria for Temporarily Delaying 
[Enrollment/Randomization/Administration of Study 
Intervention Administration] ..........................................................................................37 
6. 
Study Intervention(s) and Concomitant Therapy .....................................................38 
6.1. 
Study Intervention(s) Administered................................................................................38 
6.1.1. 
Medical Devices..............................................................................................................39 
6.2. 
Preparation/Handling/Storage/Accountability ................................................................39 
6.3. 
Measures to Minimize Bias: Randomization and Blinding ............................................39 
6.4. 
Study Intervention Compliance ......................................................................................40 
6.5. 
Dose Modification ..........................................................................................................40 
6.5.1. 
Retreatment Criteria ........................................................................................................41 
6.6. 
Continued Access to Study Intervention after the End of the 
Study ...............................................................................................................................41 
6.7. 
Treatment of Overdose ...................................................................................................41 
6.8. 
Concomitant Therapy .....................................................................................................42 
6.8.1. 
Rescue Medicine .............................................................................................................42 

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7. 
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal........................................................................................43 
7.1 
Criteria for early termination of the trial 
7.2. 
Discontinuation of Study Intervention ............................................................................43 
7.2.1. 
Liver Chemistry Stopping Criteria ..................................................................................43 
7.2.2. 
Arrhythmia and QTc Stopping Criteria ..........................................................................43 
7.2.3. 
Temporary Discontinuation ............................................................................................44 
7.2.4. 
Rechallenge .....................................................................................................................44 
7.3. 
Participant Discontinuation/Withdrawal from the Study ................................................44 
7.4. 
Lost to Follow up ............................................................................................................45 
8. 
Study Assessments and Procedures.............................................................................46 
8.1. 
[Efficacy and/or Immunogenicity] Assessments ............................................................46 
8.2. 
Safety Assessments .........................................................................................................46 
8.2.1. 
Physical Examinations ....................................................................................................46 
8.2.2. 
Vital Signs .......................................................................................................................46 
8.2.3. 
Electrocardiograms .........................................................................................................47 
8.2.4. 
Clinical Safety Laboratory Assessments ........................................................................47 
8.2.5. 
Pregnancy Testing ...........................................................................................................47 
8.2.6. 
Suicidal Ideation and Behavior Risk Monitoring ...........................................................48 
8.3. 
Adverse Events (AEs), Serious Adverse Events (SAEs), and 
Other Safety Reporting ...................................................................................................48 
8.3.1. 
Time Period and Frequency for Collecting AE and SAE 
Information .....................................................................................................................48 
8.3.2. 
Method of Detecting AEs and SAEs ..............................................................................49 
8.3.3. 
Follow-up of AEs and SAEs ...........................................................................................49 
8.3.4. 
Regulatory Reporting Requirements for SAEs ...............................................................49 
8.3.5. 
Pregnancy ........................................................................................................................50 
8.3.6. 
Cardiovascular and Death Events ...................................................................................50 
8.3.7. 
Disease-Related Events and/or Disease-Related Outcomes Not 
Qualifying as AEs or SAEs.............................................................................................51 
8.3.8. 
Adverse Events of Special Interest .................................................................................51 
8.3.9. 
Medical Device Deficiencies ..........................................................................................51 
8.4. 
Pharmacokinetics ............................................................................................................51 
8.5. 
[Genetics and/or Pharmacogenomics] ............................................................................51 
8.6. 
Biomarkers ......................................................................................................................52 
8.7. 
Immunogenicity Assessments.........................................................................................52 
8.8. 
[Health Economics OR Medical Resource Utilization and Health 
Economics] .....................................................................................................................52 
9. 
Statistical Considerations .............................................................................................53 
9.1. 
Statistical Hypotheses .....................................................................................................53 
9.2. 
Sample Size Determination ............................................................................................53 
9.3. 
Analysis Sets ...................................................................................................................53 
9.4. 
Statistical Analyses .........................................................................................................53 
9.4.1. 
General Considerations ...................................................................................................53 
9.4.2. 
Primary Endpoint(s) ........................................................................................................53 

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9.4.3. 
Secondary Endpoint(s) ....................................................................................................53 
9.4.4. 
Tertiary/Exploratory Endpoint(s)....................................................................................54 
9.4.5. 
[Other/safety] Analysis ...................................................................................................54 
9.4.6. 
Other Analysis ................................................................................................................54 
9.5. 
Interim Analysis ..............................................................................................................54 
10. 
Supporting Documentation and Operational Considerations ..................................55 
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations ................................................................................................................55 
10.1.1. Regulatory and Ethical Considerations ...........................................................................55 
10.1.2. Financial Disclosure........................................................................................................55 
10.1.3. Informed Consent Process ..............................................................................................55 
10.1.4. Data Protection................................................................................................................57 
10.1.5. Committees Structure......................................................................................................57 
10.1.6. Dissemination of Clinical Study Data.............................................................................57 
10.1.7. Data Quality Assurance ..................................................................................................57 
10.1.8. Source Documents ..........................................................................................................58 
10.1.9. Study and Site Start and Closure ....................................................................................59 
10.1.10. Publication Policy ...........................................................................................................60 
10.2. 
Appendix 2: Clinical Laboratory Tests ...........................................................................61 
10.3. 
Appendix 3: AEs and SAEs: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting .........................................................63 
10.3.1. Definition of AE .............................................................................................................63 
10.3.2. Definition of SAE ...........................................................................................................64 
10.3.3 
Definition of suspected unexpected serious adverse reaction 
(SUSAR) 
10.3.4. Recording and Follow-Up of AE and/or SAE ................................................................65 
10.3.5. Reporting of SAEs ..........................................................................................................68 
10.3.6  Reporting of SUSAR 
10.4. 
Appendix 4: Contraceptive and Barrier Guidance ..........................................................70 
10.4.1. Definitions.......................................................................................................................70 
10.4.2. Contraception Guidance..................................................................................................70 
10.5. 
Appendix 5: Genetics......................................................................................................71 
10.6. 
Appendix 6: Liver Safety: Suggested Actions and Follow-up 
Assessments [and Study Intervention Rechallenge Guidelines].....................................72 
10.7. 
Appendix 7: AEs, ADEs, SAEs, SADEs, USADEs and Device 
Deficiencies: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting in Medical Device Studies ................................73 
10.7.1. Definition of Medical Device AE and ADE ....................................................................... 
10.7.2. Definition of Medical Device SAE, SADE and USADE ................................................... 
10.7.3. Definition of Device Deficiency ......................................................................................... 
10.7.4. Recording and Follow-Up of AE and/or SAE and Device 
Deficiencies......................................................................................................................... 
10.7.5. Reporting of SAEs .............................................................................................................. 
10.7.6. Reporting of SADEs ........................................................................................................... 
10.8. 
Appendix 8: Country-specific Requirements .................................................................73 
10.9. 
Appendix 9: Abbreviations [and Definitions] ................................................................74 

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10.10. 
Appendix 10: Protocol Amendment History ..................................................................76 
11. 
References ...................................................................... Feil! Bokmerke er ikke definert. 

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1. 
Protocol Summary 
1.1. 
Synopsis 
Protocol Title:  
THeophyllIne Effects in the Fontan circulation (THIEF pilot study) 
A single group treatment phase 2 single-arm no-masking study to assess safety and efficacy of a 
short-term oral treatment with theophylline (ATC-no. R03D A04) in terms of improvements in 
cardiorespiratory fitness, health-related quality of life, cardiac performance and respiratory 
function in male and female adolescents aged 16 to 25 years with a Fontan-type surgical 
palliation of univentricular congenital heart disease. 
Brief Title:  
THeophyllIne EFfects in the Fontan circulation - potential improvements in cardiorespiratory 
fitness, quality of life, cardiac performance and respiratory function from oral treatment with 
theophylline in adolescent males and females with Fontan-type palliation of univentricular 
congenital heart disease 
Rationale: 
The effects of theophylline match in a remarkable way several pathophysiological mechanisms 
of Fontan failure. Hence, theophylline, even if it is an old and well-proven drug, is an intriguing 
substance to study for its potential to improve performance of the Fontan circulation, and it has 
not been studied in this context before. 
Objectives, endpoints and Estimands:  
 
Objectives 
Estimands and Endpoints 
Primary 
 
• To investigate feasibility and safety of 
a 12 weeks treatment study design 
with remote dosage titration and 
ambulatory heart rhythm monitoring 
during treatment phase 
Endpoints:  
• Frequency of treatment emerged 
AE/SAE 
• Freedom from participant dropout 
based on tolerability of the study 
intervention 
• Number of participants requiring dose 
reduction after first serum 
concentration assessment 
• Freedom of arrhythmogenic side 
effects of the study treatment leading 
to patient dropout 

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Primary 
 
• To provide an estimate of the effect 
size of 12 weeks of oral treatment 
with theophylline on exercise capacity 
in adolescents aged 16-25 years with 
univentricular congenital heart disease 
and Fontan circulation. 
Estimand: 
• Circulatory reserve during exercise 
Endpoint: 
• Difference in oxygen uptake at 
anaerobic/ventilatory threshold 
pre/post treatment. 
Secondary 
 
• To provide an estimate of the effect 
size of 12 weeks of oral treatment 
with theophylline on quality of life in 
adolescents aged 16-25 years with 
univentricular congenital heart disease 
and Fontan circulation. 
Estimand: 
• Health-related quality of life 
Endpoint: 
• Difference inn total scores from SF-36 
and EQ-5D questionnaires 
Secondary 
 
• To provide an estimate of the effect 
size of 12 weeks of oral treatment 
with theophylline on cardiac 
performance in adolescents aged 16-
25 years with univentricular 
congenital heart disease and Fontan 
circulation currently not treated with 
pulmonary vasodilators. 
Estimand 
• Cardiac performance at rest 
Endpoint 
• Ventricular function as assessed by 
echocardiography at rest 
 
Secondary 
 
• To provide an estimate of the effect 
size of 12 weeks of oral treatment 
with theophylline on respiratory 
function including diffusion capacity 
in adolescents aged 16-25 years with 
univentricular congenital heart disease 
and Fontan circulation currently not 
treated with pulmonary vasodilators. 
Estimand: 
• Pulmonary function 
Endpoint: 
• Diffusion capacity  
Secondary 
 
• To provide an estimate of the effect 
size of 12 weeks of oral treatment 
with theophylline on sleep disordered 
breathing in adolescents aged 16-25 
years with univentricular congenital 
Estimand 
• Sleep apnea 
Endpoint 

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heart disease and Fontan circulation 
currently not treated with pulmonary 
vasodilators. 
• Change in Apnea Hypopnea Index 
during home-based sleep study pre-
/post-treatment 
 
Overall Design: 
Single-group uncontrolled single-center open-label treatment study in adolescents (age 16-25 
years) with univentricular congenital heart defects surgically palliated with a Fontan-type 
operation. Inclusion of eligible patients from inpatient and outpatient contacts at participating 
departments at Oslo University Hospital Rikshospitalet.  
Study inclusion visit, drug treatment, remote dose adjustment, heart rhythm monitoring, and final 
post-treatment assessment study visit will be performed at the clinical research ward for children, 
Division of Paediatric and Adolescent Medicine. Data Monitoring by Clinical Trials Unit at Oslo 
University Hospital Research Support. 
Dose adjustment decisions and heart rhythm monitoring will be effectuated by a joint group of 
associated specialists (pediatric cardiology, cardiology) with continuous service through the 
entire study period. 
 
Brief Summary: 
The purpose of this study is to assess safety and efficacy of a short-term oral treatment with 
theophylline for improvement of cardiorespiratory fitness, health-related quality of life, cardiac 
and respiratory function in adolescents with Fontan-type palliation of univentricular congenital 
heart disease. 
The study hypothesis is that a 12-week oral treatment with theophylline improves the circulatory 
reserve in the Fontan which results in measurable improvement of cardiorespiratory fitness, 
health-related quality of life, cardiac and respiratory function. 
Study details: 
Study duration: approximately 18 months (depending on inclusion progress, from inclusion of 
first participant until final visit of last enrolled participant) 
Individual treatment duration: 12 weeks 
Visit frequency: two study visits, at inclusion and at end of treatment period 
Number of Participants: Ten participants of both sexes will be enrolled and invited to the study 
inclusion visit to achieve an intervention group of 10 individuals starting the oral treatment. In 
terms of being a pilot study, the study will also help to estimate the expected fractions of 
evaluable and non-evaluable participant in a subsequent full scale randomized clinical trial. 
Evaluability means the participant absolving all included study tests during inclusion and final 
study visit and completing scheduled dosage control and ECG monitoring tasks. 
Note: “Enrolled” means a participant’s or his/her legally acceptable representative’s, agreement 
to participate in a clinical study following completion of the informed consent process. Potential 
participants who are screened for the purpose of determining eligibility for the study, but do not 
participate in the study, are not considered enrolled, unless otherwise specified by the protocol.  

