Autoimmune Pulmonary Alveolar Proteinosis
Conditions
Brief summary
SAV006-03 is an open-label extension study for participants who had completed the IMPALA study. At the baseline visit, eligible participants may continue or re-start treatment with 300 µg inhaled molgramostim (recombinant human Granulocyte-Macrophage Colony Stimulating Factor; GM-CSF) administered intermittently in cycles of seven days molgramostim, administered once daily, and seven days off treatment. Participants will be treated with inhaled molgramostim for up to 36 months. During the trial, whole lung lavage will be applied as rescue therapy.
Interventions
DRUGMolgramostim
300 µg inhaled molgramostim in cycles of once daily administration for 7 days, then 7 days off treatment.
Sponsors
Savara Inc.
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Open label, non-controlled.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Completer of the IMPALA trial. * Females who have been post menopausal for \>1 year, or females of child-bearing potential who are not pregnant or lactating and are using acceptable contraceptive methods. * Males agreeing to use using acceptable contraceptive methods. * Willing and able to provide signed informed consent.
Exclusion criteria
* Treatment with GM-CSF products other than molgramostim nebuliser solution within three months of Baseline. * Treatment with any investigational medicinal product other than inhaled molgramostim within four weeks of Baseline. * 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. * Apparent pre-existing concurrent pulmonary fibrosis. * Any other serious medical condition which in the opinion of the investigator would make the subject unsuitable for the trial.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Treatment-emergent Adverse Events (TEAEs) | 139 weeks | The primary objective of this trial was safety assessed by adverse event (AE) reporting. Definitions and reporting procedures for AEs were done according to current regulatory standards. AEs were collected by the investigator by a non-leading question and by reporting events directly observed or spontaneously volunteered by participants. Participants were also encouraged to contact the clinic in between visits if they experienced AEs or had any concerns. Treatment-emergent was defined as events occurring on study drug and up to 7 days after last dose of study drug. |
| Number of Serious TEAEs | 139 weeks | Serious TEAEs were defined as any untoward medicinal occurrence or effect that at any dose: * Results in death * Is life-threatening * Requires hospitalisation or prolongation of existing hospitalisation * Results in persistent or significant disability or incapacity * Is a congenital abnormality or birth defect * May jeopardise the participant or may require medical intervention to prevent one or more of the outcomes listed above (Important Medical Events). |
| Number of Treatment-emergent Adverse Drug Reactions (ADRs) | 139 weeks | All AEs were assessed by the investigator for causality (unlikely, possible, probable, not applicable) according to current regulatory standards. AEs which had a 'possible' or 'probable' causality were classified as ADRs. |
| Number of TEAEs Leading to Treatment Discontinuation | 139 weeks | — |
Countries
Denmark, France, Germany, Greece, Israel, Italy, Netherlands, Russia, Turkey (Türkiye), United Kingdom
Participant flow
Recruitment details
SAV006-03 was an open-label extension trial for participants who had completed the IMPALA study. Among the 30 clinical sites enrolling participants in IMPALA, 13 sites participated in SAV006-03. First participant was enrolled on 16 April 2018 and last participant completed the study on 14 January 2021.
Participants by arm
| Arm | Count |
|---|---|
| Molgramostim Nebulizer Solution (300 μg) Open-label treatment with molgramostim nebulizer solution (300 μg) administered intermittently (repetitive cycles of 7 days of treatment followed by 7 days off-treatment).
Molgramostim: 300 µg inhaled molgramostim in cycles of once daily administration for 7 days, then 7 days off treatment. | 60 |
| Total | 60 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | 1 participant died 24 days after last dose ie outside the definition of treatment-emergent | 1 |
| Overall Study | Lost to Follow-up | 1 |
| Overall Study | Withdrawal by Subject | 2 |
Baseline characteristics
| Characteristic | Molgramostim Nebulizer Solution (300 μg) |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 5 Participants |
| Age, Categorical Between 18 and 65 years | 55 Participants |
| Age, Continuous | 46.8 years STANDARD_DEVIATION 13.5 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 2 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 3 Participants |
| Race (NIH/OMB) White | 54 Participants |
| Region of Enrollment Denmark | 3 participants |
| Region of Enrollment France | 4 participants |
| Region of Enrollment Germany | 12 participants |
| Region of Enrollment Greece | 4 participants |
| Region of Enrollment Israel | 4 participants |
| Region of Enrollment Italy | 9 participants |
| Region of Enrollment Netherlands | 6 participants |
| Region of Enrollment Russia | 7 participants |
| Region of Enrollment Turkey | 7 participants |
| Region of Enrollment United Kingdom | 4 participants |
| Sex: Female, Male Female | 24 Participants |
| Sex: Female, Male Male | 36 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 1 / 59 |
| other Total, other adverse events | 38 / 59 |
| serious Total, serious adverse events | 8 / 59 |
Outcome results
Primary
Number of Serious TEAEs
Serious TEAEs were defined as any untoward medicinal occurrence or effect that at any dose: * Results in death * Is life-threatening * Requires hospitalisation or prolongation of existing hospitalisation * Results in persistent or significant disability or incapacity * Is a congenital abnormality or birth defect * May jeopardise the participant or may require medical intervention to prevent one or more of the outcomes listed above (Important Medical Events).
Time frame: 139 weeks
Population: Safety analysis set.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Molgramostim Nebulizer Solution (300 μg) | Number of Serious TEAEs | 8 events |
Primary
Number of TEAEs Leading to Treatment Discontinuation
Time frame: 139 weeks
Population: Safety analysis set.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Molgramostim Nebulizer Solution (300 μg) | Number of TEAEs Leading to Treatment Discontinuation | 0 events |
Primary
Number of Treatment-emergent Adverse Drug Reactions (ADRs)
All AEs were assessed by the investigator for causality (unlikely, possible, probable, not applicable) according to current regulatory standards. AEs which had a 'possible' or 'probable' causality were classified as ADRs.
Time frame: 139 weeks
Population: Safety analysis set.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Molgramostim Nebulizer Solution (300 μg) | Number of Treatment-emergent Adverse Drug Reactions (ADRs) | 3 events |
Primary
Number of Treatment-emergent Adverse Events (TEAEs)
The primary objective of this trial was safety assessed by adverse event (AE) reporting. Definitions and reporting procedures for AEs were done according to current regulatory standards. AEs were collected by the investigator by a non-leading question and by reporting events directly observed or spontaneously volunteered by participants. Participants were also encouraged to contact the clinic in between visits if they experienced AEs or had any concerns. Treatment-emergent was defined as events occurring on study drug and up to 7 days after last dose of study drug.
Time frame: 139 weeks
Population: Safety analysis set.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Molgramostim Nebulizer Solution (300 μg) | Number of Treatment-emergent Adverse Events (TEAEs) | 165 events |