Hydroxychloroquine in ANCA Vasculitis Evaluation
Hydroxychloroquine in ANCA Vasculitis Evaluation
The purpose of this study is to find out whether hydroxychloroquine, in addition to
 background treatments, reduces disease activity in patients with Anti-Neutrophilic
 Cytoplasmic Autoantibodies (ANCA) Vasculitis, a group of autoimmune diseases.

 Hydroxychloroquine and is an established, effective, safe and inexpensive therapy, widely
 used in other autoimmune diseases such as lupus and rheumatoid arthritis.

 The study is open to adults diagnosed with certain types of vasculitis, called Granulomatosis
 Polyangiitis (GPA), Microscopic Polyangiitis (MPA) or Eosinophilic Granulomatosis with
 Polyangiitis (EGPA). Participants will be eligible if they are treated with background
 medication to control their vasculitis disease and have a low level of disease activity as
 defined by a Birmingham Vasculitis Activity Score (BVAS) of greater than 3.

 Participants will be randomly placed in 1 of 2 groups. Both groups will be given background
 medication. One group will receive hydroxychloroquine and the other will receive placebo.
 Participants will be on treatment for 1 year.

 76 ANCA Vasculitis participants will be recruited (38 in each treatment arm) from UK
 vasculitis specialist centres over 2 years.
This is a multi-centre, randomised, placebo-controlled, double-blind study to evaluate if
 hydroxychloroquine in combination with background maintenance therapy improves the clinical
 response and quality of life in patients with AAV. 76 participants who have Granulomatosis
 with Polyangiitis, Microscopic Polyangiitis or Eosinophilic Granulomatosis with Polyangiitis
 will be recruited from 10 sites over 2 years.

 They will be randomised in a 1:1 ratio of hydroxychloroquine or placebo. Neither the patient
 nor the research team will know which treatment group the participant is in.

 Once the participant agrees to take part and has signed informed consent, they will undergo
 the following assessments, tests and procedures to find out if they can take part in the
 study. Some may be routinely done by the study doctor as part of regular vasculitis care even
 if the participants are not in the study:

 -  Medical history

 -  Birmingham Vasculitis Activity Score (BVAS)

 -  Physical exam

 -  Blood tests

 -  Pregnancy test

 -  Urine drug test

 -  Electrocardiogram

 -  Arrange for optician review

 If the patient is eligible to take part in the study, they will be randomised to receive
 either hydroxychloroquine or placebo in addition to background medication. Participants will
 receive 2 tablets to take once a day over the course of a year. Participants may have their
 dose reduced to 1 tablet dependent on their weight at baseline and renal function. All
 participants will have their prednisolone dose tapered down over the course of the study.
 Participants will be asked to fill in a patient diary on a weekly basis to record whether
 they've taken their medication, and if they've experienced any change of symptoms.

 Participants will be asked to attend the hospital at weeks 4, 16, 28, 40, 44, 48, 52 and 56.
 At each of these visits, participants will undertake some or all of the following
 tests/assessments:

 -  Physical exam including visual acuity

 -  Weight and vital signs

 -  BVAS assessment and Vasculitis Damage Index (VDI)

 -  Patient questionnaires

 -  If there are any changes to their medicines and health status

 -  If they experiencing any side effects

 -  Blood samples and urine tests to see how the study drug is affecting the body.

 -  At three visits, participants will also be asked to undergo an electrocardiogram (ECG).

 Patients will be followed up by phone in weeks 10, 22, and 34. This phone call will be based
 on the ANCA-associated Vasculitis Patient Reported Outcome (AAV PRO) questionnaire and
 patients will also be encouraged to report any adverse events. Patients reporting new or
 worsening symptoms will be invited to the hospital for an unscheduled visit.

 In addition to clinical bloods, 76ml of blood will be taken for research purposes for all
 participants. These will be taken at the same time as clinical bloods to minimise discomfort
 for the participant. Participants at Guy's and St Thomas' will have an additional 200ml of
 blood taken for isolation of cells. These bloods will be stored and kept for future research,
 with the written consent of the participant.
Inclusion Criteria

 1. Are at least 18 years of age at screening.

 2. Have a clinical diagnosis of Granulomatosis Polyangiitis (GPA) or a diagnosis of
 Microscopic Polyangiitis (MPA) or a diagnosis of Eosinophilic Granulomatosis with
 Polyangiitis (EGPA) according to the Chapel Hill criteria.

