| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Idiopathic Inflammatory Myopathy (IIM) |
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| E.1.1.1 | Medical condition in easily understood language |
| Inflammation of muscle tissue which can lead to profound weakness, fatigue and disability |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Musculoskeletal Diseases [C05] |
| 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 | 10028653 |
| E.1.2 | Term | Myositis |
| E.1.2 | System Organ Class | 10028395 - Musculoskeletal and connective tissue disorders |
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| 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 research objective is to assess the clinical response across treatment arms after 24 weeks of active treatment. |
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| E.2.2 | Secondary objectives of the trial |
a) To assess the extent of clinical response across treatment arms after 24 weeks of active treatment
b) To compare the clinical response between treatment arms: (i) at 12 weeks and (ii) at 24 weeks
c) To compare the clinical response between treatment arms after 24 weeks of active treatment.
d) To assess the time taken to achieve clinical response across treatment arms up to 24 weeks of active treatment.
e) To compare the change from baseline between treatment arms: at (i) 12 weeks, (ii) 24 weeks and (iii) after 24 weeks of active treatment in the following outcomes:
- individual components of the IMACS CSMs
- physical functioning
- muscle endurance
- pain
- fatigue
- health-related quality of life
f) To assess harms across treatment arms: (i) after 12 weeks of active treatment and (ii) after 24 weeks of active treatment.
g) To assess the steroid-sparing effect of baricitinib across treatment arms: (i) after 12 weeks of active treatment and (ii) after 24 weeks of active treat |
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| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Muscle biopsy sub-study
Incorporated into main study protocol
PIS V1 date 19Feb2020
ICF V1 date 19Feb2020
Muscle contains a number of biomarkers which vary in abundance in IIM patients compared to non-IIM controls. Biomarkers will be analysed in muscle samples of participants with IIM at baseline and in response to treatment.
Magnetic resonance scanning (MR) sub study
PIS V1 date 19Feb2020
ICF V1 date 19Feb2020
The optional MR scans will allow the assessment of the sensitivity, specificity and responsiveness of quantitative muscle MR scanning in patients with IIM at baseline, and in response to treatment.
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| E.3 | Principal inclusion criteria |
1. Participant meets EULAR/ACR classification criteria for PM or DM (at least 55% probability).
2. Persisting disease activity as defined in (3), after a minimum of 12 weeks treatment with prednisolone or equal drug. The history of treatment with prednisolone (or equal) should include the dose of 20mg/day for at least 4 weeks. Prednisolone should be at a stable dose of ≤ 20 mg/day for at least 4 weeks prior to the baseline visit.
3. Inflammatory active disease based on persisting or worsening muscle weakness; MMT < 150 or low endurance (FI-3 < 20% of upper value), together with at least one other sign of active disease: elevated serum levels of at least one muscle enzyme (CK, LDH, AST, ALT) above upper limit of normal and being explained by muscle involvement and no other cause e.g. liver disease, inflammation in recent muscle biopsy or on MRI scans (<12 weeks), or active extra muscular disease: dermatomyositis-specific skin rash, arthritis or interstitial lung disease (ILD) (as suggested by chest x-ray/ high resolution computerised tomography (HRCT) or pulmonary function test (reduction of TLCO by 15% and/or FVC by 10% from baseline)) and on the treating physicians’ judgement. In particular, patients who meet the inclusion criteria but with less than moderate disease activity should only be included at the discretion of the PI.
4. If criteria in (2) not met, then to fulfil sum of Physician global assessment, participant global assessment and extra muscular global assessment visual analogue scale (VAS) score ≥ 10 cm (all scales individually on 0-10 cm scale).
5. For polymyositis, a participant can be included if they are is positive for myositis specific (anti-synthetase, NXP2, SAE1, TIF1g, Mi2, MDA5) or myositis-associated autoantibodies (Ro52, Ro60, PmScl, RNP). Polymyositis will be included after a judicial process by the three PIs.
