| 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 |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Skin and Connective Tissue Diseases [C17] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10003641 |
| E.1.2 | Term | Atopic eczema |
| E.1.2 | System Organ Class | 100000004858 |
|
| 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 |
There are two co-primary endpoints:
1.To assess the change in atopic ezcema severity between baseline & 12 weeks of treatment in the two treatment arms
and
2.To examine disease remission (time to first significant flare) after treatment cessation in the MTX vs CyA groups |
|
| E.2.2 | Secondary objectives of the trial |
1Examine atopic eczema severity using EASI,IGA,oSCORAD&POEM scores between 0,12,36,48,60weeks
2Compare the number of flares&the proportion of children who reflared following treatment cessation
3Study the impact on quality of life: change in CDLQI/IDQOL&DFI scores between 0,12,36,48,60weeks
4Determine the proportion of participants achieving 50%improvement in the oSCORAD&EASI index at 12,36,48,60weeks
5Capture the proportion of participants who withdraw from treatment due to AEs
6Assess the costeffectiveness of CyA vs MTX,
7Study the immunometabolic effects of MTX&CyA, in relation to markers of glycolytic activation and Tcell cytokine signature, at baseline, during treatment& after treatment cessation
8Compare the drug side effects/toxicity profiles of both MTX&CyA,
9Examine the association between MTX polyglutamate&CyA trough levels&reduction in atopic eczema severity&drugrelated side effects
10Study the impact of FLG carriage on reduction in atopic eczema severity |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Written informed consent for study participation obtained from the patient or parents / legal guardian, with assent as appropriate by the patient, depending on the level of understanding.
2. Aged 2-16 years at the time of the screening and randomisation visit
3. Diagnosis of severe recalcitrant atopic eczema
4. History of inadequate clinical response (in the opinion of the treating clinician) to mild to potent topical corticosteroids on the body and moderate strength topical steroids on the face.
5. An objective (o)-SCORAD severity score of at least 30
6. Participants must live within travelling distance of the recruiting centre
7. Females of childbearing potential and males, who are sexually active, must commit to consistent and correct use of an highly effective method of contraception (e.g. combined hormonal contraception, intrauterine device, physical barrier or abstinence) for the duration of the trial and for 6 months after the last dose of study drug.
a. Females of childbearing potential for this study are: Females, regardless of their age, with functioning ovaries and no documented impairment of oviductal or uterine function that would cause sterility. This category includes young females who have begun to menstruate, or females with oligomenorrhea.
8. Willingness to comply with study requirements
9. Ability to swallow tablets/capsules
10. Baseline visit within 2 weeks of the screening visit
|
|
| E.4 | Principal exclusion criteria |
1.Serious underlying medical condition which in the opinion of the Investigator would compromise the safety of the patient.
2.Pregnant or nursing (lactating) females, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive hCG laboratory test.
3.Any active and/or chronic infection at screening or baseline (randomisation) visit that, based on the investigator's clinical assessment, makes the subject an unsuitable candidate for the study.
4.Presence of moderate to severe impaired renal function as indicated by clinically significantly abnormal creatinine (≥ 1.5 x upper normal limit (ULN) for age and sex) AND eGFR <60ml/min/1.73m2 at screening visit.*
5.Clinical evidence of liver disease or liver injury at screening visit as indicated by abnormal liver function tests such as AST, ALT, GGT, alkaline phosphatase, or serum bilirubin (must not exceed 1.5 x the upper limit value of the normal range for age and sex).
6.Total WBC count <3x109/L, or platelets <150x109/L or neutrophils <1.5x109/L or haemoglobin <8.5 g/dL at screening visit.
7.Blood pressure values > 95th percentile for age and sex at screening and baseline visit.**
8.Received systemic cortico-steroids within 14 days prior to screening visit and 28 days of baseline visit.
9.Received phototherapy within 4 weeks prior to screening visit and 6 weeks of the baseline visit.
10.Previous exposure to any biologic agents or systemic immuno-suppressive therapy, except for oral corticosteroids (CS) for acute flare management.
11.Concomitant use of disease-modifying and/or immunosuppressive drugs.
