Daily administration of interferon-alpha (IFN-α) nasal spray significantly reduced COVID-19 infection rates in adult cancer patients, according to results from a multicenter phase 3 randomized controlled trial published in Clinical Infectious Diseases. The study represents the first randomized trial to demonstrate safe and effective COVID-19 prevention using intranasal interferon-alpha in this vulnerable population.
Trial Design and Patient Population
The double-blinded, placebo-controlled trial (NCT04534725) enrolled 433 cancer patients who were randomized 1:1 to receive either daily 40,000 IU of interferon-α nasal spray or saline placebo. The median patient age in the IFN-α arm was 62 years, with 51% female participants and 91% White patients. Primary cancers included hematologic malignancies (48%) and solid tumors (52%).
Patients received a reformulation of IFN-α-2a/β delivered as a nasal spray at 20,000 IU/mL per 100 μL actuation. The 40,000 IU daily dose was selected based on previously available literature. Participants were provided self-testing kits including nasal swabs, viral medium, and symptom diaries for monitoring influenza-like symptoms.
Primary Efficacy Results
In the intention-to-treat population, the overall incidence of COVID-19 infection was 11.3%. The IFN-α arm demonstrated a significantly lower infection rate of 8.3% compared to 14.4% in the placebo arm (relative risk [RR], 0.60; 95% credible intervals [CrI], 0.33-0.97), representing a 40% reduction in infection risk. The cumulative incidence of COVID-19 was also lower in the IFN-α arm compared with placebo (HR, 0.55; 95% CI, 0.32-0.97; P = 0.04).
The per-protocol analysis of 389 patients showed even more pronounced results, with COVID-19 incidence rates of 7.7% in the interferon-α arm versus 16.0% in the placebo arm (RR, 0.50; 95% CrI, 0.26-0.84). Other respiratory viral infections occurred at similar rates between groups (4.6% vs 5.7%).
Subgroup Analysis Reveals Key Beneficiaries
Subgroup analyses identified specific patient populations that derived the greatest benefit from interferon-α prophylaxis. In the intention-to-treat population, patients younger than 65 years showed a 52% reduction in infection risk (RR, 0.48; 95% CrI, 0.20-0.92), while women experienced a 56% reduction (RR, 0.44; 95% CrI, 0.19-0.85). Patients who had received COVID-19 vaccination demonstrated a 50% reduction in infection risk when using the nasal spray (RR, 0.50; 95% CrI, 0.26-0.82).
"IFN-α nasal spray reduced the incidence of COVID-19 and, in particular, in those younger than 65 years and female. It may be that, during the study period, being younger and female was a marker of high risk with working and caring responsibilities and thus higher community exposure to COVID-19," wrote lead author Michelle K. Yong, MBBS, FRACP, MPH, PhD, and colleagues.
The per-protocol analysis showed additional benefits for patients with solid tumors (RR, 0.39; 95% CrI, 0.14-0.82). Notably, no differences in COVID-19 incidence were observed based on cancer type or whether patients were receiving active cancer treatment.
Safety Profile
The interferon-α nasal spray demonstrated an acceptable safety profile. Adverse events occurred in 10.1% of patients in the IFN-α arm compared to 6.0% in the placebo arm (RR, 0.56; 95% CrI, 0.16-1.33). Serious adverse events were reported in 4.1% versus 2.8% of patients (RR, 1.23; 95% CrI, 0.36-3.12), while grade 2 adverse events of special interest occurred at similar rates (0.5% vs 0.5%). All-cause mortality rates were comparable between groups, with one death in each arm deemed unrelated to the intervention.
Clinical Implications
"This is the first randomized, controlled trial to show that an intranasal interferon-α spray can safely and effectively prevent COVID-19 in this group," stated lead study author Michelle K. Yong from Peter MacCallum Cancer Centre. "Even with vaccination, cancer patients remain more vulnerable to COVID-19 and its complications. It's an additional layer of defense, especially for those who can't mount strong responses to vaccines."
Senior author Monica Slavin emphasized the broader potential applications: "A safe, easy-to-use nasal spray with broad antiviral activity could benefit not just cancer patients, but other high-risk groups such as transplant recipients, people with chronic illnesses, and the elderly. While it's not a replacement for vaccination, it adds to our prevention toolkit and could help reduce illness, treatment delays, and hospitalizations."
The trial was stopped early, but post-hoc analysis confirmed the study had 95.1% power with a 5% alpha error rate to detect the observed treatment effect. The results suggest that interferon-α nasal spray could serve as an important prophylactic tool for protecting immunocompromised cancer patients from COVID-19 infection.