6. Are receiving at least one of the following standard of care medications within the required timeframe:
• A single antimalarial (e.g. hydroxychloroquine) for 3 months and at a stable therapeutic dose for at least 8 weeks prior to the screening visit
• A single immunosuppressant (such as methotrexate (MTX), azathioprine, mycophenolate) for 3 months and at a stable therapeutic dose for at least 4 weeks prior to the screening visit
• An oral corticosteroid, at a stable dose ≤ 20 mg/day prednisone (or equivalent) for at least 4 weeks prior to baseline (visit 1)
7. Age ≥18 years.
8. Full capability of providing informed consent.
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| E.4 | Principal exclusion criteria |
1. Participants with other types of inflammatory myopathies including:
• Drug induced myositis
• Inclusion body myositis
• Malignancy-associated myositis
• Immune-mediated necrotizing myopathy
2. Participants unable to participate in clinical assessments or provide biological specimens as per the study protocol
3. Participants where the use of bariticinib would be contraindicated
4. Participants with known allergies to IMP or excipients
5. Women with a positive pregnancy test on enrolment or prior to start of study drug administration
6. Women who are known to be pregnant or breastfeeding
7. Women of child bearing potential (WOCBP) who are unwilling or unable to use an acceptable method to avoid pregnancy for the entire study period and for at least 1 week after treatment (Please see Appendix 3 for definitions and acceptable methods of contraception).
8. Current symptoms of severe, progressive, or uncontrolled renal, hepatic, haematological, gastrointestinal, pulmonary, cardiac, neurological, ophthalmologic or cerebral disease with the exception of those symptoms that are a manifestation of polymyositis or dermatomyositis.
9. Concomitant medical conditions that in the opinion of the investigator might place the subject at unacceptable risk for participation in this study.
10. Participants with a history of venous thromboembolism including deep vein thrombosis and pulmonary embolism.
11. Participants with a history of cancer within the last five years (other than non-melanoma skin cell cancers cured by local resection), including carcinoma-in-situ. Existing non-melanoma skin cell cancers must be removed prior to IMP dosing. Participants with dermatomyositis need to be screened for malignancies according to routine procedures.
12. Participants who have a history of clinically significant drug or alcohol abuse. Subjects currently taking MTX who admit to consumption of more than an average of 1 alcoholic drink per day.
13. Participants with any serious bacterial infection (such as pneumonia, other renal infection and sinusitis), unless treated and resolved with antibiotics.
14. Participants with any chronic bacterial infection (such as pyelonephritis and chest infection with bronchiectasis) in the previous 12 weeks before screening.
15. Participants with active tuberculosis (TB) requiring treatment within the previous 3 years. Subjects with a positive PPD and/or Quantiferon assay at screening will not be eligible for the study unless they have completed at least 4 weeks of treatment for latent TB, have a negative chest x-ray at enrolment, and commit to completing the course during the study. Such cases should be discussed with a respiratory physician as per local guidelines. A PPD response that is equal to or greater than 10 mm should be considered a positive test, although more conservative criteria may be applied as determined by the clinical circumstance and investigator according to published guidelines and/or local standards endorsed by the medical society. PPD and/or Quantiferon positive participants who have previously completed treatment for latent tuberculosis according to the local guidelines may be considered for enrolment. Equivocal Quantiferon results will need to be discussed with a local respiratory physician.
16. Participants with herpes zoster that resolved less than 8 weeks prior to the screening visit.
17. Participants with evidence (as assessed by the Investigator) of active or latent bacterial or viral infections at the screening visit, including subjects with evidence of Human Immunodeficiency Virus (HIV) infection, positive HepBsAg, HepBcAb or hepatitis C antibody.
18. Significant toxicities associated with concomitant or previous immunosuppressive/biologic therapy that would preclude subjects from participating and completing the study.
19. Participants with clinically apparent immunodeficiency syndrome, (IgA deficiency alone is not an exclusion criterion).
20. Participants with any of the following laboratory values at screening:
• Haemoglobin (Hb) < 80 g/litre
• Absolute lymphocyte count (ALC) < 500 cells/mm3
• Absolute neutrophil count (ANC) < 1000 cells/mm3
• Platelets <100,000/mm3 (100 x 109/L)
• Creatinine clearance <30ml/min. Note: participants with creatinine clearance between 30-60mL/min should receive a reduced oral dose of 2mg baricitinib OD.
