Primary Objectives* To estimate the effect size, at 4 and 8 weeks, of change from baseline in high- resolution computed tomography (HRCT)-based measurements of lobar volumes at functional residual capacity (FRC) and total lung capacity (TLC) in…
ID
Source
Brief title
Condition
- Lower respiratory tract disorders (excl obstruction and infection)
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Primary Endpoint: HRCT
Description:
* HRCT-based metrics of Sarcoid activity and progression, lobar volumes at TLC
and FRC, and airway wall volumes
Secondary outcome
Exploratory Endpoint: HRCT
Description:
* Lung volumes at FRC and TLC
* (specific) CFD- based Airway resistance at FRC and TLC
* (specific) Airway volume down to generation 8-10 at TLC
* (specific) Airway volume down to generation 4-5 at FRC
* Air Trapping at FRC
* Internal airflow distribution based on lobar expansion
* Emphysema score on lobar level
Exploratory Endpoints: Pulmonary Function Tests (PFTs)
Description:
* forced vital capacity (FVC), forced expiratory volume in 1 second (FEV1),
diffusing capacity of lung for carbon monoxide (DLCO), total lung capacity
(TLC) and functional residual capacity (FRC), six-minute walk test (6MWT)
For other Exploratory Endpoints see protocol under Table 2: Study Endpoints
Background summary
Sarcoidosis is a multisystemic disorder characterized by the formation of
granulomas. It affects people of all racial and ethnic groups and occurs at all
ages, although it usually develops before the age of 50 years, with the
incidence peaking at 20 to 39 years. The lung parenchyma and the mediastinal
lymph nodes are affected in > 90% of patients, often resulting in dyspnea, dry
cough, and chest pain. Of the patients diagnosed with pulmonary sarcoidosis
(PS), approximately 9% to 37% have concurrent skin involvement (cutaneous
sarcoidosis [CS]) presenting as maculopapular lesions erupting on the face,
trunk and/or the extremities. Although little is known about the causes of the
pathologic inflammatory response seen in sarcoidosis, it is characterized by an
accumulation of activated lymphocytes, predominantly expressing the helper T
cell Type 1 (Th1) phenotype, as well as macrophages, resulting in the formation
of granulomas. While it is generally accepted that T cell activation is
required for the initiation of this process, granuloma formation involves other
cell types, including macrophages, epithelioid cells, and multinucleated giant
cells.
Macrophage colony stimulating factor (M-CSF) and granulocyte macrophage colony
stimulating factor (GM-CSF) induce alveolar macrophage proliferation,
differentiation, and multinucleated giant cell formation, which is integral to
granuloma formation. The alveolar macrophage is a major source of
proinflammatory cytokines, such as tumor necrosis factor-alpha (TNF-*) in the
lung, which are strongly linked to the pathogenesis of sarcoidosis.
Additionally, there is clinical evidence that inhibition of TNF-* may be an
effective treatment for sarcoidosis.
Although remission occurs within three years in more than 50% of patients
diagnosed with sarcoidosis, approximately one-third of patients develop damage
in a number of organs. Patients with lung, heart, or brain involvement, or
with lupus pernio, a sarcoidosis-related disfiguring skin condition that does
not remit spontaneously, are at greater risk of less favorable outcomes.
While sarcoidosis often responds to corticosteroids and other immunosuppressive
or immuno- modulatory drugs, the latter are not curative and relapses
frequently occur. Drugs used to date in current clinical practice include
glucocorticoid, hydroxychloroquine, methotrexate, thalidomide, and infliximab.
Nevertheless, the precise role of immunosuppressive drugs and anti-TNF agents
in the treatment of sarcoidosis remains uncertain, and, with the exception of
glucocorticoids, there are no products approved for sarcoidosis by the European
Medicines Agency (EMA) or the Food and Drug Administration (FDA). Because of
the chronic nature of the disease and the toxicities often associated with
these drugs, there is an unmet medical need for more effective treatments.
The assessment of sarcoidosis has been significantly aided by recent imaging
technology. Standard chest radiography is typically employed to evaluate and
classify patients with suspected pulmonary sarcoidosis. High resolution
computed tomography (HRCT) is superior to conventional chest radiography and
can identify characteristic features of sarcoidosis. Certain HRCT features may
also differentiate active inflammation from fibrosis which may help guide
treatment. This study will investigate the ways that certain HRCT-based
measures can serve.
Study objective
Primary Objectives
* To estimate the effect size, at 4 and 8 weeks, of change from baseline in
high- resolution computed tomography (HRCT)-based measurements of lobar volumes
at functional residual capacity (FRC) and total lung capacity (TLC) in response
to glucocorticoid induction therapy (eg, prednisone or prednisolone) in
subjects with pulmonary sarcoidosis.
* To estimate the effect size, at 4 and 8 weeks, of change from baseline in
HRCT-based measurements of airway wall volume in response to glucocorticoid
induction therapy in subjects with pulmonary sarcoidosis.
