Hydroxychloroquine in Colchicine-Resistant Glucocorticoid-Dependent Idiopathic Recurrent Pericarditis (RESTORE)

Efficacy and Safety of Hydroxychloroquine in Colchicine-RESistant Glucocorticoid-DependenT IdiOpathic REcurrent Pericarditis: A Randomized Clinical Trial (The RESTORE Randomized Clinical Trial)

Among patients with colchicine-resistant glucocorticoid-dependent idiopathic RP (idiopathic recurrent pericarditis during at least a second recurrence, having met the 2015 European Society of Cardiology criteria for pericarditis at least once), HCQ 400mg daily is associated with a reduce the risk of recurrence.

The above hypothesis will be tested with a randomized, prospective, parallel, open label clinical trial. The expected study duration is approximately 12 months from the time the first subject is enrolled (planned for February 2023) to the time of study's termination date (December 2024). The researchers will obtain approval by the institutional review board (IRB).

Study Overview

• Status: Not yet recruiting
• Conditions: Pericarditis Idiopathic Recurrent
• Intervention / Treatment: Drug: Hydroxychloroquine; Drug: Colchicine

Detailed Description

Recurrent pericarditis (RP) along with pericardial tamponade and constrictive pericarditis are potential complications of acute pericarditis. They appear most frequently in secondary forms of pericarditis as compared with idiopathic acute pericarditis. Among the above-mentioned complications, RP is a highly problematic and disabling condition, which severely impairs the quality of life of affected patients, since it often requires emergency department visits and hospitalizations.

Moreover, the side effects of treatment constitute an additional concern both for the managing physicians and affected patients. In the most recent guidelines for the diagnosis and management of pericardial diseases of the European Society of Cardiology (ESC), a stepwise approach has been proposed for the treatment of RP including 4 treatment lines according to disease severity and individual response to treatment. Among them hydroxychloroquine (HCQ), an anti-malarial drug with immunomodulatory properties could potentially have a role as a third step treatment. HCQ, is an established treatment for all patients with systemic lupus erythematosus (SLE) including those with serositis (pericarditis, pleuritis) but data on HCQ efficacy for refractory idiopathic RP (IRP) are very scant.

The potential Anti-interleukin-1 agents are characterized by some disadvantages such as a long duration of therapy as well as high costs. In addition to this, only patients with a clear inflammatory pattern are candidates. Patients with mild or doubtful symptoms and/or normal or near normal levels of C-Reactive protein are not good candidates for anti-IL-1 therapy.

The investigators propose a randomized, prospective, parallel, open label, clinical trial, which will provide data on the efficacy and safety of HCQ in colchicine-resistant glucocorticoid-dependent idiopathic RP. The trial will have two study arms: HCQ 400mg daily vs. Colchicine continued. Patients with RP (idiopathic recurrent pericarditis during at least a second recurrence, having met the 2015 European Society of Cardiology criteria for pericarditis at least once) will be randomized to HCQ vs. Colchicine and will receive optimal post-recurrence care (increase the dose of methylprednisolone by 8 mg and then decrease by 2 mg every 2 weeks) in both arms.

• Study Type: Interventional
• Enrollment (Anticipated): 30
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: George Lazaros, MD, PhD, FESC; Phone Number: +30‭6974389238‬; Email: glaz35@hotmail.com

Study Locations

• Greece
  • Attiki
    • Athens, Attiki, Greece, 11527
      • "Hippokration" General Hospital of Athens
      • Contact: George Lazaros, MD, PhD, FESC; Email: glaz35@hotmail.com
      • Principal Investigator: George Lazaros, MD, PhD, FESC
      • Principal Investigator: Konstantinos Tsioufis, MD, PhD, FESC
      • Sub-Investigator: Ioannis Doundoulakis, MD, MSc (Res)
      • Sub-Investigator: Panagiotis Tsioufis, MD, MSc

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Male or female patients aged≥18 years
• Idiopathic recurrent pericarditis with at least 2 recurrences
• Recurrent pericarditis defined as a first episode of acute pericarditis followed by recurrences (at least two recurrences for this study). First episode of pericarditis is diagnosed when at least two of the following criteria were present: pericarditis typical chest pain (sharp and pleuritic, improved by sitting up and leaning forward), pericardial friction rubs, widespread ST segment elevation or PR interval (PR) depressions not previously reported, and new or worsening pericardial effusion. Recurrence is diagnosed when chest pain recurs and one or more of the following signs is present: fever, pericardial friction rub, ECG changes, echocardiographic evidence of new or worsening pericardial effusion, and elevations in the white blood cell count, erythrocyte sedimentation rate or C-reactive protein. To be enrolled in this study, elevation of C-reactive protein is mandatory both in the first attack and in the following recurrences. The investigators differentiate recurrences from incessant pericarditis, term used to define patients with continued activity of pericarditis (with a symptom-free interval of < 6 weeks)
• Specific aetiologies excluded, including tuberculous, neoplastic or purulent aetiologies, post-cardiac injury syndromes, and rheumatic autoimmune diseases.
• Female subjects must be postmenopausal, or incapable of pregnancy or permanently sterile, or if of childbearing potential must agree to use highly-effective method of contraception.
• Signed written informed consent by the patient for participation in the study and agreement to comply with the medication and the follow-up schedule.