12.Received live vaccines within 4 weeks prior to baseline visit.
13.Radiology report of abnormal chest x-ray at the screening visit (at the discretion of the PI/medically qualified physician - see section 7.1 for further details)
14.Receiving treatment with medicines that are substrates for the multidrug efflux transporter P-glycoprotein or the organic anion transporter proteins (OATP) for which elevated plasma concentrations are associated with serious and/or life-threatening events; this includes bosentan, dabigatran etexilate and aliskiren.
15.Receiving treatment with products containing Hypericum perforatum (St. John's wort)
16.Receiving oral treatment with tacrolimus
17.Receiving oral treatment with everolimus and sirolimus
18.Receiving oral treatment with lercanidipine
19.Currently participating in a conflicting study or participation in a clinical study involving a medicinal product in the last 28 days or less than 5 half-lives of the medicinal product prior to the screening visit.
20.Known hypersensitivity to methotrexate or ciclosporin products.
21.Insufficient understanding of the trial.
*Please ensure the following formula is used for calculating eGFR: eGFR= height (cm) x 40/plasma creatinine (micromol/l)
** If an accurate blood pressure reading is unobtainable (e.g. due the patient being distressed), the patient’s GP may be approached in order to obtain an accurate reading if a blood pressure measurement has been carried out within 4 weeks of the screening and baseline visit. A community nurse may also carry out a blood pressure measurement at the patient’s home to confirm eligibility and also during the follow up visits. Without an accurate blood pressure measurement below the 95th centile of systolic BP for age and sex, a patient cannot be randomised into the trial. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
1. Change in atopic ezcema severity between baseline and 12 weeks of treatment, using the oSCORAD index.
2. Time to first significant after treatment cessation in the MTX vs CyA groups.
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
For the first primary outcome, the timepoints are between baseline and 12 weeks of treatment.
For the second primary outcome, this is evaluated following treatment cessation (from 36 weeks to 60 weeks). |
|
| E.5.2 | Secondary end point(s) |
1. Change in atopic ezcema severity using the EASI, IGA, oSCORAD and POEM between baseline and 12, 36, 48, and 60 weeks.
2. Number of flares in each study arm as well as the proportion of children who re-flared after treatment cessation.
3. Proportion of participants achieving 50% improvement in the oSCORAD index at 12, 36, 48, and 60 weeks.
4. Proportion of participants who withdraw from treatment because of AEs.
5. Disease-specific patient and parental quality of life (QoL) measured with the CDLQI/IDQOL and DFI scores between baseline and 12, 36, 48 & 60 weeks.
6. Assess the cost-effectiveness of CyA vs MTX, based on utility measured using the CHU-9D.
7. Immuno-metabolic effects of MTX and CyA, especially in relation to markers of glycolytic activation and T cell cytokine signature, at baseline, during treatment and after treatment cessation.
8. Drug-related side effects of both MTX and CyA and their association with MTX polyglutamate and CyA trough levels.
9. The association between MTX polyglutamate and CyA trough levels and treatment response (reduction in disease severity).
10. The association between FLG carriage (yes/no) and treatment response. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. Between baseline and 12, 36 and 48 weeks
2. Following treatment cessation (from week 36 to week 60)
3. 12, 36, 48 and 60 weeks
4. From baseline and up until weeks following treatment (week 40)
5. Between baseline, 12, 36, 48 and 60 weeks
6. Evaluated at the end of the trial
7. At baseline, during treatment and up to 6 months after completion of treatment
8. During treatment (from baseline to week 40)
9. Evaluated throughout treatment
10. One off sample collected at baseline |
|
| 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 | No |
| E.6.7 | Pharmacodynamic | No |
| 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) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| 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 | Yes |
| 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 | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| 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 | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 14 |
| 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
|
| The end of the trial is defined to be the date on which data for all participants is frozen and data entry privileges are withdrawn from the trial database. |
|
| 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 | 7 |
| E.8.9.1 | In the Member State concerned days | 30 |
| 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 | 7 |
| E.8.9.2 | In all countries concerned by the trial days | 30 |
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