Treating Paroxysmal Nocturnal Haemoglobinuria Patients With rVA576

Study Overview
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Brief Summary
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rVA576 for patients with Paroxysmal Nocturnal Hemoglobinuria (PNH).

Detailed Description
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rVA576, a small protein complement C5 inhibitor which prevents the cleavage of C5 by C5 convertase into C5a and C5b, will be used in an open label, non-comparative clinical trial in patients with PNH. Patients will be treated with rVA576 by daily subcutaneous injection in order to determine the safety and efficacy of the drug in these circumstances. If satisfactory control of the PNH is achieved, and at the discretion of the Principal Investigator (PI), patients will have the option of remaining on rVA576 and being entered into the long term follow-up study.

Official Title
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Investigational Product ; Coversin. Phase III Safety and Efficacy in Three-Part, Two-Arm, Randomised Open Label Evaluation in Patients With Paroxysmal Nocturnal Haemoglobinuria (PNH)

Conditions
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Paroxysmal Nocturnal Hemoglobinuria (PNH)

Intervention / Treatment
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* Drug: rVA576
* Other: Standard of care (SOC)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Willing to give informed consent to treatment with rVA576 Diagnosed with paroxysmal nocturnal haemoglobinuria (PNH) Have not received any complement inhibitor within the 4 months prior to screening ≥ 18 years of age at the time of screening Weight ≥50kg Complete transfusion medical history for 12 months Transfusion dependent LDH ≥1.5 x the ULN Willing to receive appropriate prophylaxis against Neisseria meningitidis infection, by both immunisation and continuous or intermittent antibiotics Willing to avoid prohibited medications such as other complement inhibitors and chemotherapeutic agents Patients must agree to avoid pregnancy and fathering children from the time of signing the Informed Consent Form until 90 days after the last dose of rVA576. Patients who are on erythropoietin and/or immunosuppressant treatment should be on stable doses for at least 6 months. Patients who are taking systemic corticosteroids should be on a stable dose for at least 4 weeks. Patients on anticoagulant therapy should be well-controlled prior to entry. Patients taking iron and/or folic acid supplements should be on a stable dose for at least 4 weeks Exclusion Criteria: Patients whose mean haemoglobin level over the previous 12 months prior to screening was greater than 105 g/L (10.5g/dL) Severe bone marrow failure Patients with a platelet count of ≤ 70 x 109/L Patients with known or suspected acquired somatic mutations affecting the bone marrow (e.g. acute myeloid leukaemia) which may be associated with PNH Chemotherapy within 3 months of screening visit History of recurrent bacterial infections or suspicion of active bacterial infections requiring antibiotic therapy Planned or actual pregnancy or breast feeding (females) Known allergy to ticks or severe reaction to arthropod venom (e.g. bee or wasp venom) Unresolved N. meningitidis infection. Patients who are not willing to receive adequate immunisation against N. meningitidis unless, in the opinion of the investigator, the risks of delaying therapy outweigh the risks of developing a meningococcal infection Impaired hepatic function unless, in the opinion of the investigator, the risks of delaying therapy outweigh the risks of treatment in the presence of impaired hepatic function Patients with a glomerular filtration rate (GFR) of <30mL/min/1.73m2 unless, in the opinion of the investigator, the risks of delaying therapy outweigh the risks of treatment in the presence of impaired renal function Participation in other clinical trials within 4 weeks of signing the consent form History of active systemic autoimmune diseases. Any other systemic disorders that could interfere with the evaluation of the study treatment Failure to comply with protocol requirements Known Hepatitis B or Hepatitis C

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm 1 - 9 months of treatment (rVA576 plus SOC)<br>6 months (SOC plus rVA576), Followed by a further 3 months of (SOC plus rVA576). | Drug: rVA576<br>* 6 months of treatment, rVA576 plus SOC. Followed by a further 3 months of rVA576 plus SOC. In total, 9 months on rVA576 plus SOC.<br>Other: Standard of care (SOC)<br>* 6 months on SOC followed by 3 months of treatment with rVA576 plus SOC. In total, 3 months on rVA576 plus SOC.<br>|
| Experimental: Arm 2 - 6 months on SOC<br>6 months on SOC only. Followed by 3 months (SOC plus rVA576). | Drug: rVA576<br>* 6 months of treatment, rVA576 plus SOC. Followed by a further 3 months of rVA576 plus SOC. In total, 9 months on rVA576 plus SOC.<br>Other: Standard of care (SOC)<br>* 6 months on SOC followed by 3 months of treatment with rVA576 plus SOC. In total, 3 months on rVA576 plus SOC.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| HB (Haemoglobin) stabilisation rate and the avoidance of packed red blood cells (PRBC) transfusions | Haemoglobin stabilisation rate defined as haemoglobin greater than the set point for each patient during the pre-study randomisation period and the avoidance of PRBC transfusions during the treatment period. | 9 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of units of packed red blood cells (PRBC) transfused | Number of units of packed red blood cells (PRBC) transfused from Baseline Day 1 to Day 180 | Day 1 to Day 180 | 
| Percentage of patients who achieve transfusion avoidance | Percentage of patients who achieve transfusion avoidance | Day 1 to Day 180 | 
| Change in (QOl) Quality of Life score | Change in Quality of Life score | Day 1 to Day 180 | 
| AUC (LDH) | AUC (Area under the curve) (LDH) Lactate Dehydrogenase | Day 1 to Day 180 | 
| CH50 | CH50 (Classical haemolytic 50% lysis) | Day 1 to Day 180 |