Mepolizumab for Chronic Rhinosinusitis

(ISS-RESMEPO Trial)

Overseen By Leandra Mfuna Endam, Msc

Age: 18+

Sex: Any

Trial Phase: Phase 4

Sponsor: Centre hospitalier de l'Université de Montréal (CHUM)

Must be taking: Intranasal corticosteroids

Must not be taking: Systemic corticosteroids, Immunosuppressives

Disqualifiers: Cystic fibrosis, HIV, Acute sinusitis, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 12

Duration: 48 weeks

36 Participants Needed

Trial Summary

What is the purpose of this trial?

The investigators propose a real-world study to assess the mechanism of action of long-lasting response to mepolizumab in patients with chronic rhinosinusitis with nasal polyposis (CRSwNP) and identify clinically useful predictors of response. Mepolizumab is a monoclonal antibody targeting IL-5 and is approved for use in asthma and CRSwNP. In clinical studies, 12 months of treatment with mepolizumab improved signs and symptoms of CRSwNP and reduced the need for surgery. While several biologic medications targeting facets of the Type 2 mechanism are currently indicated for chronic rhinosinusitis with nasal polyps mepolizumab alone appears capable of modifying the disease's biological behaviour and producing long-standing improvements after the cessation of treatment. In the mepolizumab for CRSwNP regulatory trial (SYNAPSE), a subset of patients experienced dramatic and long-lasting, which is over 48 months after cessation of administration of the investigational medicinal product (IMP) in our experience. This has been partially captured in a follow-on study to the registration trail, which showed that a subset of patients followed for 24 weeks after cessation of biologic therapy (with continued use of mometasone furoate) demonstrated persistent improvements over baseline. However, the mechanism of the long-lasting effect in a subset of patients is not well understood, and it is impossible currently to identify patients who will derive this maximal benefit. The mechanism for the prolonged improvements in CRSwNP seen in certain patients with mepolizumab remains to be established but suggests that effects beyond eosinophil trafficking are implicated. The investigators believe that mepolizumab has IL-5-mediated pleiotropic effects which contribute to disease modification with effects extending beyond eosinophil activation and trafficking. This may include the following primary or secondary effects: i) Improving epithelial barrier function ii) Altering mast cell dynamics iii) Reversing epigenetic modifications iv) Altering the immune response to better clear pathogenic bacteria or viruses.

Will I have to stop taking my current medications?

The trial requires that you stop using systemic corticosteroids (oral steroids) at least 4 weeks before screening and avoid them during the study. You must also stop any biological or immunosuppressive treatments (except Xolair) before the trial, and you cannot start or change allergen immunotherapy doses within 3 months before the trial.

What data supports the effectiveness of the drug Mepolizumab for chronic rhinosinusitis?

Research shows that Mepolizumab can reduce the size of nasal polyps, improve symptoms, and enhance quality of life for patients with chronic rhinosinusitis with nasal polyps. It also decreases the need for corticosteroids and sinus surgeries, making it an effective treatment option. ^{1 2 3 4 5}

Is Mepolizumab safe for humans?

Mepolizumab has been used in patients with chronic rhinosinusitis with nasal polyps, and while the specific study did not report safety data, Mepolizumab is generally considered safe based on its use in other conditions. Always consult with a healthcare provider for personalized advice. ^{6 7 8 9 10}

How does the drug mepolizumab differ from other treatments for chronic rhinosinusitis?

Mepolizumab is unique because it targets interleukin-5 (IL-5), a protein involved in inflammation, which helps reduce nasal polyps and nasal obstruction in chronic rhinosinusitis. Unlike some other treatments, it is a monoclonal antibody given by injection, and it has shown effectiveness in patients with severe eosinophilic asthma and chronic rhinosinusitis. ^{2 3 5 11 12}

Research Team

Martin Yvon Desrosiers, MD

Principal Investigator

Centre hospitalier de l'Université de Montréal (CHUM)

Eligibility Criteria

This trial is for people with severe nasal polyps and chronic rhinosinusitis who've had at least one related surgery in the last 10 years. They must have ongoing symptoms despite using nasal steroid treatments for over 4 weeks. Excluded are those with recent nose surgeries, certain allergies, HIV, or reactions to similar drugs; also excluded are pregnant women not using effective contraception.

