Theophylline Effects in the Fontan Circulation
Condition: Congenital Heart Disease
MeSH terms: Heart Diseases; Heart Defects, Congenital
Study type: Interventional
Phase: Phase 2

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 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.
    

Intervention name(s): Theophylline Tablets
Intervention type(s): Drug
Intervention description(s): 12 week oral treatment
Other intervention name(s): ATC R03D A04
Intervention MeSH terms: Theophylline
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Fontan circulation; Cardiorespiratory fitness; Pulmonary function; Cardiac function; Quality of life