HAVEN: Hydroxychloroquine in ANCA Vasculitis Evaluation, a Phase II Multicentre, Randomised, Double Blind, Placebo Controlled Trial
Lead Research Organisation:
Guy's and St Thomas' NHS Foundation Trust
Department Name: GRIDA
Abstract
ANCA vasculitis is a life-threatening disease where the body's defence system becomes overactive, causing inflammation of small blood vessels and damage to the kidneys, lungs and other vital organs. New treatments are needed because: 1) 20% of patients do not respond to treatment. 2) In half the patients who respond, vasculitis disease activity flares when medicines are reduced. 3) The side effects of medicines can cause more problems than the disease.
Safer medicines are needed for non-life threatening ANCA vasculitis, where aggressive immune suppressing treatment is not appropriate. Hydroxychloroquine has been used for many years to treat related diseases such as lupus and rheumatoid arthritis with fewer harmful effects than conventional immune suppressing drugs. It is therefore an ideal candidate to treat ANCA vasculitis.
We have preliminary data from our clinics and research laboratories showing that hydroxychloroquine has effects on cells which cause inflammation of blood vessels and tissues and is therefore expected to work in treating ANCA vasculitis.
We have pilot data on 30 patients with ANCA vasculitis, showing that hydroxychloroquine is well tolerated and improves symptoms of disease activity. This now needs to be confirmed in a controlled study.
The potential of hydroxychloroquine to reduce infections, cancer, blood clots and heart disease are useful properties, as these risks are higher in ANCA vasculitis patients compared to the general public. To our knowledge, no studies have been published on hydroxychloroquine in ANCA vasculitis, although the benefits of hydroxychloroquine in related diseases such as lupus and rheumatoid arthritis are clear.
Our proposed study aims to demonstrate that hydroxychloroquine reduces disease activity and flares, the need for steroids and their side effects, damage to vital organs and improves quality of life. 76 patients with non-severe ANCA vasculitis who meet the entry criteria for the trial will be invited to participate. After giving their informed consent, patients will be allocated by chance (like tossing a coin) by a computer to receive 2 tablets of hydroxychloroquine in addition to their usual medications (38 patients) or two placebo ("dummy") tablets (38 patients) and their usual medications. Treatment will continue for 1 year and, in order to improve the quality of the study, neither the doctors nor the patients will know if they are taking hydroxychloroquine or placebo. Patients will be seen and have blood tests and safety assessments monthly for the first and last 3 months of the study and every 3 months in between for 1 year. We plan to measure blood levels of hydroxychloroquine to assess adherence to the study medication after the study has been completed. This information will also allow correlations with the response of the disease to treatment.
If the trial shows a small beneficial effect that is not statistically significant, but provides evidence that hydroxychloroquine could work, we will proceed to a larger study with more patients (Phase III trial). However, if our study shows a large beneficial effect of hydroxychloroquine, similar to that seen in lupus patients, a larger trial would not be needed and hydroxychloroquine could become part of the standard treatment for ANCA vasculitis patients. This would represent a significant advance in the care of these patients. Given that hydroxychloroquine is a relatively inexpensive treatment, the overall cost to the health service could be reduced.
Safer medicines are needed for non-life threatening ANCA vasculitis, where aggressive immune suppressing treatment is not appropriate. Hydroxychloroquine has been used for many years to treat related diseases such as lupus and rheumatoid arthritis with fewer harmful effects than conventional immune suppressing drugs. It is therefore an ideal candidate to treat ANCA vasculitis.
We have preliminary data from our clinics and research laboratories showing that hydroxychloroquine has effects on cells which cause inflammation of blood vessels and tissues and is therefore expected to work in treating ANCA vasculitis.
We have pilot data on 30 patients with ANCA vasculitis, showing that hydroxychloroquine is well tolerated and improves symptoms of disease activity. This now needs to be confirmed in a controlled study.
The potential of hydroxychloroquine to reduce infections, cancer, blood clots and heart disease are useful properties, as these risks are higher in ANCA vasculitis patients compared to the general public. To our knowledge, no studies have been published on hydroxychloroquine in ANCA vasculitis, although the benefits of hydroxychloroquine in related diseases such as lupus and rheumatoid arthritis are clear.
