The main objective of this trial is to investigate the efficacy of inhaled molgramostim compared to placebo.
ID
Source
Brief title
Condition
- Autoimmune disorders
- Lower respiratory tract disorders (excl obstruction and infection)
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The primary endpoint is the change in % predicted DLCO from baseline to Week
24. The aim of this endpoint is to demonstrate treatment effect on gas
exchange, using a standardized lung function test that has been shown to
predict need for rescue treatment.
Secondary outcome
- The secondary efficacy endpoints are Saint George*s Respiratory Questionnaire
(SGRQ) Total, SGRQ Activity, exercise capacity (EC) and change in % predicted
DLCO from baseline to Week 48. The aim of these endpoints is to serve as
clinically meaningful endpoints that address health status and function.
Background summary
Savara ApS has developed a solution for inhalation of the known product
molgramostim for the treatment of aPAP. Molgramostim contains the active
substance recombinant human Granulocyte-Macrophage Colony-Stimulating Factor
(GM-CSF).
GM-CSF is a protein that is naturally present in the human body as part of the
immune system. Patients with aPAP have increased levels of antibodies towards
the specific protein. These antibodies bind to the patient's GM-CSF and block
its function. As a result, a protein-rich material builds up in the air sacs of
the lungs, making it difficult to transfer oxygen to the blood. It is suggested
that inhaling molgramostim might enable the immune system in the lungs to clear
this material to allow oxygen to enter the blood.
Study objective
The main objective of this trial is to investigate the efficacy of inhaled
molgramostim compared to placebo.
Study design
This is an interventional, randomized, double-blind, 2-arm, parallel,
placebo-controlled, multi-center, phase 3 trial in adult subjects who are
diagnosed with aPAP.
The trial consists of a 6-week screening period, a 48-week randomized,
double-blind treatment period, a 48-week open-label treatment period and a
4-week safety follow-up period.
Intervention
Eligible subjects will be centrally assigned through an Interactive Response
Technology (IRT) system to 48-week double-blind once-daily treatment with
either molgramostim 300 µg nebulizer solution or placebo.
Subjects who complete the double-blind 48-week treatment period and who have
not permanently discontinued the investigational product due to unacceptable AE
will continue into the open-label treatment period where they will receive
once-daily open-label treatment with molgraqmotim nebulizer solution.
Study burden and risks
- Type I hypersensitivity reactions: This is considered a risk due to the
inherent risk of
immunogenicity reactions to therapeutic proteins.
- Use in pregnancy: nonclinical studies have shown higher frequency of
abortions and early deliveries in cynomolgus monkeys treated with molgramostim
compared to control animals. Studies in humans to determine effects of
molgramostim nebulizer solution on fertility have not been undertaken.
- Cough: In a previous clinical trial, there was a higher proportion of
subjects reporting non-serious, mild to moderate Cough or Productive cough.
- Chest pains: In a previous clinical trial, there was a higher proportion of
subjects reporting non-serious, mild *Chest pain*.
- Blood sampling: Blood sampling is invasive and there is always a slight risk
of bruising, infections, pain etc.
- DLCO test: During the test, subjects will need to inspire minute amounts of
carbon monoxide and tracer gases (e.g. 10% helium) and he/she needs to
temporarily come off oxygen supply.
- Exercise treadmill test: In subjects with preexisting heart and respiratory
disease, e.g. angina, there may be a risk of exacerbation of these conditions
during the test. The test must be performed without supplementary oxygen and
this might induce a risk of desaturation. The assessment involves exercise on a
treadmill which might cause a risk of fall.
- CT scans: slightly increase risk of developing cancer, although at the low
doses used for CT, the risk is very small. The amount of X-ray radiation that
you will be exposed to at each CT scan corresponds to approximately 3 years
worth of background radiation.
- Use of placebo: 50% of the subjects will be treated with placebo during the
48-week double-blind period. This might result in deterioration of aPAP.
Herman Heijermansweg 20
Amsterdam 1077 WL
NL
Herman Heijermansweg 20
Amsterdam 1077 WL
NL
Listed location countries
Age
Inclusion criteria
1. Subject must be >=18 years of age, at the time of signing the informed
consent. Specific for Japan; Subject must be >=20 years of age, at the time of
signing the informed consent.
