An Observer-blind Study to Evaluate the Efficacy, Safety, Reactogenicity and Immunogenicity of the GSK Biologicals' Investigational Vaccine GSK3277511A When Administered to COPD Patients
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 606
- 试验地点
- 68
- 主要终点
- Rate of Moderate and Severe AECOPD (Any Cause)-Analysis (87% Confidence Interval [CI]), Post-dose 2 and Lasting for 1 Year
研究概览
简要总结
The purpose of this study is to test if the vaccine is working well in COPD patients aged 40 to 80 years old to reduce episodes of worsening symptoms ("exacerbations") and to gather further information on safety and immune response.
In the current study, COPD patients with a history of acute exacerbations will receive 2 doses of the investigational vaccine or placebo intramuscularly according to a 0, 2 month vaccination schedule, in addition to standard care.
The effect of vaccination against two pathogens known to cause exacerbations (Non-typeable Haemophilus influenza [NTHi] and Moraxella catarrhalis [Mcat]) will be evaluated at pre-defined timepoints (scheduled study visits).
In addition to the scheduled study visits, additional study visit(s) and/ or phone contact(s) will take place for each acute exacerbation of COPD occurring from first vaccination up to study conclusion.
详细描述
The purpose of this Phase IIB proof-of-concept (POC) study in moderate to very severe COPD patients (i.e. GOLD grade 2, 3 and 4) aged 40 to 80 years with a history of moderate or severe acute exacerbations of COPD (AECOPD) in the previous 12 months is to evaluate whether the NTHi-Mcat vaccine can reduce the frequency of AECOPD in this population and to assess the vaccine's safety, reactogenicity and immunogenicity.
Several formulations of a vaccine containing the NTHi antigens (low or high formulation) either non-adjuvanted or combined with different adjuvants (aluminium [Al], adjuvant system) were already evaluated in two previous Phase I clinical trials (NTHI-002 in healthy adults aged 18 - 40 years and NTHI-003 in current and former healthy smokers of 50-70 years old). The investigational vaccines were well-tolerated, with an acceptable safety and reactogenicity profile. These studies allowed the dose selection of the NTHi antigens (low formulation) and the adjuvant system currently evaluated for the first time in moderate and severe COPD patients aged 45 - 81 years in the Phase II study NTHI-004.
The safety, reactogenicity and immunogenicity of different formulations of the NTHi-Mcat investigational vaccine have been evaluated in the Phase I study in healthy adults aged 19 - 40 years and in current and former smokers aged 50 - 70 years (study NTHI MCAT-001). Based on results obtained up to 30 days post-Dose 2 from this study, the adjuvanted formulation containing NTHi proteins PD and PE-PilA and of UspA2 has been selected for evaluation in the current NTHI MCAT-002 study. Placebo will be used as a control. The NTHi-Mcat investigational vaccine and placebo will be given on top of standard of care to subjects in the respective study groups.
In the current study, moderate, severe and very severe COPD patients (i.e. GOLD grade 2, 3 and 4) with a history of AECOPD will receive 2 doses of the NTHi-Mcat investigational vaccine or placebo intramuscularly (IM) according to a 0, 2 month vaccination schedule, in addition to standard care.
Scheduled study visits, during which the effect of immunisation against NTHi and Mcat will be evaluated, will take place at pre-defined timepoints.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Prevention
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
盲法说明
Data will be collected in an observer-blind manner. By observer-blind, it is meant that during the course of the study, the vaccine recipient and those responsible for the evaluation of any study endpoint (e.g. safety, reactogenicity and efficacy) will all be unaware of whether vaccine or placebo was administered. Each study site is responsible for having a blinding plan. To work in an observer-blind manner, vaccine preparation and administration will be done by authorised medical personnel who will not participate in any of the study clinical evaluation assays. Two teams of study personnel will hence be set up:
- A team of unblinded personnel (responsible for the preparation and the administration of the vaccines)
- A team of blinded personnel (responsible for the clinical evaluation of the subjects).
入排标准
- 年龄范围
- 40 Years 至 80 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Subjects who, in the opinion of the investigator, can and will comply with the requirements of the protocol.
- •Written informed consent obtained from the subject prior to performing any study specific procedure.
- •A male or female between, and including, 40 and 80 years of age at the time of the first vaccination.
- •Confirmed diagnosis of COPD with forced expiratory volume in 1 second (FEV1) over forced vital capacity (FVC) ratio (FEV1/FVC) < 0.7, AND FEV1 < 80% predicted (GOLD 2, 3 and 4).
