Hydroxychloroquine in ANCA Vasculitis Evaluation

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Brief Title

Hydroxychloroquine in ANCA Vasculitis Evaluation

Official Title

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

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 over 2 years.
    

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 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.
    

Study Phase

Phase 4

Study Type

Interventional


Primary Outcome

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

Secondary Outcome

 Cumulative number of visits BVAS = 0

Condition

ANCA Associated Vasculitis

Intervention

Hydroxychloroquine

Study Arms / Comparison Groups

 Hydroxychloroquine
Description:  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.

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Drug

Estimated Enrollment

76

Start Date

December 17, 2020

Completion Date

June 2023

Primary Completion Date

December 2022

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) 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.
      

Gender

All

Ages

18 Years - N/A

Accepts Healthy Volunteers

No

Contacts

David D'Cruz, 02071889756, david.d'[email protected]

Location Countries

United Kingdom

Location Countries

United Kingdom

Administrative Informations


NCT ID

NCT04316494

Organization ID

251987

Secondary IDs

2018-001268-40

Responsible Party

Sponsor

Study Sponsor

Guy's and St Thomas' NHS Foundation Trust

Collaborators

 Medical Research Council

Study Sponsor

David D'Cruz, Principal Investigator, Guy's and St Thomas' NHS Foundation Trust


Verification Date

December 2020