| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
Asthma
Chronic obstructive pulmonary disease
Rheumatoid arthritis
Psoriasis |
|
| E.1.1.1 | Medical condition in easily understood language |
Asthma
Chronic obstructive pulmonary disease - sometimes called emphysema, chronic bronchitis or smoker's cough
Rheumatoid arthritis
Psoriasis |
|
| 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 | 14.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10039073 |
| E.1.2 | Term | Rheumatoid arthritis |
| E.1.2 | System Organ Class | 10028395 - Musculoskeletal and connective tissue disorders |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 14.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10003553 |
| E.1.2 | Term | Asthma |
| E.1.2 | System Organ Class | 10038738 - Respiratory, thoracic and mediastinal disorders |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 14.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10010952 |
| E.1.2 | Term | COPD |
| E.1.2 | System Organ Class | 10038738 - Respiratory, thoracic and mediastinal disorders |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 14.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10037153 |
| E.1.2 | Term | Psoriasis |
| E.1.2 | System Organ Class | 10040785 - Skin and subcutaneous tissue disorders |
|
| 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 |
| That treatment of patients who have chronic inflammation with oral FX125L for 8 weeks results in a robust, generalisable and statistically significant biological response compared with placebo treatment, irrespective of the particular tissue or organ affected in each individual. |
|
| E.2.2 | Secondary objectives of the trial |
• To determine the safety of once daily oral dosing with FX125L 600 mg for up to 8 weeks in patients with chronic inflammatory diseases
• To estimate the effect of FX125L on surrogate markers for clinically-relevant end-points in each of the different chronic inflammatory diseases, to inform the selection of appropriate indications for future Phase II studies
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Willing and able to give written informed consent and to comply with the requirements of the study.
2. Male or female aged 18–77 years, inclusive.
3. Body mass index 18–35 kg/m2, inclusive.
4. Females of child-bearing potential must be using an adequate and medically acceptable contraception method.
5. Females of child-bearing potential must not be lactating or pregnant (negative serum beta-human chorionic gonadotropin on Screening or urine pregnancy test at Day -1 visit).
6. Male patients must agree not to donate sperm, and to take appropriate precautions to avoid fathering a child, throughout the study and until 90 days after the end of treatment.
7. Ability to produce an analysable sample of sputum at Screening. This is defined as a) a sputum plug with a weight exceeding 500 mg and b) more than 300 intact leukocytes on a cytospin slide.
In addition, patients must meet the inclusion criteria for a chronic inflammatory disease as follows:
Asthma:
1. Documented diagnosis of asthma at least 6 months prior to Screening or equivalent that confirms the diagnosis meets this criteria
2. Forced expiratory volume in 1 second ≥60% and ≤90% of predicted at Screening and Randomisation (Day -1).
3. Sputum eosinophilia ≥3% at Screening.
Chronic Obstructive Pulmonary Disorder:
1. Documented diagnosis of moderate to severe COPD, according to Global Initiative for Chronic Obstructive Lung Disease criteria, at least 6 months prior to the screening visit, and who meet the criteria for Stage II–III disease at Screening , and who meet the criteria for Stage II–III disease at Screening.
2. Stable disease for at least 1 month prior to Screening.
3. Sputum neutrophils ≥ 40% at Screening.
Rheumatoid Arthritis:
1. Documented diagnosis of rheumatoid arthritis according to the 1996 American College or Rheumatology (ACR) / European League Against Rheumatism criteria.
2. Global functional class I, II or III according to the ACR 1991 revised criteria at Screening and Day -1.
3. At least six swollen joints and at least six tender joints during the 28-joint assessment performed at Screening and Day -1.
4. C-reactive protein ≥7.0 mg/L at Screening.
5. Presence of anti-cyclic citrullinated peptide antibodies >50 ELISA Units (or above the median titre among RA patients for the anti-cyclic citrullinated peptide assay used at the clinical site) at Screening.
Psoriasis
1. Documented diagnosis of moderate/severe chronic plaque psoriasis for more than 6 months, and eligible for systemic treatment , or equivalent that confirms the diagnosis meets this criteria.
2. Plaque psoriasis covering greater than 5% of total body surface area and a Psoriasis Area and Severity Index score of 12.0 or more at Screening and Day -1.
3. At least one evaluable plaque psoriasis lesion with a Psoriatic Lesion Severity Sum total score (erythema, induration and scaling) of 5–12 and an induration score of 2–4 at Screening and Day -1.
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|
| E.4 | Principal exclusion criteria |
1. Any condition, including findings in the medical history or in the pre-study assessments, which, in the opinion of the Investigator, constitute a risk or contraindication for the participation of the subject in the study, or that could interfere with the study objectives, conduct, or evaluation including, but not limited to:
- Any clinically significant abnormality in the results of screening safety laboratory tests.
- Positive test for drugs of abuse.
- Positive alcohol breath test.
- Positive results from serum tests for hepatitis B surface antigen (except if due to vaccination), hepatitis C, or HIV.