Exploratory Objectives
* To estimate the effect size, at 4 and 8 weeks, of change from baseline in
total lung volumes, airway resistance, airway volume at FRC and TLC, air
trapping at FRC, internal airflow distribution based on lobar expansion, and
emphysema score in response to glucocorticoid induction therapy in subjects
with pulmonary sarcoidosis, as measured by HRCT.
* To estimate the effect size, at 4 and 8 weeks, of change from baseline in
forced vital capacity (FVC), forced expiratory volume in 1 second (FEV1),
diffusing capacity of lung for carbon monoxide (DLCO), the inhalation (TLC) and
exhalation capacity (FRC), and six-minute walk test (6MWT) in response to
glucocorticoid induction therapy in subjects with pulmonary sarcoidosis.
* To estimate changes, at 4 and 8 weeks, from baseline in pharmacodynamic (PD)
biomarkers in response to glucocorticoid induction therapy in subjects with
pulmonary sarcoidosis.
* To estimate changes from baseline in patient-reported pulmonary endpoints
using the St. George's Respiratory Questionnaire (SGRQ), baseline/transition
dyspnea indices (BDI/TDI) and King*s Sarcoidosis Questionnaire in response to
glucocorticoid induction therapy for 4 and 8 weeks in subjects with pulmonary
sarcoidosis.
* To describe AE frequency and type in symptomatic pulmonary sarcoidosis
patients receiving glucocorticoid treatment.
Study design
This is a multicenter, single-arm, unblinded/open-label study in subjects with
a diagnosis of pulmonary sarcoidosis with dyspnea and evidence of disease on
chest radiograph (Stage II or III) who are not receiving initial induction
treatment for their disease.
This study will evaluate the effect of glucocorticoid therapy on functional
respiratory imaging (FRI) parameters and also pulmonary function tests (PFTs)
during treatment with glucocorticoid in patients with pulmonary sarcoidosis.
The study follows a multiple dose design with 24 subjects receiving
glucocorticoid (* 30 mg/day prednisone or prednisolone).
Length of Study
The estimated duration of the study from first-subject-first-visit (FSFV) to
last-subject-last-visit (LSLV), is approximately 12 months.
The estimated duration of each subject*s participation in the study, from
screening through the follow-up phone call is approximately 4 months.
The End of Trial is defined as either the date of the last visit of the last
subject to complete the post-treatment follow-up, or the date of receipt of the
last data point from the last subject that is required for primary, secondary
and/or exploratory analysis, as prespecified in the protocol, whichever is the
later date.
Intervention
Geen onderzoeksmedicatie
Study burden and risks
This study evaluates the effect size in response to standard treatment,
operational ease, and general suitability of high resolution computed
tomography (HRCT)-based variables as endpoints. Certain HRCT features may also
differentiate active inflammation from fibrosis which may help guide treatment.
This study will investigate the ways that certain HRCT-based measures can
serve.The standard treatment for sarcoidosis in the lungs is prednisone or
prednisolone. There is always a risk when taking medication. However, the
subjects will be carefully monitored for any problems that may arise during the
treatment.
Please refer to ICF for more details.
Morris Avenue 86
Summit, New Jersey NJ 07901
US
Morris Avenue 86
Summit, New Jersey NJ 07901
US
Listed location countries
Age
Inclusion criteria
1. Subject are male or female * 18 and * 65 years of age, inclusive, at the
time of signing the informed consent form (ICF)., 2. Subject must understand
and voluntarily sign an ICF prior to any study-related assessments/procedures
being conducted., 3. Subject is willing and able to adhere to the study visit
schedule and other protocol requirements., 4. Subject has not received
glucocorticoid as initial sarcoidosis therapy (* 20 mg/day prednisone or
prednisolone) or other sarcoidosis therapy for at least 3 months or 5 PK
half-lives, whichever is longer, prior to enrollment., 5. Subjects have a
diagnosis of pulmonary sarcoidosis:, a. According to the ATS/ERS/WASOG
(Appendix J) statement, supported by clinical presentation and biopsy-proven
noncaseating granulomatous inflammation with no alternative cause of the
granulomas;, b. With radiographic stage II or III disease;, c. With dyspnea
(MRC grade * 1);, d. With an FVC as follows - * 45% and * 80% of predicted
normal value at screening (for at least 10 subjects) - * 45% and * 90% of
predicted normal value at screening (for no more than 14 subjects);, e. With or
without concurrent extra-pulmonary sarcoidosis;, f. Without clinically
significant neurosarcoidosis or cardiac sarcoidosis;, g. Without history of
resistance or refractoriness to glucocorticoid induction therapy., 6. Subject
is in good health (except for sarcoidosis) as determined by a physical
examination at screening., a. Stable and mild syndromes associated with normal
ageing, that are not expected to affect safe participation or data
interpretation are allowed. Examples include, but are not limited to, systemic
hypertension, hypothyroidism, prostatic hypertrophy, etc., 7. Contraception
Requirements: Must comply with the following acceptable forms of contraception.