- •Current or former smoker with a cigarette smoking history of ≥ 10 pack-years.
- •Stable COPD patient* with documented history** of at least 1 moderate or severe AECOPD within the 12 months before Screening.
- •Patient for whom the last episode of AECOPD is resolved for at least 30 days at the time of first vaccination.
- •A documented history of a COPD exacerbation is a medical record of worsening COPD symptoms that required systemic/oral corticosteroids and/or antibiotics (for a moderate exacerbation) or hospitalization (for a severe exacerbation). Prior use of antibiotics alone does not qualify as an exacerbation history unless the use was associated with treatment of worsening symptoms of COPD, such as increased dyspnea, sputum volume, or sputum purulence. Subject verbal reports are not acceptable.
- •Capable of complying with the daily electronic Diary Card completion throughout the study period, according to investigator's judgement at Visit
- •Female subjects of non-childbearing potential may be enrolled in the study. Non-childbearing potential is defined as pre-menarche, current bilateral tubal ligation or occlusion, hysterectomy, bilateral ovariectomy or post-menopause.
- •Female subjects of childbearing potential may be enrolled in the study, if the subject:
- •has practiced adequate contraception for 30 days prior to vaccination, and has a negative pregnancy test on the day of vaccination, and has agreed to continue adequate contraception during the entire treatment period and for 2 months after completion of the vaccination series.
排除标准
- •Use of any investigational or non-registered product other than the study vaccine during the period starting 30 days before the first dose of study vaccine (Day -29 to Day 1), or planned use during the study period.
- •Any medical condition that in the judgment of the investigator would make intramuscular injection unsafe.
- •Administration of immunoglobulins or any blood products within the 3 months preceding the first dose of study vaccine or planned administration during the study period.
- •Any confirmed or suspected immunosuppressive or immunodeficient condition, based on medical history and physical examination.
- •Planned administration/ administration of a vaccine not foreseen by the study protocol in the period starting 30 days before the first dose and ending 30 days after the last dose of vaccine, with the exception of any influenza or pneumococcal vaccine which may be administered ≥15 days preceding or following any study vaccine dose.
- •Concurrently participating in another clinical study, at any time during the study period, in which the subject has been or will be exposed to an investigational or a non-investigational vaccine/product.
- •Chronic administration of immunosuppressants or other immune-modifying drugs during the period starting six months prior to the first vaccine dose (e.g. methotrexate).
- •Administration of systemic corticosteroids within the 30 days before first vaccination.
- •Subjects who received systemic corticosteroids within this period may be enrolled at a later date if enrolment is still open.
- •Inhaled and topical steroids are allowed.
- •Administration of systemic antibiotics within the 30 days before first vaccination.
- •Subjects who received systemic antibiotics within this period may be enrolled at a later date if enrolment is still open.
- •Chronic use of antibiotics for prevention of AECOPD (e.g. azithromycin).
- •Acute disease and/or fever at the time of first vaccination. Fever is defined as temperature ≥37.5°C. The preferred location for measuring temperature in this study will be the oral cavity or the axilla.
- •Subjects with a minor illness (such as mild diarrhoea, mild upper respiratory infection) without fever may be enrolled at the discretion of the investigator.
- •Oxygen therapy: Use of long-term oxygen therapy (LTOT) described as resting oxygen therapy >3L/min (Oxygen use ≤3L/min flow is not exclusionary).
- •Planned lung transplantation.
- •Lung resection: Subjects with planned lung volume reduction surgery during the study or within the 12 months prior to first vaccination.
- •Diagnosis of α-1 antitrypsin deficiency as the underlying cause of COPD.
- •Diagnosed with a respiratory disorder other than COPD at time of enrolment (such as sarcoidosis, active tuberculosis, clinically significant bronchiectasis, clinically significant lung fibrosis, clinically significant pulmonary embolism, clinically significant pneumothorax, current diagnosis of asthma in the opinion of the investigator), or chest X-ray/ CT scan revealing evidence of clinically significant abnormalities not believed to be due to the presence of COPD. Subjects with allergic rhinitis do not need to be excluded and may be enrolled at the discretion of the investigator.
- •History of immune-mediated disease other than COPD. If the subject has any condition on the non-exhaustive list of potential immune-mediated diseases defined in the protocol, they must be excluded unless the aetiology is clearly documented to be non-immune mediated.
- •Previous vaccination with any vaccine containing NTHi and/ or Mcat antigens.
- •History of any reaction or hypersensitivity likely to be exacerbated by any component of the vaccines and/ or the bronchodilator used for spirometry assessment during the study.
