Inhaled GM-CSF Reduces the Need for Whole Lung Lavage and Improves Gas Exchange in Autoimmune PAP Patients
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 发起方
- 入组人数
- 18
- 试验地点
- 1
- 主要终点
- Time to Rescue WLL
研究概览
简要总结
This is a prospective, randomized, open-label, long-term, phase 2 study of inhaled granulocyte/macrophage-colony stimulating factor following whole lung lavage therapy in patients with autoimmune pulmonary alveolar proteinosis.
详细描述
Autoimmune pulmonary alveolar proteinosis (aPAP) is a rare disorder of progressive surfactant accumulation and resulting hypoxemic respiratory failure caused by disruption of granulocyte/macrophage-colony stimulating factor (GM-CSF) signaling, which alveolar macrophages require to remove pulmonary surfactant.
The current therapy of aPAP, whole lung lavage (WLL), is a procedure requiring general anesthesia, endotracheal intubation to isolate each lung, and mechanical ventilation of the untreated lung while the treated lung repeatedly filled with saline and drained while percussing the chest to loosen and emulsify the surfactant and saline to physically remove the excess surfactant.
Inhaled GM-CSF is a promising pharmacotherapeutic approach shown in case reports, small series, moderate open-label studies, and two randomized, double-blinded, placebo-controlled trials to be safe and improve the clinical, physiological, radiological, and biochemical disease manifestations in patients with mild-moderate aPAP. In contrast to the present study, prior studies were too short in duration to permit an evaluation on the requirement for WLL, which aPAP patients require a mean of every 15 months. The present study addressed the effects on WLL by studying patients with moderate-severe aPAP and by utilizing a long-term follow up period.
The study design included a screening visit (month -3) to establish eligibility, an observation period (-3 to 0 months) to establish the presence of progressive/unremitting aPAP and establish disease severity, a pre-WLL visit (-1 month), a baseline visit (month 0) during which all patients received a scheduled, baseline, bilateral WLL, a 10-month, open-label treatment period, and a 20-month follow-up period. Study visits were scheduled at months -3, -1, 0, 1, 3, 6, 10, 18, and 30 months. Patients were randomized by the statistician to the GM-CSF Group (n=9) or the Control Group (n=9). Investigators were blinded to group assignment until after the participant's baseline visit.
Patients randomized to the GM-CSF group (n=9) received inhaled GM-CSF (sargramostim (Leukine®), 250 mcg daily every other week for 12 weeks beginning 1 week after the baseline WLL - termed GM-CSF induction therapy period, followed by a 4-week washout period during which no GM-CSF was administered), and then received inhaled GM-CSF (sargramostim, 250 mcg/day on days 1 and 3 of every 14-day period for 6 months - termed GM-CSF maintenance therapy period). Inhaled GM-CSF (Leukine®) was administered using AKITA2 APIXNEB nebulizer system (Activaero, Vectura GmbH, Germany). Patients randomized to the Control Group (n=9) received no further scheduled treatment. Any patient in either group experiencing with disease progression resulting in respiratory failure (defined as peripheral artery oxygen concentration (PaO2) <60 mmHg at rest or PaO2 >60 mmHg at rest AND a peripheral blood oxygen saturation (SpO2) < 90% OR a decline in SpO2 of 5% or more during exercise), received (unscheduled) rescue WLL and were considered to have failed their assigned intervention (GM-CSF or Control).
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
- None
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
- •Female of male 18 years of age or older
- •Diagnosis of autoimmune PAP
- •Able and willing to provide written informed consent
- •Eligible for whole lung lavage determined as the presence of persistent or progressive respiratory failure (PaO2 at rest < 60 mm Hg) or desaturation < 90% or > 5 percentage points during standard exercise
排除标准
- •Diagnosis with secondary PAP, congenital PAP, or hereditary PAP
- •Contraindication to whole lung lavage
- •Contraindication to administration of inhaled GM-CSF
- •Chronic lung disease associated with already existing respiratory failure, such as emphysema or pulmonary fibrosis, chronic heart failure, ischemic heart disease, active pulmonary embolism, progressive cancer, and other severe metabolic conditions
研究组 & 干预措施
GM-CSF Group
Scheduled Baseline WLL: All participants will receive scheduled bilateral WLL at baseline (month 0).
GM-CSF induction treatment: All participants will receive inhaled GM-CSF (250 mcg daily, 7 consecutive days every other week for 12 weeks beginning 1 week after the scheduled baseline WLL).
Washout period: All participants will not receive inhaled GM-CSF treatment for 4 weeks immediately following GM-CSF induction treatment.
GM-CSF maintenance treatment: All participants will receive inhaled GM-CSF (250 mcg daily on days 1 and 3 of every consecutive 14-day period for 6 months beginning 17 weeks after the scheduled baseline WLL).