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Health measurement / observation:  
At inclusion and final visit: 
 
− Demographics, biometric data, medical history 
− Quality of life assessment by questionnaire (SF-36, EQ-5D) 
− Echocardiography for cardiac function assessment 
− Pulmonary function test incl. diffusion capacity 
− Cardiopulmonary exercise test (bicycle ergometer) 
− Home-based polysomnography 
During treatment phase: 
− Dosage monitoring by analysis of theophylline concentration in blood sample (obtained 
locally) in addition to analysis of liver and renal parameters (ALT, bilirubin, creatinine), 
repeated on indication (after dose adjustment, in case of arrhythmic events) 
− Treatment compliance and AE monitoring by symptom report in electronic participant 
log book in ViedocMe (part of the eCRF-database) 
− ECG-monitoring (rhythm storage at least every hour) by tape-on ECG-device (ECG247®) 
connected to via smartphone app to an online database with 24/7 accessibility for medical 
monitor (5).  
o During early intervention phase until 5-7 days after therapeutic through 
concentration is achieved, the participant will continuously use the ECG247 
device. In case of symptoms (palpitations or other arrhythmia-suspect symptoms), 
the participant will be able to notify the medical monitor (cardiologist) for 
immediate review of ECG readings. 
o After cessation of continuous ECG-monitoring, the participant will be equipped 
with additional ECG-tapes for symptom-initiated ECG-readings and contact with 
medical monitor as needed. 
Drug regimen / adjustments: 
After inclusion visit, the participant starts on oral study medication (theophylline depot tablets 
200mg, start dose 200mg bid). In case of baseline bilirubin above 1.5 the upper normal limit, the 
start dose is 100 mg BID). 
After 3-5 days, the participant visits the family physician or a nearby hospital laboratory to 
collect a blood sample 4-6 hours after drug intake which is shipped to OUS for analysis (serum 
concentration of theophylline, creatinine, ALAT, bilirubin). For details of sample handling and 
shipment see section 10.2 appendix 2: Clinical Laboratory Tests.  
Target concentration of theophylline during study period is 30-80 μmol/Liter (4-6 hours after 
intake). Dose adjustments, if needed, are made by a physician at the research unit in 
collaboration with the PI. Dose increase or decrease depending on serum concentration by 
100mg steps up or down, i.e., from 200mg bid to either 100mg bid or 300mg bid. A dose 
reduction from 100 mg BID will be 100 mg OD. Any dosing changes have to followed by repeat 
blood work after 3-5 days. For dose modification algorithm see section 6.5. 
Data Monitoring/Other Committee: No 

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1.2. 
Schema 
 
 

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1.3. Schedule of Activities (SoA) 
 
Procedure 
Screening  
(up to 28 
days before 
Day 1) 
Baseline 
Assessment 
Intervention Period [Days or Weeks, etc.] 
E/D 
Follow-up 
(12-15 
weeks after 
treatment 
start) 
Notes 
 
E/D = Early 
Discontinuation 
* = may be postponed
1-2 days until 1st 
workday 
Up to 
4 
days 
be-
fore 
Day 1 
-1 
1 
Day 
2-4 
Day 
5* 
Day 
6-11 
Day 
12* 
Week 
3-12 
(-15) 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion and exclusion criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Demography 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Full physical examination including 
height and weight 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history (includes history of 
heart surgery and cardiac 
interventions, arrhythmia history) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Quality of life assessment (SF-36, EQ-
5D) 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
Pregnancy test (WOCBP only) 
X 
X 
 
 
 
 
 
 
 
 
 
X 
X 
 
Echocardiography 
 
X 
 
 
 
 
 
 
 
 
 
X 
X 
 
12-lead ECG  
X 
X 
 
 
 
 
 
 
 
 
 
X 
X 
 
Cardio-pulmonary exercise test 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
Pulmonary function test (incl. DLCO)  
X 
 
 
 
 
 
 
 
 
 
 
X 
 
Screening laboratory tests 
X*** 
 
 
 
 
 
 
 
 
 
 
 
 
 
Follow-up laboratory tests (include 
liver enzymes and renal function) 
 
X 
 
 
 
X 
 
X**  
 
 
X 
X 
** only if dose 
adjustment after day 5 
theophylline conc. 

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Procedure 
Screening  
(up to 28 
days before 
Day 1) 
Baseline 
Assessment 
Intervention Period [Days or Weeks, etc.] 
E/D 
Follow-up 
(12-15 
weeks after 
treatment 
start) 
Notes 
 
E/D = Early 
Discontinuation 
* = may be postponed
1-2 days until 1st 
workday 
Up to 
4 
days 
be-
fore 
Day 1 
-1 
1 
Day 
2-4 
Day 
5* 
Day 
6-11 
Day 
12* 
Week 
3-12 
(-15) 
 
 
Blood sample for theophylline serum 
concentration (4-6 hours after intake)  
 
 
 
 
X 
 
X**  
 
 
X 
 
 
Vital signs 
 
X 
 
 
 
 
 
 
 
 
 
X 
X 
 
ECG home device instruction 
(ECG247
®) 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Home-based ECG (review of online 
stored ECG readings and alarms) 
 
X 
X 
X 
X 
X 
X 
Y 
Y 
 
 
 
 
X = daily/continuously 
(incl. 5 days after dose 
adjustment) 
Y= symptom-
dependent 
Home based sleep study – instruction 
and equipment delivery* (1 day loan)  
 
X 
X 
 
 
 
 
 
 
 
 
X 
 
Oral treatment with Theophylline 
(Theo-Dur®) 
 
 
 
============================= 
 
 
 
AE review (weekly phone call from 
trial staff during intervention phase) 
 
X 
 
============================= 
 
 
 
Unsolicited AEs 
 
X 
 
============================= 
X 
X 
See Appendix 3 for 
definitions 
Consider separate 
tables for days with 
multiple assessments 
SAE review 
 
X 
 
============================= 
X 
X 
 

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Procedure 
Screening  
(up to 28 
days before 
Day 1) 
Baseline 
Assessment 
Intervention Period [Days or Weeks, etc.] 
E/D 
Follow-up 
(12-15 
weeks after 
treatment 
start) 
Notes 
 
E/D = Early 
Discontinuation 
* = may be postponed
1-2 days until 1st 
workday 
Up to 
4 
days 
be-
fore 
Day 1 
-1 
1 
Day 
2-4 
Day 
5* 
Day 
6-11 
Day 
12* 
Week 
3-12 
(-15) 
 
 
Concomitant medication review 
 
X 
 
============================= 
X 
X 
 
 
 
*** To avoid futile long-distance travel due to screening failure by laboratory results, samples for screening lab work might be 
collected locally and shipped to the study centre up to 28 days before screening visit and repeated on the day of visit if 
informed consent has been signed previously.

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2. 
Introduction 
 
Since  the  1970’s,  the  development  of  open  heart  surgery  has  allowed  patients  with  the  most 
complicated  congenital  heart  malformations  to  survive  into  adulthood (6).  Patients  with 
univentricular  heart  malformations  do  not  have  two  heart  chambers  supporting  a  normal 
circulation  with  
two  circuits.  
Instead,  a  series  of  heart  surgery  
interventions  create  a  so-called 
Fontan circulation, which is a common palliative surgical solution to a diversity of univentricular 
congenital heart defects. The surgical Fontan pathway leaves the patients with a single pumping 
heart chamber and a passive lung perfusion which powered by elevated central venous pressure. 
Due  
to  
improved  perioperative  and  
long-term  survival,  an  
increasing  number  of  patients  with 
Fontan circulation reach adulthood(7).  
One of the major problems of the Fontan circulation is the very limited ability to augment cardiac 
output(8). Follow-up studies in these patients shows low aerobic exercise capacity compared to 
healthy individuals already during childhood(9-11). Furthermore, an inevitable decline of exercise 
capacity starts in adolescence or early adulthood (12). Exercise capacity in this patient group is 
closely linked to and predicts quality of life(13, 14). 
Another long-term consequence is part of the complex entity of a failing Fontan circulation, which 
encloses heart failure symptoms, liver fibrosis and cirrhosis,  protein-losing enteropathy, plastic 
bronchitis, immunodeficiency, and thromboembolic events(15, 16). The main limiting factors of 
exercise capacity and the factors responsible for late failure of the Fontan circulation are limitation 
of transpulmonary blood flow, resistance in the pulmonary vessels and diastolic function of the 
single ventricle(16, 17). Furthermore, a recent study has demonstrated a large proportion of adults 
with Fontan circulation showing sleep-disordered breathing which potentially impacts negatively 
on pulmonary vascular resistance(18, 19). Other factors contributing to the eventual failing of the 
Fontan circulation are: 
1. Impaired heart rate response to exercise (chronotropic incompetence)(20). 
2. Physical  deconditioning  of  
the  patient  with  weakening  of  respiratory  musculature  (i.e. 
muscular  diaphragm)  and  less  effective  inspiratory  forces  supporting  venous  blood 
return(21-23). 
3. Reduced  pulmonary  function,  decrease  in  respiratory  efficiency  on  the  alveolar  and 
capillary level(24-27). 
4. Neuro-humoral and inflammatory activation(28-31). 
The  
final  
treatment  
for  survivors  of  Fontan  surgery  
is  heart  
transplantation.  However,  as  adult 
recipient candidates, patients with complex congenital heart disease have to compete with other 
recipient groups with less organ complications and better transplantation outcomes. Consequently, 
a significant research effort during the last decade has done to find therapeutic options to improve 
physical  and  cardiac  
function  
in  Fontan  patients  when  no  
further  surgical  
improvement  of  
the 
palliative circulation is possible. Non-surgical options would be pharmacological, skeletal and/or 
respiratory muscle training(32-35) or mechanical circulatory assist devices(36, 37).  

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2.1. Study Rationale 
Our study aims to investigate the short-term effect of oral treatment with theophylline on exercise 
capacity, health-related quality of life, cardiac function and respiratory function in clinically stable 
adolescent  Fontan  patients  who  are  not  
treated  with  sildenafil,  bosentan  or  any  other  specific 
pulmonary  vasodilator.  The  effects  of  theophylline, like  other  xanthine  derivates, match  in  a 
remarkable way several pathophysiological mechanisms of Fontan failure: 
1. Pulmonary vasodilation(38, 39) 
2. Positive (inotrop) effect on myocardial contractility(40, 41) 
3. Adenosine antagonism(42, 43) 
4. Positive effect on contractility of the muscular diaphragm(44-46) 
5. Increased renal perfusion(47, 48) 
6. Anti-inflammatory effect(49-51) 
7. Reduction of apnea/hypopnea episodes(52) 
We have reviewed previous published data on methylxanthine effects in heart failure and other 
comparable cardiovascular conditions i.e., with elevated pulmonary vascular pressure. Parker et 
al.  found  in  their  experimental  study  in  nine  heart  failure  patients  that  theophylline  ethylene 
diamine  (aminophylline)  reduces  markedly  the  pressures  in  the  right  heart  and  pulmonary 
circulation, and theophylline increases cardiac output (62). Al-Damluji et al. demonstrated that a 
single oral dose of theophylline given to nine patients with chronic heart failure increased cardiac 
index and systemic arterial pressure, whereas left ventricular filling pressure and mean right atrial 
pressures fell (57). All of these representing favorable hemodynamic effects. Murphy et al. studied 
the effects of aminophylline in 28 patients with elevated pulmonary vascular pressures due to left 
heart disease (63). They demonstrated a positive inotropic effect documented by a decrease in left 
ventricular filling pressures and simultaneous increase in the maximum rate of ventricular pressure 
rise (dP/dT). 
In summary, experimental studies in comparable cardiac conditions have demonstrated favorable 
hemodynamic  effects  of  methylxanthines,  namely  as  positive  
inotropic  effect  and  by  
lowering 
pulmonary vascular pressure. 
Hence, theophylline, even if it is and old and well-proven drug, is an intriguing substance to study 
for its potential to improve performance of the Fontan circulation, and it has not been studied in 
this context before. 
The primary endpoint oxygen uptake at anaerobic/ventilatory threshold (VO2@VAT) is chosen as 
primary  endpoint from submaximal  cardio-respiratory  exercise  parameters  because  it  is 
representative of the circulatory part of cardiorespiratory fitness. Thereby VO2@VAT measures 
pharmacologically achieved improvements of circulatory reserve with no regard if the participant 
achieves maximum exhaustion during cardiopulmonary exercise test. 
2.2. Background 
Through  
the  
last  
two  decades  pharmacological  studies  
to  
improve  performance  
in  
the  Fontan 
circulation for patients’ benefit have investigated effects of substances that are dilatators of the 
pulmonary  vascular  bed  like  the  phosphodiesterase  inhibitor  sildenafil,  and  the  endothelin 
antagonist bosentan(53).  

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Oral  sildenafil  has  repeatedly  been  shown  
to  
improve  both  
respiratory  efficiency  and  exercise 
capacity in Fontan patients(54, 55). Results from studies with bosentan are more conflicting. A 
Dutch study failed to show an effect on exercise capacity(56), whereas a Danish study has proven 
a significant, but minor improvement of exercise capacity and functional class(57). Even if the 
effect  of  both  drugs  on  exercise  capacity  
is  small  (sildenafil)  or  uncertain  (bosentan)  and  
the 
treatment is expensive, they are currently the only pharmacological treatment options. Long-term 
beneficial  effects  of  either  of  the  two  drugs  on  transplant-free  survival  are  unknown.  Most 
international centers are using bosentan, sildenafil or a  combination in the treatment of  Fontan 
patients of all ages when functional decline or failing of the Fontan circulation occurs. Cheaper 
and more effective pharmacological treatment strategies are still to be found. 
The xanthine derivates aminophylline (intravenously) and theophylline (orally) have been used for 
decades  in  the  treatment  of  obstructive  pulmonary  disease,  either  in  the  acute  or  the  chronic 
phase(50). The main cellular mechanism of xanthine derivates leading to bronchodilation are still 
unknown. Xanthine derivates have several others effects that contribute to their positive impact 
not only on airway obstruction but also on the heart, the circulation and respiration (43). Due to 
the  diverse  and  beneficial  circulatory  effects,  the  old  drug  theophylline  recently  has  gained 
attention in treatment of heart failure and other cardiac disease(49, 58, 59). 
The spectrum of effect mechanisms of theophylline matches remarkably with the different aspects 
of the limitation and/or eventual failure of the Fontan circulation. We therefore hypothesize that 
theophylline  might  have  a  positive  effect  on  quality  of  life,  exercise  capacity,  cardiac  and 
pulmonary function in patients with a Fontan circulation. As theophylline has been used for many 
decades, pharmacokinetic, adverse effects, toxicology and safety profiles are well known(50). 
 
2.3. Benefit/Risk Assessment 
More detailed information about the known and expected benefits and risks and reasonably 
expected adverse events of theophylline may be found in the Summary of Product 
Characteristics for Theo-Dur® 200/300 mg 
(https://www.legemiddelsok.no/_layouts/15/Preparatomtaler/Spc/0000-06607.pdf). 
2.3.1. 
Risk Assessment 
The theophylline-derived baseline heart rate increase and the risk of arrhythmia due to intoxication 
warrants special attention towards the proarrhythmic risk in patients with congenital heart disease. 
However, accelerated AV-node conduction due to theophylline has been associated with beneficial 
effects on bradycardia of different genesis and atrial fibrillation with slow ventricular rate (59). In 
an unselected hospitalized sample of 100 patients, Bittar & Friedman reviewed signs of arrhythmia 
in the ECG in relationship to theophylline serum concentration (60). Serum concentration was the 
strongest predictor of arrhythmia with atrial ectopic tachycardia  being the  predominant type of 
arrhythmia. No concomitant ventricular ectopy was found.  
Treatment studies and experimental studies using theophylline in other heart disease populations 
with assumed comparable arrhythmic vulnerability have been published. Javaheri et al. treated 15 
males  with  decompensated  heart  failure  with  reduced  ejection  fraction  and  sleep-disordered 
breathing with oral theophylline for five days. Theophylline trough concentration during treatment 
was 11±2 mcg/L with no difference in ventricular arrhythmia in terms of frequency of isolated 

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ventricular  depolarizations,  couplets  during  sleep  or  numbers  of  episodes  of  ventricular 
tachycardia defined as three or more premature ventricular beats in a row. (52). One of the patients 
in  this  study  encountered  supraventricular  tachycardia  with  theophylline  concentration  in 
therapeutic range (8.6 mcg/L). Al-Damluji et al. studied the effects of a single intravenous dose of 
600 mg theophylline in nine patients with chronic left ventricular failure (61). Seven patients had 
no changes to their heart rhythm. One patient in this study, with previous episodes of ventricular 
tachycardia before the study enrollment, had a non-sustained episode of ventricular tachycardia. 
This patient also had a toxic level of theophylline concentration. Andreas et l. studied the effects 
of intravenous theophylline in a double-blinded placebo-controlled study in eleven heart failure 
patients compared to both heart failure patients and healthy volunteers. They observed no change 
in heart rate in the theophylline / heart failure group and no arrhythmia episodes were reported 
(58). In a case-control study by Huerta et al. investigating the risk of arrhythmias due to different 
respiratory  medications,  ventricular  arrhythmias  were  not  associated  with  
theophylline  use,  by 
short term use of theophylline was weakly associated with atrial fibrillation and supraventricular 
tachycardia (62). This study was conducted in non-cardiac patients and all arrhythmia types were 
also associated with steroid use and beta-adrenoreceptors. 
The reduced elimination of theophylline shown in patients with chronic congestive heart failure is 
assumed to be related to liver function and galactose elimination capacity (63),  which indicate 
cautious theophylline dosage in individuals with Fontan circulation and varying degrees of Fontan-
associated liver disease. Hence, the first clinical trial with a new drug in this patient group should 
probably  be  performed  
in  young  adult  
individuals  before  Fontan-related  organ  complications, 
especially Fontan-associated liver disease, become more prevalent during adulthood (64). 
Potential Risk of Clinical 
Significance 
Summary of Data/Rationale for 
Risk 
Mitigation Strategy 
Study Intervention (oral theophylline treatment) 
Clinical risks 
Side-effects from 
theophylline without 
overdosage and serum 
concentration within 
therapeutic limits: 
- Mild side-effects:  
tremor, headache, 
gastrointestinal disturbances 
(nausea, vomiting, anorexia) 
Moderate side-effects: 
eczema, urticaria 
Severe: new-onset atrial or 
ventricular tachyarrhythmia, 
in particular atrial ectopic 
Side effects, toxicity and 
drug-drug-interactions 
according to SmPC 
(Preparatomtale) for Theo-
Dur® 200/300 mg, section 
4.8, 4.9 and 4.5 respectively. 
Risk consideration during 
pregnancy according to 
SmPC (Preparatomtale) for 
Theo-Dur® 200/300 mg, 
section 4.6. 
 
Mild/moderate side-effects: 
Report to clinical research 
ward for children for 
consideration of actions by 
supervising physician 
(pediatric/adult). 
 
 
 
 
Severe side-effects:  
ECG home monitoring (as 
per schedule and symptom 
dependent), ECG review by 

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tachycardia (see section 
7.1.2) 
Risk of increased toxicity or 
overdosage despite stable 
dose due to individual 
factors: 
- reduced theophylline 
clearance (heart failure) 
- liver disease (Fontan-
associated) 
- viral infection/fever 
- hypokalemia due to 
coadministration of high-dose 
beta2-agonists in case of 
severe bronchial asthma 
- electro-convulsive treatment 
- hyperthyroidism 
- severe hypertension 
- interaction with other 
medication which increases 
serum concentration of 
theophylline, i.e., cimetidine, 
chinoline derivates like 
enoxacin, ciprofloxacin, 
perfloxacin, viloxazin, 
makrolid antibiotics like 
erytromycin, troleandomycin, 
allopurinol, propranolol, 
disulfiram, isoniazid, oral 
contraconceptives, flu 
vaccine, mexiletine, 
nifedipine, norfloxacine, 
ranitidin, tiabendazol, 
verapamil, fluvoxamine. 
 
Effects due to theophylline 
overdosage before serum 
concentration above 
therapeutic limit is detected: 
- seizures 
team of supervising 
cardiologists (pediatric/adult). 
Serum concentration 
monitoring of theophylline, 
with a target concentration 
range well below the levels 
where tachyarrhythmias are 
most frequently reported. 
 
Unexpected toxicity and 
interactions: 
- Grading of Fontan-
associated liver disease as 
per inclusion assessment, 
exclusion from study due 
to severe liver disease 
according to exclusion 
criteria 
- Report of viral/bacterial 
infections with fever to 
clinical research ward for 
children (decision of 
theophylline 
concentration monitoring 
by team of supervising 
cardiologists) 
- Written instruction to 
report/discuss with 
clinical research ward for 
children any current or 
intended other medical 
therapies during treatment 
phase 
- Written information about 
diminished effect of 
theophylline from intake 
of St John
's-wort 
(Johannesurt, Hypericum 
perforatum) 
 

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Overdosage prevention and 
handling: 
-low starting dose (200mg 
BID), theophylline serum 
concentration monitoring as 
per schedule and symptom-
dependent 
- written information to 
general practitioner (fastlege) 
about study participation and 
symptoms of theophylline 
overdosage. 
 
 
Study Procedures 
Non-clinical risks 
Risk of accidents during 
transportation to study related 
visits at hospital or laboratory 
Clinical risks 
Risk of injury during 
cardiopulmonary exercise 
testing (CPET) 
 
 
 
 
CPET is generally considered 
a safe procedure with < 5 
adverse events per 100 000 
tests(65) 
Minimizing the number of 
study-related visits 
 
 
Test supervision by 
experienced test leader and 
physician. Use of ergometer 
bicycle as exercise method 
Other 
Non-clinical risks 
Risk of physical harm by 
misuse of ECG device is 
considered negligible. 
 
 
2.3.2. 
Benefit Assessment 
Potential benefits for the patients according to main effects of the drug are to be explored by 
the study, but presumably they include better exercise tolerance and an improved general 
experience of physical well-being. 
Experimental studies in comparable cardiac conditions have demonstrated favorable 
hemodynamic effects of methylxanthines, namely as positive inotropic effect and by 
lowering pulmonary vascular pressure. 
For patients with univentricular heart disease and Fontan-type palliation the age span 
between 16 and 25 years of age corresponds to the most appropriate period in life for a first 

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trial of a new drug in this patient group. Impaired cardiorespiratory fitness (CRF) (potentially 
improved by theophylline) is a common experience in patients with Fontan circulation of all 
ages (11, 12). However, the subjective experience of being very different from peers starts in 
teenage years, and the gap between the CRF of patients and healthy peers only increases with 
impact on mental health and quality of life (13, 66). Hence the teenage years would be a 
good time to be able to initiate pharmacological treatment intended to improve CRF. And 
even if 16 years means to be minor in terms of clinical trials, the definition of an adult patient 
with full control of his/her medical treatment starts at 16 years of age in Norway. 
 
2.3.3. 
Overall Benefit: Risk Conclusion 
Taking into account the measures taken to minimize risk to participants participating in this 
study, the potential risks identified in association with oral theophylline treatment are 
justified by the anticipated benefits that may be afforded to participants with Fontan 
circulation.

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3. 
Objectives, endpoints and estimands 
 
Objectives 
Estimands and Endpoints 
Primary 
 
• To investigate feasibility and safety of 
a 12 weeks treatment study design 
with remote dosage titration and 
handhold heart rhythm monitoring 
during treatment phase 
Endpoints:  
• Frequency of treatment emerged 
AE/SAE 
• Freedom from participant dropout 
based on tolerability of the study 
intervention 
• Number of participants requiring dose 
reduction after first serum 
concentration assessment 
• Freedom of arrhythmogenic side 
effects of the study treatment leading 
to patient dropout 
Primary 
 
• To provide an estimate of the effect 
size of 12 weeks of oral treatment 
with theophylline on exercise capacity 
in adolescents aged 16-25 years with 
univentricular congenital heart disease 
and Fontan circulation. 
Estimand: 
• Circulatory reserve during exercise 
Endpoint: 
• Difference in oxygen uptake at 
anaerobic/ventilatory threshold 
pre/post treatment. 
Secondary 
 
• To provide an estimate of the effect 
size of 12 weeks of oral treatment 
with theophylline on quality of life in 
adolescents aged 16-25 years with 
univentricular congenital heart disease 
and Fontan circulation. 
Estimand: 
• Health-related quality of life 
Endpoint: 
• Difference in total scores from SF-36 
and EQ-5D questionnaires pre/post 
treatment 
Secondary 
 
• To provide an estimate of the effect 
size of 12 weeks of oral treatment on 
cardiac performance in adolescents 
Estimand 
• Cardiac performance at rest 

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aged 16-25 years with univentricular 
congenital heart disease and Fontan 
circulation currently not treated with 
pulmonary vasodilators. 
Endpoint 
• Difference in ventricular function as 
assessed by echocardiography at rest 
pre/post treatment 
 
Secondary 
 
• To provide an estimate of the effect 
size of 12 weeks of oral treatment on 
respiratory function including 
diffusion capacity in adolescents aged 
16-25 years with univentricular 
congenital heart disease and Fontan 
circulation currently not treated with 
pulmonary vasodilators. 
Estimand: 
• Pulmonary function 
Endpoint: 
• Difference in diffusion capacity 
pre/post treatment 
Secondary 
 
• To provide an estimate of the effect 
size of 12 weeks of oral treatment on 
sleep disordered breathing in 
adolescents aged 16-25 years with 
univentricular congenital heart disease 
and Fontan circulation currently not 
treated with pulmonary vasodilators. 
Estimand 
• Sleep apnea 
Endpoint 
• Change in Apnea Hypopnea Index 
during home-based sleep study pre-
/post-treatment 
 

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4. 
Study Design 
4.1. Overall Design 
Single-group uncontrolled single-center open-label treatment study in adolescents (age 16-25 
years) with univentricular congenital heart defects surgically palliated with a Fontan-type 
operation. Inclusion of eligible patients from inpatient and outpatient contacts at participating 
departments at Oslo University Hospital Rikshospitalet.  
Study inclusion visit, drug treatment, remote dose adjustment, heart rhythm monitoring, and final 
post-treatment assessment study visit will be performed at the clinical research ward for children, 
Division of Paediatric and Adolescent Medicine.  
Dose adjustment decisions and heart rhythm monitoring will be effectuated by a joint group of 
associated specialists (pediatric cardiology, cardiology) with continuous service through the 
entire study period. 
Study duration: approximately 18 months (depending on inclusion progress, from inclusion of 
first participant until final visit of last enrolled participant) 
Individual treatment duration: minimum 12 weeks, maximum 15 weeks or until final study visit. 
Visit frequency: two study visits, at inclusion and at end of treatment period (earliest after 12 
weeks of treatment and latest after 15 weeks of treatment). 
Number of Participants: Ten participants of both sexes will be enrolled and invited to the study 
inclusion visit to achieve an intervention group of 10 individuals starting the oral treatment. In 
terms of being a pilot study, the study will also help to estimate the expected fractions of 
evaluable and non-evaluable participant in a subsequent full scale randomized clinical trial. 
Evaluability means the participant absolving all included study tests during inclusion and final 
study visit and completing scheduled dosage control and ECG monitoring tasks. 
Note: “Enrolled” means a participant’s or his/her legally acceptable representative’s, agreement 
to participate in a clinical study following completion of the informed consent process. Potential 
participants who are screened for the purpose of determining eligibility for the study, but do not 
participate in the study, are not considered enrolled, unless otherwise specified by the protocol.  
Health measurement / observation:  
At inclusion and final visit:   
− Demographics, biometric data, medical history 
− Quality of life assessment by questionnaire (SF-36, EQ-5D) 
− Echocardiography for cardiac function assessment 
− Pulmonary function test incl. diffusion capacity 
− Cardiopulmonary exercise test (bicycle ergometer) 
− Home-based polysomnography 
During treatment phase: 

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− Dosage monitoring by analysis of theophylline concentration in blood sample (obtained 
locally) in addition to analysis of liver and renal parameters (ALT, bilirubin, creatinine), 
repeated on indication (after dose adjustment, in case of arrhythmic events) 
− Treatment compliance and AE monitoring by symptom report in electronic participant 
log book in ViedocMe (part of the eCRF-database) 
− ECG-monitoring (rhythm storage at least every hour) by tape-on ECG-device (ECG247
®) 
connected to via smartphone app to an online database with 24/7 accessibility for medical 
monitor (5).  
o Starting from baseline visit during early intervention phase until 5-7 days after 
therapeutic concentration is achieved, the participant will continuously use the 
ECG247 device. In case of symptoms (palpitations or other arrhythmia-suspect 
symptoms), the participant will be able to notify the medical monitor 
(cardiologist) for immediate review of ECG readings. 
o After cessation of continuous ECG-monitoring, the participant will be equipped 
with additional ECG-tapes for symptom-initiated ECG-readings and contact with 
medical monitor as needed. 
Drug regimen / adjustments: 
After inclusion visit, the participant starts on oral study medication (theophylline depot tablets 
200mg, start dose 200mg bid). In case of baseline bilirubin above 1.5 the upper normal limit, the 
start dose is 100 mg BID). 
After 3-5 working days, the participant visits the family physician or a nearby hospital laboratory 
to collect a blood sample 4-6 hours after drug intake which is shipped to OUS for analysis 
(serum concentration of theophylline, creatinine, ALAT, bilirubin). Target concentration of 
theophylline during study period is 30-80 μmol/Liter. Dose adjustments, if needed, are made by a 
physician at the research unit in collaboration with the PI. Dose increase or decrease depending 
on serum concentration and drug tolerance by 100 mg steps up or down, i.e., from 200mg bid to 
either 100mg bid or 300mg bid (see also algorithm in section 6.5 Dose Modification). Any 
dosing change has to be followed by repeat blood work after 3-5 days and renewed review of 
theophylline concentration. A dose reduction from 100 mg BID will be 100 mg OD. 
Data Monitoring/Other Committee:   
Data Monitoring will be effectuated by Clinical Trials Unit at Oslo University Hospital Research 
Support. 
A safety monitoring committee (see section 10.1.5 committee structure) consists of a patient 
representative and to external specialists in adult cardiology and pediatric medicine (committee 
leader) respectively. The safety monitoring committee is assigned for general safety discussions 
regarding study protocol, planning and trial intervention. The committee has no continuous 
participant monitoring tasks, but serves as a consultant for the medical monitors during trial 
execution in case of AE/SAE/SUSAR and the need to consider participant exclusion or trial 
termination. 
 