Our proposed study aims to demonstrate that hydroxychloroquine reduces disease activity and flares, the need for steroids and their side effects, damage to vital organs and improves quality of life. 76 patients with non-severe ANCA vasculitis who meet the entry criteria for the trial will be invited to participate. After giving their informed consent, patients will be allocated by chance (like tossing a coin) by a computer to receive 2 tablets of hydroxychloroquine in addition to their usual medications (38 patients) or two placebo ("dummy") tablets (38 patients) and their usual medications. Treatment will continue for 1 year and, in order to improve the quality of the study, neither the doctors nor the patients will know if they are taking hydroxychloroquine or placebo. Patients will be seen and have blood tests and safety assessments monthly for the first and last 3 months of the study and every 3 months in between for 1 year. We plan to measure blood levels of hydroxychloroquine to assess adherence to the study medication after the study has been completed. This information will also allow correlations with the response of the disease to treatment.
If the trial shows a small beneficial effect that is not statistically significant, but provides evidence that hydroxychloroquine could work, we will proceed to a larger study with more patients (Phase III trial). However, if our study shows a large beneficial effect of hydroxychloroquine, similar to that seen in lupus patients, a larger trial would not be needed and hydroxychloroquine could become part of the standard treatment for ANCA vasculitis patients. This would represent a significant advance in the care of these patients. Given that hydroxychloroquine is a relatively inexpensive treatment, the overall cost to the health service could be reduced.
Technical Summary
There is an unmet need for therapies for ANCA vasculitis (AAV), an uncommon but serious group of autoimmune diseases, to reduce disease activity, prevent damage and minimise glucocorticoid toxicity. Hydroxychloroquine (HCQ) is an established, safe, effective and inexpensive therapy for lupus, rheumatoid arthritis and cutaneous vasculitis but has not been studied in AAV. HCQ has pleiotropic effects on cellular biology pathways central to AAV pathogenesis, providing a mechanistic rationale for its potential value in AAV. HCQ has useful effects on lipids, glucose, arterial stiffness and antithrombotic, antimicrobial and antineoplastic properties relevant to AAV patients.
We propose a Phase II UK multicentre randomized double-blind placebo-controlled trial in active non-life threatening AAV patients with no major Birmingham Vasculitis Activity Score (BVAS) items, to investigate if HCQ treatment for 1 year ranks better than placebo at reducing uncontrolled disease, defined as BVAS>3. 76 subjects (38 in each arm) will be recruited from 10 UK centres over 2 years. Patients will be randomised 1:1 to adjunctive HCQ 400 mg daily or placebo with maintenance therapy, stable for 4 weeks pre-randomization, with azathioprine, equivalent methotrexate or rituximab>6 months ago. Both groups will receive oral glucocorticoids with a suggested schedule for maximum doses, tapering to a minimum according to disease activity.
This trial will use outcome tools and research methodology validated by the European Vasculitis Society (EUVAS). The primary endpoint at 52 weeks will be the percentage of patients with BVAS>3. Secondary outcomes will evaluate HCQ effects on complete remission (BVAS=0), ANCA titres and flare rates, cumulative glucocorticoid dosage, vasculitis damage index (VDI), adverse events, health-related quality of life (SF-36, EQ5D) and fatigue (FACIT score). This trial addresses an unmet need for patients with AAV.
We propose a Phase II UK multicentre randomized double-blind placebo-controlled trial in active non-life threatening AAV patients with no major Birmingham Vasculitis Activity Score (BVAS) items, to investigate if HCQ treatment for 1 year ranks better than placebo at reducing uncontrolled disease, defined as BVAS>3. 76 subjects (38 in each arm) will be recruited from 10 UK centres over 2 years. Patients will be randomised 1:1 to adjunctive HCQ 400 mg daily or placebo with maintenance therapy, stable for 4 weeks pre-randomization, with azathioprine, equivalent methotrexate or rituximab>6 months ago. Both groups will receive oral glucocorticoids with a suggested schedule for maximum doses, tapering to a minimum according to disease activity.
This trial will use outcome tools and research methodology validated by the European Vasculitis Society (EUVAS). The primary endpoint at 52 weeks will be the percentage of patients with BVAS>3. Secondary outcomes will evaluate HCQ effects on complete remission (BVAS=0), ANCA titres and flare rates, cumulative glucocorticoid dosage, vasculitis damage index (VDI), adverse events, health-related quality of life (SF-36, EQ5D) and fatigue (FACIT score). This trial addresses an unmet need for patients with AAV.
Planned Impact
WHO MIGHT BENEFIT FROM THIS RESEARCH?
The proposed studies will generate data on the use of HCQ as an adjunctive treatment for patients with active but not life-threatening ANCA associated vasculitis (AAV).