All FCBP1 must use one of the approved contraceptive options as described below
while participating in the study and for at least 28 days after the last study
visit., At the time of study entry, and at any time during the study when a
FCBP*s contraceptive measures or ability to become pregnant changes, the
Investigator will educate the subject regarding contraception options and the
correct and consistent use of effective contraceptive methods in order to
successfully prevent pregnancy. All FCBP must have a negative pregnancy test at
screening, Baseline (Day 1/Visit 1), Visit 3 and Visit 5. All FCBP subjects who
engage in activity in which conception is possible must use one of the approved
contraceptive options described below:, Option 1: Any one of the following
highly effective methods: hormonal contraception (oral, injection, implant,
transdermal patch, vaginal ring); intrauterine device (IUD); tubal ligation; or
partner*s vasectomy; OR, Option 2: Male or female condom (latex condom or
non-latex condom NOT made out of natural [animal] membrane [for example,
polyurethane]); PLUS one additional barrier(c) contraceptive sponge with
spermicide. Male subjects (including those who have had a vasectomy) who engage
in activity in which conception is possible must use barrier contraception
(latex or non-latex condoms NOT made out of natural [animal] membrane [for
example, polyurethane]) while on the study and for at least 28 days after the
last study visit., 8. Subject has body mass index (BMI) * 17 and * 40 kg/m2 at
screening., 9. Subject has clinical laboratory safety test results that are
within normal limits or acceptable to the Investigator. Platelet count,
absolute neutrophil count, and absolute lymphocyte count must be above the
lower limit of normal at screening., 10. Subject is afebrile, with supine
systolic blood pressure (BP) * 90 and * 150 mmHg, supine diastolic BP * 50 and
* 90 mmHg, and pulse rate * 40 and * 110 bpm at screening., 11. Subject has a
normal or clinically acceptable 12-lead ECG at screening.
Exclusion criteria
1. Subject has any significant medical condition, laboratory abnormality,
neurological disease or psychiatric illness that would prevent the subject from
safely completing the study. Prior evidence of neurological disease must be
documented., 2. Subject has any condition that confounds the ability to
interpret data from the study., 3. Subject is a pregnant or a nursing female.,
4. Subject has received another interventional investigational drug for
sarcoidosis within the 3 months prior to screening or 5 PK half-lives,
whichever is longer*., 5. Subject has clinically significant lung disease,
other than sarcoidosis, such as asthma, chronic obstructive pulmonary disease
(COPD), interstitial lung disease (ILD) or lung cancer., a. Subject has a
history of significant (greater than a wedge) lung resection., 6. Subject is
receiving therapy for sarcoidosis associated pulmonary hypertension, or has an
indication for such therapy., 7. Subject has uncontrolled diabetes and/or other
contraindications to glucocorticoid therapy., 8. Subject has a history of
listeriosis, coccidioidomycosis, histoplasmosis, blastomycosis, treated or
untreated tuberculosis or exposure to individuals with tuberculosis., 9.
Subject is an active smoker or has > 10 pack-year smoking history. Previous
smokers must have discontinued smoking for at least 1 year., 10. Subject is
unable to perform any study-related procedure or maneuver., 11. Subject has had
any biologic anti-tumor necrosis factor (anti-TNF) therapy within the previous
year., 12. Subject has active infection requiring treatment within 30 days
prior to screening*., 13. Subject has a positive QuantiFERON-TB Gold
tuberculosis test., a. In case of an indeterminate result, the test may be
repeated once. The repeat result must be negative to permit entry into the
study., 14. Subject has active fungal infection (other than candidiasis of the
urinary tract*) or active infection with hepatitis B or hepatitis C or a
history of either HCV infection or chronic HBV infection., 15. Subject has a
history of congenital and/or acquired immunodeficiencies (eg, common variable
immunodeficiency, HIV, etc.)., 16. Subject has aspartate transaminase (AST),
alanine aminotransferase (ALT) or total bilirubin > 2 x the upper limit of
normal at screening (unless the increase is considered to be due to sarcoidosis
by the Investigator and/or Sponsor*s medical monitor)., 17. Subject has a serum
creatinine level > 1.8 mg/dL (> 159.12 *mol/L), 18. Subject has
clinically significant organic heart disease (eg, congestive heart failure),
myocardial infarction requiring initiation or change in medical treatment
within six months prior to screening., 19. Subject has QTcF of > 450
milliseconds or findings on electrocardiogram (ECG) at screening (eg, an
arrhythmia, heart block, etc.) that suggest either significant cardiac
sarcoidosis or significant risk of cardiac adverse event over the duration of
this study., 20. Subject has a history of malignancy within 5 years (except
basal cell carcinoma of the skin that is surgically cured, remote history of
cancer now considered cured or positive pap smear with subsequent negative
follow-up)., 21. Subject is expecting to have elective surgery in the time
interval between screening and 10 weeks after the last study visit if the
surgery would be expected to confound evaluation of study endpoints or AE
assessment., *Candidate subjects having these conditions may be re-evaluated
upon resolution and entered into the study if all other criteria are met.
Design
Recruitment
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 |
|---|---|
| CCMO | NL63613.078.18 |
| Other | SF NIHR CRN reference: RESP 35694 |