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    EudraCT Number:2018-001268-40
    Sponsor's Protocol Code Number:HAVEN
    National Competent Authority:UK - MHRA
    Clinical Trial Type:EEA CTA
    Trial Status:GB - no longer in EU/EEA
    Date on which this record was first entered in the EudraCT database:2019-09-13
    Trial results
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    A. Protocol Information
    A.1Member State ConcernedUK - MHRA
    A.2EudraCT number2018-001268-40
    A.3Full title of the trial
    Hydroxychloroquine in ANCA Vasculitis Evaluation - A Multicentre, Randomised, Double-blind, Placebo-controlled Trial
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Hydroxychloroquine in ANCA vasculitis
    A.3.2Name or abbreviated title of the trial where available
    A.4.1Sponsor's protocol code numberHAVEN
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorGuy's and St. Thomas' NHS Foundation Trust
    B.1.3.4CountryUnited Kingdom
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportMedical Research Council
    B.4.2CountryUnited Kingdom
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationGuy's and St Thomas' NHS Foundation Trust
    B.5.2Functional name of contact pointProf David D'Cruz
    B.5.3 Address:
    B.5.3.1Street AddressLouise Coote Lupus Unit, 4th Floor Tower Wing, Guy's Hospital
    B.5.3.2Town/ cityLondon
    B.5.3.3Post codeSE1 9RT
    B.5.3.4CountryUnited Kingdom
    B.5.4Telephone number442071889756
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D. name Plaquenil - Hydroxychloroquine 200mg Film coated tablets
    D. of the Marketing Authorisation holderZentiva Pharma UK Limited
    D.2.1.2Country which granted the Marketing AuthorisationUnited Kingdom
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.4Pharmaceutical form Film-coated tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D. cell therapy medicinal product No
    D. therapy medical product No
    D. Engineered Product No
    D. ATIMP (i.e. one involving a medical device) No
    D. on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboTablet
    D.8.4Route of administration of the placeboOral use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    The term ANCA-associated vasculitis (AAV) describes a subset of primary small vessel vasculitides characterized by the presence of anti-neutrophil cytoplasmic antibodies (ANCA): Granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA) and Eosinophilic Granulomatosis with Polyangiitis (EGPA). AAV are serious multisystem autoimmune disorders that can affect any organ in the body and commonly involve the ear-nose-throat, lungs, kidneys, eyes and joints
    E.1.1.1Medical condition in easily understood language
    ANCA vasculitis is the name of a group of autoimmune conditions characterized by the inflammation of the blood vessels caused by the immune system mistakenly attacking them.
    E.1.1.2Therapeutic area Body processes [G] - Immune system processes [G12]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level SOC
    E.1.2Classification code 10021428
    E.1.2Term Immune system disorders
    E.1.2System Organ Class 10021428 - Immune system disorders
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To investigate if adjunctive hydroxychloroquine is ranked superior to placebo in controlling active disease.
    E.2.2Secondary objectives of the trial
    To investigate if adjunctive hydroxychloroquine reduces the cumulative prednisolone dosage, vasculitis related damage, adverse events, ANCA titres and improves quality of life.
    E.2.3Trial contains a sub-study No
    E.3Principal 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 (Appendix 1).
    3. Have a Birmingham Vasculitis Activity Score >3 BVAS v.3 (Appendix 2) 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
    • 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:
    o Oral contraceptive, either combined or progestogen alone
    o Injectable progestogen
    o Implants of levonorgestrel or etonogestrel
    o Estrogenic vaginal ring
    o Percutaneous contraceptive patches
    o 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.

    E.4Principal exclusion criteria
    1. Patients currently taking hydroxychloroquine or related antimalarial such as mepacrine or chloroquine.
    2. Patients with 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 CTCAE toxicity scale (version 5), unless considered by the investigator to be related to the underlying disease or induction therapy.
    16. Screening 12-lead 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.

    E.5 End points
    E.5.1Primary end point(s)
    The primary endpoint will be the percentage of patients with
    • uncontrolled AAV disease activity (defined as BVAS>3)
    • controlled AAV disease activity (BVAS ≤3) but prednisolone dose for AAV> 7.5mg daily
    • controlled AAV disease activity (BVAS ≤3) but any corticosteroid use > 7.5mg daily for any reason
    at any point during the final 12 weeks of the study (±7 days).
    Inhaled corticosteroids will not contribute to the primary endpoint, nor will methylprednisolone given for rituximab maintenance therapy.
    BVAS will be scored every 4 weeks during the final 12 weeks (±7 days). The assessment of BVAS in the final 12 weeks (±7 days) will come from the week 44, 48, and 52 visits, at each of which BVAS will be assessed for the previous 4 weeks.
    E.5.1.1Timepoint(s) of evaluation of this end point
    during the final 12 weeks (+-7 days) of the study. BVAS will be scored every 4 weeks during the final 12 weeks (±7 days). The assessment of BVAS in the final 12 weeks (±7 days) will come from the week 44, 48, and 52 visits, at each of which BVAS will be assessed for the previous 4 weeks.
    E.5.2Secondary end point(s)
    Secondary outcomes will evaluate:
    • Cumulative number of visits where BVAS = 0 (excluding screening, baseline and week 56)
    • Proportion of patients with treatment failure at week 52
    • Cumulative prednisolone dosage
    • Total number of adverse events
    • Total number of infections per patient
    • Total number of vasculitis flares (major and minor) per patient excluding screening, baseline and week 56
    • Time to remission
    • Time to first severe flare
    • Time to first limited flare
    • Proportion of patients categorized as having a severe flare at each of the time points in the trial schedule (section 5.4) 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 (section 5.4) 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 (section 5.4).
    Exploratory outcomes will evaluate:
    • Incidence of new diabetes mellitus
    • Prevalence of dyslipidaemia
    • Fatigue (FACIT score)
    • Quality of life (SF-36, EQ5D, HAQ, AAV PRO (patient reported outcome) forms)
    • Glucocorticoid toxicity index
    • Physician’s Global Assessment (PGA) as per trial schedule 5.4
    • ANCA titres as per trial schedule 5.4
    • Proportion of patients with medicine compliance of ≤80% (see section 8.10)
    • Absolute values and relative change from baseline in the renal variables: serum creatinine, serum albumin, urine protein: creatinine ratio at each time point outlined in the trial schedule (section 5.4).
    E.5.2.1Timepoint(s) of evaluation of this end point
    Throughout the trial
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety No
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E. trial type description
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) Yes
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial2
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned10
    E.8.5The trial involves multiple Member States No
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.7Trial has a data monitoring committee Yes
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    Database lock
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years4
    E.8.9.1In the Member State concerned months2
    E.8.9.1In the Member State concerned days0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 76
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 76
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state76
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    Study medication will not be provided after the end of the trial. If patients wish to take hydroxychloroquine, this will be at the discretion of the treating physician and local guidelines for the prescription and monitoring of hydroxychloroquine will be followed.
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2019-10-09
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2020-01-23
    P. End of Trial
    P.End of Trial StatusGB - no longer in EU/EEA
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