IMPALA-EX
Research type
Research Study
Full title
AN OPEN-LABEL, NON-CONTROLLED, MULTICENTRE CLINICAL TRIAL OF INHALED MOLGRAMOSTIM IN AUTOIMMUNE PULMONARY ALVEOLAR PROTEINOSIS PATIENTS
IRAS ID
241436
Contact name
Cliff Morgan
Contact email
Sponsor organisation
Savara ApS
Eudract number
2017-004078-32
Duration of Study in the UK
3 years, 0 months, 0 days
Research summary
Research Summary
The main objective of IMPALA-EX is to investigate safety of long term use of inhaled molgramostim by collecting information on the side effects.\nThe study is an open label where the subjects will receive treatment with the trial drug for a period of up to 3 years. At the first visit, subjects may continue or re-start treatment with inhaled molgramostim (300 μg) administered intermittently in cycles of seven days molgramostim, administered once daily, and seven days off treatment.\nTrial visits will be conducted at 6-monthly intervals until the end of trial. Participating subjects will be encouraged to contact the clinic between visits if they experience adverse events or worsening of aPAP, or if they have any other concerns.Summary of Results
1. What was the objective of the study?
Why was the research needed?
Pulmonary alveolar proteinosis, commonly known as PAP, is a rare disease. In patients with PAP a fluid naturally produced in the lungs accumulates leading to difficulty in breathing and increased risk of other serious respiratory issues, including disease progression.
No medicines are available to cure PAP. Lung washing (whole lung lavage) with a saltwater solution is currently the only available option to eliminate the excess of fluid in the lungs, but this is invasive for the patient and is not widely available.
In most patients with PAP the accumulation of fluid in the lungs is caused by a reduction in the protein responsible for removing the fluid. This protein is called GM-CSF (granulocyte-macrophage colony-stimulating factor) and, in patients with PAP, is wrongly attacked by the immune system and eliminated. The resulting disease is called autoimmune PAP (aPAP).
The medicine that was tested in the study, molgramostim, contains a form of GM-CSF that can be inhaled by patients to replace the missing GM-CSF in the body.What were the main questions studied?
Researchers had already tested molgramostim in a previous study (IMPALA study) and observed that, when given for 6 months to patients with aPAP, the drug improves the function of the lungs without causing important unwanted side effects. In that study they divided the patients into 3 groups. One group took molgramostim continuously once a day, another group took molgramostim intermittently at intervals of 1 week (1 week on molgramostim once a day, 1 week off molgramostim) and the third group took no medicine.
With this study researchers wanted to test molgramostim for a longer period to find out first, if the medicine is safe and second, if it continues to improve the function of the lungs and symptoms when taken at intervals of 1 week for 3 years.
Like all medicine, molgramostim can cause unwanted effects. Researchers analysed the type and number of unwanted effects that occurred in patients during the study and decided which and how many unwanted effects were related to molgramostim. At each visit, doctors also checked the overall health of the patients and the progression of the disease.
To understand if molgramostim improved the patient’s lung function, researchers measured the amount of oxygen in the blood, the ability of the lung to transfer oxygen from air breathed in to the blood and the volume of air in the lungs that can be blown out by the patient after taking a deep breath. Researchers also asked patients several questions about their overall health and daily life using a questionnaire. They also assessed their capacity to exercise and counted how many patients needed lung washing or extra oxygen during the study.2. Was the study carried out as planned?
This study began before all the results from the previous study (IMPALA) were collected and analysed. When this was done, researchers realised that molgramostim worked better when given continuously rather than at 1-week intervals. Therefore, this study was stopped early and another study currently ongoing was started with continuous daily administration of molgramostim.
However, when this study was stopped, 44 patients had already taken molgramostim for more than a year and 15 patients for more than 2 years. Researchers analysed the data collected from these patients to understand if molgramostim caused unwanted side effects and improved the function of the lungs when taken for more than 1 year.3. Who carried out the research?
The company organising and funding the research is Savara ApS.4. When and where did this study take place?
When was it performed?
This study started in April 2018 and ended in January 2021.Where the clinical trial took place?
The study included 60 patients from the following 10 countries:
Denmark Italy
France Netherlands
Germany Russia
Greece Turkey
Israel United Kingdom5. Who participated in the study?
What patients were included in the study?
