Congenital Heart DiseasePhase 2THIEFNCT05717049
Theophylline Effects in the Fontan Circulation
A Phase 2 study testing Theophylline Tablets in people with Congenital Heart Disease, run by Oslo University Hospital at 1 site in Norway.
Trial summary
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… Read more about this study
- Who is it for?
- Ages 16 to 25 years
- Conditions the study is for
- Congenital Heart Disease
- What is being tested?
- Theophylline Tablets
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 10 participants
- Where
- 1 siteNorway
- Study dates
- 9 Feb 2023to 15 Sep 2023
- Phase
- Phase 2
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 16 to 25 years
- All sexes
- No healthy volunteers
- Child, Adult
Who may be able to join
- Participants with univentricular congenital heart disease with a Fontan-type palliation
- 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.
- With available hepatic imaging results (ultrasound or magnetic resonance imaging) from less than 12 months before inclusion
- Without biochemical indications of more than mild liver disease or liver failure (se exclusion criteria) of more than mildly reduced kidney function.
- Considered and assessed eligible for administration of Theo-Dur® (theophylline) as specified in the SmPC.
- Body mass index (BMI) within the range 18.5 - 34.9 kg/m2 (inclusive).
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- Contraceptive use by women is not under any national / local regulations in Norway.
- Male participants: no restrictions.
- 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.
- 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.
Who cannot join
- Current or previous (last 12 months) tachyarrhythmia which has been cause of medical investigation or hospitalization.
- 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
- Systemic hypertension (systolic or diastolic blood pressure above 95 percentile)
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- Biochemical signs of more than mild liver disease or liver failure indicated by one of the following:
- INR > 1.5 in the absence of warfarin treatment,
- ALAT more than twice the upper normal limit
- Bilirubin more than twice the upper normal limit
- Imaging signs from the recent 12 months indicating more than mild Fontan-associated liver disease, indicated by imaging findings that need further diagnostic work-up to rule out hepato-cellular carcinoma
- Biochemical indication of more than mildly reduced kidney function indicated by:
- Creatinine > 150 μmol/L (male) or > 120 μmol/L (female)
- Pregnancy
- Inherited forms of galactose intolerance (Lapp lactase deficiency or glucose-galactose malabsorption
- Hypersensitivity to theophylline
- Current treatment with pulmonary vasodilator medication (sildenafil, tadalafil, udenafil, bosentan, ambrisentan, macicentan, or any prostacyclin derivate)
- Ongoing pharmacological treatment with the risk of drug-drug interactions. (Examples: cimetidine, quinolone derivates like enoxacin, ciprofloxacin, perfloxacin, viloxazine, macrolide antibiotics like erythromycin, troleandomycin, allopurinol, propranolol, disulfiram, isoniazid, oral contraceptives, flu vaccine, mexiletine, nifedipine, norfloxacin, ranitidin, tiabendazol, verapamil, fluvoxamine, carbamazepine, felodipine, phenobarbital, phenytoin, rifampicin, lithium, ketamine, glucagon)
- Pregnancy or breastfeeding
Trial locations and contacts
1 site in 1 country.
Norway1 site
Oslo University Hospital, Rikshospitalet, Department of Paediatric Cardiology
Oslo, 0424
About this study
Official 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.
Read the detailed description
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 the medical monitors (pediatric cardiology, cardiology) with continuous service through the entire study period.
Study duration: approximately 6 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 with both genders represented 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.
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 (1).
During early intervention phase until 5-7 days after therapeutic drug 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. 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).
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). 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 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.
- Conditions
- Congenital Heart Disease
- Being tested
- Theophylline Tablets
- Keywords
- Fontan circulation, Cardiorespiratory fitness, Pulmonary function, Cardiac function, Quality of life
- Medical subject headings
- Heart Defects, Congenital
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Theophylline TabletsDrug
Also called ATC R03D A04
12 week oral treatment
| Study group | Role | What they receive |
|---|---|---|
| Treatment | Experimental | 12 week oral treatment (theophylline) Receives: Drug: Theophylline Tablets |
What is being measured
The primary outcome is the main question the study is designed to answer.
Feasibility and safety - adverse events
Frequency of treatment emerged AE/SAE
Measured: 12 weeks
Feasibility and safety - tolerability
Freedom from participant dropout based on tolerability of the study intervention
Measured: 12 weeks
Feasibility and safety - drug dosing
Number of participants requiring dose reduction after first serum concentration
Measured: 12 weeks
Feasibility and safety - arrhythmia
Freedom of arrhythmogenic side effects of the study treatment leading to patient dropout
Measured: 12 weeks
Cardiorespiratory fitness
Difference in oxygen uptake at anaerobic/ventilatory threshold pre/post treatment
Measured: 12 weeks
Secondary outcomes (5)
Health-related quality-of-life
Difference inn total scores from EQ-5D-5L questionnaires pre/post treatment (single digit score (0-5 = "no problems" to "extreme problems") for five dimensions (mobility, self-care, usual activities, pain/discomfort and anxiety/depression))
Measured: 12 weeks
Health-related quality-of-life (SF 36)
Difference inn total scores from SF-36 questionnaire pre/post treatment (36 items scored scored on a 0 to 100 range so that the lowest and highest possible scores are 0 and 100 respectively)
Measured: 12 weeks
Cardiac performance
Ventricular function as assessed by echocardiography at rest pre/post treatment
Measured: 12 weeks
Respiratory function
Diffusion capacity pre/post treatment
Measured: 12 weeks
Sleep disordered breathing
Change in Apnea Hypopnea Index during home-based sleep study pre-/post-treatment
Measured: 12 weeks
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted8 Feb 2023
- Study start9 Feb 2023
- Primary completion15 Sep 2023
- Study completion15 Sep 2023
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Congenital Heart DiseaseStudies of the same condition, open and under way.
