An Open Label Randomised Controlled Trial of Mycophenolate Mofetil Versus Cyclophosphamide for the Induction of Remission of Childhood Polyarteritis Nodosa - MYPA

Phase 1

• Conditions: Childhood systemic polyarteritis nodosa (PAN); MedDRA version: 19.0Level: LLTClassification code 10036026Term: Polyarteritis nodosa of childhoodSystem Organ Class: 100000004866; Therapeutic area: Diseases [C] - Immune System Diseases [C20]

• Registration Number: EUCTR2013-004668-71-IT
• Lead Sponsor: niversity College London

Brief Summary

Not available

Detailed Description

Not available

Study Timeline

• Results First Posted: 1900-01-01
• Study Start: 2015-07-14
• Study Completion: 2020-06-26
• Last Update Posted: 21 December 2021

Recruitment & Eligibility

• Status: ot Recruiting
• Sex: All
• Target Recruitment: 11

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

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.
9. Urinary outflow obstruction
Exclusions related to medications
10.History of a severe allergic or anaphylactic reaction to any of the study medications or their excipients
11.More than 3g of IV methylprednisolone within one month (4 weeks) prior to randomisation
12.More than 3 weeks of oral prednisolone/prednisone at dose of 2mg/Kg once daily within one month (4 weeks) prior to randomisation
13.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
14.Rituximab or high dose intravenous immunoglobulin within the last twelve months (48 weeks)
15.Intolerance or contraindications to intravenous glucocorticoids
16.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
17.Positive urine human chorionic gonadotropin (hCG) measured at screening / (if appropriate) or a positive urine pregnancy test prior to study entry or breastfeeding
18.Positive tests for hepatitis B surface antigen (HBsAg), hepatitis B core antibody (HBcAb) or hepatitis C serology at randomisation
19.Absolute neutrophil count <1.5 x 109/l
20.Estimated GFR <15 mL/min/1.73m2 (calculated using the Schwartz GFR formula – See section 7.4.2 for formula) at randomisation

Study & Design

• Study Type: Interventional clinical trial of medicinal product
• Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
Main Objective: Is mycophenelate mofetil (MMF) as effective as cyclophosphamide (CYC) at inducing remission in children with polyarteritis nodosa (PAN)?;Secondary Objective: 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. ;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.