Only patients who had completed the IMPALA study were included in this study. These were adult patients with aPAP, male and female of at least 18 years of age who agreed to use birth control methods up until 1 month after the last dose of the molgramostim.How many men and women were in the clinical trial?
There were 36 men (60%) and 24 women (40%) in the study.How old were the patients?
The average age was 47 years. The youngest patient was 20 years, the oldest patient was 76 years.6. What treatment did patients received?
All patients took 300 g molgramostim nebuliser solution once a day at intervals of 1 week (1 week on molgramostim, 1 week off molgramostim). Molgramostim was taken by inhalation using an electronic eFlow Nebulizer System.
The patients visited the doctors every 6 months. During these visits, the doctors assessed the status of the disease, collected information about patient’s health and checked the patient’s lung function.7. What were the unwanted side effects?
Thirty-eight patients had 138 unwanted side effects. The most common unwanted side effects were cough and inflammation of the throat (pharynx) and nasal cavities, each reported by 7 patients. These unwanted effects did not cause major health problems and did not make patients stop taking molgramostim or leave the study.
Researchers need to consider the results of many studies to understand if a medical problem is related to a new medicine. Among all the unwanted side effects reported in this study, doctors think that only three were probably related to molgramostim. These were muscle ache, infection caused by the herpes simplex virus, and accumulation of protein in the lungs.
Most (30) patients fully recovered from unwanted side effects. No patient died during the study.How many serious unwanted side effects occurred?
An unwanted side effect is serious when it leads to the patient’s hospitalization, or is life-threatening, or causes permanent damage or when it requires a medical intervention to prevent any of these situations.
In this study 8 patients had 8 serious unwanted side effects, but none were considered to be related to molgramostim by researchers. The serious unwanted side effects that were reported were moderate or severe accumulation of proteins in the lungs, respiratory failure (a condition in which the blood does not have enough oxygen), infection from human immunodeficiency virus (HIV), inflammation of the voice box (larynx), back pain and bacterial skin infection. All but back pain and HIV infection resolved before the end of the study.Type of unwanted side effects Total
All unwanted side effects reported during the study 138 (in 38 patients)
Serious unwanted side effects 8 (in 8 patients)
Non-serious unwanted side effects 130 (in 38 patients)
Unwanted side effects related to molgramostim 3 (in 3 patients)
Fatal unwanted effects 0What were the other unwanted effects?
The table below shows the other unwanted side effects found in the study. Only the most common (reported by more than 3 patients) are presented.Unwanted effects that occurred in 3 or more patients Total
Cough 7 (in 7 patients)
Inflammation of the pharynx and nasal cavities 7 (in 7 patients)
Infection of body parts involved in breathing (for example throat and lungs) 7 (in 7 patients)
Joint pain 6 (in 4 patients)
Accumulation of proteins in the lungs 5 (in 4 patients)
Covid-19 infection 4 (in 4 patients)
Infections of the main airways of the lungs (bronchi) 6 (in 3 patients)
Shortness of breath 4 (in 3 patients)
Infection of the lungs 4 (in 3 patients)
Tiredness 3 (in 3 patients)What was the effect on blood?
In some patients, the amount of a protein called C-reactive protein was higher than normal. The levels of this protein usually rise when there is an inflammation. In some patients, the amount of haemoglobin and ferritin was lower than normal. These proteins carry and store iron in the body. None of these alterations were deemed important by the doctors.8. What were the study results?
After analysing the number and type of unwanted side effects and the effects on the patients’ blood and health, researchers believe that molgramostim does not cause harm to patients at the tested dose.
Because the study was stopped early, not enough patients took molgramostin long enough (for more than 1 year and half) to decide whether it can improve the lung function long-term.
However, results from tests that were performed showed some evidence that the majority of patients whose disease severity was categorised as “improved” or “unchanged” (based on presence of symptoms and the pressure of oxygen in the blood) remained stable throughout the study (Visit 3 = month 12 and Visit 4 = month 18; see figure).
None of the patients stopped taking molgramostin because it did not have benefits and only 2 patients needed a lung wash as rescue treatment to remove excess fluid.9. How has this study helped patients and researchers?
This study helped researchers to establish that even when taken for more than a year, molgramostim does not pose safety concerns at the tested dose. This is essential to determine whether this can become a long-term treatment. Another study with continuous administration of molgramostim, is required to understand whether this can be an effective long-term treatment option for patients with aPAP.10. Are there plans for further studies?
