Prophylactic Trimethoprim/Sulfamethoxazole to Prevent Severe Infections in Patients With Lupus Erythematous

Prophylactic Trimethoprim-Sulfamethoxazole for the Prevention of Serious Infections in Patients With Systemic Lupus Erythematosus: a Randomized Placebo Controlled Trial

The purpose of this study is to determine whether trimethoprim/sulfamethoxazole is effective in preventing serious infectious complications (those that require hospitalization or lead to death) in patients with lupus erythematosus that receive intermediate or high dose steroids.

Study Overview

• Status: Unknown
• Conditions: Lupus Erythematosus, Systemic
• Intervention / Treatment: Drug: Trimethoprim-Sulfamethoxazole; Drug: Placebo Oral Tablet

• Study Type: Interventional
• Enrollment (Anticipated): 310
• Phase: Phase 4

Contacts and Locations

Study Locations

• Mexico
  • DF
    • Mexico Distrito Federal, DF, Mexico, 14080
      • Recruiting
      • Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran
      • Contact: Andrea Wisniowski, MD; Phone Number: 2420 5554870900; Email: andiewsk@gmail.com
      • Contact: Jennifer Cuellar-Rodriguez, MD; Phone Number: 2421 5554870900; Email: jennifer.cuellar@infecto.mx
      • Principal Investigator: Jennifer M Cuellar-Rodriguez

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:

• Systemic Lupus Erythematosus according to the American College of Rheumatology Criteria
• On a daily dose of prednisone of ≥ 15 mg/d or equivalent, and that are expected to remain on the this dose for at least 1 month.
• Have signed an informed consent

Exclusion Criteria:

• Absolute contraindication to receive TMP-SMX (known allergy to TMP-SMX or sulfa drugs; TMP-SMX induced thrombocytopenia)
• Received TMP-SMX treatment in the previous month
• Creatinine clearance <30ml/min/m2
• Chronic viral infection (Hepatitis C virus, Hepatitis B virus, Human immunodeficiency virus)
• Malignant neoplasm, except for skin neoplasm
• Primary immune deficiencies
• Solid organ or hematopoietic stem cell transplant recipients
• Pregnancy or Breastfeeding
• Current active infection, except mild active infections that to the judgement of the primary investigator do not jeopardize the study outcomes (e.g. tinea).
• Uncontrolled chronic infection (e.g. tuberculosis- intensive phase treatment), except mild active chronic infections that to the judgement of the primary investigator do not jeopardize the study outcomes (e.g. onychomycosis).
• Controlled chronic infection, that needs to be treated or prevented with TMP-SMX.
• Absolute Neutrophil Count < 750/mm3, platelets <30x10^9/L, o hemoglobin <7 g/dL
• Patients receiving Methotrexate
• Patients participating in another research study that to the judgement of the principal investigator could jeopardize the safety or efficacy of the study drug.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: PREVENTION
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: QUADRUPLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Trimethoprim-Sulfamethoxazole (TMP-SMX); Trimethoprim-Sulfamethoxazole 180mg/800mg oral tablet, 3 times a week, for 6 months. Subjects may remain on the drug longer (maximum 1 year), if they continue to receive intermediate or high dose steroids at the end of 6 months.	Drug: Trimethoprim-Sulfamethoxazole; oral tablets, 3 times a week, for a minimum of 6 months and maximum of 1 year.
PLACEBO_COMPARATOR: Placebo; Tablets that look exactly the same as the experimental drug, 3 times a week, for 6 months. Subjects may remain on the placebo longer (maximum 1 year), if they continue to receive intermediate or high dose steroids at the end of 6 months.	Drug: Placebo Oral Tablet; oral tablets, 3 times a week, for a minimum of 6 months and maximum of 1 year.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Frequency of non-viral severe infections	Infections that lead to hospitalization for >24 hours or lead to death.	Time on the intervention (maximum 1 year)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Serious Adverse Events	A serious adverse event is an adverse event that leads to death, persistent disability, leads to hospitalization or increase in length of hospitalization. Additionally, an adverse event that does not immediately put life at risk, but that requires a medical or surgical intervention to prevent a serious adverse event.	Time on the intervention (maximum 1 year)
Frequency of non-viral infections	All non-viral infections (severe and non-severe)	Time on the intervention (maximum 1 year)
Time to first episode of non-viral severe infection	Infections that lead to hospitalization for >24 hours or lead to death, that are not of viral etiology.	From 2 weeks after randomization until the date of the first episode of a non-viral severe infection, up to 1 year after randomization.
All cause mortality or hospitalization	Death or hospitalization due to any cause infectious or non-infectious	Time on the intervention (maximum 1 year)
Proportion of patients that develop infections resistant to TMP-SMX	Infections that would traditionally be considered susceptible to TMP-SMX	Time on the intervention (maximum 1 year)
Drug discontinuation	Number of patients that require drug discontinuation due to safety concerns	1 year