Unscheduled Rescue WLL: Any participant experiencing progression of aPAP lung disease (defined as the disease progression resulting in respiratory failure (PaO2 at rest <60 mmHg of PaO2 > 60 mmHg at rest AND desaturation <90% at rest OR decline in SpO2 of 5% or more during exercise testing) will receive unscheduled rescue WLL.
干预措施: Baseline WLL (Procedure)
GM-CSF Group
Scheduled Baseline WLL: All participants will receive scheduled bilateral WLL at baseline (month 0).
GM-CSF induction treatment: All participants will receive inhaled GM-CSF (250 mcg daily, 7 consecutive days every other week for 12 weeks beginning 1 week after the scheduled baseline WLL).
Washout period: All participants will not receive inhaled GM-CSF treatment for 4 weeks immediately following GM-CSF induction treatment.
GM-CSF maintenance treatment: All participants will receive inhaled GM-CSF (250 mcg daily on days 1 and 3 of every consecutive 14-day period for 6 months beginning 17 weeks after the scheduled baseline WLL).
Unscheduled Rescue WLL: Any participant experiencing progression of aPAP lung disease (defined as the disease progression resulting in respiratory failure (PaO2 at rest <60 mmHg of PaO2 > 60 mmHg at rest AND desaturation <90% at rest OR decline in SpO2 of 5% or more during exercise testing) will receive unscheduled rescue WLL.
干预措施: Sargramostim (Drug)
GM-CSF Group
Scheduled Baseline WLL: All participants will receive scheduled bilateral WLL at baseline (month 0).
GM-CSF induction treatment: All participants will receive inhaled GM-CSF (250 mcg daily, 7 consecutive days every other week for 12 weeks beginning 1 week after the scheduled baseline WLL).
Washout period: All participants will not receive inhaled GM-CSF treatment for 4 weeks immediately following GM-CSF induction treatment.
GM-CSF maintenance treatment: All participants will receive inhaled GM-CSF (250 mcg daily on days 1 and 3 of every consecutive 14-day period for 6 months beginning 17 weeks after the scheduled baseline WLL).
Unscheduled Rescue WLL: Any participant experiencing progression of aPAP lung disease (defined as the disease progression resulting in respiratory failure (PaO2 at rest <60 mmHg of PaO2 > 60 mmHg at rest AND desaturation <90% at rest OR decline in SpO2 of 5% or more during exercise testing) will receive unscheduled rescue WLL.
干预措施: Rescue WLL (Procedure)
Control Group
Scheduled Baseline WLL: All participants will receive a scheduled bilateral WLL at baseline (month 0).
Unscheduled Rescue WLL: Any participant experiencing progression of aPAP lung disease (defined as the disease progression resulting in respiratory failure (defined by a resting PaO2 <60 mmHg or > 60 mmHg and desaturation <90% at rest or decline in SpO2 of 5% or more during exercise testing) will receive unscheduled rescue WLL.
干预措施: Baseline WLL (Procedure)
Control Group
Scheduled Baseline WLL: All participants will receive a scheduled bilateral WLL at baseline (month 0).
Unscheduled Rescue WLL: Any participant experiencing progression of aPAP lung disease (defined as the disease progression resulting in respiratory failure (defined by a resting PaO2 <60 mmHg or > 60 mmHg and desaturation <90% at rest or decline in SpO2 of 5% or more during exercise testing) will receive unscheduled rescue WLL.
干预措施: Rescue WLL (Procedure)
结局指标
主要结局
Time to Rescue WLL
时间窗: 30 months
Time (in months) between the scheduled baseline WLL (at Study Month 0) and the first administration of an unscheduled rescue WLL (during the 30-months after Study Month 0)
次要结局
- Number of Patients Requiring a Rescue WLL(30 months)
- Between-Group Difference in Mean Diffusion Capacity of the Lungs for Carbon Monoxide (DLCO)(30 months)
- Between-Group Difference in Median Serum Carcinoembryonic Antigen (CEA) Levels(30 months)
- Between-Group Difference in Mean Serum Cytokeratin-19 Fragment (Cyfra21.1) Levels(30 months)
- Between-Group Difference in Mean White Blood Cell (WBC) Counts(30 months)
- Between-Group Difference in Mean Platelet Counts(30 months)
- Between-Group Difference in Mean Partial Pressure of Oxygen (PaO2)(30 months)
- Between-Group Difference in Mean Alveolar-arterial Difference in Oxygen Concentration (A-aDO2)(30 months)
- Between-Group Difference in Mean Vital Capacity (VC)(30 months)
- Between-Group Difference in Mean Chest Computed Tomography Ground Glass Opacification (GGO) Score(30 months)
- Between-Group Difference in Mean Serum Krebs Von-Lungren 6 Antigen (KL-6) Levels(30 months)
- Between-Group Difference in Median Serum GM-CSF Autoantibody (GMAb) Levels(30 months)
- Between-Group Difference in Mean 36-Item Short Form Survey (SF-36) General Health Score(30 months)
研究者
Ilaria Campo
Study coordinator
Fondazione IRCCS Policlinico San Matteo di Pavia