- History or presence of liver disease.
- History or presence of endocrine disorders or diseases affecting the hypothalamic-pituitary-adrenal axis, including acromegaly, growth hormone deficiency, adrenal insufficiency, Cushing’s syndrome, Grave’s Disease, Hashimoto’s Disease, uncontrolled diabetes mellitus, with the exception of idiopathic hypothyroidism in patients > 60 years.
- History of hypofertility.
- History of cancer in the preceding 5 years (except adequately treated basal cell carcinoma of the skin and squamous cell carcinoma in situ of the skin)
2. History or presence of drug or alcohol abuse.
3. History or active manifestation of a serious psychiatric illness including depression, suicidal ideation or psychosis.
4. Positive test for latent tuberculosis.
5. Requirement for immunisations or vaccinations within 7 days of any visit during the entire study period (including the screening, treatment and follow-up phases).
6. Previous participation in the current study, or administration of any investigational product within 12 weeks (or at least 5 times the half-life of the product, if longer) prior to entry into the study.
7. Acute infection requiring a visit to a doctor or hospital, or treatment with a prescription-only medication, within 2 weeks prior to Day 1.
8. Any condition that may affect the absorption of an orally administered drug, for example, but not limited to, ulcerative colitis or resection of the stomach or small bowel.
9. Required to take a proscribed drug during the study.
10. History of treatment with corticosteroids, whether systemic, topical or inhaled, within 1 month of screening.
11. History of treatment with a biological anti-inflammatory therapy within 6 months of screening.
12. History of exposure to FX125L.
Patients must not meet any exclusion criteria for at least 1 of the chronic inflammatory disease(s) for which they met the disease-specific inclusion criteria:
Asthma:
1. Received treatment with topical or oral asthma or allergy medications except β-agonists within 4 weeks prior to Screening.
2. Suffer from respiratory diseases, other than asthma or allergic rhinitis, which would interfere with asthma disease assessments.
3. Respiratory infections within 8 weeks prior to Day 1.
4. Asthma exacerbation leading to hospitalisation for >2 days within the last 6 months or a hospital accident and emergency visit due to asthma exacerbation in the last 3 months.
COPD:
1. Exacerbation of COPD requiring treatment with oral steroids or hospitalisation within 3 months prior to screening, or >2 such exacerbations with the 6 months prior to screening.
2. Suffer from respiratory diseases other than COPD that would interfere with COPD disease assessments.
3. Evidence of cor pulmonale, clinically significant pulmonary hypertension or chronic use of oxygen.
4. History of lung resection or lung reduction surgery.
Rheumatoid Arthritis (RA)
1. Treatment with a disease modifying anti-rheumatic drug, including methotrexate (MTX) at any dose, within 4 weeks prior to Screening.
2. Any other joint disease that prevents assessment of the symptoms of RA.
3. In the event that 10 RA patients have not been accrued onto the study within 3 months of the start of enrolment on the study, the Sponsor may elect to alter the exclusion criteria for RA patients such that patients on a stable dose of MTX (7.5-25 mg/week for >= 1 month prior to randomization) may be enrolled on the study. In such an event, because the biologic response to FX125L would be expected to be different between RA patients on a stable dose of MTX compared to those not on MTX, accrual of the minimum number of 20 RA patients would need to start again. In such a case, the total number of subjects enrolled on the study would be increased above 100 by the number of RA patients enrolled prior to the change of the MTX exclusion criterion.
Psoriasis
1. Evidence of skin conditions other than chronic plaque psoriasis (e.g., psoriasis guttate, erythrodermic or pustular psoriasis, eczema or atopic dermatitis) that would interfere with psoriasis disease assessments.
2. Clinically significant psoriasis flare during Screening or on Day -1 necessitating immediate relief (at the Investigator’s discretion).
3. Treatment with ultraviolet within 4 weeks prior to Screening.
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|
| E.5 End points |
| E.5.1 | Primary end point(s) |
For all subjects:
• Full differential leukocyte count in blood
• Serum C-reactive protein, tissue inhibitor of metalloproteinases 1, plasminogen activator inhibitor-1 (PAI-1), a multiplex panel of cytokines and a multiplex panel of matrix metalloproteinases (MMPs) and optionally other biomarkers
• Full differential leukocyte count in sputum plugs (and optionally sputum non-plug samples)
• Tissue inhibitor of MMP 1, myeloperoxidase, tryptase, eosinophil cationic protein, granulocyte colony-stimulating factor (G-CSF), interleukin (IL)-8, IL-16, Interferon gamma-induced protein 10 (IP-10), PAI-1, Chemerin, monokine Induced by Gamma interferon, neutrophil-activating protein-2, macrophage inflammatory protein 3 alpha, a multiplex cytokine panel and a multiplex MMP panel in cell-free supernatant from sputum sample
• Cell surface cluster of differentiation (CD)11b, L-selectin CD3+CD4+, CD3+CD8+, CD16 and optionally other cell surface biomarkers in fixed preparations of leukocytes, prepared from blood and sputum with CD45 as an additional biomarker only for the sputum population.