- More trials run by Oslo University HospitalThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 10 participants (actual)
Sponsor and investigators
- Lead sponsor
- Oslo University Hospital
- Sponsor type
- University, hospital or other
- Collaborators
- South-Eastern Norway Regional Health Authority, Norwegian Health Association, Norwegian Association for Children with Congenital Heart Disease
- Responsible party
- Principal investigator, Thomas Möller, Oslo University Hospital
- Investigators
- Thomas Möller, MD PhD, Principal investigator, Oslo University Hospital
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT05717049
- Sponsor's protocol ID
- EU CT 2022-500301-41-00
- Acronym
- THIEF
- Status last verified
- Sep 2023
- First submitted
- 16 Jan 2023
- Last updated
- 21 Sep 2023
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Study at a glance
From the registry record, last updated by the sponsor on 21 Sep 2023. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Theophylline Effects in the Fontan Circulation (THIEF Pilot Study)
- ClinicalTrials.gov ID
- NCT05717049
- Acronym / sponsor ID
- THIEF / EU CT 2022-500301-41-00
- Conditions
- Congenital Heart Disease
- Keywords
- Fontan circulation, Cardiorespiratory fitness, Pulmonary function, Cardiac function, Quality of life
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 10 participants (actual)
- Lead sponsor
- Oslo University HospitalUniversity, hospital or other
- Collaborators
- South-Eastern Norway Regional Health Authority, Norwegian Health Association, Norwegian Association for Children with Congenital Heart Disease
- Study start
- 9 Feb 2023 (actual)
- Primary completion
- 15 Sep 2023 (actual)
- Study completion
- 15 Sep 2023 (actual)
- First posted
- 8 Feb 2023 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Detailed description
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 the medical monitors (pediatric cardiology, cardiology) with continuous service through the entire study period.
Study duration: approximately 6 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 with both genders represented 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.
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 (1).
During early intervention phase until 5-7 days after therapeutic drug 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. 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).
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). 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 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.
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Treatment | Experimental | Drug: Theophylline Tablets12 week oral treatment (theophylline) |
Who may qualify
- Ages
- 16 to 25 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult
Key inclusion criteria (11 listed)
- Participants with univentricular congenital heart disease with a Fontan-type palliation
- Body mass index (BMI) within the range 18.5 - 34.9 kg/m2 (inclusive).
- Contraceptive use by women is not under any national / local regulations in Norway.
- 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.
Key exclusion criteria (19 listed)
- Current or previous (last 12 months) tachyarrhythmia which has been cause of medical investigation or hospitalization.
- Heart rhythm during inclusion visit other than:
- Systemic hypertension (systolic or diastolic blood pressure above 95 percentile)
- Biochemical signs of more than mild liver disease or liver failure indicated by one of the following:
- Imaging signs from the recent 12 months indicating more than mild Fontan-associated liver disease, indicated by imaging findings that need further diagnostic work-up to rule out hepato-cellular carcinoma
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Theophylline TabletsAlso: ATC R03D A0412 week oral treatment | Drug | Treatment |
Primary outcome
Feasibility and safety - adverse events
Time frame: 12 weeks
Frequency of treatment emerged AE/SAE
Feasibility and safety - tolerability
Time frame: 12 weeks
Freedom from participant dropout based on tolerability of the study intervention
Feasibility and safety - drug dosing
Time frame: 12 weeks
Number of participants requiring dose reduction after first serum concentration
Feasibility and safety - arrhythmia
Time frame: 12 weeks
Freedom of arrhythmogenic side effects of the study treatment leading to patient dropout
Cardiorespiratory fitness
Time frame: 12 weeks
Difference in oxygen uptake at anaerobic/ventilatory threshold pre/post treatment
5 secondary outcomes
Health-related quality-of-life
Time frame: 12 weeks
Health-related quality-of-life (SF 36)
Time frame: 12 weeks
Cardiac performance
Time frame: 12 weeks
Respiratory function
Time frame: 12 weeks
Sleep disordered breathing
Time frame: 12 weeks
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 21 Sep 2023.
- EU Clinical Trials database, use search term "theophylline"Link provided by the sponsor.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Thomas Möller, MD PhD principal investigator
Oslo University Hospital
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Theophylline Tablets in people with Congenital Heart Disease, run by Oslo University Hospital at 1 site in Norway.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 11 inclusion and 19 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 21 Sep 2023. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Norway. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Feasibility and safety - adverse events (time frame: 12 weeks). The study lists 5 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 21 Sep 2023.