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4.2. Scientific Rationale for Study Design 
Xanthine derivates have several others effects that contribute to their positive impact not only on 
airway obstruction but also on the heart, the circulation and respiration (43). Due to the diverse 
and beneficial circulatory effects, the old drug theophylline recently has gained attention in 
treatment of heart failure and other cardiac disease(49, 58, 59). 
The spectrum of effect mechanisms of theophylline matches remarkably with the different 
aspects of the limitation and/or eventual failure of the Fontan circulation. We therefore 
hypothesize that theophylline might have a positive effect on exercise capacity, health-related 
quality of life, cardiac and respiratory function in patients with a Fontan circulation.  
Our study aims to investigate the short-term effect of oral treatment with theophylline on 
exercise capacity, health-related quality of life, cardiac function and respiratory function in 
clinically stable adolescent Fontan patients who are not treated with sildenafil, bosentan or any 
other specific pulmonary vasodilator. The effects of theophylline, like other xanthine derivates, 
match in a remarkable way several pathophysiological mechanisms of Fontan failure. 
Furthermore, a recent study has demonstrated a large proportion of adults with Fontan circulation 
showing sleep-disordered breathing which potentially impacts negatively on pulmonary vascular 
resistance(18, 19). Potential beneficial effects of theophylline in the setting of Fontan circulation 
are: 
1. Pulmonary vasodilation(38, 39) 
2. Positive (inotrop) effect on myocardial contractility(40, 41) 
3. Adenosine antagonism(42, 43) 
4. Positive effect on contractility of the muscular diaphragm(44-46) 
5. Increased renal perfusion(47, 48) 
6. Anti-inflammatory effect(49-51) 
7. Reduction of apnea/hypopnea episodes(52) 
Hence, theophylline, even if it is and old and well-proven drug, is an intriguing substance to study 
for its potential to improve performance of the Fontan circulation, and it has not been studied in 
this context before. 
The  difference  in VO2@VAT before/after  treatment is  chosen  as  primary  endpoint  from 
submaximal  cardio-respiratory  exercise  parameters  because  
it represents  
the  circulatory  part  of 
cardiorespiratory  fitness.  Thereby  VO
2@VAT  measures  pharmacologically  achieved 
improvements  of  circulatory  reserve  with  no  regard  if  the  participant  achieves  maximum 
exhaustion during cardiopulmonary exercise test or not. 
Secondary endpoints are assessments either of beneficial effects of increased cardio-circulatory 
reserve  on  subjective  well-being  (health-related  quality  of  life)  or  of  beneficial  effects  of 
theophylline on other organ systems (lungs/airways, kidneys, musculature). 
The study aims to study theophylline effects in the Fontan circulation, and hence a non-Fontan 
control group would not add to study results or scientific knowledge gain. 
The participants minimum age was chosen by the required age to provide informed consent and 
the lower age limit of adult quality-of-life assessment instruments. For patients with univentricular 
heart disease and Fontan-type palliation the age span between 16 and 25 years of age corresponds 

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to the most appropriate period in life for a first trial of a new drug in this patient group. Impaired 
cardiorespiratory fitness (CRF) (potentially improved by theophylline) is a common experience in 
patients with Fontan circulation of all ages (11, 12). However, the subjective experience of being 
very different from peers starts in teenage years, and the gap between the CRF of patients and 
healthy peers only increases with impact on mental health and quality of life (13, 66). Hence the 
teenage years would be a good time to be able to initiate pharmacological treatment intended to 
improve CRF. And even if 16 years means to be minor in terms of clinical trials, the definition of 
an adult patient with full control of his/her medical treatment starts at 16 years of age in Norway. 
On the other side, the first clinical trial with a new drug in this patient group should probably be 
performed  in  young  adult  individuals  before  Fontan-related  organ  complications,  especially 
Fontan-associated  liver  disease,  become  more  prevalent  during  adulthood  (64).  Thus,  the 
maximum  participant  age  was  chosen  to  avoid  interference  by  other  Fontan-related  organ 
involvement  in  older  adults,  and  to  enable  study  coordination  through  the  pediatric  clinical 
research unit.  
The 1:1 ratio of male/female inclusion was chosen to avoid gender bias and to ensure that sex-
related differences in theophylline metabolism would not distort study results (67). 
The study results in terms of safety and efficacy will be compared to three comparable drugs that 
have been tested in previous clinical trials in this patient population, namely enalapril, sildenafil 
and bosentan. Hence, to enable a comparison of drug safety and effects between different drugs, 
the  duration  of  our  study  
intervention  
for  12  weeks  was  chosen  by  both clinical  
judgment  and 
oriented towards duration of interventions in the previous comparable trials.  
Enalapril:  
10 weeks (Kouatli et.al. 1997) (68) 
Sildenafil:  6 weeks (Goldberg et al. 2011) (54) 
Bosentan:   14 weeks (Hebert et al. 2014) (57) 
  
  
6 months (Schuuring et al. 2013) (56) 
 
4.2.1. 
Participant Input into Design 
 
4.3. Justification for Dose 
According to the SmPC (Preparatomtale) for Theo-Dur® 200/300 mg, section 4.2, normal start 
dosage for adults is 300mg BID. However, a reduced start dosage of 200mg BID is 
recommended in case of liver disease or heart failure. As theophylline has not been tested 
specifically in individuals with Fontan circulation, one cannot rule out a higher risk of 
theophylline side effects in this population. Hence, a stat dosage of 200mg BID with 
concentration measurements and dose titration, if necessary, was chosen for this study. 

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4.4. End of Study Definition 
The end of the study is defined as the date of last study related procedure in any participant 
which might be either a completed final study visit, or finishing of a post-treatment home-based 
polysomnography and return of equipment.  
A participant is considered to have completed the study if he/she has completed all phases of the 
study including a completed final study visit and finishing of a post-treatment home-based 
polysomnography and return of equipment. 

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5. 
Study Population 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, is not permitted. 
5.1. Inclusion Criteria 
Participants are eligible to be included in the study only if all of the following criteria apply: 
Age 
1. Participant must be 16 to 25 years of age inclusive, at the time of signing the informed 
consent. 
Type of Participant and Disease Characteristics 
2. Participants with univentricular congenital heart disease with a Fontan-type palliation  
a. Who are able to perform all diagnostic and monitoring procedures necessary during 
trial period, in particular being able to perform a symptom-limited cardiopulmonary 
exercise test on an upright ergometer bicycle. 
b. With available hepatic imaging results (ultrasound or magnetic resonance imaging) 
from less than 12 months before inclusion 
c. Without biochemical indications of severe liver disease or liver failure (se 
exclusion criteria) of more than mildly reduced kidney function. 
d. Considered and assessed eligible for administration of Theo-Dur® (theophylline) 
as specified in the SmPC. 
Weight 
3. Body mass index (BMI) within the range 18.5 – 34.9 kg/m2 (inclusive). 
Sex and Contraceptive/Barrier Requirements 
4. Contraceptive use by women is not under any national / local regulations in Norway. 
a. Male participants: no restrictions. 
b. Female participants: female participants should have a negative pregnancy test at 
inclusion and they receive information prior to consent that onset of pregnancy during 
treatment period has to be reported to the study team and leads to exclusion. 
Acceptable methods of contraception are defined in section 10.4.1 and 10.4.2 
Informed Consent 
5. Capable of giving signed informed consent as described in Appendix 1 which includes 
compliance with the requirements and restrictions listed in the informed consent form 
(ICF) and in this protocol. 
For participants < 18 years, all (both) parents or caregivers with parental 
responsibilities have to sign the consent form in addition to the participant. 
 

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5.2. Exclusion Criteria  
Participants are excluded from the study if any of the following criteria apply: 
Medical Conditions 
1. Current or previous (last 12 months) tachyarrhythmia which has been cause of medical 
investigation or hospitalization. 
2. Heart rhythm during inclusion visit other than: 
- sinus rhythm or regular supraventricular rhythm (visible P-waves) regardless P-wave 
angle 
- nodal rhythm 
- isolated extra beats (supraventricular or ventricular) of a frequency considered 
clinically non-significant 
3. Systemic hypertension (systolic or diastolic blood pressure above 95 percentile) 
4. Biochemical signs of more than mild liver disease or liver failure indicated by one of 
the following: 
a. INR > 1.4 in the absence of warfarin treatment or treatment with direct oral 
anticoagulants, 
b. ALAT more than twice the upper normal limit 
c. Bilirubin more than twice the upper normal limit 
5. Imaging signs from the recent 12 months indicating severe Fontan-associated liver 
disease, indicated by: 
a. Imaging findings that need further diagnostic work-up to rule out hepato-cellular 
carcinoma 
6. Biochemical indication of more than mildly reduced kidney function indicated by: 
a. Creatinine > 150 μmol/L (male) or > 120 μmol/L (female) 
7. Pregnancy 
8. Inherited forms of galactose intolerance (Lapp lactase deficiency eller glucose-
galactose malabsorption 
9. Hypersensitivity to theophylline 
 
Prior/Concomitant Therapy 
10. Current treatment with pulmonary vasodilator medication (sildenafil, tadalafil, 
udenafil, bosentan, ambrisentan, macicentan, or any prostacyclin derivate) 
11. Ongoing pharmacological treatment with the risk of drug-drug interactions. 
(Examples: cimetidine, chinoline derivates like enoxacin, ciprofloxacin, perfloxacin, 
viloxazin, makrolid antibiotics like erytromycin, troleandomycin, allopurinol, 
propranolol, disulfiram, isoniazid, oral contraconceptives, flu vaccine, mexiletine, 
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carbamazepine, felodipine, phenobarbital, phenytoin, rifampicine, lithium, ketamine, 
glucagon) 
Prior/Concurrent Clinical Study Experience 
12. No restrictions 
Diagnostic assessments 
13. No restrictions 
Other Exclusions 
14. Pregnancy or breastfeeding 
 
 
5.3. Lifestyle Considerations 
If applicable, describe any of the lifestyle considerations (diet, smoking habits, alcohol, or 
recreational drug consumption etc.) that could be of relevance for the study and any restrictions 
during any of the study periods. For example, include a statement about exposure to sunlight for 
study interventions with photosensitivity potential. 
5.3.1. 
Meals and Dietary Restrictions 
Refrain from consumption of any formulations containing St John’s-wort (Johannesurt, 
Hypericum perforatum) from 14 days before the start of study intervention until after the final 
dose. 
5.3.2. 
Caffeine, Alcohol, and Tobacco 
 
1. No restrictions for use of caffeine or alcohol. 
2. Participants who use tobacco products will be instructed to keep their level of tobacco use 
during treatment phase because of reduction of serum half-time in smokers and risk of 
overdosage in case of smoke cessation during study treatment phase. 
5.3.3. 
Activity 
No restrictions. 
5.4. Screen Failures 
Screen failures are defined as participants who consent to participate in the clinical study but are 
not subsequently examined during an inclusion and final visit or treated with the study drug. A 
minimal set of screen failure information is required to ensure transparent reporting of screen 
failure participants to meet the Consolidated Standards of Reporting Trials (CONSORT) 
publishing requirements and to respond to queries from regulatory authorities. Minimal 
information includes demography, screen failure details, eligibility criteria, and any serious 
adverse event (SAE). 
Individuals who do not meet the criteria for participation in this study (screen failure) by other 
than imaging criteria may be rescreened for a maximum of two times. 

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5.5. Criteria for Temporarily Delaying  
Not applicable. 

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6. 
Study Intervention(s) and Concomitant Therapy 
 
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according to the 
study protocol. 
6.1. Study Intervention(s) Administered 
 
ARM Name 
Treatment 
 
 
Intervention 
Name 
Theophylline 
 
 
Type  
Drug 
 
 
Dose 
Formulation 
Tablet 
 
 
Unit Dose 
Strength(s) 
200 mg 
 
 
Dosage 
Level(s) 
200 mg BID start dose 
(in case of elevated 
bilirubin 100 mg BID) 
 
 
Route of 
Administration 
Oral 
 
 
Use 
experimental 
 
 
IMP and 
NIMP 
IMP 
 
 
Sourcing 
Provided centrally by 
the Sponsor 
 
 
Packaging and 
Labeling 
Study drug will be 
provided in packages. 
Each package will be 
labeled as required per 
country requirement 
 
 
Aliases / drug 
names 
Theo-Dur® 
 
 

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Teofyllin Aurora 
Medical® 
6.1.1. 
Medical Devices 
 
1. Medical devices (not manufactured by or for Oslo University Hospital) provided for use 
in this study are: 
a. ECG247® (manufacturer: Appsens, Senterveien 30, 4790 Lillesand, Norway) (5) 
EC Conformity Certificate No. 10000366191.PA-NA-NOR Rev.0.0 
2. Instructions for medical device use are provided in written form to every participant and 
available online at: https://ecg247.no/forbruker/bruk/  
3. All device deficiencies (including malfunction, use error and inadequate labelling) shall 
be documented and reported by the investigator throughout the clinical investigation (see 
Section 8.3.9) and appropriately managed by the sponsor. 
6.2. Preparation/Handling/Storage/Accountability 
 
1. The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study intervention received and any discrepancies are 
reported and resolved before use of the study intervention. 
2. Only participants enrolled in the study may receive study intervention and only 
authorized site staff may supply or administer study intervention. All study intervention 
must be stored in a secure, environmentally controlled, and monitored (manual or 
automated) area in accordance with the labeled storage conditions with access limited to 
the investigator and authorized site staff. 
3. The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study intervention accountability, reconciliation, and record maintenance 
(i.e., receipt, reconciliation, and final disposition records). 
4. Further guidance and information for the final disposition of unused study interventions 
are provided in the [Study Reference Manual or other specified location]. 
 
6.3. Measures to Minimize Bias: Randomization and Blinding 
 
Open-label, No 
blinding at site level 
This is an open-label pilot study with no randomization. 
 

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6.4. Study Intervention Compliance 
 
When the individual dose for a participant is prepared from a bulk supply, the preparation of the 
dose will be confirmed by a second member of the study site staff.  
When participants self-administer study intervention(s) at home, compliance with study 
intervention will be assessed by a weekly participant log book review performed by the study 
nurse, and during each visit. Compliance deviations discovered by either log book entries or by 
study visit will be followed up and assessed by the study nurse in terms of direct questioning and 
by counting returned study medication at final visit. During the site visits and documented in the 
source documents and relevant form. Deviation(s) from the prescribed dosage regimen should be 
recorded. 
Compliance deviations will be reported by the study nurse to the medical monitor as soon as 
practically possible, but within maximum two working days. The medical monitor has to 
evaluate the assessed compliance. The medical monitor has to decide by clinical judgement if the 
study intervention can continue without affecting study outcome, or if study participation has to 
be discontinued. 
A record of the quantity of theophylline tablets dispensed to and administered by each participant 
must be maintained and reconciled with study intervention and compliance records.  Intervention 
start and stop dates, including dates for intervention delays and/or dose reductions will also be 
recorded. 
6.5. Dose Modification 
The decision to proceed to the next dose level of theophylline (either an increase or a decrease) 
will be made by the Study Team and the investigator based on serum concentration 4-6 hours 
after drug intake, safety, tolerability, and PK and pharmacodynamic data from SmPC 
(Preparatomtale). 
Drug modification algorithm: 
Target concentration of theophylline during study period is 30-80 μmol/Liter. Dose adjustments, 
if needed, are made by a physician at the research unit in collaboration with the PI. Dose increase 
or decrease depending on serum concentration and drug tolerance by 100mg steps up or down, 
i.e., from 200mg bid to either 100mg bid or 300mg bid (see also graphic algorithm). A dose 
reduction from 100 mg BID will be 100 mg OD. Any dosing change has to be followed by repeat 
blood work after 3-5 days and renewed review of theophylline concentration. 

