Working…
COVID-19 is an emerging, rapidly evolving situation.
Get the latest public health information from CDC: https://www.coronavirus.gov.

Get the latest research information from NIH: https://www.nih.gov/coronavirus.
ClinicalTrials.gov
ClinicalTrials.gov Menu

Hydroxychloroquine in ANCA Vasculitis Evaluation (HAVEN)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04316494
Recruitment Status : Not yet recruiting
First Posted : March 20, 2020
Last Update Posted : March 20, 2020
Sponsor:
Collaborator:
Medical Research Council
Information provided by (Responsible Party):
Guy's and St Thomas' NHS Foundation Trust

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.


Condition or disease Intervention/treatment Phase
ANCA Associated Vasculitis Microscopic Polyangiitis Churg-Strauss Syndrome Wegener Granulomatosis Drug: Hydroxychloroquine Drug: Placebo Phase 4

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.

Layout table for study information
Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 76 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description: Central trial pharmacist will be unblinded during trial.
Primary Purpose: Treatment
Official Title: Hydroxychloroquine in ANCA Vasculitis Evaluation - A Multicentre, Randomised, Double-blind, Placebo-controlled Trial
Estimated Study Start Date : April 2020
Estimated Primary Completion Date : December 2022
Estimated Study Completion Date : June 2023


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 Name: 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 Name: Control




Primary Outcome Measures :
  1. 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 [ Time Frame: BVAS will be assessed during the final 12 (±7 days) weeks that the patient is on the study drug in the trial. ]

    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.



Secondary Outcome Measures :
  1. Cumulative number of visits BVAS = 0 [ Time Frame: Week 4 through to week 52 ]
    Excluding screening, baseline and week 56

  2. Proportion of patients with treatment failure at week 52 [ Time Frame: Week 52 ]
    As above

  3. Cumulative prednisolone dosage [ Time Frame: From date of randomisation through to week 56 follow up ]
    As above

  4. Total number of adverse events [ Time Frame: From date of randomisation through to week 56 follow up ]
    As above

  5. Total number of infections per patient [ Time Frame: From date of randomisation through to week 56 follow up ]
    As above

  6. Total number of vasculitis flares (severe and limited) per patient [ Time Frame: From date of randomisation through to week 56 follow up ]
    As above

  7. Time to remission [ Time Frame: From date of randomisation through to week 56 follow up ]
    As above

  8. Time to first severe flare [ Time Frame: From date of randomisation through to week 56 follow up ]

    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.


  9. Time to first limited flare [ Time Frame: From date of randomisation through to week 56 follow up ]
    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.

  10. 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 [ Time Frame: Weeks 1-52 excluding screening, baseline and week 56 ]
    As above

  11. 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 [ Time Frame: Weeks 1-52 excluding screening, baseline and week 56 ]
    As above

  12. Absolute values and relative change from baseline in the Vasculitis Damage Index (VDI) at each time point outlined in the trial schedule. [ Time Frame: From date of randomisation through to week 56 follow up ]
    As above



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Layout table for eligibility information
Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04316494


Contacts
Layout table for location contacts
Contact: David D'Cruz 02071889756 david.d'cruz@kcl.ac.uk

Sponsors and Collaborators
Guy's and St Thomas' NHS Foundation Trust
Medical Research Council
Investigators
Layout table for investigator information
Principal Investigator: David D'Cruz Guy's and St Thomas' NHS Foundation Trust
Layout table for additonal information
Responsible Party: Guy's and St Thomas' NHS Foundation Trust
ClinicalTrials.gov Identifier: NCT04316494    
Other Study ID Numbers: 251987
2018-001268-40 ( EudraCT Number )
First Posted: March 20, 2020    Key Record Dates
Last Update Posted: March 20, 2020
Last Verified: February 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Plan Description: N/A - no plan to share identifiable patient data with other researchers.

Layout table for additional information
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
Keywords provided by Guy's and St Thomas' NHS Foundation Trust:
Granulomatosis Polyangiitis
Eosinophilic Granulomatosis with Polyangiitis
Additional relevant MeSH terms:
Layout table for MeSH terms
Granulomatosis with Polyangiitis
Microscopic Polyangiitis
Vasculitis
Systemic Vasculitis
Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis
Churg-Strauss Syndrome
Vascular Diseases
Cardiovascular Diseases
Lung Diseases, Interstitial
Lung Diseases
Respiratory Tract Diseases
Autoimmune Diseases
Immune System Diseases
Cerebral Small Vessel Diseases
Cerebrovascular Disorders
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Granuloma
Lymphoproliferative Disorders
Lymphatic Diseases
Hydroxychloroquine
Antimalarials
Antiprotozoal Agents
Antiparasitic Agents
Anti-Infective Agents
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Antirheumatic Agents