 3. Have a Birmingham Vasculitis Activity Score >3 (BVAS v.3) with minor BVAS items only
 (no major BVAS items) and be receiving maintenance therapy at a stable dose for 4
 weeks prior to randomisation. BVAS should be > 3 at screening and at randomisation.

 4. Patients receiving corticosteroids for reasons other than vasculitis must be on a
 stable regimen for four weeks prior to randomisation.

 5. A female patient is eligible to enter the study if she is:

 Not pregnant or nursing; OR Of non-childbearing potential (i.e., women who have had a
 hysterectomy, are postmenopausal defined as ≥1 year without menses, have both ovaries
 surgically removed or have documented tubal ligation or other permanent sterilization
 procedure); OR

 Of childbearing potential. These women must have a negative urine pregnancy test at
 screening and at baseline and be using at least one effective method of contraception.
 Periodic abstinence (e.g. calendar, ovulation, symptothermal, post-ovulation methods)
 and withdrawal are not acceptable methods of contraception. Consistent and correct use
 of one of the following acceptable methods of birth control for 1 month prior to the
 start of the study agent, during the study, and 16 weeks after the last dose of study
 agent:

 Oral contraceptive, either combined or progestogen alone Injectable progestogen
 Implants of levonorgestrel or etonogestrel Estrogenic vaginal ring Percutaneous
 contraceptive patches Intrauterine device (IUD) or intrauterine system (IUS) with <1%
 failure rate as stated in the product label

 6. No contraindications to hydroxychloroquine therapy and normal baseline visual fields
 at screening.

 7. Willing and able to give written informed consent to participate in the trial.

 8. Patients should have sufficient English in order to provide informed consent and
 complete the patient questionnaires.

 Exclusion Criteria:

 1. Patients currently taking hydroxychloroquine or related antimalarial such as mepacrine
 or chloroquine.

 2. Patients with an estimated glomerular filtration rate (eGFR) <30 ml/min.

 3. Patients weighing <40kg.

 4. Sensitivity, anaphylaxis or allergy to hydroxychloroquine or any other
 4-aminoquinoline compound.

 5. Known glucose 6 phosphate dehydrogenase deficiency.

 6. Known lactose intolerance.

 7. Evidence of plaque psoriasis.

 8. Concomitant use of the following medications:

 Tumour necrosis factor inhibitor treatment (e.g. etanercept) Cyclophosphamide
 Abatacept Alemtuzumab Any experimental or biological therapies Intravenous,
 intramuscular or sub-cutaneous immunoglobin Plasma exchange Antithymocyte globulin
 Tamoxifen Live vaccines

 9. B cell depleting therapy (rituximab) for remission induction. Rituximab maintenance
 therapy is permitted.

 10. Severe or rapidly progressive ANCA vasculitis with at least one major BVAS item.

 11. Have clinical evidence of significant unstable or uncontrolled acute or chronic
 diseases not due to vasculitis (i.e., cardiovascular, pulmonary, hematologic,
 gastrointestinal, hepatic, renal, neurological, malignancy or infectious disease)
 which, in the opinion of the principal investigator, could confound the results of the
 study or put the patient at undue risk.

 12. Have a history of malignant neoplasm within the last 5 years, except for adequately
 treated cancers of the skin (basal or squamous cell) or carcinoma in situ of the
 uterine cervix.

 13. Have current drug or alcohol abuse or dependence, or a history of drug or alcohol
 abuse or dependence within 364 days prior to randomisation. A urine drug screen should
 be performed and confirmed negative prior to study entry.

 14. Have a historically positive test or test positive at screening for hepatitis B
 surface antigen, hepatitis B core antibody or hepatitis C antibody or are known to be
 HIV-1 positive.

 15. Have a Grade 3 or greater laboratory abnormality based on the Common Terminology
 Criteria for Adverse Events (CTCAE) toxicity scale (version 5), unless considered by
 the investigator to be related to the underlying disease or induction therapy.

 16. Screening 12-lead electrocardiogram (ECG) that demonstrates clinically relevant
 abnormalities that may affect patient safety or interpretation of study results,
 including: - QT interval corrected using the same consistent formula at each visit
 (QTc) > 470 msec for female > 450 msec for male patients demonstrated by at least two
 ECGs.

 17. Participation in any other interventional trial within the last 6 months.

 18. Have a current symptomatic COVID-19 infection.

 19. Have been admitted to the ICU in the past 6 months due to a COVID-19 infection.