Another study is ongoing in patients with aPAP. In this study molgramostim is taken continuously once a day to understand whether this treatment regimen improves lung function long-term and could therefore be used as an effective long-term treatment for patients with aPAP. The study will finish in 2025.11. Further information
What is the full title name of the clinical trial?
The full title of this study is “An open-label, non-controlled, multicentre clinical trial of inhaled molgramostin in autoimmune pulmonary alveolar proteinosis patients”How can you contact the sponsor?
Contact us on the Savara ApS website (https://eur03.safelinks.protection.outlook.com/?url=http%3A%2F%2Furl6570.hra.nhs.uk%2Fls%2Fclick%3Fupn%3DXv3JSvJ-2B3M71ppf7N9agbb463Ysxph-2BKWgc4kfS3qZS-2Faw0Cs4lKmXQ98w3YCCE1Eb3w_E1aO2-2BZlVOSJJV-2FajQqskegTd6IRomHYTi-2Fbt8SH3YJgg0tgoMowoE02oPnzUa58lEFdhssk6xc3W-2BbzMViJB3aXctndSx6J6inbQJVngN0mnhWGuYkUUPN4ZTLZg822AX1cTjaLjqlw-2BqPZPNPl6TpwB73u8tlQedeFpPuDO-2F1aiqSTmUd6IiCngx3doiXUPVU-2FHaGeDhKt-2FiBtBxtJ1g-3D-3D&data=04%7C01%7Capprovals%40hra.nhs.uk%7Cb780354d66c344fd5edb08da00d89317%7C8e1f0acad87d4f20939e36243d574267%7C0%7C0%7C637823227422817919%7CUnknown%7CTWFpbGZsb3d8eyJWIjoiMC4wLjAwMDAiLCJQIjoiV2luMzIiLCJBTiI6Ik1haWwiLCJXVCI6Mn0%3D%7C3000&sdata=mDKNq3AV8diE0a8VuX0D0A0wcnokaGtpOfG1ljJpXR0%3D&reserved=0Where can I learn more about the study?
You can find the study details here:
https://eur03.safelinks.protection.outlook.com/?url=http%3A%2F%2Furl6570.hra.nhs.uk%2Fls%2Fclick%3Fupn%3DXv3JSvJ-2B3M71ppf7N9agbRehJ-2Fi4xyo44sEgJVCl5BcbW9wgc64X2JjNxW-2BqMpAMJTPL4o6QZPHlhToWPOW8WA-3D-3DDpGG_E1aO2-2BZlVOSJJV-2FajQqskegTd6IRomHYTi-2Fbt8SH3YJgg0tgoMowoE02oPnzUa585LL-2F-2FHEnKaLfUrDrneH3DAsOY6G7rN4QSIqnHF13B65FKpdYQeOxDHtqHjYcz9VSYcGDs-2FmVQR66YAcQWjAasv4qny2jPC3QmRkxhg8-2BdbdVsKssyNaXbZYHekeX-2B0no32nNrd-2FgbfVNe8sxCwH3Qg-3D-3D&data=04%7C01%7Capprovals%40hra.nhs.uk%7Cb780354d66c344fd5edb08da00d89317%7C8e1f0acad87d4f20939e36243d574267%7C0%7C0%7C637823227422817919%7CUnknown%7CTWFpbGZsb3d8eyJWIjoiMC4wLjAwMDAiLCJQIjoiV2luMzIiLCJBTiI6Ik1haWwiLCJXVCI6Mn0%3D%7C3000&sdata=5YB%2FwzqvM6KpIp%2BdFTfxAnXgq3ud7lt3eHkxZEXPKxY%3D&reserved=0Important notice
This summary is provided by Savara ApS to publicly share clinical study results. This summary only shows the results from this one study. However, other studies may find different results.
Usually, more than one study is carried out to find out which medicines work best and are safest. It takes lot of people in many studies all around the world to advance medical science.
This lay summary is not intended to promote any product or indication, to guide treatment decisions, or to replace the advice of a healthcare professional. You should not change your therapy on the basis of the results of this study. Always consult with your treating physician about your therapyREC name
South West - Central Bristol Research Ethics Committee
REC reference
18/SW/0115
Date of REC Opinion
5 Jun 2018
REC opinion
Further Information Favourable Opinion