2. A serum anti-GM-CSF autoantibody test result confirming autoimmune PAP.
3. History of PAP, based on examination of a lung biopsy, bronchoalveolar
lavage (BAL) cytology, or a high-resolution computed tomogram (HRCT) of the
chest.
4. DLCO 70% predicted or lower at the first Screening and Baseline visits.
5. Change in % predicted DLCO of <15% points during the screening period.
6. Willing and able to come off supplemental oxygen use prior to and during the
treadmill exercise test, the DLCO assessment, and the arterial blood gas
sampling.
7. Resting SpO2 >85% during 15 minutes without use of supplemental oxygen at
the Screening visits.
8. Male or female
9. Contraceptive use by men or women should be consistent with local
regulations regarding the methods of contraception for those participating in
clinical studies.
a. Male subjects: Males agreeing to use condoms during and until 30 days after
last dose of trial treatment, or males having a female partner who is using
adequate contraception as described below.
b. Female subjects: 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, vasectomized partner, sexual abstinence***), during
and until 30 days after last dose of trial treatment. Females of childbearing
potential must have a negative serum pregnancy test at the screening visits,
and a negative urine pregnancy test at Baseline visit (Visit 3) and must not be
lactating.
* Post-menopausal is defined as no menses for at least 12 months without an
alternative medical cause. A high follicle stimulating hormone (FSH) level in
the postmenopausal range may be used to confirm a post-menopausal state in
women not using hormonal contraception or hormonal replacement therapy.
However, in the absence of 12 months of amenorrhea, a single FSH measurement is
insufficient.
** A female is considered of childbearing potential following menarche and
until becoming post-menopausal unless permanently sterile. Permanent
sterilization methods include hysterectomy, bilateral salpingectomy and
bilateral oophorectomy.
***Sexual abstinence is considered a highly effective method only if defined as
refraining from heterosexual intercourse during the entire period of risk
associated with the trial treatments. The reliability of sexual abstinence
needs to be evaluated in relation to the duration of the clinical trial and the
preferred and usual lifestyle of the subject.
10. Capable of giving signed informed consent as described in Appendix 1 which
includes compliance with the requirements and restrictions listed in the
informed consent form (ICF) and in this protocol.
11. 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.
Exclusion criteria
1. Diagnosis of hereditary or secondary PAP, or a metabolic disorder of
surfactant production.
2. WLL performed within 3 months prior to baseline.
3. Requirement for WLL at screening or baseline.
4. GM-CSF treatment within 6 months prior to baseline.
5. Treatment with rituximab within 6 months prior to baseline.
6. Treatment with plasmapheresis within 6 weeks months prior to baseline.
7. Treatment with any investigational medicinal product within 5 half-lives or
3 months (whichever is longer) prior to baseline.
8. Previously randomized in this trial.
9. History of allergic reactions to GM-CSF or any of the excipients in the
nebulizer solution.
10. Inflammatory or autoimmune disease of a severity that necessitates
significant (e.g. more than 10 mg/day systemic prednisolone) immunosuppression.
11. Previous experience of severe and unexplained side-effects during aerosol
delivery of any kind of medicinal product.
12. History of, or present, myeloproliferative disease or leukemia.
13. Apparent pre-existing concurrent pulmonary fibrosis, or diagnosis of
interstitial lung disease other than aPAP.
14. Acute or unstable cardiac or pulmonary disease that may be aggravated by
exercise or confound assessment of the primary endpoint: including presence of
pulmonary edema, or diagnosis of chronic obstructive pulmonary disease (COPD),
pulmonary vasculitis, or pulmonary hypertension.
15. Known active infection (viral, bacterial, fungal, or mycobacterial) that
may affect the efficacy evaluation in the trial.
16. Physical disability or other condition that precludes safe and adequate
exercise testing.
17. Any other serious medical condition which in the opinion of the
Investigator would make the subject unsuitable for the trial.
18. Pregnant, planning to become pregnant during the trial, or breastfeeding
woman.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2020-001263-85-NL |
| CCMO | NL74588.100.20 |