| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| E.1.1.1 | Medical condition in easily understood language |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Immune System Diseases [C20] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 13.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10039486 |
| E.1.2 | Term | Sarcoidosis |
| E.1.2 | System Organ Class | 10021428 - Immune system disorders |
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| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| The primary objective is to evaluate the safety and efficacy of treatment with ustekinumab or golimumab in subjects with chronic sarcoidosis with pulmonary involvement despite current therapy. |
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| E.2.2 | Secondary objectives of the trial |
1. To evaluate the safety of ustekinumab or golimumab in subjects with chronic sarcoidosis with pulmonary and/or skin involvement
2. To evaluate the efficacy of ustekinumab or golimumab in improving the symptoms, functional capacity, and patient reported outcomes at Week 28 in subjects with chronic pulmonary sarcoidosis who are symptomatic despite current treatment
3. To evaluate the efficacy of ustekinumab or golimumab in improving the symptoms and patient reported outcomes at Week 28 in subjects with skin manifestations of chronic sarcoidosis who are symptomatic despite current treatment
4. To assess the ability to taper off of OCS in subjects with chronic pulmonary and/or skin sarcoidosis who are symptomatic despite current OCS treatment
5. To assess the pharmacodynamics (PD) and pharmacokinetics (PK) of ustekinumab or golimumab in subjects with chronic sarcoidosis with pulmonary and/or skin involvement
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Male or female ≥18 to ≤ 85 years of age
2. Have histologically proven sarcoidosis with an onset date of ≥ 2 years prior to screening with at least 1 of the following:
a. pulmonary sarcoidosis defined as requiring:
1) A diagnosis of sarcoidosis with evidence of lung parenchymal disease (Stage II, III or IV on chest radiograph). For subjects with Stage IV sarcoidosis, the chest radiograph should be interpreted as having interstitial infiltrates without cavitating disease, AND
2) a FVC of ≥45% and ≤ 80% of the predicted normal value at screening, AND
3) an MRC dyspnea score of > 2 at screening, AND
4) a 6 minute walk distance between 100 to 550 meters at screening, AND
5) ≤ 15% absolute change in percent-predicted FVC at the baseline visit relative to the screening visit
AND/OR
b. skin sarcoidosis defined as requiring:
1) active chronic skin lesions for ≥3 months either on the face (eg, lupus pernio) or elsewhere on the body (typically indurated lesions consisting of papules, nodules and/or plaques) that have not resolved on current systemic and/or local therapy (ie, intralesional injections). Subjects, excluding those with only lupus pernio facial lesions confirmed by a dermatologist, will be required to have a skin biopsy, performed at screening or between the screening and baseline (Week 0) visit, which is diagnostic of sarcoidosis, AND
2) have either:
* a single lesion of ≥2 cm in longest dimension, OR
* multiple (3 or more) lesions with at least 1 lesion having a longest dimension of ≥1 cm, AND
3) have an SPGA score ≥2 (with an induration subscore ≥1) at screening
3. Have been receiving treatment with oral corticosteroids (≥10 mg/day of prednisone or equivalent dose of corticosteroid) and/or 1 or more immunomodulators (eg, methotrexate, AZA, chloroquine, hydroxychloroquine, mycophenolate, or leflutamide) for ≥3-month period immediately prior to screening. Subjects must be on a stable dose of these medications for ≥4 weeks before screening. For those subjects taking OCS, the dose at the screening visit must be ≤ 25 mg of prednisone (or equivalent dose of corticosteroid).
4. Women of childbearing potential and men must be using adequate birth control measures (abstinence, hormonal contraceptives, intrauterine device, barrier method with spermicide, or surgical sterilization) and must agree to continue such precautions, and not become pregnant or plan a pregnancy for 6 months after receiving their last treatment with study agent. Women of childbearing potential must test negative on a serum pregnancy test at screening.
5. Are considered eligible according to the following tuberculosis (TB) screening criteria:
a. Have no history of latent or active TB prior to screening.
b. Have no signs or symptoms suggestive of active TB upon medical history and/or physical examination.
c. Have had no recent close contact with a person with active TB.
d. Within 2 months prior to the first administration of study agent, have a negative QuantiFERON-TB Gold test result
e. Have a chest radiograph (both posterior-anterior and lateral views), taken within 2 months prior to the first administration of study agent and read by a qualified radiologist, with no evidence of current, active TB or old, inactive TB.
6. The investigator has discussed with the subject the information contained within the informed consent regarding anti-TNFα and anti IL-12/23 therapies and the potential risk of cancer, and has reviewed with the subject country-specific guidance (local practice) on cancer screening and the impact of life-style choices (eg, smoking) on the risk of developing cancer.
7. Are capable of reading and understanding subject assessment forms and providing written informed consent.
8. Are willing and able to adhere to the study visit schedule and other protocol specified procedures. |
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| E.4 | Principal exclusion criteria |
1. Have a diagnosis of other significant respiratory disorder other than sarcoidosis that in the opinion of the investigator would complicate the evaluation of response to treatment.
2. Have a smoking history of ≥ 20 pack years.
3. Have used any investigational drug within 1 month prior to screening or within 5 half lives of the investigational agent, whichever is longer.