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6.5.1. 
Retreatment Criteria 
Not applicable.  
 
6.6. Continued Access to Study Intervention after the End of the Study 
Continued access to theophylline treatment is possible on a strictly individual basis with 
approval of the participant after subjectively (health-related quality of life) or objectively 
(exercise capacity) improved health status. Continued off-label access to theophylline treatment 
is within responsibility of the participant’s cardiologist and outside responsibility of the Study 
Team.  
6.7. Treatment of Overdose / Intoxication 
For this study, any dose of theophylline greater than twice the current treatment dosage within a 
24-hour time period will be considered an overdose. Any serum concentration ≥ 110 μmol/Liter 
is considered suspicious of intoxication and should lead to immediate action and to verification 
(re-measurement) of serum concentration of theophylline. 
Oslo University Hospital does recommend treatment for an overdose and/or intoxication in 
accordance with the SmPC (Preparatomtale). 
In the event of an overdose and/or intoxication, the treating physician should: 
• Contact the Medical Monitor immediately. 

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• Evaluate the participant to determine, in consultation with the Medical Monitor, whether 
study intervention should be interrupted or whether the dose should be reduced. 
• Closely monitor the participant for any AE/SAE and laboratory abnormalities until 
theophylline concentration is within therapeutic range, or, in case of planned 
discontinuation, until theophylline can no longer be detected systemically (after at least 2 
days). 
• Obtain a plasma sample for PK analysis within 1 day from the date of the last dose of 
study intervention if requested by the Medical Monitor (determined on a case-by-case 
basis). 
• Document the quantity of the excess dose as well as the duration of the overdose. 
 
6.8. Concomitant Therapy 
Any medication or vaccine (including over-the-counter or prescription medicines, recreational 
drugs, vitamins, and/or herbal supplements) or other specific categories of interest, that the 
participant is receiving at the time of enrollment or receives during the study must be recorded 
along with: 
• Reason for use 
• Dates of administration including start and end dates 
• Dosage information including dose and frequency 
The Medical Monitor should be contacted if there are any questions regarding concomitant or 
prior therapy. 
Participants must abstain from taking prescription or nonprescription drugs (including vitamins 
recreational drugs, and dietary or herbal supplements) within 7 days (or 14 days if the drug is a 
potential enzyme inducer) or 5 half-lives (whichever is longer) before the start of study 
intervention until completion of the follow-up visit, unless, in the opinion of the investigator and 
sponsor, the medication will not interfere with the study. Herbal supplements containing St 
John’s-wort (Johannesurt, Hypericum perforatum) must not be used from 14 days before 
treatment until the end of treatment. 
Paracetamol/Acetaminophen, at doses of ≤ 2 grams/day, and Ibuprofen at doses of ≤ 800 mg/day 
are permitted for use any time during the study. Other concomitant medication may be 
considered on a case-by-case basis by the investigator in consultation with the Medical Monitor.  
6.8.1. 
Rescue Medicine 
Not applicable. 

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7. 
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal 
7.1. Criteria for early termination of the trial 
The trial will be terminated if any of the following criteria are fulfilled: 
− New or emerging safety information affect the benefit/risk assessment of the clinical trial 
negatively 
− Two or more participants have to stop study intervention due to liver chemistry stopping 
criteria 
− Two or more participants have to stop study intervention due to arrhythmia and QTc 
stopping criteria 
7.2. Discontinuation of Study Intervention 
In rare instances, it may be necessary for a participant to permanently discontinue study 
intervention. If study intervention is permanently discontinued, the participant will not remain in 
the study to be evaluated. See the SoA for data to be collected at the time of discontinuation of 
study intervention and follow-up and for any further evaluations that need to be completed. 
 
7.2.1. 
Liver Chemistry Stopping Criteria 
Discontinuation of study intervention for abnormal liver tests is required by the investigator 
when a participant meets one of the conditions outlined in section 5.1.4 (exclusion criteria) or in 
the presence of abnormal liver chemistries not meeting protocol-specified stopping rules if the 
investigator believes that it is in best interest of the participant. 
 
7.2.2. 
Arrhythmia and QTc Stopping Criteria 
If a clinically significant finding is identified (including, but not limited to changes from baseline 
heart rhythm and changes in QT interval corrected using Bazett’s formula [QTcB]) after 
enrollment, the investigator or qualified designee will determine if the participant can continue in 
the study and if any change in participant management is needed. This review of the 12-channel 
hospital ECG printed at the time of inclusion or review of ECG readings obtained by 12-channel 
ECG or ECG247 device during intervention phase must be documented. Any new clinically 
relevant finding should be reported as an AE. 
The following arrhythmic events during intervention phase will lead to termination of study 
intervention in a participant (immediate cessation of theophylline treatment), if practically 
possible with immediate blood sample for theophylline serum concentration assessment and 
clinical outpatient visit at OUS Rikshospitalet as soon as possible: 

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− Sustained non-sinus supraventricular or junctional tachycardia of any type (atrial flutter, 
atrial fibrillation, ectopic atrial tachycardia, atrioventricular node reentrant tachycardia, 
atrioventricular reentrant tachycardia) with resting atrial rate of 100 minute-1 or higher 
and disregarding ventricular rate 
− Premature supraventricular or ventricular beats with significantly increased rate (extra 
beats per minute) or different occurrence pattern (i.e.bigemini) compared to baseline 
ECG recording and combined with symptoms or otherwise considered clinically relevant  
− New onset non-sustained or sustained ventricular tachycardia 
− Any syncopal or near-syncopal event in close timely relationship to a documented 
arrhythmia in ECG247 recordings or in 12-channel ECG fulfilling discontinuation criteria 
7.2.3. 
Temporary Discontinuation 
Not applicable 
7.2.4. 
Rechallenge 
Not applicable 
7.2.4.1. Study Intervention Restart or Rechallenge After Liver Stopping Criteria Met 
Study intervention restart or rechallenge after liver chemistry stopping criteria are met by any 
participant in this study is not allowed. 
7.3. Participant Discontinuation/Withdrawal from the Study 
 
• A participant may withdraw from the study at any time at his/her own request or may be 
withdrawn at any time at the discretion of the investigator for safety, behavioral, or 
compliance reasons. This is expected to be uncommon. 
• At the time of discontinuing from the study, if possible, an early discontinuation visit or 
phone/video call should be conducted, as shown in the SoA. See SoA for data to be 
collected at the time of study discontinuation and follow-up and for any further 
evaluations that need to be completed. 
• The participant will be permanently discontinued both from the study intervention and 
from the study at that time. 
• If the participant withdraws consent for disclosure of future information, the sponsor may 
retain and continue to use any data collected before such a withdrawal of consent. 
• If a participant withdraws from the study, he/she may request destruction of any samples 
taken and not tested, and the investigator must document this in the site study records. 

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7.4. Lost to Follow up 
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site. 
The following actions must be taken if a participant fails to return to the clinic for a required 
study visit: 
• The site must attempt to contact the participant and reschedule the missed visit as soon as 
possible and counsel the participant on the importance of maintaining the assigned visit 
schedule and ascertain whether or not the participant wishes to and/or should continue in 
the study. 
• Before a participant is deemed lost to follow up, the investigator or designee must make 
every effort to regain contact with the participant (where possible, three telephone calls or 
SMS). These contact attempts should be documented in the participant’s medical record. 
• Should the participant continue to be unreachable, he/she will be considered to have 
withdrawn from the study.  
Discontinuation of specific sites or of the study as a whole are handled as part of Appendix 1. 

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8. 
Study Assessments and Procedures 
• Study procedures and their timing are summarized in the SoA. Protocol waivers or 
exemptions are not allowed. 
• Immediate safety concerns should be discussed with the sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or discontinue 
study intervention. 
• Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct. 
• All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable. 
• Procedures conducted as part of the participant’s routine clinical management (e.g., blood 
count) and obtained before signing of the ICF may be utilized for screening or baseline 
purposes provided the procedures met the protocol-specified criteria and were performed 
within the time frame defined in the SoA. 
8.1. Efficacy Assessments 
Planned time points for all efficacy assessments are provided in the SoA. 
8.2. Safety Assessments 
Planned time points for all safety assessments are provided in the SoA. 
8.2.1. 
Physical Examinations 
 
• A complete physical examination will include, at a minimum, assessments of the 
Cardiovascular and Respiratory systems. Height and weight will also be measured and 
recorded. 
• A brief physical examination will include, at a minimum, assessments of the lungs and 
cardiovascular system. 
• Investigators should pay special attention to clinical signs related to previous serious 
illnesses. 
8.2.2. 
Vital Signs 
 
• Pulse rate, respiratory rate, and blood pressure will be assessed. 
• Blood pressure and pulse measurements will be assessed in semi-supine position with a 
completely automated device. Manual techniques will be used only if an automated 
device is not available. 

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• Blood pressure and pulse measurements should be preceded by at least 5 minutes of rest 
for the participant in a quiet setting without distractions (e.g., television, cell phones). 
• Vital signs (to be taken before blood collection for laboratory tests) will consist of 1 pulse 
and 3 blood pressure measurements (3 consecutive blood pressure readings will be 
recorded at intervals of at least 1 minute). The average of the 3 blood pressure readings 
will be recorded. 
• Electrocardiograms: Single 12-lead ECG will be obtained as outlined in the SoA (see 
Section 1.3) using an ECG machine that automatically calculates the heart rate and 
measures PR, QRS, QT, and QTc intervals. Refer to Section 7.1.2 for QTc withdrawal 
criteria and any additional QTc readings that may be necessary. 
8.2.3. 
Clinical Safety Laboratory Assessments 
 
• See Appendix 2 for the list of clinical laboratory tests to be performed and to the SoA 
(Section 1.3) for the timing and frequency. 
• The investigator must review the laboratory report, document this review, and record any 
clinically significant changes occurring during the study as an AE. The laboratory reports 
must be filed with the source documents.  
• Abnormal laboratory findings associated with the underlying disease are not considered 
clinically significant unless judged by the investigator to be more severe than expected 
for the participant’s condition. 
• Laboratory tests with values considered clinically significantly abnormal during 
participation in the study (together with theophylline serum concentration assessment) or 
within 1 week after the last dose of study intervention should be repeated until the values 
return to normal or baseline or are no longer considered clinically significant by the 
investigator or medical monitor. 
o If clinically significant values do not return to normal/baseline within a period of time 
judged reasonable by the investigator, the etiology should be identified, and the 
sponsor notified. 
o All protocol-required laboratory tests, as defined in Appendix 2, must be conducted in 
accordance with the laboratory manual (https://labfag.no) and the SoA (Section 1.3). 
o If laboratory values from non-protocol specified laboratory tests performed at the 
institution’s local laboratory require a change in participant management or are 
considered clinically significant by the investigator (e.g., SAE or AE or dose 
modification), then the results must be recorded. 
8.2.4. 
Pregnancy Testing 
A pregnancy test from a urine sample is performed in females during the inclusion visit. 

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8.2.5. 
Suicidal Ideation and Behavior Risk Monitoring 
Oral theophylline is NOT considered to be a CNS-active intervention and therefore monitoring 
for suicidal ideation and behavior or any other unusual changes in behavior apart from usual 
attention by medical professionals is not required. 
8.3. Adverse Events (Aes), Serious Adverse Events (SAEs), and Other 
Safety Reporting 
 
The definitions of adverse events (Aes) and serious adverse events (SAEs) can be found in 
Appendix 3. 
Aes will be reported by the participant (or, when appropriate, by a caregiver, surrogate, or the 
participant’s legally authorized representative).  
The investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE and remain responsible for following 
up all Aes OR Aes that are serious, considered related to the study intervention or study 
procedures, or that caused the participant to discontinue the oral theophylline treatment (see 
Section 7). 
All events that might qualify for being considered as Ae or SAEs recorded by any team member 
of the trial team has to be forwarded to the team of Medical Monitors as soon as practically 
possible, at the latest within 24 hours. Events in minor participants should preferably be reported 
to the principal investigator with pediatric qualification, events in adult participants should 
preferably be reported initially to the Medical Monitor with adult cardiology qualification. The 
latter will then evaluate the report and forward to the principal investigator based on an 
individual judgement. 
The method of recording, evaluating, and assessing causality of Aes and SAEs and the 
procedures for completing and transmitting SAE reports are provided in Appendix 3. 
8.3.1. 
Time Period and Frequency for Collecting AE and SAE Information 
All SAEs will be collected from the start of intervention until the follow-up visit at the time 
points specified in the SoA (Section 1.3). 
All Aes will be collected from the start of intervention until the follow-up visit at the time points 
specified in the SoA (Section 1.3). 
Medical occurrences that begin before the start of study intervention but after obtaining informed 
consent will be recorded as Medical History/Current Medical Conditions, not as Aes. 
All SAEs will be recorded and reported to the sponsor or designee immediately and under no 
circumstance should this exceed 24 hours, as indicated in Appendix 3. The investigator will 
submit any updated SAE data to the sponsor within 24 hours of it being available. 
Investigators are not obligated to actively seek information on Aes or SAEs after conclusion of 
the study participation. However, if the investigator learns of any SAE, including a death, at any 
time after a participant has been discharged from the study, and he/she considers the event to be 

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reasonably related to the study intervention or study participation, the investigator must promptly 
notify the sponsor. 
8.3.2. 
Method of Detecting Aes and SAEs 
Care will be taken not to introduce bias when detecting Aes and/or SAEs. Open-ended and 
non-leading verbal questioning of the participant is the preferred method to inquire about 
AE occurrences. 
During intervention phase, a research nurse from the pediatric clinical research unit will call the 
participant every week for a short interview to detect AE/SAE. To detect solicited AE, the 
participant will specifically be asked about symptoms with potential relation to arrhythmia 
events (palpitations, syncopal/near-syncopal events). 
Detection of Aes might happen by entries into the electronic participant log book (ViedocMe), or 
by phone call initiated by either the study nurse or the participant (or representative). Also, 
phone calls from a participant (or representative) to one of the investigators (study phone 1-3) 
has to be considered a potential Ae and it has to be evaluated accordingly. 
During the first period of study intervention (for every participant until 5 days after last 
necessary dose adjustment), one of the medical monitors will at least every 48 hours review the 
ECG recording portal for heart rhythm monitoring (ECG247, see section 6.1.1) as long as any of 
the participants is under continuous rhythm monitoring with ECG247. After that period, the 
medical monitor will review the ECG recording portal upon notification from the research nurse 
if any participant has reported AE suspicious symptoms and been asked to reapply the ECG247 
for recording. 
Results from the ECG247 review will be entered into the eCRF. A copy of the ECG recordings 
which are the basis of the evaluation report, will be stored in the patient’s hospital record 
together with the report itself. 
8.3.3. 
Follow-up of Aes and SAEs 
 
After the initial AE/SAE report, the investigator is required to proactively follow each participant 
at subsequent visits/contacts. All SAEs will be followed until resolution, stabilization, the event 
is otherwise explained, or the participant is lost to follow-up (as defined in Section 7.4). Further 
information on follow-up procedures is provided in Appendix 3. 
8.3.4. 
Regulatory Reporting Requirements for SAEs 
 
• Prompt notification by the investigator to the sponsor of an SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of 
a study intervention under clinical investigation are met. 
• The sponsor has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a study intervention under clinical 
investigation. The sponsor will comply with country-specific regulatory requirements 
relating to safety reporting to the regulatory authority, Institutional Review Boards 
(IRB)/Independent Ethics Committees (IEC), and investigators. 

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• An investigator who receives an investigator safety report describing an SAE or other 
specific safety information (e.g., summary or listing of SAEs) from the sponsor will 
review and will notify the IRB/IEC, if appropriate according to local requirements. 
8.3.5. 
Pregnancy 
 
• Details of all pregnancies in female participants will be collected after the start of study 
intervention and until follow-up visit. 
• If a pregnancy is reported, the investigator will record pregnancy information on the 
appropriate form and submit it to the sponsor within 24 hours of learning of the female 
participant’s pregnancy. 
• While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy for medical reasons will be reported 
as an AE or SAE. 
• Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAEs and will be reported as 
such. 
• The participant will be followed to determine the outcome of the pregnancy. The 
investigator will collect follow-up information on the participant and the neonate and the 
information will be forwarded to the sponsor. 
• Any post-study pregnancy-related SAE considered reasonably related to the study 
intervention by the investigator will be reported to the sponsor as described in 
Section 8.3.4. While the investigator is not obligated to actively seek this information in 
former study participants, he or she may learn of an SAE through spontaneous reporting. 
• Any female participant who becomes pregnant while participating in the study will 
discontinue study intervention or be withdrawn from the study. 
 
8.3.6. 
Cardiovascular and Death Events 
Any negative change from initial heart rhythm in the 12 channel ECG (inclusion visit, see 
exclusion criteria) on home-based ECG-monitoring has to be reviewed by a study physician / 
medical monitor. Change from supraventricular rhythm to nodal rhythm or vice versa are 
considered habitual/normal. 
Tachycardic arrhythmic events have to be considered either as AE’s or SAE’s depending on 
medical consequences (need for medical intervention or hospital admission, spontaneous 
resolution). Possible events are: 
− Sustained or non-sustained atrial/supraventricular tachycardia of any kind (ectopic 
automatism, supraventricular/nodal reentry) 
− Sustained or non-sustained ventricular tachycardia 
− Supraventricular or ventricular extra beats with frequency considered clinically 
significant by medical monitor. 

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In case of any tachyarrhythmia events, cessation of study intervention has to be considered by a 
medical monitor. 
 
8.3.7. 
Disease-Related Events and/or Disease-Related Outcomes Not Qualifying as Aes 
or SAEs 
The following disease-related events (DREs) are common in participants with Fontan-type 
palliation of univentricular congenital heart disease and can be serious/life threatening: 
• Heart failure 
• Thromboembolism 
• Non-tachycardic arrhythmic events 
• Cerebral abscess 
Because these events are typically associated with the disease under study, they will not be 
reported according to the standard process for expedited reporting of SAEs even though the 
event may meet the definition of an SAE. These events will be recorded within the intervention 
phase. These DREs will be monitored on a routine basis. See Section 10.1 
NOTE: However, if either of the following conditions applies, then the event must be recorded 
and reported as an AE/SAE (instead of a DRE): 
• Event onset within 24 hours after initiation of study treatment  
• Event onset within 24 hours after dosage uptitration. The investigator considers that there 
is a reasonable possibility that the event was related to study intervention (i.e., preceding 
suspected or documented arrhythmia event). 
 
8.3.8. 
Adverse Events of Special Interest 
Not applicable. 
8.3.9. 
Medical Device Deficiencies 
Medical devices are not being provided for use in this study as the study intervention. 
 
8.4. Pharmacokinetics 
PK parameters are not evaluated in this study. 
Pharmacodynamic parameters are not evaluated in this study. 
8.5. 
Genetics and/or Pharmacogenomics 
Genetics are not evaluated in this study. 

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8.6. Biomarkers 
 
Biomarkers are not evaluated in this study. 
8.7. Immunogenicity Assessments 
 
Antibodies will not be evaluated in the study.  
 
8.8. Health Economics OR Medical Resource Utilization and Health 
Economics 
 
Health Economics OR Medical Resource Utilization and Health Economics parameters are not 
evaluated in this study. 
 

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9. 
Statistical Considerations 
9.1. Statistical Hypotheses 
The study hypothesis is that the study intervention positively affects Estimands leading to 
statistically significant changes from pre-intervention to post-intervention in primary and 
secondary endpoint variables.  
Effects size on primary and secondary endpoint variables will allow for group size calculation in 
a future randomized clinical trial. 
9.2. Sample Size Determination 
The group size in this pilot study has been set voluntarily. 
9.3. Analysis Sets 
Not applicable 
9.4. Statistical Analyses 
9.4.1. 
General Considerations 
Simple paired sample comparison (parametric or non-parametric) will be applied. No further 
statistical analysis plan is designed due to small pilot sample size. 
Two-sided tests will be used on a 5% level of significance. 
9.4.2. 
Primary Endpoint(s) 
Safety – freedom from intervention-related adverse events or discontinuation.  
Not statistically analyzable. 
Difference in oxygen uptake at anaerobic/ventilatory threshold pre/post treatment (ml/min/kg) 
Analysis by paired sample Student t-test or non-parametric paired samples test as appropriate. 
 
9.4.3. 
Secondary Endpoint(s) 
Difference in total scores from SF-36 and EQ-5D questionnaires pre/post treatment 
Difference in ventricular function as assessed by echocardiography at rest pre/post treatment 
Difference in diffusion capacity pre/post treatment 
Change in Apnea Hypopnea Index during home-based sleep study pre-/post-treatment 
Analysis of all secondary endpoint by paired sample Student t-test or non-parametric paired 
samples test as appropriate. 
 

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9.4.4. 
Tertiary/Exploratory Endpoint(s) 
Not applicable 
9.4.5. 
Safety Analysis 
Not applicable 
9.4.6. 
Other Analysis 
Not applicable 
9.5. Interim Analysis 
Not applicable due to short intervention phase. 

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10. 
Supporting Documentation and Operational Considerations 
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations 
10.1.1. Regulatory and Ethical Considerations 
• This study will be conducted in accordance with the protocol and with the following: 
o Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences (CIOMS) International Ethical Guidelines 
o Applicable ICH Good Clinical Practice (GCP) Guidelines 
o Applicable laws and regulations 
• The protocol, protocol amendments, ICF, Investigator Brochure, and other relevant 
documents (e.g., advertisements) must be submitted to an IRB/IEC by the investigator 
and reviewed and approved by the IRB/IEC before the study is initiated. 
• Any amendments to the protocol will require IRB/IEC approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an 
immediate hazard to study participants.  
• Protocols and any substantial amendments to the protocol will require health authority 
approval prior to initiation except for changes necessary to eliminate an immediate 
hazard to study participants. 
• The investigator will be responsible for the following: 
o Providing written summaries of the status of the study to the IRB/IEC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/IEC 
o Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures 
o Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 CFR, ICH guidelines, the IRB/IEC, European regulation 536/2014 
for clinical studies (if applicable), European Medical Device Regulation 2017/745 for 
clinical device research (if applicable), and all other applicable local regulations 
10.1.2. Financial Disclosure 
Investigators and sub-investigators will provide the sponsor with sufficient, accurate financial 
information as requested to allow the sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators are 
responsible for providing information on financial interests during the course of the study and for 
1 year after completion of the study. 
10.1.3. Informed Consent Process 
 

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• Identification of eligible patients: 
Eligible patients according to inclusion criteria will be identified by search in the patient 
registry on patients with congenital heart disease (all ages) at Oslo University Hospital, 
named BERTE. Only patients within ≤ 1 hour travel distance to the nearest hospital will 
be considered eligible. In case recruitment of patients who reside at long distance from 
the study site, the possibility of unplanned follow-up visits at the local hospital will be 
prepared by the study team by informing relevant health care providers. All regular study 
visits are performed at Oslo University Hospital. 
A search in the hospital’s patient registry will involve access to identifiable information. 
Only lawful access by a medical monitor (pediatric or adult cariology) will be performed 
for eligibility identification purposes. 
• Recruitment procedure: 
Eligible patients for study recruitment will be contacted by medical staff at Oslo 
University Hospital in different ways depending on previously planned inpatient or 
outpatient appointments: 
o Patients (caregivers for minors) with planned appointments within a short time (less 
than 3 months) will be recruited by oral information from a physician from the team 
of investigators at the time of their clinical appointment. 
o Patients (caregivers for minors) with no planned appointment in the near future will 
be contacted by phone. If the patient I generally interested in adjusting outpatient 
appointment schedule, an outpatient appointment will be offered for both clinical 
follow-up and for information / recruitment. 
• The investigator or his/her representative will explain the nature of the study to the 
participant and for participants < 18 years also to their legally authorized representative 
and answer all questions regarding the study. 
• Obtaining informed consent will be performed by study staff with no current involvement 
in the participants medical treatment (either physician [specialist in pediatric medicine] or 
research nurse 
• Participants must be informed that their participation is voluntary. Participants or their 
legally authorized representative [in participants < 18 years defined as parents or 
caregivers will be required to sign a statement of informed consent that meets the 
requirements of 21 CFR 50, local regulations, ICH guidelines, Health Insurance 
Portability and Accountability Act (HIPAA) requirements, where applicable, and the 
IRB/IEC or study center. 
• The medical record must include a statement that written informed consent was obtained 
before the participant was enrolled in the study and the date the written consent was 
obtained. The authorized person obtaining the informed consent must also sign the ICF. 
• Participants must be re-consented to the most current version of the ICF(s) during their 
participation in the study. 
• A copy of the ICF(s) must be provided to the participant or their legally authorized 
representative. 

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10.1.4. Data Protection 
 
• Participants will be assigned a unique identifier by the sponsor. Any participant records 
or datasets that are transferred to the sponsor will contain the identifier only; participant 
names or any information which would make the participant identifiable will not be 
transferred. 
• The participant must be informed that his/her personal study-related data will be used by 
the sponsor in accordance with local data protection law. The level of disclosure must 
also be explained to the participant who will be required to give consent for their data to 
be used as described in the informed consent  
• The participant must be informed that his/her medical records may be examined by 
Clinical Quality Assurance auditors or other authorized personnel appointed by the 
sponsor, by appropriate IRB/IEC members, and by inspectors from regulatory authorities. 
10.1.5. Committees Structure 
A safety monitoring committee consists of a patient representative and to external specialists in 
adult cardiology and pediatric medicine (committee leader) respectively. The safety monitoring 
committee is assigned for general safety discussion regarding study protocol, planning and trial 
intervention. The committee has no continuous participant monitoring tasks, but serves as a 
consultant for the medical monitors during trial execution in case of AE/SAE/SUSAR and the 
need to consider participant exclusion or trial termination. 
A user/patient committee with three members is assigned for user communication and input 
during all study phases. 
Due to small sample size and open-label non-randomized pilot study design with short 
intervention phase, no additional committees er assigned. 
10.1.6. Early Safety Data Review AND/OR Committee 
 
Due to small sample size and open-label non-randomized pilot study design with short 
intervention phase, no such review or committee is applicable. 
 
10.1.7. Dissemination of Clinical Study Data 
 
Study results will be published as scientific conference abstracts and as scientific manuscripts 
in peer-reviewed journals in an open-access-way of publishing. 
10.1.8. Data Quality Assurance 
 
• All participant data relating to the study will be recorded on printed or electronic CRF 
unless transmitted to the sponsor or designee electronically (e.g., laboratory data). The 
investigator is responsible for verifying that data entries are accurate and correct by 
physically or electronically signing the CRF. 

