Clinical trial NCT06472219: PREDICATE Trial For Respiratory Tract Infections
Official title: Early Prednisolone for Suspected Community-acquired Acute Respiratory Tract Infection (PREDICATE): A Double-blind, Randomised, Multi-centre, Adaptive Platform, Controlled Trial
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: Respiratory Tract Infections
Keywords: Emergency Care
Inflammation
Mortality
Pneumonia
Prednisolone
Randomised Controlled Trial
Respiratory Tract Infections
Safety
Sepsis
Steroids
Lead sponsor: The University of Hong Kong
Sponsor class: OTHER
First posted: 2024-06-25
Enrollment: 1300
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Background

The goal of this clinical trial is to learn if prednisolone works to treat moderate to severe respiratory tract infections in adults admitted to hospital. It will also learn about the safety of prednisolone in this context. The main questions it aims to answer are:

Does prednisolone lower the number of participants who develop sepsis or who survive? What medical problems do participants have when taking prednisolone? Researchers will compare prednisolone to a placebo (a look-alike substance that contains no drug) to see if prednisolone works to treat respiratory tract infections in adults.

Participants will:

Take prednisolone 30mg or a placebo every day for 5 days. Complete a daily diary of symptoms for 30 days and have telephone follow up. Investigators propose to recruit 1300 patients, 650 in each group. The Trial will be conducted in the Emergency Departments and wards of hospitals in Hong Kong.

Investigators expect the proportion of patients admitted to the hospital who develop sepsis or who die within 30 days to be reduced from 25% to 18% after taking active treatment. Secondly, investigators expect any difference in the proportion of patients with Serious adverse events(SAEs) not to exceed 5% between active treatment group and control.

Benefits to Hong Kong and Worldwide: Active treatments (e.g. prednisolone are cheap, HK$0.2 per 5mg tablet) are widely available across the world. Any reduction of progression to sepsis and death if applied worldwide would improve the lives of millions of patients and save millions of dollars of healthcare costs.

Detailed description: Introduction Acute Respiratory Infections (ARIs) are the fourth leading cause of death worldwide, third in China and second in Hong Kong. They are usually caused by bacteria or viruses and are associated with an early hyperinflammatory response. Evidence for the early detection of the disease and pathogen, risk-stratification and management are high priorities for the World Health Organisation (WHO).

The pathogens most likely to cause annual epidemics and pandemics are respiratory viruses although bacteria may cause up to 50% of ARI in hospitalised patients. Despite individual variation, the clinical course of ARIs generally involves an incubation period that lasts hours to days; and an early inflammatory prodrome which lasts days to a week and is characterised by symptoms such as a cough, fever, lethargy, headache (stage I). Whilst most patients recover, some progress to Stage II respiratory deterioration in the subsequent week; and Stage III severe respiratory failure may occur over subsequent weeks. The kinetics of bacterial and viral replication can last up to and even longer than 21 days. This prolonged and relatively slow progression provides several windows of opportunity in which early anti-inflammatory and immunomodulatory therapies could influence the course of the disease, reduce early hyperinflammation, facilitate recovery and well-being, and reduce hospital stay, disease progression, need for intensive care and mortality.

Usual care (UC) for patients with ARI presenting to EDs in Hong Kong is like other primary care settings in the world. For example, in Europe, early treatments are highly variable and consist of paracetamol, non-steroidal anti-inflammatory drugs, low-dose corticosteroids, over-the-counter medicines, fluids, rest, time off school/work, and antibiotics or antivirals. Rapid diagnostic tests (RDTs) are rarely available in the emergency department (ED) and even after admission a pathogen may not be identified in up to 70% of cases. Thus, treatment is usually begun and continued without an identifiable bacterial and/or viral pathogen. As many ARIs follow generic hyperinflammatory pathways, evaluating and repurposing existing anti-inflammatory drugs (e.g. prednisolone, 12) is a common and reasonable strategy which could have relevance not only for Hong Kong but worldwide.

