E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Pulmonary emphysema |
patients between age 45 and 65 with moderate to severe emphysema; a gradient of emphysema severity towards the lung apex as assessed by CT-derived lung densitometry and equally distributed between left and right lung; FEV1 between 25% and 45% pred; Gas diffusion capacity between 30% and 45% pred. |
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E.1.1.1 | Medical condition in easily understood language |
long emfyseem |
Patienten in de leeftijd tussen 45 en 65 jaar die matig tot ernstig longemfyseem hebben en die een gradient van emfyseem hebben zoals gemeten m.b.v. beelden van een long CT scan. |
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E.1.1.2 | Therapeutic area | Body processes [G] - Circulatory and Respiratory Physiological Phenomena [G09] |
MedDRA Classification |
E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
Primary Objective is two fold: First, to detect the difference in the level of expression of PECAM-1 (CD31) on pulmonary microvascular endothelial cells (pMVECs) present in lung tissue harvested from patients at LVRS2 after 4 weeks of treatment with autologous BM-MSCs and patients treated with placebo. Second, to assess the safety and clinical efficacy (by CO diffusion capacity) of autologous MSC treatment up to 3 years following the last MSC dose |
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E.2.2 | Secondary objectives of the trial |
1.to demonstrate safety of i.v. adm. of MSC to pts with mod. to sev emphysema 2.the diff in the level of expr of CD31 on pMVECs present in lung tissue harvested from pts at LVRS2 after 12 wks of treatment with placebo and pts treated with MSC. 3.the diff in the nr of CD3+ and CD4+ T-cells present in lung tissue harvested from LVRS2 from pts after 4 or 12 wks of treatment with placebo and pts treated with BMSC. 4.As in 2 & 3, but then the diff between LVRS2 and 1. 5.the diff in the nr of type II alveolar cells present in lung tissue harvested from LVRS2 from pts after 4 or 12 wks of treatment with placebo and pts treated with BMSC. 6.The diff. in shear stress response of isolated pMVECs from LVRS1 and 2 of pts treated with either MSC or placebo 7.The diff. in Cytosplore resp of isolated immune cells from LVRS1 and 2 of pts treated with either BMSCs or placebo. 8.The corr with lung phys response prm and the outcome of the primary obj of the study for pts treated with BM-MSCs.
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
In order to be eligible to participate in this study, a subject must meet all of the following criteria:
-Age lower than 65; -emphysema as reported by a radiologist present in CT images of the lung; -gradient of emphysema severity towards the lung apex as assessed by CT-derived lung densitometry by Pulmo CMS software (Medis, NL) and equally distributed between left and right lung; -FEV1 between 25% and 45% pred ; -TLCO between 30% and 45% pred.; -patients in a stable clinical condition.
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E.4 | Principal exclusion criteria |
A potential subject who meets any of the following criteria will be excluded from participation in this study:
-Significant cardiac failure; or active smoking, or -< 6 months smoking cessation; -or failure to complete pulmonary rehab program before randomization; -or women of child bearing potential; -or any other condition of the patient that the clinical investigator deemed harmful for study participation.
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E.5 End points |
E.5.1 | Primary end point(s) |
First: The difference in expression of PECAM-1 (CD31) on pulmonary microvascular endothelial cells per micrometer alveolar septum present in lung tissue harvested from patients at LVRS 2 after 4 weeks of treatment with autologous MSC or placebo. Second: . To assess the safety and clinical efficacy (by CO diffusion capacity) of autologous MSC treatment up to 3 years following the last MSC dose |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
When all randomized patients have completed the study, all lung tissue samples will be investigated in one run for immunohistochemistry. |
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E.5.2 | Secondary end point(s) |
1. The differences in expression of Surfactant Protein-C expression by alveolar type II cells in lung tissue obtained from study patients treated with placebo or MSC. 2. The difference in immunostaining of various leukocytes in resected lung tissue, including T lymphocytes, B lymphocytes, macrophages and neutrophils obtained from study patients treated with placebo or MSC. 3. The difference in the composition of the immune cells present in surgically resected lung tissue parts and paired peripheral blood mononuclear cell samples analysed by CyTOF obtained from patients treated with MSC or placebo. 4. The difference in shear stress responses, expressed as % elongation of 100 cells, of isolated pMVECs ex vivo obtained from study patients treated with placebo or MSC. 5. The difference in immune-modulatory and regenerative capacity, determined by flow cytometry value, of MSC from emphysema patients and healthy controls stored in our biobank. 6. The difference in endothelial microparticles concentration and concentration of immunological markers in blood samples from study patients treated with placebo or MSC. 7. The correlation between arterial pO2 or gas transfer value TLCO at 12 weeks after discharge of admission for LVRS 2 (measured as standard of care) and the outcome of the primary objective of the study for patients treated with MSC or placebo. In addition Safety parameters will be measured during and up to 2 hr after i.v. infusion of autologous bone marrow derived MSC or placebo and will be evaluated according to the WHO toxicity criteria by grade. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
When all randomized patients have completed the study, all lung tissue samples will be investigated in one run for immunohistochemistry or CytoF experiments, except for the MSC that will be studied for item number 5. This work will be performed will the bone marrow is harvested from all study particpants during the first lung volume reduction surgery session. Safety parameters will be measured during MSC treatment of each randomized study participant. |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.5 | The trial involves multiple Member States | No |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial has a data monitoring committee | No |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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The last study visit is at 3 years after the last patient had its second lung volume reduction surgery perfomed. |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 1 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |