Hydroxychloroquine in ANCA Vasculitis Evaluation (HAVEN)

Hydroxychloroquine in ANCA Vasculitis Evaluation - A Multicentre, Randomised, Double-blind, Placebo-controlled Trial

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.

Study Overview

• Status: Recruiting
• Conditions: Microscopic Polyangiitis; Churg-Strauss Syndrome; ANCA Associated Vasculitis; Wegener Granulomatosis
• Intervention / Treatment: Drug: Hydroxychloroquine; Drug: Placebo

Detailed Description

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 20 sites.

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

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 two 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.

• Study Type: Interventional
• Enrollment (Estimated): 76
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: David D'Cruz; Phone Number: 02071889756; Email: david.d'cruz@kcl.ac.uk

Study Locations

• United Kingdom
  • Cardiff, United Kingdom, CF14 4XW
    • Recruiting
    • Cardiff & Vale University Health Board
    • Contact: Siân Griffin, MD
  • Epsom, United Kingdom
    • Recruiting
    • Epsom and St Helier University Hospitals NHS Trust
    • Contact: Bhrigu Sood, MD
  • Llantrisant, United Kingdom
    • Recruiting
    • Cwm Taf Morgannwg University Health Board
    • Contact: Ceril Rhys-Dillon, MD
  • London, United Kingdom, SE5 9RS
    • Recruiting
    • King's College Hospital NHS Foundation Trust
    • Contact: Arti Mahto, MD
  • London, United Kingdom, SE1 9RT
    • Recruiting
    • Guy's and St Thomas' NHS Foundation Trust
    • Contact: Shirish Sangle, MD
  • London, United Kingdom, W12 0HS
    • Recruiting
    • Imperial College Healthcare NHS Trust
    • Contact: Stephen McAdoo, MD
  • Maidstone, United Kingdom
    • Withdrawn
    • Maidstone and Tunbridge Wells NHS Trust
  • Oxford, United Kingdom
    • Recruiting
    • Oxford University Hospitals NHS Foundation Trust
    • Contact: Raashid Luqmani, MD
  • Sunderland, United Kingdom
    • Recruiting
    • South Tyneside and Sunderland NHS Foundation Trust
    • Contact: Rebecca Batten, MD
  • Torquay, United Kingdom
    • Recruiting
    • Torbay and South Devon NHS Foundation Trust
    • Contact: Kirsten Mackay, MD
  • Berkshire
    • Reading, Berkshire, United Kingdom, RG1 5AN
      • Recruiting
      • Royal Berkshire NHS foundation trust
      • Contact: Oliver Flossmann, MD
  • Cambridgeshire
    • Cambridge, Cambridgeshire, United Kingdom, CB2 0QQ
      • Recruiting
      • Cambridge University Hospitals NHS Foundation Trust
      • Contact: David Jayne, MD
  • Hertfordshire
    • Stevenage, Hertfordshire, United Kingdom, SG1 4AB
      • Recruiting
      • East and North Hertfordshire NHS Trust
      • Contact: Gayathri Rajakaruna, MD
  • Inverness-shire
    • Inverness, Inverness-shire, United Kingdom, IV2 3JH
      • Recruiting
      • NHS Highland
      • Contact: Jan Sznajd, MD
  • Leicestershire
    • Leicester, Leicestershire, United Kingdom, LE3 9QP
      • Recruiting
      • University Hospitals of Leicester NHS Trust
      • Contact: Chee Kay Cheung, MD
  • Merseyside
    • Liverpool, Merseyside, United Kingdom, L9 7AL
      • Recruiting
      • Liverpool University Hospitals NHS Foundation Trust
      • Contact: Jagdish Nair, MD
  • Somerset
    • Bath, Somerset, United Kingdom, BA1 3NG
      • Recruiting
      • Royal United Hospitals Bath NHS Foundation Trust
      • Contact: Sarah Tansley, MD
  • Surrey
    • Redhill, Surrey, United Kingdom, RH1 5RH
      • Recruiting
      • Surrey and Sussex Healthcare Nhs Trust
      • Contact: Raad Makadsi, MD
  • Sussex
    • Brighton, Sussex, United Kingdom, BN2 5BE
      • Recruiting
      • University Hospitals Sussex NHS Foundation Trust
      • Contact: Teresa Doherty, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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 (Appendix 2) with minor BVAS items only (no major BVAS items).BVAS should be >3 at screening and at randomisation.
4. Patients should be receiving maintenance therapy at a stable dose for 4 weeks prior to randomisation. Maintenance therapy is defined as prednisolone and/or azathioprine, methotrexate, mycophenolate, co-trimoxazole or maintenance rituximab therapy.
5. Patients receiving corticosteroids for reasons other than vasculitis must be on a stable regimen for four weeks prior to randomisation.

