E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
|
E.1.1.1 | Medical condition in easily understood language |
The disease is characterized by the buildup of immune system cells in organs that form small clusters called granulomas, a type of inflammation of the involved tissues. |
|
E.1.1.2 | Therapeutic area | Diseases [C] - Respiratory Tract Diseases [C08] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10037430 |
E.1.2 | Term | Pulmonary sarcoidosis |
E.1.2 | System Organ Class | 10038738 - Respiratory, thoracic and mediastinal disorders |
|
E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
The primary objective of this study is to evaluate the safety and tolerability of multiple ascending intravenous (IV) doses of ATYR1923 in patients with pulmonary sarcoidosis. |
|
E.2.2 | Secondary objectives of the trial |
The secondary objectives are:
- To assess the potential steroid-sparing effect of multiple ascending doses of ATYR1923 in patients with pulmonary sarcoidosis.
- To assess the potential immunogenicity of multiple ascending IV doses of ATYR1923 in patients with pulmonary sarcoidosis.
- To characterize the pharmacokinetics (PK) of multiple ascending IV doses of ATYR1923 in patients with pulmonary sarcoidosis. |
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Male or female patients aged ≥18 to ≤70 years inclusive at time of informed consent
2. Diagnosis of pulmonary sarcoidosis for ≥6 months (cutaneous and ocular involvement allowed), defined as:
• Histologically proven diagnosis of sarcoidosis by bronchoscopy, biopsy (any organ) or bronchioalveolar lavage.
• Evidence of parenchymal lung involvement by historical radiological evidence (eg, computed tomography [CT], magnetic resonance imaging [MRI], 18F-FDG PET/CT or chest X-ray) or on the Screening 18F-FDG PET/CT.
3. Must have symptomatic and/or active pulmonary sarcoidosis as evidence by:
• Clinical findings of dyspnea, as indicated by a Modified Medical Research Council (MRC) Dyspnea Scale grade of at least 1; and
• FVC% predicted ≥50%; and
• Positive 18F-FDG PET/CT scan showing increased metabolic activity (maximum standardized update value [SUVmax] >1) in lung parenchyma within 4 weeks prior to Day 1.
4. Must be receiving treatment with 10 to 25 mg/day of oral prednisone (or oral equivalent; eg, methylprednisolone), at a stable dose for ≥4 weeks prior to Day 1, and be determined by the Investigator to be capable of undergoing the protocol-specified steroid taper regimen.
• Treatment with one oral immunomodulatory therapy (eg, methotrexate, azathioprine, hydroxychloroquine) at a stable dose for ≥1 months prior to Day 1 is allowed but not required. The dose of this therapy should remain constant throughout the study.
5. Body weight ≥45 kg and <160 kg.
6. Female patients may be of childbearing potential or of non-childbearing potential (either surgically sterilized or at least 1 year postmenopausal (confirmed by amenorrhea duration of at least 12 months and serum follicle-stimulating hormone [FSH] ≥30 mIU/mL).
• Female patients of childbearing potential must be non-pregnant and non-lactating, and have a negative pregnancy test at Screening (serum) and at Day 1 (urine) prior to first study drug infusion.
• Additionally, female patients of childbearing potential must be willing to use highly-effective contraception from Screening until 90 days after the last follow-up visit.
7. Male patients, if not infertile or surgically sterilized, must agree to use highly-effective contraception and not donate sperm from Screening until 90 days after the last follow-up visit.
8. Provision of written informed consent.
9. Be able to communicate well with the Investigator and site personnel, and agree to comply with all study procedures and requirements. |
|
E.4 | Principal exclusion criteria |
1. Current disease presentation consistent with Lofgren’s syndrome (ie, presence of the triad of erythema nodosum, bilateral hilar lymphadenopathy on chest X-ray, and joint pain).
2. History of severe allergic or anaphylactic reactions to therapeutic proteins or known sensitivity to ATYR1923 or to its inactive components (L histidine, sodium chloride, sucrose, L-methionine, and polysorbate-20).
3. Treatment (within 6 months of Screening) with biological immunomodulators such as tumor necrosis factor-alpha (TNF-α) inhibitors (eg, infliximab, adalimumab).
4. Current evidence of clinically significant cardiovascular, neurological, hepatic, renal, hematological, lymphatic, metabolic, or gastrointestinal disease, or has a condition that requires other treatment, may not allow safe participation, or which in the opinion of the Investigator should preclude the patient’s participation in the clinical study.
5. Clinically significant pulmonary hypertension requiring vasodilator treatment.
6. Any history of tuberculosis or evidence of active systemic non-tuberculous fungal or mycobacterial infection within 1 year of Screening.
7. History of clinically significant cardiac, neurological, gastrointestinal, and/or renal manifestations of their sarcoidosis.
8. Any history of malignancy.
9. Major surgery within 3 months prior to Day 1 or anticipated surgery during the study.
10. Any condition that necessitated hospitalization within the 3 months prior to Day 1 or is likely to require so during the study.
11. Participation in another clinical study of an investigational agent or device within 3 months (small molecules) / 6 months (biologics) or 5 half-lives (if known) of the agent, whichever is longer.
12. History of or positive results of screening for hepatitis B (hepatitis B surface antigen [HBsAg]), hepatitis C (anti-hepatitis C virus [HCV] antibodies [Ab]) or human immunodeficiency virus (HIV) (HIV Ab type 1 and 2).
13. Has been an active smoker (including e-cigarettes or e-vaporizers) within 3 months prior to Screening.
14. Active substance abuse (drugs or alcohol) or history of substance abuse within the 12 months prior to Screening.
15. Clinically significant abnormalities in the Screening physical examination, vital signs, ECG, or clinical laboratory test results that, in the opinion of the Investigator and Medical Monitor should preclude the patient’s participation in the clinical study.
16. Patient has received a live vaccination within 8 weeks before Day 1 or inoculation with a live vaccine is planned during study participation.
17. Jo-1 Ab levels >7 U/mL at Screening, or past history of Jo-1 Ab positivity.
18. Any other condition or circumstance that, in the opinion of the investigator, would be likely to prevent adequate compliance with the study protocol.
19. Significant and/or acute illness (eg, change in pulmonary status, infection requiring antibiotics) within 5 days prior to (the first) drug administration that may impact safety assessments, in the opinion of the Investigator. |
|
E.5 End points |
E.5.1 | Primary end point(s) |
Safety and tolerability of multiple IV doses of ATYR1923 in patients with pulmonary sarcoidosis based on the following analyses:
• Incidence of TEAEs and serious adverse events (SAEs). |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
From Day 1 to end of study. |
|
E.5.2 | Secondary end point(s) |
Potential to Decrease Background Oral Corticosteroid Dose
• Total cumulative steroid dose administered over the primary study period (Day 1 through Week 24).
• Number of patients who achieve the targeted tapered dose of prednisone 5 mg/day (or equivalent) and maintain it through Week 24.
• Exposure response analysis comparing steroid dose area under the curve (AUC) with ATYR1923 PK parameters through Week 28.
Immunogenicity
Immunogenicity of multiple IV doses of ATYR1923 in patients with pulmonary sarcoidosis based on the following endpoints:
• Incidence and titer of positive ADA (anti-ATYR1923) and anti-Jo 1 Ab. |
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
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 | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
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 | Yes |
E.6.13.1 | Other scope of the trial description |
Tolerability, Immunogenicity |
|
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 | Yes |
E.8.1.7.1 | Other trial design description |
|
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 | 4 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
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 | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
|
E.8.7 | Trial has a data monitoring committee | Yes |
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
|
|
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 2 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |