| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Childhood systemic polyarteritis nodosa (PAN) |
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| E.1.1.1 | Medical condition in easily understood language |
| Polyarteritis nodosa (PAN) |
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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 | 17.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10036026 |
| E.1.2 | Term | Polyarteritis nodosa of childhood |
| E.1.2 | System Organ Class | 100000004866 |
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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 |
| Is mycophenelate mofetil (MMF) as effective as cyclophosphamide (CYC) at inducing remission in children with polyarteritis nodosa (PAN)? |
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| E.2.2 | Secondary objectives of the trial |
| To determine whether there is a difference between CYC and MMF in terms of time to remission, vascular damage, side effects, impact on the patient (quality of life) and cost effectiveness to the health care provider. |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Age at screening ≥ 4 and ≤ 18 years
2. Children to be included must fulfil the new EULAR/PRINTO/PReS classification criteria for childhood systemic PAN (4) as defined by:
Histopathological evidence of necrotising vasculitis in medium- or small-sized arteries or angiographic abnormality as a mandatory criterion (4); plus one of the following five:
i. skin involvement
ii. myalgia or muscle tenderness
iii. hypertension
iv. peripheral neuropathy
v. renal involvement
3. Newly diagnosed* and with active disease that would normally require treatment with CYC:
i. One or more of major PVAS items (see below)
ii. and / or three or more minor PVAS items,
iii. and/or either of the two additional entry criteria:
1. Severe systemic inflammation and/or features of macrophage activation syndrome due to PAN where the investigator would routinely use cyclophosphamide
2. Demonstration of severe angiographic changes consistent with systemic PAN with other compatible clinical features, but not necessarily including the major PVAS items listed above
4. 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.
Sufficient disease activity for trial entry (see inclusion criteria 3 above) requires at least one major or 3 minor PVAS items as listed below, and/or at least one of the additional criteria listed:
Major PVAS items (indicated in bold in the PVAS form):
Trial entry criteria or major relapse require the recurrence or new appearance of major organ involvement, if they are attributable to active vasculitis:
1. Severe cutaneous vasculitis: significant infarct, ulcer or gangrene. Other significant cutaneous vasculitis such as widespread bullous vasculitic skin disease would also be an inclusion criterion.
2. Threatened vision from any of: retinal vasculitis, retinal vessel thrombosis, scleritis, retinal exudates, or retinal haemorrhages.
3. Major chest involvement: major pulmonary bleeding, with shifting pulmonary infiltrates; other causes of bleeding should be excluded if possible.
4. Cardiovascular involvement: loss of pulses, bruits over accessible arteries, blood pressure discrepancy more than 10 mmHg in any limb, claudication of extremities, ischaemic cardiac pain, cardiomyopathy, congestive cardiac failure, valvular heart disease, pericarditis.
5. Abdominal involvement: abdominal pain, blood in stools or bloody diarrhoea, or bowel ischaemia. Pancreatitis, whilst not specifically listed as a PVAS item, would also be an indication for inclusion.
6. Renal involvement: hypertension, significant proteinuria, significant haematuria (if microscopic haematuria > 5 red blood cells per high power field, or red cell casts), GFR < 80 mls/min/1.73m2 , rise in creatinine > 10% or creatinine clearance (GFR) fall > 25%. Biopsy is strongly recommended for recurrent haematuria or unexplained rise in creatinine EXCEPT where large renal arterial aneurysms have been demonstrated.
7. Nervous system involvement: meningitis or encephalitis, organic confusion /cognitive dysfunction, non-hypertensive seizures, stroke, cord lesion, cranial nerve palsy, sensory peripheral neuropathy, or motor mononeuritis multiplex. (Imaging of brain/cord providing supportive evidence that these lesions are due to vasculitis are usually present for those items pertaining to the brain or cord).
Minor PVAS items:
Minor entry criteria or minor relapse require the recurrence of disease activity of less severity, such as the following, if they are attributable to active vasculitis:
1. Myalgia, arthralgia, arthritis
2. Less severe cutaneous vasculitis: polymorphous exanthema; livedo reticularis; panniculitis; purpura; skin nodules; other less severe cutaneous vasculitic phenomena
3. Mouth ulcers
4. Non-imminently site threatening eye involvement: episcleritis; blepharitis; conjunctivitis; uveitis
*Newly diagnosed is defined for the purposes of the trial as a diagnosis of systemic PAN less than 3 months (12 weeks) prior to screening for MYPAN. If the PAN diagnosis was more than 3 months (12 weeks) prior to the date of initial screening, please discuss with the Chief Investigator.
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| E.4 | Principal exclusion criteria |
Exclusions related to vasculitis type and/ or severity
1. Diagnosis of alternative vasculitic syndrome e.g. HSP, or ANCA vasculitis
2. Patients requiring dialysis
Exclusions related to general health
3. Evidence of other significant uncontrolled concomitant disease that in the investigator’s view would preclude or interfere with patient participation. This will be recorded in the screening log.
