Anti-Inflammatory Drug and Endothelial Function (HOLD)

Effect of Hydroxychloroquine on Endothelial Function: a Clinical Trial

In this randomized double-blinded clinical trial, 400mg of hydroxychloroquine will be given daily to people over the age of 65 years with moderate-severe obstructive sleep apnea for 8 weeks. The aim of this study is to test whether hydroxychloroquine can improve endothelial function.

Study Overview

• Status: Unknown
• Conditions: Cardiovascular Diseases; Coronary Artery Disease; Atherosclerosis; Sleep Apnea; Endothelial Dysfunction
• Intervention / Treatment: Drug: Hydroxychloroquine; Drug: Placebo oral tablet

Detailed Description

Sleep apnea and coronary artery disease are prevalent and relevant diseases due to their morbidity and mortality. The mechanism by which sleep apnea leads to coronary artery disease remains unclear. It is known that intermittent hypoxia, the main characteristic of sleep apnea, leads to inflammation and consequently may lead to endothelial dysfunction. Endothelial dysfunction precedes the development of atherosclerotic disease and the occurrence of cardiovascular events. Agents that potentially act to improve endothelial function may assist in the prevention of cardiovascular events. Patients using immunomodulators due to rheumatic diseases have a lower prevalence of cardiovascular diseases. However, the cardioprotective effect of these drugs in patients without autoimmune diseases is not known. Hydroxychloroquine (HCQ) is an immunomodulator used in the treatment of rheumatoid arthritis and systemic lupus erythematosus. In addition to its anti-inflammatory properties, HCQ reduces cholesterol and glycemia levels and has antithrombotic effects. The drug is inexpensive and widely available. The adverse effects of HCQ are rare and occur more frequently when using high doses.

• Study Type: Interventional
• Enrollment (Anticipated): 50
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Maria Claudia Irigoyen; Phone Number: 55 11 985589166; Email: hipirigoyen@gmail.com
• Study Contact Backup: Name: Leticia Maria Silva; Phone Number: 55 51 993220727; Email: tedescosilva.leticia@gmail.com

Study Locations

• Brazil
  • Rio Grande Do Sul
    • Porto Alegre, Rio Grande Do Sul, Brazil, 90035-007
      • Recruiting
      • Hospital de Clinicas de Porto Alegre
      • Contact: Andrea Rambo; Phone Number: +55 51 33598943
      • Contact: Eloisa Medeiros; Phone Number: +55 51 33597604

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 60 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Apnea-Hypopnea index of 15 events/hour or higher

Exclusion Criteria:

• Contraindication for hydroxychloroquine (retinopathy, chronic liver disease, chronic renal disease)
• Rheumatologic disease

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo	Drug: Placebo oral tablet; Amido pills/daily for 8 weeks
Experimental: Hydroxychloroquine; 400mg/daily of hydroxychloroquine for 8 weeks	Drug: Hydroxychloroquine; 400mg/daily of hydroxychloroquine for 8 weeks

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in endothelial function measured by peripheral artery tonometry in the reactive-hyperemia index (RHI) scale	The reactive-hyperemia index (RHI) scale ranges from -0.4 to 1.6. Below -0.51 being endothelial dysfunction, a higher score indicates a better endothelial function	before and after eight weeks of treatment with hydroxychloroquine
Change in endothelial function measured by flow-mediated dilation (%FMD-response)	The FMD-response will be calculated as the variation in post-hyperaemia brachial artery diameter from baseline, measured in relative (percentage) change. A mean improvement in flow mediated dilatation of at least 2% would usually be required to detect a treatment benefit.	before and after eight weeks of treatment with hydroxychloroquine

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in fasting glucose blood levels (mg/dL)		before and after eight weeks of treatment with hydroxychloroquine
Change in glycosylated hemoglobin blood levels (%)		before and after eight weeks of treatment with hydroxychloroquine
Change in Lipidic profile	Determined by total cholesterol, HDL-cholesterol and triglycerides blood levels (mg/dL)	before and after eight weeks of treatment with hydroxychloroquine
Change in C-reactive protein (CRP) blood levels (mg/L)	The risk of developing cardiovascular disease is quantified as follows: low: CRP level under 1.0 mg/L average: between 1.0 and 3.0 mg/L high: above 3.0 mg/L	before and after eight weeks of treatment with hydroxychloroquine
Change in neutrophils lymphocytes ratio (NLR)	calculated by dividing the number of neutrophils by number of lymphocytes. The mean range of healthy adult subjects is between 0.78 and 3.53.	before and after eight weeks of treatment with hydroxychloroquine
Change in Autonomic Nervous System	The data will be collected through the system of acquisition of pressure waves in a continuous and non-invasive way by the Finometer® system, through a cuffing installed in the middle finger, taking this signal to an analog-to-digital signal converter. The pulse pressure signal will be acquired at 1000 Hz, continuously and non-invasively, supine (10 minutes) in a quiet environment, with controlled temperature (± 23 ° C) and illumination. The collected data will be saved in the software BeatsScope® and LabChart®, from which will be extracted the systograms for analysis.	before and after eight weeks of treatment with hydroxychloroquine
Change in apnea/hypopnea index	Apnea/Hypopnea index is provided by home respiratory polygraphy, ranging from 0-highest events/hour, zero-5 eventos/hour being normal and above 5 events/hour being abnormal	before and after eight weeks of treatment with hydroxychloroquine

Collaborators and Investigators

• Sponsor: Instituto de Cardiologia do Rio Grande do Sul
• Collaborators: Hospital de Clinicas de Porto Alegre
• Investigators: Principal Investigator: Denis Martinez, Federal University of Rio Grande do Sul

Publications and helpful links

General Publications

• Tedesco Silva LM, Cortes A, Rossi B, Boll L, Waclawovsky G, Eibel B, Cadaval Gonçalves S, Irigoyen MC, Martinez D. Effects of Hydroxychloroquine on endOthelial function in eLDerly with sleep apnea (HOLD): study protocol for a randomized clinical trial. Trials. 2021 Sep 17;22(1):638. doi: 10.1186/s13063-021-05610-0. Erratum in: Trials. 2021 Oct 18;22(1):709.

Study record dates

Study Major Dates

• Study Start (Actual): July 1, 2019
• Primary Completion (Anticipated): June 30, 2020
• Study Completion (Anticipated): June 30, 2020

Study Registration Dates

• First Submitted: October 29, 2019
• First Submitted That Met QC Criteria: November 11, 2019
• First Posted (Actual): November 13, 2019

Study Record Updates

• Last Update Posted (Actual): November 13, 2019
• Last Update Submitted That Met QC Criteria: November 11, 2019
• Last Verified: October 1, 2019

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Myocardial Ischemia; Heart Diseases; Vascular Diseases; Arteriosclerosis; Arterial Occlusive Diseases; Coronary Disease; Coronary Artery Disease; Cardiovascular Diseases; Atherosclerosis; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Antirheumatic Agents; Antiprotozoal Agents; Antiparasitic Agents; Antimalarials; Hydroxychloroquine
• Other Study ID Numbers: 5351/17

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No