The multiplex panel of cytokines measured consists of: Epidermal growth factor, Eotaxin, fibroblast growth factor-2, FMS-like tyrosine kinase 3 ligand, Fractalkine, G-CSF, Granulocyte-Macrophage Colony Stimulating Factor, growth regulated oncogene, interferon (IFN)-α2, IFN-γ, IL-10, IL-12 (p40), IL-12 (p70), IL-13, IL-15, IL-17, IL-1Rα, IL-1α, IL-1β, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IP-10, monocyte chemotactic protein (MCP)-1, MCP-3, Macrophage Derived Chemokine (CCL22), Macrophage Inflammatory Protein (MIP)-1α, MIP-1β, transforming growth factor alpha, tumour necrosis factor (TNF)-α, TNF-β, Vascular endothelial growth factor, sCD40L, IL-2Rα
The multiplex panel of MMPs measured consists of: MMP1, MMP2, MMP3, MMP7, MMP9 and optionally also MMP8, MMP12, MMP13
Asthma patients:
• Forced expiratory volume in one second (FEV1)
• Asthma Control Days and frequency of inhaled β-agonist rescue medication
• Asthma Control Test
• Patient and Physician Global Assessment using a Visual Analog Scale
Chronic obstructive pulmonary disease (COPD) patients
• Spirometry (FEV1, forced vital capacity [FVC] and peak expiratory flow) and degree of dyspnoea (assessed using the baseline and transition dyspnoea index [BDI/TDI])
• COPD-AQ Test score
• Patient and Physician Global Assessment using a Visual Analog Scale
• Number of moderate to severe acute exacerbations in COPD
• Frequency of inhaled rescue medication use
Rheumatoid arthritis
• Disease Activity Score 28 (DAS28) score
• American College of Rheumatology (ACR) 20, ACR50 and ACR70 responses
• ACR core set of measures (swollen joint count, tender joint count, patient’s assessment of pain, patient’s and physician’s global assessment of disease activity, Health Assessment Questionnaire Disability Index score)
• Titre of anti-cyclic citrullinated peptide antibodies
• Patient and Physician Global Assessment using a Visual Analog Scale
Psoriasis
• Psoriatic Lesion Severity Sum (PLSS) total score of index psoriasis lesions
• The Psoriasis Area and Severity Index score
• Psoriasis Area and Severity Index (PASI)50, PASI75, PASI90 responses and physician’s global assessment of clear or almost clear score
• Body surface area (BSA) involvement
• Patient and physician global assessment of disease activity using a Visual Analog Scale
• Short Form 36 (SF-36) Health Survey questionnaire
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|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
All endpoints will be measured at Screening, Days -1, 42 and 56 with the exception of the following:
Screening, Days -1, 10, 42 and 56: FEV1, FVC, TDI, PEF, patient and physician global assessment, DAS28, ACR core set of measures, PASI, PLSS, BSA involvement
Screening, Days -1, 10, 42, 56 and 84: full differential leukocyte count in blood
Day 56 only: ACR20, ACR50, ACR 70, PASI50, PASI75, PASI90
Throughout the study: asthma control days, frequency of inhaled (beta-agonist) rescue medication, number of moderate to severe acute exacerbations in COPD |
|
| E.5.2 | Secondary end point(s) |
• Physical examination, vital signs, 12-lead ECGs, clinical laboratory assessments
• Adverse events
• Markers of endocrine function, including free T4, free T3, adrenocorticotropic hormone (ACTH), Thyrotrophin-stimulating hormone (TSH), Follicle-stimulating hormone (FSH) and Insulin-Like Growth Factor (IGF)-1
In addition, the endpoints measured as part of the primary endpoint will be examined to estimate the effect of FX125L on surrogate markers for clinically-relevant end-points in each of the different chronic inflammatory diseases
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
• Physical examination and clinical laboratory assessments at Screening, Day -1, Day 10, Day 42, Day 56 and Day 84
• Vitals and 12-lead ECG at Screening, Day 1, Day 10, Day 42, Day 56 and Day 84
• Adverse events throughout the study
• Markers of endocrine function, including free T4, free T3, ACTH, TSH, FSH and total IGF-1, will be assessed at Screening, Day -1 (total IGF-1 only), Day 10 (excluding total IGF-1), Day 42 (total IGF-1 only), Day 56 and Day 84 (excluding total IGF-1).
The endpoints measured to estimate the effect of FX125L on surrogate markers for clinically-relevant end-points in each of the different chronic inflammatory diseases will be examined at the same time points as for the primary endpoint. |
|
| 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 | No |
| 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 | 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 | Yes |
| E.8.1.5 | Parallel group | No |
| 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 | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| 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 | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | No |
| 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
|
| The end of the study is defined as the last patient’s last visit. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 0 |
| E.8.9.1 | In the Member State concerned months | 9 |
| E.8.9.1 | In the Member State concerned days | 5 |
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