Inclusion Criteria

You have a condition affecting both sides of your nasal passages, diagnosed by a doctor using an endoscope or historical CT scan.

I have had symptoms like nasal blockage, discharge, facial pain, or loss of smell for over 12 weeks.

I have had nasal polyp surgery in the last 10 years.

Exclusion Criteria

I have been diagnosed with a specific lung condition like Churg Strauss syndrome.

I have not had nose or sinus surgery in the last 6 months.

I am currently experiencing a persistent stuffy nose due to long-term nasal spray use.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive mepolizumab 100mg SC once every 4 weeks for 48 weeks

48 weeks

12 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

12 months

Long-term follow-up

Persistent clinical response to mepolizumab is assessed after cessation of treatment

18 months

Treatment Details

Interventions

• Mepolizumab

Trial Overview The study tests Mepolizumab's long-term effects on patients with chronic rhinosinusitis and nasal polyps. It explores how this drug might lead to lasting improvements even after treatment ends by affecting various biological processes beyond just reducing inflammation caused by eosinophils.

Participant Groups

Group I: Mepolizumab 100mg injection Experimental Treatment 1 Intervention

Mepolizumab 100mg SC once every 4 weeks for 48 weeks (twelve injections)

Who Is Running the Clinical Trial?

Centre hospitalier de l'Université de Montréal (CHUM)

Lead Sponsor

Trials

389

Recruited

143,000+

Findings from Research

In the 52-week Phase III SYNAPSE study, mepolizumab significantly reduced nasal polyp size and improved symptoms in patients with severe chronic rhinosinusitis with nasal polyps (CRSwNP), showing sustained benefits even 24 weeks after treatment discontinuation.

Among 134 patients followed up, those who received mepolizumab had better outcomes, such as lower nasal polyp scores and reduced need for sinus surgery, compared to placebo, indicating that the treatment's effects can last beyond the treatment period.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Sustained efficacy of mepolizumab in patients with severe chronic rhinosinusitis with nasal polyps: SYNAPSE 24-week treatment-free follow-up. Desrosiers, M., Diamant, Z., Castelnuovo, P., et al.[2023]

In the phase III SYNAPSE study involving 407 patients, mepolizumab significantly reduced nasal polyp size and nasal obstruction in chronic rhinosinusitis with nasal polyps, showing efficacy across various subgroups including those with asthma and aspirin-exacerbated respiratory disease (AERD).

Patients receiving mepolizumab demonstrated a higher rate of improvement in nasal polyp scores and nasal obstruction compared to those on placebo, indicating that mepolizumab is effective regardless of baseline blood eosinophil counts.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Mepolizumab for chronic rhinosinusitis with nasal polyps: Treatment efficacy by comorbidity and blood eosinophil count. Bachert, C., Sousa, AR., Han, JK., et al.[2022]

In a study involving 20 adult patients with eosinophilic chronic rhinosinusitis, treatment with mepolizumab for 24 weeks significantly reduced eosinophil counts in sinonasal tissue, indicating its efficacy in targeting IL-5 to suppress eosinophil trafficking.

Despite the reduction in eosinophils, levels of type-2 cytokines (IL-5, IL-4, IL-13, and GM-CSF) increased in the tissue, suggesting a potential local inflammatory feedback loop that may contribute to incomplete treatment responses.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Mepolizumab decreases tissue eosinophils while increasing type-2 cytokines in eosinophilic chronic rhinosinusitis. Walter, S., Ho, J., Alvarado, R., et al.[2023]

In a study of 55 patients with severe chronic rhinosinusitis with nasal polyps (CRSwNP) treated with mepolizumab, significant improvements were observed in nasal symptoms and polyp scores after 6 months, particularly in patients with aspirin-exacerbated respiratory disease (AERD).