• Any other laboratory test results that, in the opinion of the investigator, might place the subject at unacceptable risk for participation in this study.
22. For all participants who have received prior rituximab, a normal CD19 B cell count must be documented at the time of screening for this study.
See protocol for complete list. This has been cropped in IRAS system. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| Response (yes/no): where ‘response’ is defined as ‘achieving at least minimal clinical response according to the IMACS criteria at 24 weeks post-active treatment (at 24 weeks in the immediate-start arm and at 36 weeks in the delayed-start arm)’ |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Immediate start arm: week 24 post baseline
Delayed start arm: week 36 post baseline
Both of these are after 24 weeks of active IMP treatment. |
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| E.5.2 | Secondary end point(s) |
a) Response (yes/no): where ‘response’ is defined as ‘achieving : i) at least moderate and ii) major clinical response according to the IMACS criteria at 24 weeks post-active treatment (at 24 weeks in the immediate-start arm and at 36 weeks in the delayed-start arm)’
b) Response (yes/no): where ‘response’ is defined as ‘achieving at least minimal clinical response according to the IMACS criteria: (i) at 12 weeks and (ii) at 24 weeks’
c) Response (yes/no): where ‘response’ is defined as ‘achieving moderate or major clinical response according to the IMACS criteria at 24 weeks post-active treatment (at 24 weeks in the immediate-start arm and at 36 weeks in the delayed-start arm)’.
d) Time taken to achieve minimal, moderate or major clinical response up to 24 weeks post-active treatment (at 24 weeks in the immediate-start arm and at 36 weeks in the delayed-start arm).
e) Change from baseline: (i) at 12 weeks, (ii) at 24 weeks and (iii) at 24 weeks post-active treatment (at 24 weeks in the immediate-start arm and at 36 weeks in the delay-started arm), in the following:
- Individual components of the IMACS CSMs for disease activity
- Physical functioning as measured by the PROMIS PF-20 questionnaire
- Muscle endurance as tested by the myositis functional index (FI-3)
- Perceived pain measured by
• a visual analogue scale (VAS)
• the two body pain related items of the SF-36v2
- Fatigue as measured by
• the FACIT-Fatigue questionnaire v4 and
• components of SF-36v2
- Health status as measured by the mental and physical sub-scales of the SF-36v2 and health utility as measured by the EQ-5D-5L
f) Cumulative (S)AEs and (S)ARs:
(i) at 12 weeks post-active treatment (i.e., at 12 weeks in the immediate-start arm and at 24 weeks in the delay-started arm) and
(ii) at 24 weeks post-active treatment (i.e., at 24 weeks in the immediate-start arm and at 36 weeks in the delay-started arm)
g) Prescribed daily dose of glucocorticoids:
(i) at 12 weeks post-active treatment (i.e., at 12 weeks in the immediate-start arm and at 24 weeks in the delay-started arm) and
(ii) at 24 weeks post-active treatment (i.e., at 24 weeks in the immediate-start arm and at 36 weeks in the delay-started arm)
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
a) Immediate start arm: week 24 post baseline, Delayed start arm: week 36 post baseline, Both of these are after 24 weeks of active IMP treatment.
b) 12 weeks post baseline and 24 weeks post baseline
c) Immediate start arm: 24 weeks post baseline; Delayed start arm: 36 weeks post baseline
d) Immediate start arm: 24 weeks post baseline; Delayed start arm: 36 weeks post baseline
e) 12 weeks post baseline, 24 weeks post baseline and after 24 weeks of active treatment (immediate start arm: 24 weeks post baseline; delayed start arm 36 weeks post baseline)
f) Immediate start arm: 12 and 24 weeks post baseline; Delayed start arm: 24 and 36 weeks post baseline
g) Immediate start arm: 12 and 24 weeks post baseline; Delayed start arm: 24 and 36 weeks post baseline
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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 | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| 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 | 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 | No |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
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| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
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| E.8.2.4 | Number of treatment arms in the trial | 2 |
| 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 | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 1 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| 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 | 1 |
| E.8.9.1 | In the Member State concerned months | 10 |
| E.8.9.1 | In the Member State concerned days | 31 |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 10 |
| E.8.9.2 | In all countries concerned by the trial days | 31 |
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