Adaptive Platform Design and Response Adaptive Randomisation An adaptive platform trial (APT) is a trial in which multiple treatments for the same disease are tested simultaneously. New interventions can be added or replace existing ones during the course of the trial in accordance with pre-specified criteria. APTs offer innovations that could reshape clinical trials, and several APTs are now funded in various disease areas. APTs enhance research efficiency, shorten the duration of futile studies, and optimise sample size and study duration based on emerging data. The platform design allows for subsequent levels of randomisation if further treatments require evaluation.

The initial randomisation ratio is fixed 1:1 for a comparison between two trial arms, but the trial has the capability for these proportions to be altered according to participants' responses to interventions. Pre-specified decision criteria allow for dropping a treatment for futility, declaring a treatment superior, or adding a new treatment to be tested. If at any point a treatment is deemed superior to the usual care arm, the superior treatment may replace the usual care arm as the new standard of care.

Unmet Clinical Need Acute Respiratory Infections (ARIs) are a leading cause of death worldwide and in Hong Kong. There is relatively little evidence for early pathology- or pathogen-specific treatments for suspected community-acquired ARI (scARI). Every year, winter crises and epidemics are such that hospital wards, and particularly intensive care facilities, are frequently overstretched. Even treatments with moderate impact on survival or on hospital resources could be worthwhile.

One important area where evidence is scant is the role for steroids in scARI requiring hospitalisation. Although many trials report benefits of using steroids that outweigh adverse events(AEs) in severe COVID and community-acquired pneumonia(CAP), the value in hospitalised patients with less severe disease, in scARI and early treatment (e.g. started in EDs) is unclear. Specifically, evidence for a safe role for early, low dose, short-course prednisolone to safely reduce excessive inflammation, progression to sepsis and mortality in adult patients with scARI is needed.

All patients will receive UC in the participating hospitals. Initially randomisation will be between two treatment arms:

Control Arm: Placebo Active Treatment Arm I: Prednisolone 30mg tablets administered once a day for five days.

Eligibility criteria: Inclusion Criteria:

Patients will be eligible for the study if ALL the following are present:

1. Adults ≥18 years of age; AND
2. scARI; AND
3. Intended hospitalisation; AND
4. No medical history that might, in the opinion of the attending clinician, put the patient at significant risk if he/she were to participate in the trial

Exclusion Criteria:

Patients will be excluded if the treating clinician considers that the patient is not suitable for the trial.

Patients may be excluded if any ONE of the following are present:

1. Vulnerable subjects (pregnancy; cognitively impaired; prisoners; students; umemployee; minorities);
2. Cardiac arrest or post-cardiac arrest ROSC;
3. Not expected to survive 3 days due to pre-existing chronic disease;
4. Palliative (comfort) care
5. Undergoing active cancer therapy;
6. Neutropenia due to chemotherapy/malignancy (but not due to sepsis)
7. Immunocompromised or being treated with immunotherapy
8. Organ transplantation
9. HIV and on HIV drugs (indinavir, atazanavir, nelfinavir, saquinavir, ritonavir)
10. Recent Surgery (within one month)
11. Dialysis (including CAPD)
12. Diabetic ketoacidosis
13. Acute asthma
14. Recurrent chest infection,
15. Cushing's or Addisonian's disease,
16. Long term systemic steroid
17. Long-term antibiotics

Primary outcomes:
measure: 30-day all-cause sepsis or all-cause mortality
timeFrame: Up to 30-days
measure: 30-day Severe Adverse Events
timeFrame: Up to 30-days
Secondary outcomes:
measure: Maximal WHO Clinical Progression Scale(WHO-CPS)
timeFrame: Up to 30-days
measure: Mortality
timeFrame: Up to 30-days
measure: Sepsis
timeFrame: Up to 30-days
measure: Length of Hospital Stay
timeFrame: Up to 30-days
measure: Patient Satisfaction
timeFrame: Up to 30-days
measure: Cost-effectiveness analysis
timeFrame: 30-days
Other outcomes:
Locations:
city: Hong Kong
country: Hong Kong
facility: Queen Mary Hospital
Study officials:
affiliation: The University of Hong Kong
name: Timothy H Rainer
role: PRINCIPAL_INVESTIGATOR
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