Corticosteroids in Community Acquired Pneumonia

Study Overview
=================
Brief Summary
-----------------
This is a single-center, blinded, placebo-controlled pilot RCT evaluating corticosteroids for the treatment of Community Acquired Pneumonia (CAP) that will enroll 100 adults hospitalized with community-acquired pneumonia. The primary goal is to assess the feasibility of proposed trial procedures for use in a subsequent phase III trial powered on 6-month cognitive outcome (MOCA-Blind score). Key outcomes are six-month cognitive and functional status, duration and severity of symptoms, and mortality.

Official Title
-----------------
Corticosteroid Treatment for Community-Acquired Pneumonia to Improve Long-term Cognition: A Pilot Randomized Controlled Trial

Conditions
-----------------
Community-acquired Pneumonia, Cognition Disorder

Intervention / Treatment
-----------------
* Drug: Prednisone
* Drug: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Age ≥ 50 years Hospital admission to ward or ICU (including observation status admissions) Acute pneumonia defined as fulfilling each of the following two criteria: (a) New (<7-day duration) or worsening symptoms consistent with a lower respiratory tract infection, including ≥ 1 of the following: cough, shortness of breath, chest pain, sputum production, or decline in mental status; (b) Radiographic findings on chest x-ray or CT consistent with acute pulmonary infection, including pulmonary opacities, infiltrates, or pleural effusion. CRP ≥ 15 mg/dL within 24 hours of enrollment Exclusion Criteria: Systemic steroid use within the past 30-days. Clinical team planning to treat with systemic steroids during this hospitalization independent of the study protocol. Unable to randomize patient within 24 hours of hospital presentation. Hospital-acquired pneumonia, defined as development of clinical and radiographic signs of pneumonia as an inpatient in an acute care hospital. (Residence in a nursing home or assisted living facility is not an exclusion criterion.) Unable to follow simple commands or non-verbal prior to this acute illness. Pre-existing severe dementia, defined as an Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE) score ≥ 4.12. Concomitant acute decompensated heart failure requiring intravenous diuretics Serum sodium > 145 mEq/L (hypernatremia) or potassium < 3.5 mEq/L (hypokalemia) at screening and randomization Systolic blood pressure > 180 mmHg or a diastolic blood pressure > 100 mmHg at the start and end of screening. Any history of diabetes mellitus, having a serum blood glucose > 250 mg/dL, or requiring an anti-diabetic medication (e.g., insulin) Previous allergic or adverse reaction to a corticosteroid Severe immunosuppression, defined as any of the following: HIV with CD4 count < 200 cells/mm3, absolute neutrophil count < 500 cells/mm3, solid organ or hematopoietic stem cell transplant with in the past 90 days. Cystic fibrosis Active cancer, defined as new diagnosis or treatment for cancer in the past 6 months. Any history of adrenal insufficiency Substance abuse (alcohol, opioid, benzodiazepines, methamphetamines, cocaine) within the past year Any history of hospitalizations due to psychiatric illnesses within the past year Gastro-intestinal bleeding treated with hospital admission and/or blood transfusion within the past 3 months. Pre-existing medical condition resulting in a life expectancy < 6 months. Clinical team does not believe the patient should enter the study due to concerns about potential steroid-related complications. Alternative non-pneumonia illness accounts for the acute clinical or radiographic findings that meet the study's inclusion criteria. Unable to take the enteral study medicine by mouth or tube Prior enrollment in this study at any time Non-English speaking Confirmed or suspected COVID-19 as the cause of the patient's acute illness -

