A Randomised, Double-blind, Placebo-controlled Multicentre Clinical Trial of Inhaled Molgramostim in Autoimmune Pulmonary Alveolar Proteinosis Patients
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 发起方
- Savara Inc.
- 入组人数
- 139
- 试验地点
- 30
- 主要终点
- Absolute Change From Baseline of Alveolar-arterial Oxygen Concentration (A-a(DO2)) After 24 Weeks of Treatment
研究概览
简要总结
This study evaluates inhaled molgramostim (recombinant human granulocyte macrophage-colony stimulating factor [rhGM-CSF]) in the treatment of autoimmune pulmonary alveolar proteinosis (aPAP) patients. A third of the patients will receive inhaled molgramostim once daily for 24 weeks, a third will receive inhaled molgramostim intermittently (7 days on, 7 days off) for 24 weeks and a third will receive inhaled matching placebo for 24 weeks.
详细描述
The trial is a phase 2, randomized, double-blind, placebo-controlled multicentre clinical trial investigating efficacy and safety of inhaled molgramostim (rhGM-CSF) in patients with aPAP.
The trial will include 2 periods; a double-blind treatment period consisting of up to 8 trial visits (Screening, Baseline, and at Weeks 4, 8,12, 16, 20 and 24 after randomisation) and a open-label follow-up period consisting of up to 5 trial visits (at Weeks 4, 12, 24, 36 and 48 post-treatment).
In the double-blind treatment period, eligible subjects will be randomised to treatment for up to 24 weeks with either: 1) inhaled molgramostim (300 µg) once daily (MOL-OD), 2) inhaled molgramostim (300 µg) and matching placebo administered intermittently (7 days on and 7 days off) (MOL-INT) or 3) inhaled placebo once daily (PBO). During the follow-up period, all participants will receive inhaled molgramostim intermittently (7 days on, 7 days off). During the trial, whole lung lavage (WLL) may be applied as rescue therapy in case of significant clinical worsening.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •aPAP diagnosed by computed tomography, or by biopsy, or by Broncho Alveolar Lavage (BAL), and by increased GM-CSF autoantibodies in serum.
- •Stable or progressive aPAP during a minimum period of 2 months prior to the Baseline visit.
- •Arterial oxygen tension (PaO2) <75 mmHg/<10 kilo Pascal (kPa) at rest, OR desaturation of >4 percentage points on the 6MWT
- •An alveolar-arterial oxygen difference [(A-a)DO2] of minimum 25 mmHg/3.33 kPa
- •Female or male ≥18 years of age
- •Females who have been post-menopausal for >1 year or females of childbearing potential after a confirmed menstrual period using a highly efficient method of contraception (i.e. a method with <1% failure rate such as combined hormonal contraception, progesterone-only hormonal contraception, intrauterine device, intrauterine hormone-releasing system, bilateral tubal occlusion, vasectomised partner, sexual abstinence), during and until 30 days after last dose of double-blind trial treatment. Females of childbearing potential must have a negative serum pregnancy test at Screening (Visit 1) and a negative urine pregnancy test at dosing at Baseline (Visit 2) and must not be lactating
- •Males agreeing to use condoms during and until 30 days after last dose of double-blind medication, or males having a female partner who is using adequate contraception as described above
- •Willing and able to provide signed informed consent
- •Willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other trial procedures specified in the protocol as judged by the investigator
排除标准
- •Diagnosis of hereditary or secondary PAP
- •WLL within 1 month of Baseline
- •Treatment with GM-CSF within 3 months of Baseline
- •Treatment with rituximab within 6 months of Baseline
- •Treatment with plasmapheresis within 3 months of Baseline
- •Treatment with any investigational medicinal product within 4 weeks of Screening
- •Concomitant use of sputum modifying drugs such as carbocysteine or ambroxol
- •History of allergic reactions to GM-CSF
- •Connective tissue disease, inflammatory bowel disease or other autoimmune disorder requiring treatment associated with significant immunosuppression, e.g. more than 10 mg/day systemic prednisolone
- •Previous experience of severe and unexplained side-effects during aerosol delivery of any kind of medicinal product
- •History of, or present, myeloproliferative disease or leukaemia
- •Known active infection (viral, bacterial, fungal or mycobacterial)
- •Apparent pre-existing concurrent pulmonary fibrosis
- •Any other serious medical condition which in the opinion of the investigator would make the participant unsuitable for the trial
研究组 & 干预措施
Double-blind molgramostim once daily
Inhalation of molgramostim nebuliser solution 300 mcg once daily for 24 weeks
干预措施: Molgramostim (Drug)
Double-blind molgramostim once daily
Inhalation of molgramostim nebuliser solution 300 mcg once daily for 24 weeks
干预措施: PARI eFlow nebulizer system (Device)
Double-blind molgramostim intermittent
Inhalation of molgramostim nebuliser solution 300 mcg for 7 days and placebo nebuliser solution for 7 days for 24 weeks (12 cycles)
干预措施: Molgramostim (Drug)
Double-blind molgramostim intermittent
Inhalation of molgramostim nebuliser solution 300 mcg for 7 days and placebo nebuliser solution for 7 days for 24 weeks (12 cycles)
干预措施: PARI eFlow nebulizer system (Device)
Double-blind placebo
Inhalation of placebo nebuliser solution once daily for 24 weeks
干预措施: Placebo (Drug)
Double-blind placebo
Inhalation of placebo nebuliser solution once daily for 24 weeks
干预措施: PARI eFlow nebulizer system (Device)
Open-label molgramostim intermittent
Inhalation of molgramostim nebuliser solution 300 mcg for 7 days and placebo nebuliser solution for 7 days for 24 or 48 weeks from completion of the double-blind period
干预措施: Molgramostim (Drug)
Open-label molgramostim intermittent
Inhalation of molgramostim nebuliser solution 300 mcg for 7 days and placebo nebuliser solution for 7 days for 24 or 48 weeks from completion of the double-blind period
干预措施: PARI eFlow nebulizer system (Device)
结局指标
主要结局
Absolute Change From Baseline of Alveolar-arterial Oxygen Concentration (A-a(DO2)) After 24 Weeks of Treatment
时间窗: From baseline to 24 weeks
Measurement of (A-a)DO2 was done by blood gas analysis. An arterial blood sample was collected in the supine position, after resting for at least 10 minutes (or longer if required to achieve stable oxygen saturation). The sample was analyzed for arterial oxygen tension (PaO2) and partial pressure of carbon dioxide (PaCO2). The calculation of (A-a)DO2 was done centrally by using a formula described in the protocol.
次要结局
- Change From Baseline in St. George's Respiratory Questionnaire (SGRQ) Total Score After 24 Weeks of Treatment(From baseline to 24 weeks)
- Number of Serious Adverse Events (SAEs) During 24 Weeks of Treatment(From baseline to 24 weeks)
- Number of Whole Lung Lavage During 24 Weeks of Treatment(From baseline to 24 weeks)
- Number of Adverse Drug Reactions (ADRs) During 24 Weeks of Treatment(From baseline to 24 weeks)
- Number of Participants With at Least 1 AE Leading to Treatment Discontinuation During 24 Weeks of Treatment(From baseline to 24 weeks)
- Change From Baseline in 6-minute Walking Distance (6MWD) After 24 Weeks of Treatment(From baseline to 24 weeks)
- Number of Adverse Events (AEs) During 24 Weeks of Treatment(From baseline to 24 weeks)
- Number of Severe AEs During 24 Weeks of Treatment(From baseline to 24 weeks)