Atorvastatin on Inflammation and Cardiac Function in Chronic Chagas Disease

NCT04984616 | Terminated Phase 2

• 1 other identifier: U1111-1267-3513
• Study Type: interventional
• Target: 300
• Locations: 1 country
• Sites: 4

Brief Summary

Chagas Disease, caused by the parasite Trypanosoma cruzi afflicts 7 million people in Latin America, and due to migration, abroad. The diagnosis lies in clinical suspicion and serologic detection of antibodies. Cardiac evaluation is essential because complications, including heart failure and arrhythmias, are the main causes of disability and death. Heart involvement is explained by a parasite-dependent, immune-mediated myocardial and microvascular injuries. Current treatment includes the administration of nifurtimox or benznidazole, although in the chronic phase their efficacy is low and may induce severe adverse events, forcing the suspension of the therapy. Therefore, finding innovative approaches to improve the efficacy of the current antichagasic drugs by modifying the inflammatory response would render the current treatment more effective. Pre-clinical evidence supports the idea that the cholesterol-lowering statin drugs, such as atorvastatin, may contribute to decrease cardiac inflammation, reduce endothelial activation, and improve cardiac function. Atorvastatin therapeutic and safety profiles are well known, as is its mechanism of action, shared by the other members of the statin class. This trial aims at evaluating whether atorvastatin, in combination with antichagasic therapy, is safe and more efficacious in reducing general inflammation than an antiparasitic therapy alone, by improving endothelial and cardiac functions. This proof-of-concept trial will be double-blinded, randomized, and multicentered with a phase II design. To achieve this aim, it will be evaluated the efficacy of the combination of atorvastatin and antichagasic therapy (nifurtimox or benznidazole) to reduce inflammatory cytokine plasma levels, soluble endothelial cell adhesion molecules, and confirm the improvement of the cardiac function by electrocardiogram and two-dimensional echocardiogram. The trial will set the safety and tolerability of the combination of atorvastatin with antichagasic therapy by monitoring the incidence of adverse events and discontinuation of the therapy. This trial will be conducted with a sample size of 300 adult patients in four hospitals located in Santiago and Valparaiso, Chile.

Conditions

Chronic Chagas Disease

Keywords

Chagas Disease; Atorvastatin; Inflammation

Outcome Measures

Primary Outcomes (1)

• Number of patients that present a change in the phase of the chronic cardiomyopathy

  To evaluate whether the effect of atorvastatin in combination with antiparasitic therapy (NFX or BZD), more effective than antiparasitic therapy alone in preventing the onset of cardiac disorders as determined by non-progression in the phase from the A-phase according to the I Latin American Guidelines for the diagnosis and treatment of Chagas cardiomyopathy (Andrade et al, Arq Bras Cardiol 2011;97 Suppl 3:1-48.).

  Twelve months

Secondary Outcomes (9)

• plasma levels of cytokines (pg/mL)

  Twelve months

• Plasma levels of endothelial adhesion molecules (pg/mL)

  Twelve months

• Proportion of patients with change in heart rate measured by electrocardiographic examination

  Twelve months

• Proportion of patients with changes in the QT interval duration (milliseconds)

  Twelve months

• Proportion of patients with abnormalities in ventricular electrical conduction determined by the duration of the QRS interval (milliseconds)

  Twelve months

Study Arms (3)

ATORVASTATIN 40

EXPERIMENTAL

40 mg Atorvastatin/day for 120 days P.O.

Drug: 40 mg Atorvastatin/day for 120 days P.O.

ATORVASTATIN 80

EXPERIMENTAL

80 mg Atorvastatin/day for 120 days P.O.

Drug: Atorvastatin 80

Placebo

PLACEBO COMPARATOR

Placebo/day for 120 days P.O.

Drug: Placebo

Interventions

40 mg Atorvastatin/day for 120 days P.O. DRUG

Oral administration of Atorvastatin 40 mg/daily for 120 days

ATORVASTATIN 40

Atorvastatin 80 DRUG

Oral administration of Atorvastatin 80 mg/daily for 120 days

ATORVASTATIN 80

Placebo DRUG

Oral administration of Placebo daily for 120 days

Placebo

Eligibility Criteria

• Age: 18 Years - 50 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

• Adults older than 18 and younger than 50 years,
• with a weight higher than 40 kg
• Positive conventional confirmatory serology for T. cruzi infection from the NAtional Public Health institute (ISPCH), and
• A positive qPCR
• Have normal laboratory test values for the following parameters: total white blood cell count, platelet count, creatine kinase (CK), alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin or creatinine, or a gamma-glutamyl transferase (GGT) \> 2 times the upper limit of normal (X ULN);
• Women of reproductive age must have a negative serum pregnancy test, must not be breastfeeding, and must consistently use a highly effective contraceptive method throughout the treatment phase
• Ability to comply with all protocol-specified follow-up tests and visits and have a permanent address;
• Signed written informed consent form

You may not qualify if:

• Signs and symptoms of the digestive form of Chagas Disease;
• Chronic cardiac Chagas Disease stage II or higher;
• Acute or chronic health conditions such as acute infections, history of HIV infection, diabetes, liver and kidney disease;
• Hypothyroidism
• Family history of muscle disorders
• Pre-existing heart disease unrelated to Chagas disease;
• Formal contraindication to receive nifurtimox or benznidazole,
• Known history of hypersensitivity, allergy or severe adverse reactions to atorvastatin, benznidazole or nifurtimox;
• History of previous treatment for Chagas Disease;
• History of prior treatment with atorvastatin, lovastatin, rosuvastatin, simvastatin or any other statin;
• Any concomitant use of antimicrobial agents;
• History of alcohol or drug abuse;
• Any condition that precludes oral medication;
• Concomitant or intended use of CYP3A4 modifiers;
• Medical history of familial short QT syndrome or concomitant therapy with medications that may shorten the QT interval.

Sponsors & Collaborators

• Juan D. Maya: lead

Study Sites (4)

Hospital San Martin

Quillota, Región de Valparaíso, 2260494, Chile

Location

Hospital Gustavo Fricke

Viña del Mar, Región de Valparaíso, 2570017, Chile

Location

Hospital Felix Bulnes

Quinta Normal, Santiago Metropolitan, 8520398, Chile

Location

Hospital San Juan de Dios

Santiago, Santiago Metropolitan, 8350533, Chile

Location

Related Publications (1)

• Campos-Estrada C, Urarte E, Denegri M, Villalon L, Gonzalez-Herrera F, Kemmerling U, Maya JD. Effect of statins on inflammation and cardiac function in patients with chronic Chagas disease: A protocol for pathophysiological studies in a multicenter, placebo-controlled, proof-of-concept phase II trial. PLoS One. 2023 Jan 13;18(1):e0280335. doi: 10.1371/journal.pone.0280335. eCollection 2023.

  PMID: 36638112 DERIVED

MeSH Terms

Conditions

Chagas Disease; Inflammation

Condition Hierarchy (Ancestors)

Trypanosomiasis; Euglenozoa Infections; Protozoan Infections; Parasitic Diseases; Infections; Vector Borne Diseases; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Study Officials

• Juan D. Maya, Ph.D.

  Full Professor

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Full Professor

Study Record Dates

• First Submitted: June 29, 2021
• First Posted: July 30, 2021
• Study Start: October 12, 2021
• Primary Completion: March 31, 2024
• Study Completion: April 1, 2024
• Last Updated: September 19, 2024

Record last verified: 2023-05

Locations

CL (4)