Exclusion Criteria:

• Ophthalmologic contraindications
• Structural heart disease
• Corrected QT interval >440msec in men and >450msec in women
• Left ventricular hypertrophy >13mm in men and >11mm in woman
• Known allergy or intolerance to hydroxychloroquine
• Life expectancy of < 12 months
• Complex congenital heart disease
• History of ventricular arrhythmias other than isolated extrasystoles
• Women who are pregnant (as evidenced by pregnancy test if pre-menopausal)
• Known channelopathy such as Brugada syndrome, long QT syndrome, or Catecholaminergic monomorphic ventricular tachycardia
• On the heart transplant list

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Hydroxychloroquine arm; Hydroxychloroquine 400mg daily	Drug: Hydroxychloroquine; Hydroxychloroquine 400mg daily
Active Comparator: Colchicine arm; Colchicine continued	Drug: Colchicine; Colchicine continued

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Recurrence Rate	The diagnosis of RP in a patient with history of a documented episode of acute pericarditis according to ESC guidelines was established in the presence of at least 2 of the following conditions: i. pleuritic chest pain, ii. pericardial friction rub, iii. ECG compatible with acute pericarditis and iv. first detected or increasing in size pericardial effusion. C-reactive protein (CRP) elevation was considered a confirmatory finding. Since RP frequently underlines a secondary etiology, an extensive work-up was performed to exclude such diseases. In particular, apart from the first line evaluation, second level investigations were additionally performed such as thyroid function tests, chest and abdominal computed tomography, serological screening for autoimmune disorders, serum tumor markers and QuantiFERON-Tuberculosis Gold test.	12 months follow-up

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time to Pericarditis Recurrence	Time to pericarditis recurrence (from randomization to 1st recurrence). Kaplan-Meier. Clinical Events Committee (CEC)-confirmed recurrences used for primary analysis.	12 months follow-up
Dose of the Corticosteroid in the time of the recurrence		12 months follow-up
Change over time of pericardial pain	Quantified using the four-point pain verbal rating scale (VRS-4). Minimum: 0, maximum: 3). Higher score indicates worse outcomes.	3,6,9,12 months follow-up
Change over time of C-reactive protein levels	Measured in mg/dL	3,6,9,12 months follow-up
Change over time of echocardiographic effusion	Measured in ml	3,6,9,12 months follow-up
Incidence and severity of Adverse Events	All adverse events (AEs) will be monitored and recorded to assess the tolerability and safety of the treatment.	3,6,9,12 months follow-up
State-Trait Anxiety Inventory (STAI)	This score measures two types of anxiety- state anxiety (S-anxiety) and trait anxiety (T-anxiety). It includes 40 self-reported items on a 4-point Likert scale. The scores range from 20 to 80, with higher scores correlating with greater anxiety. The 4-point scale for S-anxiety is as follows: 1) not at all, 2) somewhat, 3.) moderately so, 4) very much so. The 4-point scale for T-anxiety is as follows: 1) almost never, 2) sometimes, 3) often, 4) almost always.	3,6,9,12 months follow-up

Collaborators and Investigators

• Sponsor: Hippocration General Hospital

Study record dates

Study Major Dates

• Study Start (Anticipated): February 1, 2023
• Primary Completion (Anticipated): December 1, 2024
• Study Completion (Anticipated): December 1, 2024

Study Registration Dates

• First Submitted: January 30, 2023
• First Submitted That Met QC Criteria: February 10, 2023
• First Posted (Actual): February 21, 2023

Study Record Updates

• Last Update Posted (Estimate): February 22, 2023
• Last Update Submitted That Met QC Criteria: February 20, 2023
• Last Verified: February 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Heart Diseases; Cardiovascular Diseases; Disease Attributes; Recurrence; Pericarditis; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Antirheumatic Agents; Antineoplastic Agents; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Antiprotozoal Agents; Antiparasitic Agents; Antimalarials; Gout Suppressants; Colchicine; Hydroxychloroquine
• Other Study ID Numbers: RESTORE

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

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