Hydroxychloroquine in ANCA Vasculitis Evaluation

NCT ID: NCT04316494

Last Updated: 2024-07-19

Basic Information

• Recruitment Status: UNKNOWN
• Clinical Phase: PHASE4
• Total Enrollment: 43 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2020-12-17
• Study Completion Date: 2025-05-31

Brief Summary

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.

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.

Conditions

ANCA Associated Vasculitis; Microscopic Polyangiitis; Churg-Strauss Syndrome; Wegener Granulomatosis

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

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.

Group Type: EXPERIMENTAL

Hydroxychloroquine

Intervention Type: DRUG

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

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.

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

Placebo to match Hydroxychloroquine.

Excipients:

Microcrystalline cellulose Lactose Magnesium Stearate

Interventions

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

Intervention Type: DRUG

Placebo

Placebo to match Hydroxychloroquine.

Excipients:

Microcrystalline cellulose Lactose Magnesium Stearate

Intervention Type: DRUG

Other Intervention Names

Plaquenil; Control

Eligibility Criteria

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.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Medical Research Council

OTHER_GOV

Sponsor Role: collaborator

Guy's and St Thomas' NHS Foundation Trust

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

David D'Cruz

Role: PRINCIPAL_INVESTIGATOR

Guy's and St Thomas' NHS Foundation Trust

Locations

Royal Berkshire NHS Foundation Trust

Reading, Berkshire, United Kingdom

Cambridge University Hospitals NHS Foundation Trust

Cambridge, Cambridgeshire, United Kingdom

East and North Hertfordshire NHS Trust

Stevenage, Hertfordshire, United Kingdom

NHS Highland

Inverness, Inverness-shire, United Kingdom

University Hospitals of Leicester NHS Trust

Leicester, Leicestershire, United Kingdom

Liverpool University Hospitals NHS Foundation Trust

Liverpool, Merseyside, United Kingdom

Royal United Hospitals Bath NHS Foundation Trust

Bath, Somerset, United Kingdom

Surrey and Sussex Healthcare NHS Trust

Redhill, Surrey, United Kingdom

University Hospitals Sussex NHS Foundation Trust

Brighton, Sussex, United Kingdom

Cardiff & Vale University Health Board

Cardiff, , United Kingdom

Epsom and St Helier University Hospitals NHS Trust

Epsom, , United Kingdom

Cwm Taf Morgannwg University Health Board

Llantrisant, , United Kingdom

Guy's and St Thomas' NHS Foundation Trust

London, , United Kingdom

King's College Hospital NHS Foundation Trust

London, , United Kingdom

Imperial College Healthcare NHS Trust

London, , United Kingdom

Oxford University Hospitals NHS Foundation Trust

Oxford, , United Kingdom

South Tyneside and Sunderland NHS Foundation Trust

Sunderland, , United Kingdom

Torbay and South Devon NHS Foundation Trust

Torquay, , United Kingdom

Countries

United Kingdom

References

Learoyd AE, Arnold L, Reid F, Beckley-Hoelscher N, Casian A, Sangle S, Morton N, Nel L, Cape A, John S, Kim S, Shivapatham D, Luqmani R, Jayne D, Galloway J, Douiri A, D'Cruz D; HAVEN study group. The HAVEN study-hydroxychloroquine in ANCA vasculitis evaluation-a multicentre, randomised, double-blind, placebo-controlled trial: study protocol and statistical analysis plan. Trials. 2023 Apr 6;24(1):261. doi: 10.1186/s13063-023-07108-3.

Reference Type: DERIVED

PMID: 37024906 (View on PubMed)

Other Identifiers

2018-001268-40

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

251987

Identifier Type: -

Identifier Source: org_study_id