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Note: This record shows only 22 elements of the WHO Trial Registration Data Set. To view changes that have been made to the source record, or for additional information about this trial, click on the URL below to go to the source record in the primary register.
Register: EUCTR
Last refreshed on: 28 September 2020
Main ID:  EUCTR2018-001268-40-GB
Date of registration: 13/09/2019
Prospective Registration: Yes
Primary sponsor: Guy's and St. Thomas' NHS Foundation Trust
Public title: Hydroxychloroquine in ANCA vasculitis
Scientific title: Hydroxychloroquine in ANCA Vasculitis Evaluation - A Multicentre, Randomised, Double-blind, Placebo-controlled Trial - HAVEN
Date of first enrolment: 23/01/2020
Target sample size: 76
Recruitment status: Authorised-recruitment may be ongoing or finished
URL:  https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2018-001268-40
Study type:  Interventional clinical trial of medicinal product
Study design:  Controlled: yes
Randomised: yes
Open: no
Single blind: no
Double blind: yes
Parallel group: no
Cross over: no
Other: no
If controlled, specify comparator, Other Medicinial Product: no
Placebo: yes
Other: no
Number of treatment arms in the trial: 2
 
Phase:  Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): no Therapeutic confirmatory - (Phase III): no Therapeutic use (Phase IV): yes
Countries of recruitment
United Kingdom
Contacts
Name: Prof David D'Cruz   
Address:  Louise Coote Lupus Unit, 4th Floor Tower Wing, Guy's Hospital SE1 9RT London United Kingdom
Telephone: 442071889756
Email: david.d'cruz@kcl.ac.uk
Affiliation:  Guy's and St Thomas' NHS Foundation Trust
Name: Prof David D'Cruz   
Address:  Louise Coote Lupus Unit, 4th Floor Tower Wing, Guy's Hospital SE1 9RT London United Kingdom
Telephone: 442071889756
Email: david.d'cruz@kcl.ac.uk
Affiliation:  Guy's and St Thomas' NHS Foundation Trust
Key inclusion & exclusion 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 (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.


Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 76
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 76

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.






Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes
Health Condition(s) or Problem(s) studied
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
MedDRA version: 20.0 Level: SOC Classification code 10021428 Term: Immune system disorders System Organ Class: 10021428 - Immune system disorders
Therapeutic area: Body processes [G] - Immune system processes [G12]
Intervention(s)

Trade Name: Plaquenil - Hydroxychloroquine 200mg Film coated tablets
Pharmaceutical Form: Film-coated tablet
Pharmaceutical form of the placebo: Tablet
Route of administration of the placebo: Oral use

Primary Outcome(s)
Main Objective: To investigate if adjunctive hydroxychloroquine is ranked superior to placebo in controlling active disease.
Primary end point(s): The primary endpoint will be the percentage of patients with
• uncontrolled AAV disease activity (defined as BVAS>3)
OR
• controlled AAV disease activity (BVAS =3) but prednisolone dose for AAV> 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 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.
Secondary Objective: To investigate if adjunctive hydroxychloroquine reduces the cumulative prednisolone dosage, vasculitis related damage, adverse events, ANCA titres and improves quality of life.
Timepoint(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.
Secondary Outcome(s)
Secondary 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).
Timepoint(s) of evaluation of this end point: Throughout the trial
Secondary ID(s)
HAVEN
Source(s) of Monetary Support
Medical Research Council
Secondary Sponsor(s)
Ethics review
Status: Approved
Approval date: 23/01/2020
Contact:
Results
Results available:
Date Posted:
Date Completed:
URL:
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