Theophylline for Low Adenosine Syncope (THEO-USA)

Theophylline in Patients With Unexplained Syncope and Low Adenosine. Study Verified by ICM, Controlled by Propensity-score Matching

The study aims at assessing that theophylline is effective in patients with no prodromes, normal heart and with low values of plasmatic adenosine compared with a propensity-score matched untreated control population who have received an implantable cardiac monitor (ICM) for diagnosis of unexplained or atypical reflex syncope.

Study Overview

• Status: Completed
• Conditions: Syncope
• Intervention / Treatment: Drug: Theophylline

Detailed Description

Theophylline has been used for 3 decades in ordinary medical practice to tentatively prevent syncopal recurrences in patients affected by neurally-mediated syncope. Observational studies report a recurrence rate with this drug ranging between 12% and 22%. Theophylline was much more effective in selected patients with syncope without prodromes and normal heart who had ECG documentation of long pauses at the time of syncopal attack and low values of baseline plasmatic adenosine. Since theophylline is a non-selective antagonist of purinergic receptors, it has been hypothesized that purinergic receptors are involved in the mechanism of syncope in such patients. Conversely, theophylline was suspected to be ineffective (or less effective) in patients affected by other forms of neurally-mediated syncope.

The present study aims at assessing that theophylline is effective in patients with no prodromes, normal heart and with low values of plasmatic adenosine compared with a propensity-score matched untreated control population.

This will be a multicenter, non interventional study, verified by ICM, with 2 predefined subgroups:

Subgroup #1

• Low adenosine group: Patients with Low Adenosine values (<0.40 μmol/L)
• Normal/high adenosine (≥0.40 μmol/L) group: any other patient Subgroup #2
• Patients with no prodromes or very short prodromes (≤5 sec), normal heart and normal ECG (No prodrome group)
• Any other form of atypical neurally-mediated syncope with prodromes >5 sec. Remote or in-hospital periodic follow-up will be done according to centre's clinical practice for ICM monitoring.

Patients will be followed up until the first primary endpoint event with a maximum follow-up of 24 months since start of theophylline treatment.

• Study Type: Observational
• Enrollment (Actual): 77

Contacts and Locations

Study Locations

• Italy
  • Lavagna, Italy, 16033
    • Department of Cardiology, Ospedali del Tigullio

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Probability Sample

Study Population

Patients who have received an implantable cardiac monitor (ICM) for diagnosis of unexplained or atypical reflex syncope

Description

Inclusion Criteria:

1. Male or female gender with age >18 years
2. Unexplained syncope without prodrome or neurally-mediated syncope with atypical prodrome, with normal heart and normal ECG
3. Two syncopes /last year or 3 syncopes /last 2 years before start of theophylline treatment
4. Having received an ICM according to conventional guideline-based indications
5. Being treated with oral theophylline therapy, while been waiting for ICM diagnosis
6. Having signed a written informed consent to the study participation and to the treatment of personal data

Exclusion Criteria:

1. Typical vaso-vagal syncope with long prodromes and situational syncope
2. Any other form of syncope/T-LOC different from reflex syncope
3. Pregnant or breast-feeding patients -

Study Plan

How is the study designed?

Design Details

• Observational Models: Case-Control
• Time Perspectives: Prospective

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Theophylline group; Patients who have electrocardiographic documentation of asystolic syncope will be treated with oral theophylline at tailored dosage	Drug: Theophylline; Oral theophylline initially 600 mg bid and then titrated at the maximum tolerated dose
Control untreated group; A propensity-score matched control group is generated from the large database of patients who had received an implantable loop recorder

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Asystolic syncope	Number of patients. The primary objective aims to test the hypothesis that theophylline is able to reduce asystolic events in the Low-Adenosine subgroup compared with the propensity-score matched control group	24 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time to first syncope recurrence	Months from enrolment to the first recurrence of syncope	24 months
Asystolic syncope in the subgroup with low adenosine plasmatic values	Number of patients with asystolic syncope during follow-up	24 months
Asystolic syncope in patients without prodrome, normal heart and normal ECG	Number of patients with asystolic syncope during follow-up	24 months

Collaborators and Investigators

• Sponsor: Centro Prevenzione Malattie Cardiovascolari N. e V. Corbella
• Collaborators: Gruppo Italiano Multidisciplinare per lo Studio della Sincope
• Investigators: Principal Investigator: Michele Brignole, MD, Department of Cardiology, Ospedali del Tigullio

Publications and helpful links

General Publications

• Brignole M, Iori M, Strano S, Tomaino M, Rivasi G, Ungar A, Carretta D, Solari D, Napoli P, Deharo JC, Guieu R. Theophylline in patients with syncope without prodrome, normal heart, and normal electrocardiogram: a propensity-score matched study verified by implantable cardiac monitor. Europace. 2022 Jul 21;24(7):1164-1170. doi: 10.1093/europace/euab300.

Study record dates

Study Major Dates

• Study Start (Actual): May 11, 2016
• Primary Completion (Actual): November 30, 2020
• Study Completion (Actual): December 30, 2020

Study Registration Dates

• First Submitted: January 10, 2019
• First Submitted That Met QC Criteria: January 11, 2019
• First Posted (Actual): January 14, 2019

Study Record Updates

• Last Update Posted (Actual): January 20, 2021
• Last Update Submitted That Met QC Criteria: January 18, 2021
• Last Verified: January 1, 2020

More Information

Terms related to this study

• Keywords: asystole; theophylline; implantable loop recorder
• Additional Relevant MeSH Terms: Nervous System Diseases; Neurologic Manifestations; Neurobehavioral Manifestations; Unconsciousness; Consciousness Disorders; Syncope; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Vasodilator Agents; Autonomic Agents; Peripheral Nervous System Agents; Enzyme Inhibitors; Purinergic Antagonists; Purinergic Agents; Bronchodilator Agents; Anti-Asthmatic Agents; Respiratory System Agents; Phosphodiesterase Inhibitors; Purinergic P1 Receptor Antagonists; Theophylline
• Other Study ID Numbers: CPM 30102018

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No