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Coversin in Paroxysmal Nocturnal Haemoglobinuria (PNH)

Primary Purpose

Paroxysmal Nocturnal Haemoglobinuria (PNH)

Status
Completed
Phase
Phase 2
Locations
Netherlands
Study Type
Interventional
Intervention
Coversin
Sponsored by
AKARI Therapeutics
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Paroxysmal Nocturnal Haemoglobinuria (PNH)

Eligibility Criteria

18 Years - 80 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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 5mug/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)

Sites / Locations

  • Dr Saskia Langemeijer

Arms of the Study

Arm 1

Arm Type

Other

Arm Label

Coversin (Nomacopan)

Arm Description

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.

Outcomes

Primary Outcome Measures

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.
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.

Secondary Outcome Measures

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)
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)
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.
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.
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.
Dependency on Blood Transfusion
Number of participants depending on blood transfusion prior to starting the study compared to during the study.

Full Information

First Posted
September 10, 2015
Last Updated
June 20, 2023
Sponsor
AKARI Therapeutics
Collaborators
Radboud University Medical Center
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1. Study Identification

Unique Protocol Identification Number
NCT02591862
Brief Title
Coversin in Paroxysmal Nocturnal Haemoglobinuria (PNH)
Official Title
Coversin in Paroxysmal Nocturnal Haemoglobinuria (PNH) in Patients With Resistance to Eculizumab Due to Complement C5 Polymorphisms
Study Type
Interventional

2. Study Status

Record Verification Date
February 2017
Overall Recruitment Status
Completed
Study Start Date
February 2016 (Actual)
Primary Completion Date
March 20, 2018 (Actual)
Study Completion Date
March 20, 2018 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
AKARI Therapeutics
Collaborators
Radboud University Medical Center

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

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

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Paroxysmal Nocturnal Haemoglobinuria (PNH)

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
1 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Coversin (Nomacopan)
Arm Type
Other
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
Coversin
Other Intervention Name(s)
rVA576, rEV576
Intervention Description
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).
Primary Outcome Measure Information:
Title
Measurement of Ratio of LDH to the Upper Limit of Normal (ULN)
Description
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.
Time Frame
Day 0 and Day 28
Title
Number and Type of Adverse Events (AE)
Description
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.
Time Frame
2 years
Secondary Outcome Measure Information:
Title
Measurement of Haemoglobin (Hb) at Days 28, 90, and 180, Absolute and Change From Baseline
Description
Measuring change in mean Hb from Day 28, Day 90 and Day 180 (absolute and change from baseline)
Time Frame
Baseline, Day 28, Day 90 and Day 180
Title
Measurement of Haptoglobin (Hp) at Days 28, 90 and 180, Absolute and Change From Baseline
Description
Measuring change in mean Hp from Day 28, Day 90 and Day 180 (absolute and change from baseline)
Time Frame
Baseline, Day 28, Day 90 and Day 180
Title
Measurement of Lactate Dehydrogenase (LDH) at Baseline, Day 90 and Day 180
Description
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.
Time Frame
Baseline, Day 90 and Day 180
Title
Change in Functional Assessment of Chronic Illness Therapy (FACIT) Score at Days 0, 28, 90 and 180
Description
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.
Time Frame
Day 28, 90 and 180
Title
Change in Quality Of Life Questionnaire (QOQ) Score at Days 0, 28, 90 and 180
Description
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.
Time Frame
Day 28, 90 and 180
Title
Dependency on Blood Transfusion
Description
Number of participants depending on blood transfusion prior to starting the study compared to during the study.
Time Frame
Day 0 through to study completion (2 years)

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
80 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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)
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Petra Dr Muus
Organizational Affiliation
Radboud University Medical Center
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Saskia Dr Langemeijer
Organizational Affiliation
Radboud University Medical Center
Official's Role
Study Director
Facility Information:
Facility Name
Dr Saskia Langemeijer
City
Nijmegen
ZIP/Postal Code
6525 GA
Country
Netherlands

12. IPD Sharing Statement

Citations:
PubMed Identifier
31840801
Citation
Schols S, Nunn MA, Mackie I, Weston-Davies W, Nishimura JI, Kanakura Y, Blijlevens N, Muus P, Langemeijer S. Successful treatment of a PNH patient non-responsive to eculizumab with the novel complement C5 inhibitor coversin (nomacopan). Br J Haematol. 2020 Jan;188(2):334-337. doi: 10.1111/bjh.16305. Epub 2019 Dec 16. No abstract available.
Results Reference
result
Links:
URL
https://pubmed.ncbi.nlm.nih.gov/31840801/
Description
Successful treatment of a PNH patient non-responsive to eculizumab with the novel complement C5 inhibitor coversin (nomacopan)

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Coversin in Paroxysmal Nocturnal Haemoglobinuria (PNH)

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