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• Guidance on completion of CRFs will be provided in study documents provided to the 
Clinical research ward for children. 
• The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents. 
• Quality tolerance limits (QTLs) will be pre-defined to identify systematic issues that can 
impact participant safety and/or reliability of study results. These pre-defined parameters 
will be monitored during the study and important deviations from the QTLs and remedial 
actions taken will be summarized in the clinical study report. 
• Monitoring details describing strategy (e.g., risk-based initiatives in operations and 
quality such as Risk Management and Mitigation Strategies and Analytical Risk-Based 
Monitoring), methods, responsibilities and requirements, including handling of 
noncompliance issues and monitoring techniques (central, remote, or on-site monitoring) 
are provided in the Monitoring Plan provided by the Clinical Trial Unit at OUH. 
• The sponsor or designee is responsible for the data management of this study including 
quality checking of the data. 
• The sponsor assumes accountability for actions delegated to other individuals (e.g., 
Contract Research Organizations). 
• Records and documents, including signed ICFs and clinical trial master file, pertaining to 
the conduct of this study must be retained by the investigator for twenty-five years after 
study completion. Archiving of patient files / medical records will be executed according 
to Norwegian law (Pasientjournalloven). No records may be destroyed during the 
retention period without the written approval of the sponsor. No records may be 
transferred to another location or party without written notification to the sponsor. After 
the archiving period, all personal data in relation to the study, and which are not part of 
the participant’s medical record, shall be erased or made anonymous, cf. GDPR article 5 
(1) and the Norwegian act on medical and health research § 38. 
10.1.9. Source Documents 
 
• Source documents provide evidence for the existence of the participant and substantiate 
the integrity of the data collected. Source documents are filed at the investigator’s site. 
• Data reported in the eCRF that are transcribed from source documents must be consistent 
with the source documents or the discrepancies must be explained. The investigator may 
need to request previous medical records or transfer records, depending on the study. 
Also, current medical records must be available. 
• Definition of what constitutes source data can be found in the source data verification 
document.  
• The investigator must maintain accurate documentation (source data) that supports the 
information entered in the eCRF. 
• Study monitors will perform ongoing source data verification to confirm that data entered 
into the eCRF by authorized site personnel are accurate, complete, and verifiable from 

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source documents; that the safety and rights of participants are being protected; and that 
the study is being conducted in accordance with the currently approved protocol and any 
other study agreements, ICH GCP, and all applicable regulatory requirements. 
• The following data will be extracted from the participant’s medical hospital record and 
transferred into the eCRF: 
o Diagnostic and anatomic details about the congenital cardiac disease before surgical 
treatment 
o Date and technical proceeding for previous heart surgery 
o Results from diagnostic liver assessment (both imaging and biochemical) from the 
last 12 months before study inclusion 
o Information about any heart rhythm disturbances, treated or untreated, from the last 
12 months before study inclusion 
o Information about circumstances or previous test results which might fulfill any 
exclusion criterium (severe liver disease, systemic hypertension, inherited galactose 
intolerance, theophylline hypersensitivity) 
o Information about concomitant pharmacological treatment representing an exclusion 
criterium 
10.1.10. Study and Site Start and Closure 
First Act of Recruitment 
The study start date is the date on which the clinical study will be open for recruitment of 
participants. 
The first act of recruitment is the first screening of a patient meeting inclusion criteria during 
his/her clinical visit or hospital stay and will be the study start date. 
Study/Site Termination 
The sponsor or designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of the sponsor. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study supplies 
have been collected and a study-site closure visit has been performed. 
The investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by the sponsor or investigator may include but are 
not limited to: 
For site termination: 
• Failure of the investigator to comply with the protocol, the requirements of the IRB/IEC 
or local health authorities, the sponsor’s procedures, or GCP guidelines 
• Inadequate or no recruitment (evaluated after a reasonable amount of time) of participants 
by the investigator 

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• Total number of participants included earlier than expected 
If the study is prematurely terminated or suspended, the sponsor shall promptly inform the 
investigators, the IECs/IRBs, the regulatory authorities, and any contract research organization(s) 
used in the study of the reason for termination or suspension, as specified by the applicable 
regulatory requirements. The investigator shall promptly inform the participant and should assure 
appropriate participant therapy and/or follow-up 
10.1.11. Publication Policy 
 
• The results of this study may be published or presented at scientific meetings. If this is 
foreseen, the investigator agrees to submit all manuscripts or abstracts to the sponsor 
before submission. This allows the sponsor to protect proprietary information and to 
provide comments. 
• The sponsor will comply with the requirements for publication of study results. In 
accordance with standard editorial and ethical practice, the sponsor will generally support 
publication of multicenter studies only in their entirety and not as individual site data. In 
this case, a coordinating investigator will be designated by mutual agreement. 
• Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements. 
 
 
 

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10.2. Appendix 2: Clinical Laboratory Tests 
 
• The tests detailed in Table 1 will be performed by the central laboratory at Oslo 
University Hospital Rikshospitalet. 
• Local laboratory results are only required in the event of suspected AE’s or SAE’s and 
the central laboratory results are not available in time for either study intervention 
administration and/or response evaluation. If a local sample is required, it is important 
that the sample for central analysis is obtained at the same time. Additionally, if the local 
laboratory results are used to make either a study intervention decision or response 
evaluation, the results must be recorded. 
• Protocol-specific requirements for inclusion or exclusion of participants are detailed in 
Section 5 of the protocol. 
• Additional tests may be performed at any time during the study as determined necessary 
by the investigator or required by local regulations. 
• Serum samples collected for theophylline concentration measurement will be stored at -
20°C for 60 days for reanalysis purposes in case of AE/SAE and suspicion due to 
biochemical analysis failure and dosage error (69). There will be no establishment of a 
research biobank which would fall under national Norwegian rules regarding research 
biobanks. 
• Handling of biological samples is in compliance with Member State applicable rules for 
the collection, storage and future use of human biological samples (Article 7.1h) 
o Both blood samples and urine samples are collected, a maximum of one sample of 
each type per occasion 
o Urine samples are discarded immediately after bedside pregnancy test or after 
biochemical and pharmacological analysis respectively according to trial protocol  
o The clinical trial does not involve the collection of existing archive samples 
o Samples will be collected either at OUS (inclusion and final visit), or at OUS or the 
closest facility (primary care physician or closest hospital laboratory) during 
treatment phase. Externally collected samples are shipped with routine biological 
sample shipment (postal transport or hospital-to-hospital delivery service) to OUS. 
Details for sample handling and shipment are given in a letter to the participants 
health care providers (appendix 2 to the ICF) in accordance with publicly available 
instructions (https://ous.labfag.no → Oslo universitetssykehus → Teofyllin). 
o All analyses will be processed within the Sponsor’s organization (Oslo University 
Hospital). No samples are will be sent for further analysis from OUH to other 
institutions. 
o Samples will be marked with study ID and only trial personnel and laboratory 
personnel (by trial agreement) will have access to the samples 
o No biological samples will be stored beyond 60 days for any future use. 
 

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Table 1: Protocol-Required Safety Laboratory Tests 
Laboratory 
Tests 
Parameters 
Hematology 
Platelet Count  
RBC Indices: 
MCV 
MCH 
%Reticulocytes 
White blood cell 
(WBC) count with 
Differential: 
Neutrophils 
Lymphocytes 
Monocytes 
Eosinophils 
Basophils 
Red blood cell (RBC) 
Count 
Hemoglobin 
Hematocrit 
Clinical 
Chemistry1 
Blood urea 
nitrogen 
(karbamid) 
Potassium (K) 
Aspartate 
Aminotransferase 
(ASAT) 
Total bilirubin 
 
Creatinine 
Sodium (Na) 
Alanine 
Aminotransferase 
(ALAT) 
Total Protein 
 
Glucose, non-
fasting 
Calcium 
Alkaline 
phosphatase2 
INR 
Routine 
Urinalysis 
pH, glucose, protein, blood, ketones by dipstick 
Pregnancy 
testing 
• Highly sensitive [urine] human chorionic gonadotropin (hCG) 
pregnancy test (as needed for women of childbearing potential)3 
Other 
Screening 
Tests 
None 
NOTES: 
1 Details of liver chemistry stopping criteria and required actions and follow-up are given in 
Section [7.1.1 Liver Chemistry Stopping Criteria] and Appendix 6: Liver Safety: Suggested 
Actions and Follow-up Assessments  
2 If alkaline phosphatase is elevated, consider fractionating. 
3 Local urine testing will be standard for the protocol unless serum testing is required by local 
regulation or IRB/IEC. 
 
Investigators must document their review of each laboratory safety report. 
 

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10.3. Appendix 3: Aes and SAEs: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting 
10.3.1. Definition of AE 
 
AE Definition 
• An AE is any untoward medical occurrence in a clinical study participant, temporally 
associated with the use of study intervention, whether or not considered related to the 
study intervention. 
• NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of study intervention. 
Definition of Unsolicited and Solicited AE 
• An unsolicited adverse event is an adverse event that was not solicited using a 
Participant Diary and that is communicated by a participant/participant’s 
parent(s)/LAR(s) who has signed the informed consent. Unsolicited Aes include 
serious and non-serious Aes. 
• Potential unsolicited Aes may be medically attended (i.e., symptoms or illnesses 
requiring a hospitalisation, or emergency room visit, or visit to/by a health care 
provider). The participants/ participant’s parent(s)/LAR(s) will be instructed to contact 
the site as soon as possible to report medically attended event(s), as well as any events 
that, though not medically attended, are of participant/ parental /LAR’s concern. 
Detailed information about reported unsolicited Aes will be collected by qualified site 
personnel and documented in the participant’s records. 
• Unsolicited Aes that are not medically attended nor perceived as a concern by 
participant/participant’s parent(s)/LAR(s) will be collected during interview with the 
participants/participant’s parent(s)/LAR(s) and by review of available medical records 
at the next visit. 
• Solicited Aes are predefined local and systemic events for which the participant is 
specifically questioned.  
 
Events Meeting the AE Definition 
• Any abnormal laboratory test results (haematology, clinical chemistry, or urinalysis) or 
other safety assessments (e.g., ECG, radiological scans, vital signs measurements), 
including those that worsen from baseline, considered clinically significant in the 
medical and scientific judgment of the investigator (i.e., not related to progression of 
underlying disease). 
• Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition. 

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• New conditions detected or diagnosed after study intervention administration even 
though it may have been present before the start of the study. 
• Signs, symptoms, or the clinical sequelae of a suspected intervention- intervention 
interaction. 
• Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication. Overdose per se will not be reported as an 
AE/SAE unless it is an intentional overdose taken with possible suicidal/self-harming 
intent. Such overdoses should be reported regardless of sequelae. 
 
Events NOT Meeting the AE Definition 
• Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the participant’s condition. 
• The disease/disorder being studied or expected progression, signs, or symptoms of the 
disease/disorder being studied, unless more severe than expected for the participant’s 
condition. 
• Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition that 
leads to the procedure is the AE. 
• Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital). 
• Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or 
detected at the start of the study that do not worsen. 
10.3.2. Definition of SAE 
 
An SAE is defined as any serious adverse event that, at any dose: 
a. Results in death 
b. Is life-threatening 
The term ‘life-threatening’ in the definition of ‘serious’ refers to an event in which the 
participant was at risk of death at the time of the event. It does not refer to an event, which 
hypothetically might have caused death, if it were more severe. 
c. Requires inpatient hospitalization or prolongation of existing hospitalization 
• In general, hospitalization signifies that the participant has been admitted (usually 
involving at least an overnight stay) at the hospital or emergency ward for observation 
and/or treatment that would not have been appropriate in the physician’s office or 
outpatient setting. Complications that occur during hospitalization are Aes. If a 
complication prolongs hospitalization or fulfills any other serious criteria, the event is 

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serious. When in doubt as to whether “hospitalization” occurred or was necessary, the 
AE should be considered serious. 
• Hospitalization for elective treatment of a pre-existing condition that did not worsen 
from baseline is not considered an AE. 
d. Results in persistent or significant disability/incapacity 
• The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions. 
• This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (e.g., sprained ankle) which may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption. 
e. Is a congenital anomaly/birth defect 
f. Is a suspected transmission of any infectious agent via an authorized medicinal 
product 
g. Other situations: 
• Medical or scientific judgment should be exercised by a medical monitor in deciding 
whether SAE reporting is appropriate in other situations such as significant medical 
events that may jeopardize the participant or may require medical or surgical 
intervention to prevent one of the other outcomes listed in the above definition. These 
events should usually be considered serious. 
o Examples of such events include invasive or malignant cancers, intensive treatment 
for allergic bronchospasm, blood dyscrasias, convulsions or development of 
intervention dependency or intervention abuse. 
10.3.3 
Definition of suspected unexpected serious adverse reaction (SUSAR) 
 
If an event is not an SAE per definition above, then it cannot be a SUSAR 
SUSAR Definition 
Adverse Reaction: all unwanted and unintended responses to an investigational medicinal 
product related to any dose administered.  
Unexpected Adverse Reaction: an adverse reaction, the nature or severity of which is not 
consistent with the applicable Summary of Product characteristics (SmPC).  
Suspected Unexpected Serious Adverse Reaction: Unexpected Adverse Reaction that: 
• 
Results in death 
• 
Is immediately life-threatening 
• 
Requires in-patient hospitalization or prolongation of existing hospitalization 

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• 
Results in persistent or significant disability or incapacity 
• 
Is a congenital abnormality or birth defect 
Is an important medical event that may jeopardize the subject or may require medical 
intervention to prevent one of the outcomes listed above. 
10.3.4. Recording and Follow-Up of AE and/or SAE 
 
AE and SAE Recording 
• When an AE/SAE occurs, it is the responsibility of the medical monitor to review all 
documentation (e.g., hospital progress notes, laboratory reports, and diagnostics 
reports) related to the event. 
• The medical monitor will then record all relevant AE/SAE information. 
• It is not acceptable for the medical monitor to send photocopies of the participant’s 
medical records to the Sponsor in lieu of completion of the required form. 
• There may be instances when copies of medical records for certain cases are requested 
by the Sponsor. In this case, all participant identifiers, with the exception of the 
participant number, will be redacted on the copies of the medical records before 
submission to the Sponsor. 
• The medical monitor will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not the 
individual signs/symptoms) will be documented as the AE/SAE. 
Assessment of Intensity 
The team of medical monitors will make an assessment of intensity for each AE and SAE 
reported during the study and assign it to 1 of the following categories:  
• Mild: An event that is easily tolerated by the participant, causing minimal discomfort 
and not interfering with everyday activities. 
• Moderate: An event that causes sufficient discomfort to interfere with normal everyday 
activities. 
• Severe: An event that prevents normal everyday activities. An AE that is assessed as 
severe should not be confused with an SAE. Severe is a category utilized for rating the 
intensity of an event; and both Aes and SAEs can be assessed as severe. 
An event is defined as ‘serious’ when it meets at least 1 of the predefined outcomes as 
described in the definition of an SAE, NOT when it is rated as severe. 
 
Assessment of Causality 
• The team of medical monitors is obligated to assess the relationship between study 
intervention and each occurrence of each AE/SAE. 

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• A “reasonable possibility” of a relationship conveys that there are facts, evidence, 
and/or arguments to suggest a causal relationship, rather than a relationship cannot be 
ruled out. 
• The team of medical monitors will use clinical judgment to determine the relationship. 
• Alternative causes, such as underlying disease(s), concomitant therapy, and other risk 
factors, as well as the temporal relationship of the event to study intervention 
administration will be considered and investigated. 
• The team of medical monitors will also consult the Investigator’s Brochure (IB) and/or 
Product Information, for marketed products, in his/her assessment. 
• For each AE/SAE, the team of medical monitors must document in the medical notes 
that he/she has reviewed the AE/SAE and has provided an assessment of causality. 
• There may be situations in which an SAE has occurred and the team of medical 
monitors has minimal information to include in the initial report to the Sponsor. 
However, it is very important that the team of medical monitors always make an 
assessment of causality for every event before the initial transmission of the SAE data 
to the Sponsor. 
• The team of medical monitors may change his/her opinion of causality in light of 
follow-up information and send an SAE follow-up report with the updated causality 
assessment. 
• The causality assessment is one of the criteria used when determining regulatory 
reporting requirements. 
 