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Peripheral Blood Immunophenotype: B and T lymphocytes and Natural Killer (NK) cells measured by multiparametric flow cytometry. These variables will be expressed as % of total peripheral blood mononuclear cells (PBMC)	In a random sample of a subset of patients, serially examined parameters at baseline, development of a first episode of severe infection or at the end of follow-up. Variables will be described as mean and standard deviation and groups will be compared by means of student T test. Association will be assessed by ANCOVA.	Up to 1 year after randomization.
Peripheral Blood Immunophenotype: Absolute number of B and T lymphocytes and NK cells per mcl of blood, measured by multiparametric flow cytometry.	In a random sample of a subset of patients, serially examined parameters at baseline, development of a first episode of severe infection or at the end of follow-up. Variables will be described as mean and standard deviation and groups will be compared by means of student T test. Association will be assessed by ANCOVA.	Up to 1 year after randomization.
Innate Immune Cells Phagocytosis: Mean fluorescence intensity of (pHrodo) positive cells.	In a random sample of a subset of patients, serially examined parameters at baseline, development of a first episode of severe infection or at the end of follow-up. Variables will be described as mean and standard deviation and groups will be compared by means of student T test. Association will be assessed by ANCOVA.	Up to 1 year after randomization
Innate Immune Cells Phagocytosis:Percentage of (pHrodo) positive cells.	In a random sample of a subset of patients, serially examined parameters at baseline, development of a first episode of severe infection or at the end of follow-up. Variables will be described as mean and standard deviation and groups will be compared by means of student T test. Association will be assessed by ANCOVA.	Up to 1 year after randomization
Respiratory Burst from Neutrophils by dihydrorhodamine; expressed as mean fluorescence intensity.	In a random sample of a subset of patients, serially examined parameters at baseline, development of a first episode of severe infection or at the end of follow-up. Variables will be described as mean and standard deviation and groups will be compared by means of student T test. Association will be assessed by ANCOVA.	Up to 1 year after randomization
Respiratory Burst from Neutrophils by dihydrorhodamine; expressed as percentage of positive cells.	In a random sample of a subset of patients, serially examined parameters at baseline, development of a first episode of severe infection or at the end of follow-up. Variables will be described as mean and standard deviation and groups will be compared by means of student T test. Association will be assessed by ANCOVA.	Up to 1 year after randomization
Neutrophil Extracellular Traps (NETs): Mean fluorescence of Sytox Green by spectrometry from lipopolysaccharide stimulated neutrophils.	In a random sample of a subset of patients, serially examined parameters at baseline, development of a first episode of severe infection or at the end of follow-up. Variables will be described as mean and standard deviation and groups will be compared by means of student T test. Association will be assessed by ANCOVA.	Up to 1 year after randomization
Neutrophil Extracellular Traps (NETs): Normalized mean fluorescence of elastase and Hoechst in 6 optical fields for each sample.	In a random sample of a subset of patients, serially examined parameters at baseline, development of a first episode of severe infection or at the end of follow-up. Variables will be described as mean and standard deviation and groups will be compared by means of student T test. Association will be assessed by ANCOVA.	Up to 1 year after randomization
Changes in systemic lupus erythematosus (SLE) activity using SLEDAI (Lupus Erythematosus Activity Index )	Serially calculated over time at standard 3 months intervals (determined as mild, moderate or severe activity)	Up to 1 year after randomization

