Coversin in Paroxysmal Nocturnal Haemoglobinuria (PNH)

Study Overview
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Brief Summary
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Coversin in Paroxysmal Nocturnal Haemoglobinuria (PNH) in patients with resistance to Eculizumab due to complement C5 polymorphisms.

Detailed Description
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Coversin, 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 and proven resistance to eculizumab due to C5 polymorphisms. Patients will be treated with Coversin by daily subcutaneous injection for 6 months 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 Coversin and being entered into the long term follow-up study for 2 years. Please note, 'Coversin' is used throughout, but Nomacopan is the official name/INN. Please note, the end points were assessed for 6 months, but the adverse events were measured over the 2 year period.

Official Title
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Coversin in Paroxysmal Nocturnal Haemoglobinuria (PNH) in Patients With Resistance to Eculizumab Due to Complement C5 Polymorphisms

Conditions
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Paroxysmal Nocturnal Haemoglobinuria (PNH)

Intervention / Treatment
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* Drug: Coversin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with known Paroxysmal Nocturnal Haemoglobinuria (PNH) LDH >=1.5 Upper Limit of Normal (ULN) Resistance to Eculizumab proven by both a recognised C5 polymorphism on genetic screening and complement inhibition on CH50 ELISA of <100% at concentrations of Eculizumab in excess of 50 μg/mL Willing to self-inject Coversin daily or to receive daily subcutaneous injections by a home nurse or in a doctor's office or hospital clinic Males or females taking adequate contraceptive precautions if of childbearing potential, 18 - 80 years of age Body weight ≥50kg and ≤ 100kg The patient has provided written informed consent. Willing to avoid prohibited medications for duration of study Must agree to take appropriate prophylactic precautions against Neisseria infection. Must be counselled regarding the possible reproductive risks of using Coversin and be advised to use an adequate method of contraception pending further data on reproductive toxicology. Exclusion Criteria: Body weight <50kg or>100kg Pregnancy (females) Failure to satisfy the PI of fitness to participate for any other reason Known allergy to ticks or severe reaction to arthropod venom (e.g., bee or wasp venom)

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Coversin (Nomacopan)<br>This is an open label, non-comparator study. Patient will be given a single ablating dose of 0.57mg/kg per subject followed by daily repeat maintenance doses. The initial repeat dose will be 25% of the ablating dose. If this is insufficient to maintain complement inhibition at ≤10% of baseline (pre-treatment) level after 5 days of treatment the daily dose will be increased by doubling until that level of inhibition is achieved. In the event of 100% inhibition being achieved the dose may be titrated downwards at the PI's discretion until a satisfactory clinical result is obtained. If at any point in treatment complement inhibition falls to less than 50% of baseline a further ablating dose of 0.57mg/kg should be given. Coversin lyophilised powder in each vial was diluted with 0.6 mL water for injection prior to use. | Drug: Coversin<br>* Patients enrolled in this protocol will initially be treated with an ablating dose of Coversin and daily repeat maintenance doses calculated according to body weight, the ablating dose to be 0.57mg/kg. Thereafter the daily repeat dose will be titrated according to clinical response and complement inhibition determined by CH50 ELISA. The initial repeat dose will be 25% of the ablating dose and this will be adjusted up or down if necessary once steady state is reached (5 days).<br>* Other names: rEV576;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Measurement of Ratio of LDH to the Upper Limit of Normal (ULN) | LDH is an indicator of disease progression in patients with PNH and is expected to fall to within 2x upper limit of normal (ULN) within 28 days in successfully treated patients. Units are measured in ratio of LDH:ULN, where the ULN is 250 U/L. The primary efficacy endpoint was the LDH AUC from Day 0 to 28 compared with 28 days pretreatment. Data for the 28 days pre-treatment was not collected, and as only one patient was recruited, the LDH values compared with baseline and the ratio of LDH to the Upper Limit of Normal (ULN) are presented. | Day 0 and Day 28 | 
| Number and Type of Adverse Events (AE) | The number and type of reported AEs will be recorded as well as the opinion of the Principle Investigator (PI) as to their possible relationship to the study drug. | 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Measurement of Haemoglobin (Hb) at Days 28, 90, and 180, Absolute and Change From Baseline | Measuring change in mean Hb from Day 28, Day 90 and Day 180 (absolute and change from baseline) | Baseline, Day 28, Day 90 and Day 180 | 
| Measurement of Haptoglobin (Hp) at Days 28, 90 and 180, Absolute and Change From Baseline | Measuring change in mean Hp from Day 28, Day 90 and Day 180 (absolute and change from baseline) | Baseline, Day 28, Day 90 and Day 180 | 
| Measurement of Lactate Dehydrogenase (LDH) at Baseline, Day 90 and Day 180 | Measuring the change in LDH at Baseline, Day 90 and Day 180. LDH is an indicator of disease progression in patients with PNH and is expected to fall to within 2x upper limit of normal (ULN) within 28 days in successfully treated patients. Units are measured in ratio of LDH:ULN, where the ULN is 250 U/L. | Baseline, Day 90 and Day 180 | 
| Change in Functional Assessment of Chronic Illness Therapy (FACIT) Score at Days 0, 28, 90 and 180 | Functional Assessment of Chronic Illness Therapy - fatigue (FACIT-F) is a 13 item instrument designed to assess fatigue/tiredness and it's impact on daily activities and functioning in a chronic disease setting. The scale for each question in relation to quality of life ranges from 0-4 where 0= not at all, 1= a little bit, 2= somewhat, 3 = quite a bit and 4= very much. An increase in the scale score indicates an improvement in quality of life (less fatigue). A maximum score of 52 is interpreted as no fatigue . Baseline is assumed as 0.0 to demonstrate the change in units. The subscale score (as presented) is determined as per FACIT-f guidance, by multiplying the sum of the item scores by the number of items in the subscale, then divide by the number of items answered. | Day 28, 90 and 180 | 
| Change in Quality Of Life Questionnaire (QOQ) Score at Days 0, 28, 90 and 180 | The European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ)-C30 instrument measures the change in the quality of of life of patients in the trial. It comprises 30 questions on daily QOL and incorporates a global health status, five functional scales (physical, role, cognitive, emotional and social), three symptom scales (fatigue, nausea/vomiting, pain), and six single items (dyspnoea, insomnia, appetite loss, constipation, diarrhoea, financial difficulties). All of the scales range in score from 0 to 100, A high scale score represents a higher response level. Thus a high score for a functional scale represents a high / healthy level of functioning, a high score for the global health status / QoL represents a high QoL, but a high score for a symptom scale / item represents a high level of symptomatology / problems. Scale scores were calculated by averaging items within scales and transforming average scores linearly. | Day 28, 90 and 180 | 
| Dependency on Blood Transfusion | Number of participants depending on blood transfusion prior to starting the study compared to during the study. | Day 0 through to study completion (2 years) |