4. Have received previous administration of a treatment with any other therapeutic agent targeted at reducing TNFα (eg, pentoxifylline, thalidomide, etanercept, adalimumab, certolizumab, infliximab, golimumab) or anakinra within 6 months or 5 half lives of the agent, whichever is longer, prior to the screening visit. Subjects who have previously received biologic anti TNFα agents outside of the above period are allowed to enter the study; however, their prior history of usage of biologic anti TNFα agents (type, dosage, response to treatment, and reason for cessation of treatment) should be recorded.
5. Have previously used cyclophosphamide.
6. Have previously used or received local therapy (including local injections) within 3 months before the screening visit or used or received treatment with prescription topical creams within 1 month before the screening visit for treatment of sarcoidosis skin lesions.
7. Have used any therapeutic agent targeted at reducing IL 12 and/or IL 23, including but not limited to, ustekinumab and ABT 874 within 6 months or 5 half lives of the agent, whichever is longer, prior to the screening visit.
8. Have received natalizumab or agents that deplete or modulate the activity of B cells or T cells (eg, rituximab, alemtuzumab, efalizumab, or visilizumab) within 12 months of screening, or, if after receiving these agents, evidence is available at screening of persistent depletion of the targeted lymphocyte population.
9. Have used any antibody (monoclonal or polyclonal) or antibody based (antibody fragment, etc.) agents ≤ 6 months or within 5 half lives of the biologic prior to the screening visit, whichever is longer.
10 Have had any previous adverse reactions or allergic reactions (eg, anaphylaxis) associated with the administration of monoclonal antibodies or antibody fragments.
11. Have experienced an anaphylactic reaction to latex.
12. Have known clinically significant pulmonary hypertension and are receiving vasodilator therapy (eg, calcium channel blockers, prostacyclin or prostacyclin analogs, nitric oxide, adenosine).
13. Have participated in the acute phase of a pulmonary rehabilitation program within 4 weeks prior to the screening visit or plan to participate in pulmonary rehabilitation during the study.
14. Have concomitant diagnosis or any history of CHF, including medically controlled CHF, severe right-sided heart failure (ie cor pulmonale).
15. Have current signs or symptoms of severe, progressive or uncontrolled renal, hepatic, hematologic, gastrointestinal, endocrine, pulmonary, cardiac, neurologic, cerebral disease or any laboratory abnormality which would pose/suggest a risk to the subject during participation in the study. Subjects with sarcoid involvement as the cause of dysfunction in these organs will be permitted to be enrolled.
16. Have current signs or symptoms of infection or history of serious infection (eg, sepsis, pneumonia, or pyelonephritis), including any infection requiring hospitalization or IV antibiotics, for 3 months prior to screening. Established nonserious infections (eg, acute upper respiratory tract infection, simple urinary tract infection) need not be considered exclusionary at the discretion of the investigator.
17. Have had chronic or recurrent infectious disease, including, but not limited to: lung infection (eg, lung abscess); renal infection (eg, recurrent pyelonephritis); urinary tract infection (other than simple, recurrent cystitis); or skin wound or ulcer.
18. Are known to be infected with HIV.
19. Are known to be infected with hepatitis B virus (HBV) or hepatitis C virus (HCV) or have other chronic liver diseases other than sarcoidosis involving the liver.
19_1. Test positive for HBV infection at screening.
20. Have a history of latent or active granulomatous infection, including histoplasmosis or coccidioidomycosis, prior to screening. Have signs and symptoms or a history of latent or active granulomatous infection (including TB or aspergilloma).
21. Have had a nontuberculous mycobacterial infection or opportunistic infection (eg, cytomegalovirus, Pneumocystis carinii, aspergillosis) within 6 months prior to screening.
22. Have evidence of a herpes zoster infection ≤ 8 weeks prior to screening.
23. Have history of known demyelinating diseases, such as multiple sclerosis.
24. Have a chest radiograph within 2 months prior to the first administration of study agent that shows an abnormality suggestive of a malignancy or current active infection, including TB and/or cavitating disease. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary endpoint is the change from baseline in percent predicted FVC at Week 16 in the primary population. Two populations (primary and secondary populations) are considered for analysis. These 2 populations comprise 3 strata:
Stratum 1: Subjects with pulmonary involvement that fulfill the eligibility criteria for the primary population, but without skin involvement that fulfill the eligibility criteria for the secondary population,
Stratum 2: Subjects with skin involvement that fulfill the eligibility criteria for the secondary population, but without pulmonary involvement that fulfill the eligibility criteria for the primary population, and
Stratum 3: Subjects with both pulmonary and skin involvement that fulfill the eligibility criteria for both the primary and secondary populations.
The primary population will have ≥135 subjects and contain Stratum 1 and Stratum 3. The secondary population will have ≥45 subjects and contain Stratum 2 and Stratum 3. The secondary population may contain subjects with pulmonary involvement not meeting the criteria for primary population. Similarly, the primary population may contain subjects with skin involvement not meeting the criteria for the secondary population
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
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| 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 | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | Yes |
| E.6.13 | Others | No |
| 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 | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| 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 | 3 |
| 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 | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 40 |
| 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 |
| Belgium |
| Denmark |
| France |
| Germany |
| Italy |
| Netherlands |
| Norway |
| United Kingdom |
| United States |
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| 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
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| 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 | 2 |
| 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 | 2 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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