- •Contraindication for spirometry testing.
- •Unstable or life threatening cardiac disease: subjects with any of the following at Screening (Visit 1) would be excluded:
- •Myocardial infarction or unstable angina in the last 6 months. Unstable or life threatening cardiac arrhythmia requiring intervention in the last 3 months NYHA Class IV Heart failure
- •Malignancies within the previous 5 years or lymphoproliferative disorder.
- •Any known disease or condition likely to cause death during the study period.
- •Pregnant or lactating female.
- •Current alcoholism and/or drug abuse.
- •Other condition which the investigator judges may put the safety of the subject at risk through study participation or which may interfere with the study findings.
- •Planned move to a location that will complicate participation in the trial through study end.
结局指标
主要结局
Rate of Moderate and Severe AECOPD (Any Cause)-Analysis (87% Confidence Interval [CI]), Post-dose 2 and Lasting for 1 Year
时间窗: From 1-month post-Dose 2 (at Day 91) up to study end (at Day 451)
Efficacy of the investigational vaccine was measured by the rate of moderate and severe AECOPD from 1-month post dose 2 up to study end (i.e. rate expressed per year and calculated as the total number of events over the follow-up exposure time). The CIs of the rate is computed using a model which accounts for repeated events. Anthonisen criteria used to detect potential AECOPD: Worsening of 2 or more of the following major symptoms for at least 2 consecutive days: dyspnoea, sputum volume, sputum purulence, OR Worsening of any major symptom together with any of the following minor symptoms for at least 2 consecutive days: sore throat, cold, fever without other cause, increased cough, increased wheeze. Moderate AECOPD requires treatment with systemic corticosteroids and/ or antibiotics. Severe AECOPD requires hospitalization. Confirmation of any AECOPD was as per investigator's judgement.
Rate of Moderate and Severe AECOPD (Any Cause) -Analysis (95% CI), Post-dose 2 and Lasting for 1 Year
时间窗: From 1-month post-Dose 2 (at Day 91) up to study end (at Day 451)
Efficacy of the investigational vaccine was measured by the rate of moderate and severe AECOPD from 1-month post dose 2 up to study end (i.e. rate expressed per year and calculated as the total number of events over the follow-up exposure time). The CIs of the rate is computed using a model which accounts for repeated events. Anthonisen criteria used to detect potential AECOPD: Worsening of 2 or more of the following major symptoms for at least 2 consecutive days: dyspnoea, sputum volume, sputum purulence, OR Worsening of any major symptom together with any of the following minor symptoms for at least 2 consecutive days: sore throat, cold, fever without other cause, increased cough, increased wheeze. Moderate AECOPD requires treatment with systemic corticosteroids and/ or antibiotics. Severe AECOPD requires hospitalization. Confirmation of any AECOPD was as per investigator's judgement.
次要结局
- Number of Subjects Reported With Each Solicited Local Adverse Event (AE)(During the 7-day follow-up period (the day of vaccination + 6 days) after each vaccination administered approximately at Day 1 and Day 61)
- Exacerbation Rate of Any AECOPD Cases, Classified by Severity, One Year Follow up Starting 1 Month Post Dose 2, by 3 Months Period(During following periods: from 0 to 3 months, from 3 to 6 months, from 6 to 9 months, from 9 to 12 months (observation starting 1 month post-Dose 2))
- Number of Subjects Reported With Each Solicited General AE(During the 7-day follow-up period (the day of vaccination + 6 days) after each vaccination administered approximately at Day 1 and Day 61)
- Number of Subjects Reported With Any Unsolicited Adverse Event (AE)(During the 30-day follow-up period (the day of vaccination + 29 days) after each vaccination administered approximately at Day 1 and Day 61)
- Number of Subjects Reported With Any Potential Immune-mediated Diseases (pIMDs)(From first vaccination (Day 1) up to Study end (at Day 451))
- Number of Subjects Reported With Any Serious Adverse Event (SAE)(From first vaccination (Day 1) up to Study end (at Day 451))
- Rate of Moderate and Severe AECOPD in Vaccinated and Control Subjects, One Year Follow up Starting 1 Month Post Dose 2, by 3 Months Period(During following periods: from 0 to 3 months, from 3 to 6 months, from 6 to 9 months, from 9 to 12 months (observation starting 1 month post-Dose 2))
- Rate of Any AECOPD Case in Vaccinated and Control Subjects, One Year Follow up Starting 1 Month Post Dose 2, by 3 Months Period(During following periods: from 0 to 3 months, from 3 to 6 months, from 6 to 9 months, from 9 to 12 months, 0-12 months (observation starting 1 month post-Dose 2))
- Number of Subjects With First AECOPD of Any Severity(From 1-month post-Dose 2 (at Day 91) up to study end (at Day 451))
- Number of Subjects With First AECOPD Classified by Severity(From 1-month post-Dose 2 (at Day 91) up to study end (at Day 451))
- Number of Days With AECOPDs of Any Severity(From 1-month post-Dose 2 (at Day 91) up to study end (at Day 451))
- Rate of NTHi-associated and/ or Mcat-associated AECOPD of Any Severity(From 1-month post-Dose 2 (at Day 91) up to study end (at Day 451))
- Number of Subjects With First NTHi-associated and/or Mcat-associated AECOPD of Any Severity(From 1-month post-Dose 2 (at Day 91) up to study end (at Day 451))
- Number of Subjects With First NTHi-associated and/or Mcat-associated AECOPD, Classified by Severity(From 1-month post-Dose 2 (at Day 91) up to study end (at Day 451))
- Number of Days With Moderate and Severe NTHi-associated and Mcat-associated AECOPD(From 1-month post-Dose 2 (at Day 91) up to study end (at Day 451))
- Anti-PE Antibody Concentrations as Measured by ELISA(At Day 1, Day 31, Day 61, Day 91, Day 271 and at Day 451)
- Number of Subjects With First Moderate or Severe AECOPD(From 1-month post-Dose 2 (at Day 91) up to study end (at Day 451))
- Number of Days With Moderate and Severe AECOPDs(From 1-month post-Dose 2 (at Day 91) up to study end (at Day 451))
- Number of Days With AECOPDs Classified by Severity(From 1-month post-Dose 2 (at Day 91) up to study end (at Day 451))
- Number of Subjects With First Moderate or Severe NTHi-associated and/or Mcat-associated AECOPD(From 1-month post-Dose 2 (at Day 91) up to study end (at Day 451))
- Anti-PD Antibody Concentrations as Measured by the Enzyme-Linked Immunosorbent Assay (ELISA)(At Day 1, Day 31, Day 61, Day 91, Day 271 and at Day 451)
- Rate of Non-Typeable Haemophilus Influenzae (NTHi)-Associated and/ or Moraxella Catarrhalis (Mcat)-Associated Moderate and Severe AECOPD(From 1-month post-Dose 2 (at Day 91) up to study end (at Day 451))
- Exacerbation Rate of Any NTHi-associated and/ or Mcat-associated AECOPD Cases, Classified by Severity(From 1-month post-Dose 2 (at Day 91) up to study end (at Day 451))
- Number of Days With NTHi-associated and/or Mcat-associated AECOPDs of Any Severity(From 1-month post-Dose 2 (at Day 91) up to study end (at Day 451))
- Number of Days With NTHi-associated and/or Mcat-associated AECOPD, Classified by Severity(From 1-month post-Dose 2 (at Day 91) up to study end (at Day 451))
- Anti-UspA2 Antibody Concentrations as Measured by ELISA(At Day 1, Day 31, Day 61, Day 91, Day 271 and at Day 451)
- Frequency of PD Specific Cluster of Differentiation (CD)4+ T-cells Expressing at Least 2 Markers Among CD40L, IL2, TNF-Alpha, IFN-Gamma, IL-13 and IL-17 Using Background Reduced Frequency Data(At Day 1, Day 91, Day 271 and at Day 451)
- Frequency of PilA Specific CD4+ T-cells Expressing at Least 2 Markers Among CD40L, IL2, TNF-Alpha, IFN-Gamma, IL-13 and IL-17 Using Background Reduced Frequency Data(At Day 1, Day 91, Day 271 and at Day 451)
- Frequency of UspA2 Specific CD4 + T-cells Expressing at Least 2 Markers Among CD40L, IL2, TNF-Alpha, IFN-Gamma, IL-13 and IL-17 Using Background Reduced Frequency Data(At Day 1, Day 91, Day 271 and at Day 451)
- Anti-PilA Antibody Concentrations as Measured by ELISA(At Day 1, Day 31, Day 61, Day 91, Day 271 and at Day 451)
- Frequency of PE Specific (CD)4+ T-cells Expressing at Least 2 Markers Among CD40L, IL2, TNF-Alpha, IFN-Gamma, IL-13 and IL-17 Using Background Reduced Frequency Data(At Day 1, Day 91, Day 271 and at Day 451)