Theophylline Effects in the Fontan Circulation

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Oslo University Hospital Hf

Participant type

Pediatric, Patients

Age range

0-17 years, 18-64 years

Gender

Male and Female

Therapeutic area

Diseases [C] - Cardiovascular Diseases [C14]

Trial duration

20 Feb 2023 → 15 Sep 2023

Decision date (initial)

2022-09-21

Transition trial

No

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Funding sources

Norwegian Health Association · Children's Foundation at Oslo University Hospital · South-East Norway Health Authority · Research Foundation of the Norwegian Association for Children with Congenital Heart Disease

External identifiers

EU CT number

2022-500301-41-00

ClinicalTrials.gov

NCT05717049

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Efficacy

1. To investigate feasibility and safety of a 12 weeks treatment study design with remote dosage titration and ambulatory heart rhythm monitoring during treatment phase
2. 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.

Secondary objectives 4

1. 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
2. To provide an estimate of the effect size of 12 weeks of oral treatment on cardiac performance in adolescents aged 16-25 years with univentricular congenital heart disease and Fontan circulation currently not treated with pulmonary vasodilators.
3. 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.
4. 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.

Conditions and MedDRA coding

Univentricular congenital heart disease with a Fontan-type surgical palliation

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 6

1. Participant must be 16 to 25 years of age inclusive, at the time of signing the informed consent.
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 more than mild liver disease or liver failure (see exclusion criteria) of severe reduced kidney function. d. Considered and assessed eligible for administration of Theo-Dur® (theophylline) as specified in the SmPC.
3. Body mass index (BMI) within the range 18.5 – 34.9 kg/m2 (inclusive).
4. Contraceptive use by women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies.
5. 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 protocol section 10.4.1 and 10.4.2
6. 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.

Exclusion criteria 11

1. Current or previous (last 12 months) tachyarrhythmia which has been cause of medical investigation or hospitalization.
2. 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, nifedipine, norfloxacine, ranitidin, tiabendazol, verapamil, fluvoxamine, carbamazepine, felodipine, phenobarbital, phenytoin, rifampicine, lithium, ketamine, glucagon)
3. Heart rhythm during inclusion visit other than: - sinus rhythm or regular supraventricular rhythm (visible P-waves) regardless P-wave angle - nodal rhythm
4. Systemic hypertension (systolic or diastolic blood pressure above 95 percentile)
5. 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
6. 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
7. Biochemical indication of more than mildly reduced kidney function indicated by: a. Creatinine > 150 μmol/L (male) or > 120 μmol/L (female)
8. Pregnancy or breastfeeding
9. Inherited forms of galactose intolerance (Lapp lactase deficiency eller glucose-galactose malabsorption
10. Current treatment with pulmonary vasodilator medication (sildenafil, tadalafil, udenafil, bosentan, ambrisentan, macicentan, or any prostacyclin derivate)
11. Hypersensitivity to theophylline

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 2

1. Primary safety endpoints: a. Frequency of treatment emerged AE/SAE b. Freedom from participant dropout based on tolerability of the study intervention c. Number of participants requiring dose reduction after first serum concentration assessment. d. Freedom of arrhythmogenic side effects of the study treatment leading to patient dropout
2. Difference in oxygen uptake at aerobic threshold pre/post treatment.

Secondary endpoints 4

1. Difference in total scores from SF-36 and EQ-5D questionnaires pre/post treatment
2. Difference in ventricular function as assessed by echocardiography at rest pre/post treatment
3. Difference in diffusion capacity pre/post treatment
4. Change in Apnea Hypopnea Index during home-based sleep study pre-/post-treatment

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Oslo University Hospital Hf

Sponsor organisation

Oslo University Hospital Hf

Address

Taarnbygget, Kirkeveien 166 Kirkeveien 166

City

Oslo

Postcode

0450

Country

Norway

Scientific contact point

Organisation

Oslo University Hospital Hf

Contact name

Thomas Möller

Public contact point

Organisation

Oslo University Hospital Hf

Contact name

Thomas Möller

Locations

1 EU/EEA country · 1 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Summary of results Art. 37(4) CTR

Layperson summary Annex V

Documents 2 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

4 submissions — initial application plus substantial / non-substantial modifications