Mepolizumab treatment led to a marked reduction in blood eosinophil levels and decreased reliance on systemic corticosteroids, enhancing the overall quality of life for patients with CRSwNP, regardless of asthma status.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Real-Life Effectiveness of Mepolizumab in Refractory Chronic Rhinosinusitis with Nasal Polyps. Domínguez-Sosa, MS., Cabrera-Ramírez, MS., Marrero-Ramos, MDC., et al.[2023]

In a real-world study involving 950 patients with severe asthma and chronic rhinosinusitis (CRS), mepolizumab significantly reduced asthma exacerbations by 28% to 44%, with the greatest improvement seen in patients who had both CRS and sinus surgery.

After starting mepolizumab, patients experienced lower use of systemic corticosteroids and reduced healthcare costs, indicating its efficacy in managing severe asthma and CRS in clinical practice.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Real-world effectiveness of mepolizumab in severe asthma and chronic rhinosinusitis in the United States: impact of comorbidity and sinus surgery. Silver, J., Deb, A., Laliberté, F., et al.[2023]

A 62-year-old female patient with chronic rhinosinusitis with nasal polyps (CRSwNP) and severe asthma experienced complete recovery of her sense of smell after 4 months of treatment with mepolizumab, a medication typically used for severe asthma.

Mepolizumab treatment led to good control of both asthma and CRSwNP symptoms, suggesting that it may effectively reduce nasal obstruction caused by polyps, thereby improving olfactory function.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Recovery of smell sense loss by mepolizumab in a patient allergic to Dermatophagoides and affected by chronic rhinosinusitis with nasal polyps. Cavaliere, C., Incorvaia, C., Frati, F., et al.[2022]

In a comprehensive eight-year follow-up study of pediatric bone cancer patients receiving aprepitant, adverse events such as anorexia, febrile neutropenia, and headache occurred at rates exceeding 43.8 per 100 patients, which is higher than previously reported.

The findings highlight a significant concern regarding the safety of aprepitant in this population, particularly the increased risk of febrile neutropenia, suggesting a need for further safety investigations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adverse events associated with aprepitant pediatric bone cancer patients. Okumura, LM., da Silva Ries, SA., Meneses, CF., et al.[2019]

In a study of 88 patients with non-Hodgkin lymphoma receiving moderately emetogenic chemotherapy, palonosetron demonstrated increasing efficacy, with complete response rates rising from 68.2% in the first cycle to 80.5% in the second cycle, and over 90% of patients remained emesis-free without additional antiemetics.

Palonosetron showed a favorable safety profile, with only 8% of treatment-emergent adverse events related to the drug, indicating it is a safe option for managing chemotherapy-induced nausea and vomiting.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Multicenter phase IV study of palonosetron in the prevention of chemotherapy-induced nausea and vomiting (CINV) in patients with non-Hodgkin lymphomas undergoing repeated cycles of moderately emetogenic chemotherapy. Choi, BS., Borsaru, GP., Ballinari, G., et al.[2021]

A systematic review of antiemetic agents for preventing chemotherapy-induced nausea and vomiting (CINV) in children found that these medications, including aprepitant and ondansetron, are generally safe with manageable adverse effects.

While the recommended antiemetics are effective, it is important to consider individual patient risk factors, particularly for rare side effects like cardiac arrhythmia, and further research is needed to assess their long-term safety in pediatric cancer patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety of clinical practice guideline-recommended antiemetic agents for the prevention of acute chemotherapy-induced nausea and vomiting in pediatric patients: a systematic review and meta-analysis. Patel, P., Paw Cho Sing, E., Dupuis, LL.[2019]

In a study involving 200 children undergoing chemotherapy, palonosetron (PG) demonstrated comparable efficacy to ondansetron (OG) in preventing nausea and vomiting, with complete response rates of 88% for PG versus 84% for OG in the acute phase.