6. 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

7. No contraindications to hydroxychloroquine therapy.
8. Willing and able to give written informed consent to participate in the trial.
9. 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 within the last six months:

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

9. B cell depleting therapy (rituximab) for remission induction within the last six months. 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. Patients taking long term macrolide antibiotics for a chronic condition. This does not include topical preparations.
13. 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.
14. 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.
15. 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.
16. 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.
17. 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.
18. Participation in any other interventional trial within the last 6 months.
19. Have a current symptomatic COVID-19 infection.
20. Have been admitted to the ICU in the past 6 months due to a COVID-19 infection.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Hydroxychloroquine; Patients will be receive 400mg of Hydroxychloroquine (2 x 200mg) to take daily for 52 weeks. Hydroxychloroquine will be started at a dose of 200mg an up-titrated after the first week to a maximum daily dose of 400mg. Patients weighing <50kg, or those patients with an eGFR of 30-50mL/min, will receive a reduced dose of 200mg daily.	Drug: Hydroxychloroquine; White, round, film-coated tablets marked 'HCQ' on one side and 200' on the other side. Excipients: Lactose monohydrate Maize Starch Magnesium Stearate Polyvidone Opadry OY-L-28900; Other Names: Plaquenil
Placebo Comparator: Placebo; Patients will be receive 400mg of Placebo (2 x 200mg) to take daily for 52 weeks. Placebo will be started at a dose of 200mg an up-titrated after the first week to a maximum daily dose of 400mg. Patients weighing <50kg, or those patients with an eGFR of 30-50mL/min, will receive a reduced dose of 200mg daily.	Drug: Placebo; Placebo to match Hydroxychloroquine. Excipients: Microcrystalline cellulose Lactose Magnesium Stearate; Other Names: Control

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The percentage of patients with • uncontrolled AAV disease activity OR • controlled AAV disease activity but prednisolone dose >7.5mg daily OR • controlled AAV disease activity but any corticosteroid use >7.5mg daily for any reason	The primary endpoint will be the percentage of patients with: EITHER; uncontrolled AAV disease activity (defined as BVAS > 3) OR; controlled AAV disease activity (BVAS ≤ 3) but prednisolone dose >7.5mg daily OR; controlled AAV disease activity (BVAS ≤ 3) but any corticosteroid use >7.5mg daily for any reason at any point during the final 12 weeks (±7 days) of the study. Inhaled corticosteroids will not contribute to the primary endpoint, nor will methylprednisolone given for rituximab maintenance therapy.	BVAS will be assessed during the final 12 (±7 days) weeks that the patient is on the study drug in the trial.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cumulative number of visits BVAS = 0	Excluding screening, baseline and week 56	Week 4 through to week 52
Proportion of patients with treatment failure at week 52	As above	Week 52
Cumulative prednisolone dosage	As above	From date of randomisation through to week 56 follow up
Total number of adverse events	As above	From date of randomisation through to week 56 follow up
Total number of infections per patient	As above	From date of randomisation through to week 56 follow up
Total number of vasculitis flares (severe and limited) per patient	As above	From date of randomisation through to week 56 follow up
Time to remission	As above	From date of randomisation through to week 56 follow up
Time to first severe flare	Patients will be categorized as having a severe flare if they have a new or worsening major item on the BVAS. Proportion of patients with a limited disease flare defined as having a new or worsening minor BVAS item with no major items at each time point outlined in the trial flowchart.	From date of randomisation through to week 56 follow up
Time to first limited flare	Patients will be categorized as having a limited flare if they have a new or worsening minor item on the BVAS with no new major items.	From date of randomisation through to week 56 follow up
Proportion of patients categorized as having a severe flare at each of the time points in the trial schedule excluding screening, baseline and week 56	As above	Weeks 1-52 excluding screening, baseline and week 56
Proportion of patients categorized as having a limited flare at each of the time points in the trial schedule excluding screening, baseline and week 56	As above	Weeks 1-52 excluding screening, baseline and week 56
Absolute values and relative change from baseline in the Vasculitis Damage Index (VDI) at each time point outlined in the trial schedule.	As above	From date of randomisation through to week 56 follow up

Collaborators and Investigators

• Sponsor: Guy's and St Thomas' NHS Foundation Trust
• Collaborators: Medical Research Council
• Investigators: Principal Investigator: David D'Cruz, Guy's and St Thomas' NHS Foundation Trust

Study record dates

Study Major Dates

• Study Start (Actual): December 17, 2020
• Primary Completion (Estimated): September 1, 2024
• Study Completion (Estimated): March 1, 2025

Study Registration Dates

• First Submitted: February 25, 2020
• First Submitted That Met QC Criteria: March 18, 2020
• First Posted (Actual): March 20, 2020

Study Record Updates

• Last Update Posted (Actual): August 28, 2023
• Last Update Submitted That Met QC Criteria: August 25, 2023
• Last Verified: August 1, 2023

More Information

Terms related to this study

• Keywords: Eosinophilic Granulomatosis with Polyangiitis; Granulomatosis Polyangiitis
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Skin Diseases; Respiratory Tract Diseases; Immune System Diseases; Lymphoproliferative Disorders; Lymphatic Diseases; Autoimmune Diseases; Lung Diseases; Skin Diseases, Vascular; Lung Diseases, Interstitial; Cerebral Small Vessel Diseases; Granuloma; Vasculitis; Granulomatosis with Polyangiitis; Microscopic Polyangiitis; Churg-Strauss Syndrome; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Systemic Vasculitis; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Antirheumatic Agents; Antiprotozoal Agents; Antiparasitic Agents; Antimalarials; Hydroxychloroquine
• Other Study ID Numbers: 251987; 2018-001268-40 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: N/A - no plan to share identifiable patient data with other researchers.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No