Ages Eligible for Study
-----------------
Minimum Age: 50 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Other
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Prednisone<br>Patients randomized to the intervention arm will receive prednisone 50mg PO daily for 7 days. | Drug: Prednisone<br>* Prednisone 50mg will be administered enterally for 7 days.<br>|
| Placebo Comparator: Placebo<br>Patients will receive matching placebo PO daily for 7 days. | Drug: Placebo<br>* This is a matching placebo to prednisone.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Feasibility as determined by the number of subjects who are successfully recruited and complete follow-up | Feasibility will be defined as: (a) recruitment and successful protocol completion of 100 patients; (b) corticosteroids being well tolerated, as shown by similar severity and frequency of adverse events in the intervention and placebo groups; (c) successful completion of 6-month cognitive assessments by >80% of survivors; and (d) the primary cognitive outcome Montreal Cognitive Assessment-Blind (MOCA-Blind) numerically favoring the intervention group with the one-tailed upper 80% confidence interval of the difference in MOCA-Blind between the intervention and placebo groups containing the minimally-important clinical difference (2 points on the MOCA-Blind). | 1.5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Global cognition as measured by the Montreal Cognitive Assessment-Blind (MOCA-Blind) | This is a measure of global cognition based on the assessment of attention concentration, memory, language, conceptual thinking, calculations, and orientation. Scores range from 0 to 22 with higher scores indicating better cognition. | 6-months | 
| Severity of pneumonia symptoms as measured by the Community-Acquired Pneumonia Symptom (CAP-Sym) Questionnaire | This is a 18-item scale to determine the presence and severity of pneumonia symptoms. Each item is graded on a 6-point Likert scale. Scores range from 0 to 90 with higher scores indicating more severe symptoms. | 3-days | 
| Severity of pneumonia symptoms as measured by the Community-Acquired Pneumonia Symptom (CAP-Sym) Questionnaire | This is a 18-item scale to determine the presence and severity of pneumonia symptoms. Each item is graded on a 6-point Likert scale. Scores range from 0 to 90 with higher scores indicating more severe symptoms. | 7-days | 
| Severity of pneumonia symptoms as measured by the Community-Acquired Pneumonia Symptom (CAP-Sym) Questionnaire | This is a 18-item scale to determine the presence and severity of pneumonia symptoms. Each item is graded on a 6-point Likert scale. Scores range from 0 to 90 with higher scores indicating more severe symptoms. | 30-days | 
| Quality of life as measured by the EQ-5D-5L | Characterizes quality of life and contains 5-dimensions (5D) related to everyday living: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. It asks patients to rate their current global health status from 0 (worst health you can imagine) to 100 (best health you can imagine). Scores range from -0.573 to 1.000 with higher scores indicating better quality of life. | 6-months | 
| Basic activities of daily living (ADL) as measured by the Barthel's Index | Quantifies pre-illness basic ADLs such as bathing, dressing, toileting, transferring, continence, and feeding. Scores range from 0 to 20 with higher scores indicating better functioning. | 6-months | 
| Instrumental ADL as measured by Lawton Instrumental Activities of Daily Living Scale (IADLs) | Quantifies pre-illness IADLs - ability to use the phone, shopping, food preparation, housekeeping, laundry, transportation, medication management, and finances. Scores range from 0 to 8 with higher scores indicating better functioning. | 6-months | 
| Employment status as characterized by the Outcomes After Critical Illness and Surgery (OACIS) Employment Status Questionnaire | 9-item survey that characterizes the patient's baseline (prior to the critical illness) and current level of employment (full, partial, or not employed). Patients will be categorized as loss of employment or no loss of employment. | 6-months | 
| Vital status (dead / alive) | Death during the index hospitalization will be recorded. | Baseline to hospital discharge, approximately 5 days | 
| Vital status (dead / alive) | Death within 6-months will be recorded. | 6-months | 
| Intensive care unit admission (yes/no) | Intensive care unit admission at any point during the index hospitalization will be recorded. | Baseline to hospital discharge, approximately 5 days | 
| Mechanical ventilation (yes/no) | Invasive mechanical ventilation is defined as new assisted positive pressure breathing through an endotracheal tube or tracheostomy for any duration. Noninvasive ventilation through a mask or nasal prongs does not satisfy the outcome of invasive mechanical ventilation. | Baseline to hospital discharge, approximately 5 days | 
| Vasopressor use (yes/no) | defined as the administration of any of the following medications by continuous infusion for at least 1 hour during the index hospitalization: norepinephrine, epinephrine, dopamine, phenylephrine or vasopressin. | Baseline to hospital discharge, approximately 5 days | 
| Pleural drainage (yes/no) | Pleural drainage is defined as removal of fluid from the pleural space by any procedure at the bedside or in the operating room during the index hospitalization; procedures such as thoracentesis and video-assisted thorascopic surgery (VATS) may be used to drain pleural fluid. | Baseline to hospital discharge, approximately 5 days | 
| Hospital length of stay in (days) | Duration of hospitalization (presentation to hospital discharge) will be recorded. | Baseline to hospital discharge, approximately 5 days |