Palonosetron was found to be more cost-effective than ondansetron, making it a suitable option for healthcare facilities in resource-limited settings, while maintaining similar safety profiles.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Palonosetron is a Better Choice Compared With Ondansetron for the Prevention of Chemotherapy-induced Nausea and Vomiting (CINV) in a Resource-limited Pediatric Oncology Center: Results From a Randomized Control Trial. Chaudhary, NK., John, RR., Boddu, D., et al.[2019]

In a 48-week study of 11 patients with severe eosinophilic asthma and chronic rhinosinusitis, mepolizumab significantly reduced blood eosinophil counts and improved lung function and nasal symptoms, indicating its efficacy in treating both upper and lower airway issues.

All patients who were dependent on oral corticosteroids were able to successfully withdraw from these medications, highlighting the potential of mepolizumab as a safer alternative for managing severe asthma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Favorable clinical efficacy of mepolizumab on the upper and lower airways in severe eosinophilic asthma: a 48-week pilot study. Kurosawa, M., Ogawa, E., Sutoh, E.[2020]

In a study of 351 patients with severe eosinophilic asthma, initiating treatment with mepolizumab led to a significant reduction in the use of high-dose inhaled corticosteroids (ICS) over a 12-month period, with 49% of patients reducing or discontinuing ICS.

Patients who discontinued ICS after starting mepolizumab experienced lower rates of chronic oral corticosteroid (OCS) use, fewer exacerbations, and reduced reliance on short-acting β2-agonists, indicating improved clinical outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A real-world study of inhaled corticosteroid use in patients with severe eosinophilic asthma treated with mepolizumab. Corren, J., Silver, J., Molfino, NA., et al.[2022]

References

1. United States pubmed.ncbi.nlm.nih.gov

Sustained efficacy of mepolizumab in patients with severe chronic rhinosinusitis with nasal polyps: SYNAPSE 24-week treatment-free follow-up. [2023]

2. United States pubmed.ncbi.nlm.nih.gov

Mepolizumab for chronic rhinosinusitis with nasal polyps: Treatment efficacy by comorbidity and blood eosinophil count. [2022]

3. England pubmed.ncbi.nlm.nih.gov

Mepolizumab decreases tissue eosinophils while increasing type-2 cytokines in eosinophilic chronic rhinosinusitis. [2023]

4. Switzerland pubmed.ncbi.nlm.nih.gov

Real-Life Effectiveness of Mepolizumab in Refractory Chronic Rhinosinusitis with Nasal Polyps. [2023]

5. United States pubmed.ncbi.nlm.nih.gov

Real-world effectiveness of mepolizumab in severe asthma and chronic rhinosinusitis in the United States: impact of comorbidity and sinus surgery. [2023]

6. England pubmed.ncbi.nlm.nih.gov

Recovery of smell sense loss by mepolizumab in a patient allergic to Dermatophagoides and affected by chronic rhinosinusitis with nasal polyps. [2022]

7. England pubmed.ncbi.nlm.nih.gov

Adverse events associated with aprepitant pediatric bone cancer patients. [2019]

8. United States pubmed.ncbi.nlm.nih.gov

Multicenter phase IV study of palonosetron in the prevention of chemotherapy-induced nausea and vomiting (CINV) in patients with non-Hodgkin lymphomas undergoing repeated cycles of moderately emetogenic chemotherapy. [2021]

9. England pubmed.ncbi.nlm.nih.gov

Safety of clinical practice guideline-recommended antiemetic agents for the prevention of acute chemotherapy-induced nausea and vomiting in pediatric patients: a systematic review and meta-analysis. [2019]

10. United States pubmed.ncbi.nlm.nih.gov

Palonosetron is a Better Choice Compared With Ondansetron for the Prevention of Chemotherapy-induced Nausea and Vomiting (CINV) in a Resource-limited Pediatric Oncology Center: Results From a Randomized Control Trial. [2019]

11. Italy pubmed.ncbi.nlm.nih.gov

Favorable clinical efficacy of mepolizumab on the upper and lower airways in severe eosinophilic asthma: a 48-week pilot study. [2020]

12. United States pubmed.ncbi.nlm.nih.gov

A real-world study of inhaled corticosteroid use in patients with severe eosinophilic asthma treated with mepolizumab. [2022]