4. Primary or secondary immunodeficiency including known history of human immunodeficiency virus (HIV) infection
5. Known active and/or chronic infection of any kind (excluding fungal nail and/or minor fungal skin infections)
6. History of serious recurrent or chronic infection including tuberculosis (a screening chest radiograph will be performed if not performed within 12 weeks prior to randomisation)
7. History of cancer, including solid tumours, haematologic malignancies and carcinoma in situ
8. Participation in a clinical trial testing a medicinal product within 3 months (12 weeks) preceding randomisation for the MYPAN trial.
Exclusions related to medications
9. History of a severe allergic or anaphylactic reaction to any of the study medications or their excipients
10. More than 3g of IV methylprednisolone within one month (4 weeks) prior to randomisation
11. More than 3 weeks of oral prednisolone/prednisone at dose of 2mg/Kg once daily within one month (4 weeks) prior to randomisation
12. Treatment with MMF or azathioprine for more than two weeks; or more than one intravenous dose of cyclophosphamide (>500 mg/m2) within one month (4 weeks) prior to randomisation
13. Rituximab or high dose intravenous immunoglobulin within the last twelve months (48 weeks)
14. Intolerance or contraindications to intravenous glucocorticoids
15. Participant of reproductive potential not prepared to use a reliable means of contraception (e.g. hormonal contraceptive patch, intrauterine device, physical barrier) throughout study participation;
a. Sexually active female not prepared to use two reliable forms of contraception for the complete duration of the trial
Exclusions related to laboratory findings
16. Positive urine human chorionic gonadotropin (hCG) measured at screening / (if appropriate) or a positive urine pregnancy test prior to study entry or breastfeeding
17. Positive tests for hepatitis B surface antigen (HBsAg), hepatitis B core antibody (HBcAb) or hepatitis C serology at randomisation
18. Absolute neutrophil count <1.5 x 109/l
19. Estimated GFR <15 mL/min/1.73m2 (calculated using the Schwartz GFR formula – See section 7.4.2 for formula) at randomisation
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| The proportion of patients achieving remission within 6 months, as defined as a PVAS score of zero on two consecutive readings (both within six months of randomisation) more than one month apart, with adherence to the protocolised corticosteroid taper. |
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| E.5.2 | Secondary end point(s) |
1. Remission within six months (24 weeks) of randomisation defined as paediatric vasculitis activity score (PVAS) of zero on two consecutive readings ≥ one month (4 weeks) apart, irrespective of adherence to a protocolised corticosteroid taper
2. Time to remission, defined as PVAS of zero on two consecutive readings ≥ one month (4 weeks) apart, with adherence to a protocolised corticosteroid taper, measured from randomisation
3. Paediatric vasculitis damage index (PVDI; modified from the adult VDI) at 6, 12 and 18 months (24, 48 and 72 weeks) after randomisation
4. A functional outcome score (CHAQ) and quality of life measure (CHQ) both of which are validated and available in the different translations (including English) required by the PRINTO centres involved in MYPAN; at 6, 12 and 18 months (24, 48 and 72 weeks) after randomisation
5. Health economics measure: Health Utility Index II at 6, 12 and 18 months (24, 48 and 72 weeks)
6. Cumulative corticosteroid dose (at 6 months (24 weeks) and 18 months (72 weeks)): especially important in paediatrics since corticosteroid-related growth retardation (in addition to all the other well documented side effects of corticosteroids that affect adults) is an important concern
7. Growth parameters (height and weight, expressed as age/sex Z scores), and including body mass index at 18 months (72 weeks)
8. Relapses (time to first relapse, and number of relapses) within 18 months (72 weeks) from randomisation
9. Adverse events, including drug toxicity
10. Withdrawal from trial due to drug intolerance
11. MPA 12 hour trough plasma levels
12. Time from randomisation to death
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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 | No |
| E.6.5 | Efficacy | No |
| 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) | 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 | 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) | 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
| 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 | 10 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.5.1 | Number of sites anticipated in the EEA | 26 |
| 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 |
| Croatia |
| Czech Republic |
| Germany |
| Greece |
| Italy |
| Netherlands |
| Poland |
| Portugal |
| Slovenia |
| Spain |
| Sweden |
| Turkey |
| United Kingdom |
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| 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
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The end of the trial is the date of database lock as defined in the MYPAN Data Management Plan. At the time of database lock, data entry privileges are withdrawn from the trial database. However, the trial may be closed prematurely by the Trial Steering Committee, or on the recommendation of the Independent Data Safety and Monitoring Committee (IDSMC).
The end of trial is not defied as last visit of the last patient because there will still be data queries following this point.
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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 | 4 |
| E.8.9.1 | In the Member State concerned months | 8 |
| E.8.9.1 | In the Member State concerned days | 30 |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| 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 | 1 |
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