Follow-up of Aes and SAEs 
• The team of medical monitors is obligated to perform or arrange for the conduct of 
supplemental measurements and/or evaluations as medically indicated or as requested 
by the Sponsor to elucidate the nature and/or causality of the AE or SAE as fully as 
possible. This may include additional laboratory tests or investigations, 
histopathological examinations, or consultation with other health care professionals. 
• For all reported events evaluated by a medical monitor, the medical monitor has to 
consider if a hospital visit is needed for further clarification of the nature of the event. 
The medical monitor will, if necessary, arrange for an outpatient visit to either the 
outpatient clinic of the pediatric or adult cardiology service at Oslo University Hospital 
Rikshospital for the following work day. 
• If the participant reporting an event is considered by the medical monitor to need 
immediate medical attention, the medical monitor will arrange for an emergency 
outpatient visit to the pediatric or adult cardiology service at Oslo University Hospital 
Rikshospital or, if preferable due to travel distance, at the nearest qualified hospital. 
 

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• If a participant dies during participation in the study or during a recognized follow-up 
period, the team of medical monitors will provide the Sponsor with a copy of any 
post-mortem findings including histopathology.  
• New or updated information will be recorded in the originally submitted documents. 
• The team of medical monitors will submit any updated SAE data to the Sponsor within 
24 hours of receipt of the information. 
10.3.5. Reporting of SAEs 
 
SAE Reporting to the Sponsor via an Electronic Data Collection Tool 
• The primary mechanism for reporting an SAE to the Sponsor will be the electronic data 
collection tool. 
• If the electronic system is unavailable, then the site will use the paper SAE data 
collection tool (see next section) to report the event within 24 hours. 
• The site will enter the SAE data into the electronic system as soon as it becomes 
available. 
• After the study is completed at a given site, the electronic data collection tool will be 
taken off-line to prevent the entry of new data or changes to existing data. 
• If a site receives a report of a new SAE from a study participant or receives updated 
data on a previously reported SAE after the electronic data collection tool has been 
taken off-line, then the site can report this information on a paper SAE form (see next 
section) or to the Sponsor by telephone. 
• Contacts for SAE reporting are the medical monitors: 
For events in participants < 18 years of age:  
   Thomas Möller MD PhD (contact details see page 2) 
For events in adult participants: 
   Ola Gjesdal MD PhD (contact details see page 2) 
 
 
SAE Reporting to the Sponsor via Paper Data Collection Tool 
• Facsimile transmission of the SAE paper data collection tool is the preferred method 
to transmit this information to the Sponsor. 
• In rare circumstances and in the absence of facsimile equipment, notification by 
telephone is acceptable with a copy of the SAE data collection tool sent by overnight 
mail or courier service. 
• Initial notification via telephone does not replace the need for the team of medical 
monitors to complete and sign the SAE data collection tool within the designated 
reporting time frames. 

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• Contacts for SAE reporting can be found in 
https://legemiddelverket.no/english/pharmacovigilance. 
 
10.3.6. Reporting of SUSAR  
 
medical monitor will evaluate if a reported SAE also is a SUSAR, if so, the medical monitor will 
report the SUSAR to the Competent Authority through Eudravigilance (EV) 
Sponsor will ensure that all relevant information about SUSARs that are fatal or life-threatening 
is recorded and reported as soon as possible and in no case later than seven (7) days after 
knowledge by the sponsor of such a case, and that relevant follow-up information is 
subsequently communicated within an additional eight (8) days. 
Other SUSARs will be reported no later than 15 days after the incident.  
 

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10.4. Appendix 4: Contraceptive and Barrier Guidance 
Different pharmacokinetics of theophylline have not been demonstrated in pregnant women (70). 
The SmPC recommend close monitoring of serum theophylline concentrations during the third 
trimester and weighing of risk and benefits of theophylline treatment during pregnancy. 
The scientific literature concerning risks of theophylline use during pregnancy has been reviewed 
in 2006 by Chambers (71). The author concluded that “although no significantly increased risk 
for major birth defects was noted with first trimester exposure to theophylline in any of the 
studies cited above, sample sizes in each study were insufficient to rule out anything but high 
relative risks for major birth defects overall or for any specific birth defect.” Hence, even if the 
risk of major congenital defects and severe pregnancy events during the first trimester of 
pregnancy seem not to be elevated, the relatively limited available evidence still does not justify 
the conclusion that onset of pregnancy in study participants would be acceptable. 
Therefore, pregnancy is considered being an exclusion criterium at recruitment visit. Onset of 
pregnancy during treatment phase is not advised. If pregnancy during treatment phase or final 
visit is diagnosed, the participant will be excluded from the study and theophylline treatment will 
be stopped.  
10.4.1. Definitions 
Usable contraceptive methods for sexually active women living with Fontan-circulation are: 
a. Barrier method: condom, diaphragm. 
b. Hormonal contraceptive: oral contraceptive (gestagen only), gestagen-containing IUD or 
subcutaneous implant. 
 
c. Surgical sterilization  
 
10.4.2. Contraception Guidance 
Female participants who are not sexually active are informed about treatment risks related to 
pregnancy and the need of effective contraception in case of onset of sexual activity during 
treatment phase.  
Female participants of child bearing potential must be willing to ensure that they or their partner 
use effective contraception during the trial. Women of child bearing potential (WOCBP) are 
defined as sexually active women between 15 and 45 years of age, meaning all eligible female 
participants as long as they are not considered non-fertile for medical reasons. 
Acceptable contraceptive methods for WOCBP during study participation are hormonal 
contraception or previous sterilization. 
 
 
 

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10.5. Appendix 5: Genetics 
 
Not applicable. 
 

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10.6. Appendix 6: Liver Safety: Suggested Actions and Follow-up 
Assessments 
 
Any excess of liver safety parameters during treatment phase or during the final visit has to be 
evaluated by the medical monitor. Recommended action is to repeat laboratory assessment 2-4 
weeks after treatment cessation. If elevated laboratory results persist, liver imaging studies 
should be conducted in consultation with hepatology services (pediatric or adult as appropriate). 

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10.7. Appendix 7: Aes, ADEs, SAEs, SADEs, USADEs and Device 
Deficiencies: Definitions and Procedures for Recording, Evaluating, 
Follow-up, and Reporting in Medical Device Studies 
10.8. Appendix 8: Country-specific Requirements 
Not applicable. 
 

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10.9. Appendix 9: Abbreviations Delete appendix if not required. 
AE   
Adverse event 
ALAT   
Alanine-aminotransferase (enzyme) 
ASAT  
 
Aspartate-aminotransferase (enzyme) 
bid    
dosage twice daily 
BMI    
Body mass index 
CNS    
Central nervous system 
CONSORT  Consolidated Standards of Reporting Trials 
CRF   
Case record file 
CPET    
Cardiopulmonary exercise test 
DLCO   
Diffusing capacity for carbon monoxide 
DRE   
Disease-related events 
ECG   
Electrocardiogram 
ECG247  
Heart rate and rhythm monitoring devise (see: https://ecg247.no) 
eCRF   
Electronic case record form 
EQ-5D 
  
European quality-of-life questionnaire with five domains 
GCP   
Good clinical practice 
hCG    
Human chorionic gonadotropin (hormone) 
ICF    
Informed consent form 
IEC    
Independent Ethics Committees 
IMP    
Investigational medicinal product 
INR   
International normalized ratio (for anticoagulation treatment assessment) 
IRB    
Institutional Review Boards 
IUD   
Intra-uterine diaphragm (contraception) 
K  
  
Potassium 
LAR    
Legally authorized representative 
MCH    
Mean corpuscular hemoglobin content (red blood cells) 
MCV    
Mean corpuscular volume (red blood cells) 
Mg   
Milligrams 
MRI    
Magnetic resonance imaging 
Na    
Sodium 
NIMP   
Non-investigational medicinal product 

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OUH    
Oslo University Hospital 
OUS    
Oslo universitetssykehus (Norwegian term for OUH) 
PI  
 
Principal investigator 
RBC    
Red blood cell count 
SAE   
Serious adverse event 
SF-36    
Short form 36, quality-of-life questionnaire 
SmPC    
Summary of Product Characteristics 
SUSAR  
Suspected unexpected serious adverse reaction 
ULN   
Upper limit of normal 
VO2@VAT  Oxygen uptake at anaerobic/ventilatory threshold 
WBC    
White blood cell count 
WOCBP  
Woman/women of child bearing potential 
 
 

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10.10. Appendix 10: Protocol Amendment History 
The Protocol Amendment Summary of Changes Table for the current amendment is located 
directly before the Table of Contents (TOC). 
Amendment 01 (substantial modification: (Nov 04, 2022) 
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of 
Directive 2001/20/EC of the European Parliament and the Council of the European Union. 
A decision in the study team was made to use an electronic log book solution for better 
monitoring of participant compliance and AE’s. This decision was made after initial trial 
application authorization. 
 
Overall Rationale for the Amendment 
Section # and Name Description of Change 
Brief Rationale 
Signature page 
Filled in correct contact 
details 
Preliminary placeholders from 
protocol version 1 are replaced 
Protocol Amendment 
Summary of Changes 
Table 
A table and overview of 
amendment history has 
been added 
Necessary change together with 
amendment no.1 
1.1 Synopsis, Brief 
summary 
Added information about 
electronic participant log 
book in ViedocMe (part of 
the eCRF database) 
A decision in the study team was 
made to use an electronic log book 
solution. This decision was made 
after trial authorization. 
4.1 Overall design 
Added information about 
electronic participant log 
book in ViedocMe (part of 
the eCRF database) 
A decision in the study team was 
made to use an electronic log book 
solution. This decision was made 
after trial authorization. 
Whole document 
Typographic and semantic 
errors and flaws including 
institutional name changes 
were corrected 
(Non-substantial changes) 
 
Amendment 02 (substantial modification: March 28, 2023) 
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of 
Directive 2001/20/EC of the European Parliament and the Council of the European Union. 
Overall Rationale for the Amendment 
Initial screening visits of potential participants revealed frequent screening failure (6 out of 10 
visits) due to biochemical exclusion criteria, namely elevated ammonia and/or mildly elevated 
INR in the absence of signs of moderate/severe liver disease by other biochemical (bilirubin, 

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ALT) or imaging findings (MRI or ultrasound). The intention behind liver-related exclusion 
criteria was to exclude participants with either potential hepato-cellular carcinoma or with severe 
Fontan-associated liver disease with significantly impaired synthesis or significantly increased 
theophylline toxicity.  
Experiences with repeated screening failure, experiences with the initial three enrolled 
participants, and a focused review of available scientific literature resulted in the following 
considerations: 
− Porto-systemic shunting of enteral venous blood to the systemic venous system leads to 
elevated ammonia and should probably be expected frequently late (> 10 years) after the 
Fontan operation (Takefuta 2021) (1). Hence ammonia is not suited to discriminate 
different degrees of hepatic involvement in Fontan patients. 
− In a previous study of hepatic and cardiac function in Fontan patients, spontaneous INR 
had a median of 1.2 equivalent to the upper normal range (Camposilvan 2008) (2). A 
spontaneous INR above the upper normal limit (>1.2) is probably a too restrictive 
exclusion criteria in a Fontan population. In addition, the use of direct oral anti-coagulant 
drugs may cause slightly elevated INR in the absence of warfarin treatment (Ofek 2017) 
(3). 
− Bilirubin has been shown to correlate with slow theophylline clearance in cirrhotic 
patients (Mangione 1978) (4). Even in the absence of elevated ammonia and severe liver 
disease, a theophylline concentration within therapeutic range was achieved by 2/3 
participants on a low starting dose (200 mg BID) or even after dose reduction from initial 
dosage (100mg BID)  
Other  practical  protocol,  recruitment  and  consent  issues  that  became  obvious  during  the  first 
screening visits and inclusions (see table). 
 
Section # and Name Description of Change 
Brief Rationale 
1.3 (Synopsis) 
4.1 (Overall design) 
6.5 (Dose 
modification)  
Reduced starting dose of 
study drug depending on 
bilirubin level, and option 
to further reduce to OD 
depending on study drug 
concentration 
Theophylline clearance has been 
demonstrated to correlate with 
bilirubin level, and 2/3 participants 
have achieved therapeutic 
theophylline concentrations on study 
drug dosage below recommended 
staring dose in adults 
1.1 (Synopsis) 
Removed mandatory gender 
ratio of 1:1 
Both genders should be represented 
in study group, but no rationale for 
1:1 existed 
1.3 (Schedule of 
Activities) 
Screening laboratory tests 
(more comprehensive 
compared to baseline and 
follow-up) might be 
collected locally and 
Our study design has been shown to 
allow for safe participant monitoring 
independently of travel distance to 
the study center. To avoid futile long-

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shipped to the study centre 
up to 28 days before 
screening visit and repeated 
on the day of visit if 
informed consent has been 
signed previously. 
distance travel due to screening 
failure by laboratory results. 
1.4 (Schedule of 
Activities) 
4.1 (Overall design) 
Home-based ECG-
monitoring device is started 
during baseline visit 
Recording of baseline ECG-readings 
with the monitoring device for 
comparison during treatment 
monitoring 
1.3 (Schedule of 
Activities) 
A time interval of 1-3 days 
for completing baseline 
visit with polygraphy has 
been defined with 
subsequent start of study 
medication 
Practical / logistical difficulties to 
always perform polygraphy during 
first night after baseline visit (device 
shipping and device turnover 
between participants) 
5.1 (Inclusion 
criteria) 
Rephrasing of general liver-
related criteria 
Defining of only severe Fontan-
associated liver disease as safety 
issue during theophylline use 
(corresponding to bilirubin-
dependent study drug start dose) 
5.2 (Exclusion 
criteria) 
The upper limit of 
acceptable INR has been 
altered. 
Some elevation of INR in the absence 
of severe liver disease has been 
described in Fontan patients and in 
patients using direct oral 
anticoagulative drugs 
5.2 (Exclusion 
criteria) 
Liver imaging exclusion 
criteria has been rephrased 
as “Hepato-cellular-
carcinoma (HCC)-suspect 
lesions” by liver imaging. 
The imaging-related exclusion 
criteria of “nodules > 10 mm” by 
MRI or ultrasound images have been 
difficult to apply to imaging reports 
from individual patient files. We 
noted frequent descriptions of lesions 
below/above 10 mm with altered 
perfusion, but without a 
nodular/expansive structure. 
5.2 (Exclusion 
criteria) 
Ammonia has been 
removed from biochemical 
exclusion criteria 
Disease-specific alterations in liver 
circulation in patients with Fontan 
circulation have led to screening 
failure in an unexpected high 
percentage of potential participants 
due to elevated ammonia levels in the 
absence of severe liver disease. 

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5.5 (Screening 
failures) 
Re-screening permitted  
A rescreening option with optimized 
blood work circumstances will 
improve recruitment of participants 
with otherwise no signs of severe 
liver disease. 
10.4.2 (Contraception 
Guidance) 
Absence of opposite gender 
sexual activity during study 
period has been explicitly 
defined as sufficient 
contraception. 
Unnecessary use of oral 
contraception in female Fontan 
patients must be avoided due to risk 
of thromboembolism. 
 

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11. 
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