Collaborators and Investigators

• Sponsor: Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran
• Collaborators: National Council of Science and Technology, Mexico
• Investigators: Principal Investigator: Jennifer M Cuellar-Rodriguez, MD, Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran

Publications and helpful links

General Publications

• Danza A, Ruiz-Irastorza G. Infection risk in systemic lupus erythematosus patients: susceptibility factors and preventive strategies. Lupus. 2013 Oct;22(12):1286-94. doi: 10.1177/0961203313493032.
• Cervera R, Khamashta MA, Font J, Sebastiani GD, Gil A, Lavilla P, Mejia JC, Aydintug AO, Chwalinska-Sadowska H, de Ramon E, Fernandez-Nebro A, Galeazzi M, Valen M, Mathieu A, Houssiau F, Caro N, Alba P, Ramos-Casals M, Ingelmo M, Hughes GR; European Working Party on Systemic Lupus Erythematosus. Morbidity and mortality in systemic lupus erythematosus during a 10-year period: a comparison of early and late manifestations in a cohort of 1,000 patients. Medicine (Baltimore). 2003 Sep;82(5):299-308. doi: 10.1097/01.md.0000091181.93122.55.
• Barber C, Gold WL, Fortin PR. Infections in the lupus patient: perspectives on prevention. Curr Opin Rheumatol. 2011 Jul;23(4):358-65. doi: 10.1097/BOR.0b013e3283476cd8.
• Bwakura-Dangarembizi M, Kendall L, Bakeera-Kitaka S, Nahirya-Ntege P, Keishanyu R, Nathoo K, Spyer MJ, Kekitiinwa A, Lutaakome J, Mhute T, Kasirye P, Munderi P, Musiime V, Gibb DM, Walker AS, Prendergast AJ. A randomized trial of prolonged co-trimoxazole in HIV-infected children in Africa. N Engl J Med. 2014 Jan 2;370(1):41-53. doi: 10.1056/NEJMoa1214901. Erratum In: N Engl J Med. 2014 Jan 30;370(5):488. Dosage error in article text.
• Vananuvat P, Suwannalai P, Sungkanuparph S, Limsuwan T, Ngamjanyaporn P, Janwityanujit S. Primary prophylaxis for Pneumocystis jirovecii pneumonia in patients with connective tissue diseases. Semin Arthritis Rheum. 2011 Dec;41(3):497-502. doi: 10.1016/j.semarthrit.2011.05.004. Epub 2011 Sep 29.

Study record dates

Study Major Dates

• Study Start (ACTUAL): March 1, 2017
• Primary Completion (ANTICIPATED): February 1, 2021
• Study Completion (ANTICIPATED): August 1, 2021

Study Registration Dates

• First Submitted: January 10, 2017
• First Submitted That Met QC Criteria: February 1, 2017
• First Posted (ESTIMATE): February 3, 2017

Study Record Updates

• Last Update Posted (ACTUAL): February 27, 2019
• Last Update Submitted That Met QC Criteria: February 25, 2019
• Last Verified: August 1, 2018

More Information

Terms related to this study

• Keywords: Infection; Prophylaxis; trimethoprim, sulfamethoxazole drug combination
• Additional Relevant MeSH Terms: Immune System Diseases; Autoimmune Diseases; Connective Tissue Diseases; Lupus Erythematosus, Systemic; Infections; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Anti-Bacterial Agents; Cytochrome P-450 Enzyme Inhibitors; Antiprotozoal Agents; Antiparasitic Agents; Antimalarials; Folic Acid Antagonists; Anti-Dyskinesia Agents; Anti-Infective Agents, Urinary; Renal Agents; Cytochrome P-450 CYP2C8 Inhibitors; Trimethoprim; Sulfamethoxazole; Trimethoprim, Sulfamethoxazole Drug Combination
• Other Study ID Numbers: INF-2056-17/20-1

Plan for Individual participant data (IPD)

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