This will be a 5 year randomized, double blind, placebo controlled trial of 7 days of oral prednisone in cystic fibrosis (CF) patients receiving intravenous (IV) antibiotic treatment for a pulmonary exacerbation at the Hospital for Sick Children and other study sub-sites across Canada. The intervention will be oral prednisone 2 mg/kg/day (max 60 mg) divided twice daily for 7 days as an adjunctive therapy for pulmonary exacerbations in CF patients who have not recovered their baseline forced expiratory volume in 1 second (FEV1) after 7 days of IV antibiotic treatment. The primary outcome will be the proportion of subjects who achieve >90% of their baseline FEV1 % predicted at day 14 of IV antibiotic treatment for a pulmonary exacerbation in each treatment arm.

Inclusion Criteria:

1. Diagnosis of CF by newborn screening or at least one clinical feature of CF, AND either (a) or (b) as follows:
2. A documented sweat chloride ≥ 60 mEq/L by quantitative pilocarpine iontophoresis
3. A genotype with two identifiable CF-causing mutations
4. Age > 6 years old.
5. Acute pulmonary exacerbation treated with IV antibiotics as previously defined 10% relative drop in FEV1 from baseline at the time of exacerbation
6. Informed consent by patient or parent/legal guardian
7. Ability to reproducibly perform pulmonary function testing
8. Ability to comply with medication use including the ability to take capsules, study visits and study procedures as judged by the site investigator

Exclusion Criteria:

1. A respiratory tract culture positive for Burkholderia cenocepacia in the 12 months prior to enrollment
2. A respiratory tract culture positive for Mycobacterium abscessus in the 12 months prior to enrollment
3. Treatment with IV or oral corticosteroids within 2 weeks of enrollment or from Day 0-Day 7 of the pulmonary exacerbation
4. Active allergic bronchopulmonary aspergillosis (ABPA) at the time of enrollment as determined by treating physician
5. Asthma related exacerbation at enrollment as defined by the treating physician based on clinically compatible symptoms (eg. wheeze)
6. History of avascular necrosis or pathologic bone fracture
7. Uncontrolled hypertension with end organ damage
8. Active gastrointestinal bleeding
9. Status post lung or other organ transplantation
10. Pregnancy
11. Lactose intolerance (contained in placebo)
12. On Lumacaftor-Ivacaftor (Orkambi) at the time of exacerbation
13. Investigational drug use within 30 days prior to enrollment visit
14. Physical findings that would compromise the safety of the subject or the quality of the study data as determined by site investigator

placebo