Pivotal Study to Assess the Efficacy, Safety and Tolerability of Dupilumab in Patients With Moderate to Severe COPD With Type 2 Inflammation (NOTUS)

Sanofi

Status and phase: Active, not recruiting; Phase 3

Conditions: Chronic Obstructive Pulmonary Disease

Treatments: Drug: Placebo; Drug: Inhaled Long-Acting Muscarinic Antagonist; Drug: Inhaled Corticosteroid; Drug: Inhaled Long-Acting Beta Agonist; Drug: Dupilumab SAR231893

Study type: Interventional

Funder types: Industry

Identifiers

NCT04456673

EFC15805

U1111-1211-8837 (Other Identifier)

2018-001954-91 (EudraCT Number)

Details and patient eligibility

About

Primary Objective:

To evaluate the efficacy of dupilumab administered every 2 weeks in patients with moderate or severe Chronic Obstructive Pulmonary Disease (COPD) as measured by

• Annualized rate of acute moderate or severe COPD exacerbation (AECOPD)

Secondary Objectives:

To evaluate the effect of dupilumab administered every 2 weeks on

• Pre-bronchodilator forced expiratory volume in 1 second (FEV1) over 12 weeks compared to placebo
• Health related quality of life, assessed by the change from baseline to Week 52 in the St. George's Respiratory Questionnaire (SGRQ)
• Pre-bronchodilator FEV1 over 52 weeks compared to placebo
• Lung function assessments
• Moderate and severe COPD exacerbations
• To evaluate safety and tolerability
• To evaluate dupilumab systemic exposure and incidence of antidrug antibodies (ADA)

Full description

Approximately 68 weeks including a 4-week screening period, a 52-week treatment period, and 12 weeks of follow-up

Enrollment: 935 patients

Sex: All

Ages: 40 to 85 years old

Volunteers: No Healthy Volunteers

Inclusion criteria

• Participants with a physician diagnosis of COPD who meet the following criteria at screening:

  • Current or former smokers with a smoking history of ≥10 pack-years.
  • Moderate-to-severe COPD (post-bronchodilator FEV1/ forced vital capacity [FVC] ratio <0.70 and post-bronchodilator FEV1 % predicted >30% and ≤70%).
  • Medical Research Council (MRC) Dyspnea Scale grade ≥2.
  • Patient-reported history of signs and symptoms of chronic bronchitis (chronic productive cough) for 3 months in the year up to screening in the absence of other known causes of chronic cough.
  • Documented history of high exacerbation risk defined as exacerbation history of ≥2 moderate or ≥1 severe within the year prior to inclusion. At least one exacerbation should have occurred while the patient was taking inhaled corticosteroid (ICS)/long acting beta agonist (LABA)/long acting muscarinic antagonist (LAMA) (or LABA/LAMA if ICS is contraindicated). Moderate exacerbations are recorded by the investigator and defined as AECOPD that require either systemic corticosteroids (intramuscular, intravenous, or oral) and/or antibiotics. One of the two required moderate exacerbations has to require the use of systemic corticosteroids. Severe exacerbations are recorded by the investigator and defined as AECOPD requiring hospitalization or observation > 24 hours in emergency department/urgent care facility.
  • Background triple therapy (ICS + LABA + LAMA) for 3 months prior to randomization with a stable dose of medication for ≥1 month prior to Visit 1; Double therapy (LABA + LAMA) allowed if ICS is contraindicated.

• Evidence of Type 2 inflammation: Patients with blood eosinophils ≥300 cells/microliter at Visit 1.

Exclusion criteria

• COPD diagnosis for less than 12 months prior to randomization.
• Participants with current diagnosis of asthma according to the Global Initiative for Asthma (GINA) guidelines, or documented history of asthma.
• Significant pulmonary disease other than COPD (e.g., lung fibrosis, sarcoidosis, interstitial lung disease, pulmonary hypertension, bronchiectasis, Churg-Strauss Syndrome etc) or another diagnosed pulmonary or systemic disease associated with elevated peripheral eosinophil counts.
• Cor pulmonale, evidence of right cardiac failure.
• Long-term treatment with oxygen >4.0 L/min OR if a participant requires more than 2.0 L/min in order to maintain oxygen saturation >88%
• Hypercapnia requiring Bi-level ventilation.
• AECOPD as defined in inclusion criteria within 4 weeks prior to screening, or during the screening period.
• Respiratory tract infection within 4 weeks prior to screening, or during the screening period.
• History of, or planned pneumonectomy or lung volume reduction surgery. Patients who are participating in the acute phase of a pulmonary rehabilitation program, ie, who started rehabilitation <4 weeks prior to screening (Note: patients in the maintenance phase of a rehabilitation program can be included).
• Diagnosis of α-1 anti-trypsin deficiency.

The above information is not intended to contain all considerations relevant to a patient's potential participation in a clinical trial.

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Quadruple Blind

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935 participants in 2 patient groups, including a placebo group

Dupilumab

Experimental group

Description:

Dupilumab administered every 2 weeks

Treatment:

Drug: Dupilumab SAR231893

Drug: Inhaled Long-Acting Beta Agonist

Drug: Inhaled Corticosteroid

Drug: Inhaled Long-Acting Muscarinic Antagonist

Placebo

Placebo Comparator group

Description:

Placebo dose administered every 2 weeks

Treatment:

Drug: Inhaled Long-Acting Beta Agonist

Drug: Inhaled Corticosteroid

Drug: Inhaled Long-Acting Muscarinic Antagonist

Drug: Placebo