The primary beneficiaries of this work will be patients with AAV, the clinicians caring for them across the globe and the wider national health services. There are approximately 20,000 patients with ANCA associated vasculitis (AAV) in the UK, with 1,300 diagnosed annually. Approximately 4,000 patients in the UK have persistent uncontrolled vasculitis, who would benefit from better disease control. This could result in improved quality of life, lower damage accumulation from the disease and its treatment, especially lower doses of glucocorticoid therapy and could reduce the burden of these diseases on society.
The findings of these studies will also provide valuable information to scientists studying the pathobiology of AAV and the mechanisms of action of HCQ. Academic clinicians who care for ANCA vasculitis patients and basic science immunologists will benefit from this trial by gaining novel clinical and immunological insights into the efficacy and mechanisms of action of HCQ. Data from this trial may be useful to researchers in other specialties such as oncologists, infectious disease physicians, diabetologists and obstetricians where HCQ is beginning to be used in clinical practice.
HOW MIGHT THEY BENEFIT FROM THIS RESEARCH?
HCQ has the potential to reduce disease progression and the need for intensive immunosuppression such as cyclophosphamide or rituximab and their associated toxicities, the need for intravenous infusions, hospital attendance and monitoring for adverse effects.
HCQ has many other useful effects, including reduction of infection rates, improvements in lipid and glucose profiles, mild anti-thrombotic and anti-neoplastic effects and improved arterial stiffness. These are all highly relevant properties for immunosuppressed AAV patients who are at increased risk of infections, cancer, thrombosis and cardiovascular events.
There is a move away from using high doses of glucocorticoids for prolonged periods due to their well known toxicities. However, withdrawal of glucocorticoids increases the risk of disease flares. There could therefore be a role for HCQ as a known glucocorticoid sparing agent in other rheumatic disease to facilitate their withdrawal.
HCQ is an inexpensive therapy compared to conventional immunosuppressive agents. For example rituximab costs £5,700 and cyclophosphamide costs £5,500 per course. In comparison, HCQ costs only £64.60 for one year of treatment. HCQ is a convenient orally administered therapy with no need for regular blood monitoring. HCQ use is therefore likely to result in significant cost savings to the wider health service and society.
The proposed studies will generate data on the use of HCQ as an adjunctive treatment for patients with active but not life-threatening ANCA associated vasculitis (AAV).
The primary beneficiaries of this work will be patients with AAV, the clinicians caring for them across the globe and the wider national health services. There are approximately 20,000 patients with ANCA associated vasculitis (AAV) in the UK, with 1,300 diagnosed annually. Approximately 4,000 patients in the UK have persistent uncontrolled vasculitis, who would benefit from better disease control. This could result in improved quality of life, lower damage accumulation from the disease and its treatment, especially lower doses of glucocorticoid therapy and could reduce the burden of these diseases on society.
The findings of these studies will also provide valuable information to scientists studying the pathobiology of AAV and the mechanisms of action of HCQ. Academic clinicians who care for ANCA vasculitis patients and basic science immunologists will benefit from this trial by gaining novel clinical and immunological insights into the efficacy and mechanisms of action of HCQ. Data from this trial may be useful to researchers in other specialties such as oncologists, infectious disease physicians, diabetologists and obstetricians where HCQ is beginning to be used in clinical practice.
HOW MIGHT THEY BENEFIT FROM THIS RESEARCH?
HCQ has the potential to reduce disease progression and the need for intensive immunosuppression such as cyclophosphamide or rituximab and their associated toxicities, the need for intravenous infusions, hospital attendance and monitoring for adverse effects.
HCQ has many other useful effects, including reduction of infection rates, improvements in lipid and glucose profiles, mild anti-thrombotic and anti-neoplastic effects and improved arterial stiffness. These are all highly relevant properties for immunosuppressed AAV patients who are at increased risk of infections, cancer, thrombosis and cardiovascular events.
There is a move away from using high doses of glucocorticoids for prolonged periods due to their well known toxicities. However, withdrawal of glucocorticoids increases the risk of disease flares. There could therefore be a role for HCQ as a known glucocorticoid sparing agent in other rheumatic disease to facilitate their withdrawal.
HCQ is an inexpensive therapy compared to conventional immunosuppressive agents. For example rituximab costs £5,700 and cyclophosphamide costs £5,500 per course. In comparison, HCQ costs only £64.60 for one year of treatment. HCQ is a convenient orally administered therapy with no need for regular blood monitoring. HCQ use is therefore likely to result in significant cost savings to the wider health service and society.
