rVA576 (Coversin) Long Term Safety and Efficacy Surveillance Study

Patients with diseases requiring complement inhibition who have previously taken part in Akari clinical trials and who wish to continue to receive rVA576 (Coversin) after their active participation in the parent trial has completed and patients treated under compassionate use or named patient arrangements who wish to continue on rVA576 (Coversin) therapy

• rVA576 (Drug), also known as nomacopan: The study population will consist of patients who have completed participation in clinical trials under other Akari protocols and who wish to continue to receive rVA576 (Coversin).

Primary outcomes

• Long Term Safety and Efficacy of rVA576 (Coversin) Therapy Assessed by AEs, SAEs, Standard Lab Tests and ECG Results. [On entry and every 3 months thereafter, for the duration of the study (approximately 3 years and 5 months)]: To determine the safety profile of long-term rVA576 (Coversin) treatment as assessed by AEs, SAEs, Standard Lab tests and ECG results.

Secondary outcomes

• Proportion of Subjects With Thrombotic and Haemolytic Event Free Status During Each 3month Time Period Since the Start of the Study. [On entry and every 3 months thereafter, for the duration of the study (approximately 3 years and 5 months)]: Thrombotic and Haemolytic Events will include, but are not limited to, the following: haemolytic anaemia, thrombocytopenia, red blood cell haemolysis indicated by dark urine, Budd-Chiara syndrome, any other thrombotic or haemolytic event deemed to be associated with PNH. A haemolytic event will be defined as a rise in LDH or other biochemical evidence of haemolysis accompanied by an increase in symptoms and/or frank haemoglobinuria. Increased symptoms without objective haematological or biochemical evidence of haemolysis will not be counted as haemolytic events. In addition, the following signs and symptoms may be reviewed and classified as Thrombotic/Haemolytic events if appropriate: Acute kidney failure, Hypertension, Myocardial infarction, Stroke, Lung complications, Seizure, Coma, Premature death.
• Time to Thrombotic or Haemolytic Event Since Joining This Study. [Approximately 3 years and 5 months]: Time to thrombotic or haemolytic event since joining this study.
• Proportion of Subjects Who Require PRBC Transfusion During Each 3-month Period Since the Start of the Study and Over the Entire Period of the Study [On entry and every 3 months thereafter, for the duration of the study (approximately 3 years and 5 months)]: Proportion of subjects who require PRBC transfusion during each 3-month period since the start of the study and over the entire period of the study
• Time to First Transfusion Since Joining the Study. [approximately 3 years and 5 months]: Time to first transfusion since joining the study.
• Proportion of Subjects With no Adverse Change in Overall Scores of Quality of Life Using the EORTC QLQ-C30, the EQ-5D-5L and FACIT-F Instruments at Each 3-month Time Period Since the Start of the Study. [Every 3 months up to 39 months]: Proportion of subjects with no adverse change in overall scores of Quality of Life using the EORTC QLQ-C30, the EQ-5D-5L and FACIT-F instruments at each 3-month time period since the start of the study.
• Proportion of Subjects With Serum Lactate Dehydrogenase (LDH) <1.8, >1.8 to 2.4, >2.4 to 3, and >3 Times the Upper Limit of Normal (ULN) at Each 3-month Time Period Since the Start of the Study. [12 weeks]: Proportion of subjects with serum Lactate Dehydrogenase (LDH) <1.8, >1.8 to 2.4, >2.4 to 3, and >3 times the upper limit of normal (ULN) at each 3-month time period since the start of the study.
• Proportion of Subjects With Median Serum Lactate Dehydrogenase (LDH) <1.8, >1.8 to 2.4, >2.4 to 3, and >3 Times the Upper Limit of Normal (ULN) Over the Entire Duration of the Study. [Approximately 3 years and 5 months]: Proportion of subjects with median serum Lactate Dehydrogenase (LDH) <1.8, >1.8 to 2.4, >2.4 to 3, and >3 times the upper limit of normal (ULN) over the entire duration of the study.
• Proportion of Transfusion-independent Subjects at Each 3-month Time Point, With Haemoglobin (g/L) Above the Baseline Haemoglobin Value They Had at the Start of the Trial From Which They Entered CONSERVE [Baseline and every 3 months up to 39 months]: Proportion of transfusion-independent subjects at each 3-month time point, with haemoglobin (g/L) above the baseline haemoglobin value they had at the start of the trial from which they entered CONSERVE
• Proportion of Transfusion-independent Subjects Over the Entire Duration of the Study With Mean Haemoglobin (g/L) Above the Baseline Haemoglobin Value They Had at the Start of the Trial From Which They Entered CONSERVE [Approximately 3 years and 5 months]: Proportion of transfusion-independent subjects over the entire duration of the study with mean haemoglobin (g/L) above the baseline haemoglobin value they had at the start of the trial from which they entered CONSERVE
• Proportion of Patients Experiencing Major Adverse Vascular Events (MAVE) Over the Entire Period of the Study. [Approximately 3 years and 5 months]: Proportion of patients experiencing Major Adverse Vascular Events (MAVE) over the entire period of the study.
• Time to First Major Adverse Vascular Event (MAVE) for Each Subject Since Joining the Study. [Approximately 3 years and 5 months]: Time to first Major Adverse Vascular Event (MAVE) for each subject since joining the study.
• Number of Major Adverse Vascular Events (MAVE) Over the Entire Period of the Study. [Approximately 3 years and 5 months]: Number of Major Adverse Vascular Events (MAVE) over the entire period of the study.

Sex: All, ages: 18 Years to any

Inclusion Criteria:

1. Patients 18 years and above treated with rVA576 (Coversin) under other Akari clinical trial protocols and wish to remain on rVA576 (Coversin) at the conclusion of that trial.
2. In the opinion of the treating responsible clinician patient is receiving clinical benefit from continued treatment with study drug.
3. Evidence of sustained complement inhibition by CH50 assay. .
4. Women of childbearing potential (WOCBP) must agree to use effective contraception consistently throughout the study and have a negative pregnancy test at screening and a negative urine pregnancy test per the schedule of visits. Women cannot donate their eggs. Women are considered post-menopausal and not of childbearing potential if they have had 12 months of amenorrhea or have had surgical bilateral oophorectomy (with or without hysterectomy) or tubal ligation at least six weeks previously.
5. Males with a childbearing potential partner must agree to use effective contraception consistently OR have had a vasectomy
6. Weight ≥50-100kg
7. Willing to receive appropriate prophylaxis against Neisseria meningitidis infection, by both immunisation and continuous or intermittent antibiotics
8. The patient is willing to give voluntary written informed consent
9. The patient is willing in the process of preparation and self-administration of the study drug.

Exclusion Criteria:

1. Patient experienced any safety event in the previous study protocol, which puts the patient at unacceptable risk in current protocol as judged by the investigator and sponsor.
2. Patient is unwilling to complete the Quality of Life instruments and diary card
3. Active meningococcal infection (section 4.3.1 for additional information)
4. Any other reason for which, in the opinion of the Investigator, it would not be in the interests of the patient to remain on rVA576 (Coversin).
5. If female, the subject is pregnant or lactating or intending to become pregnant before, during, or within 90 days after last dose; or intending to donate ova during such time period.
6. If male, the subject intends to donate sperm while on the study this study or for 90 days after last dose.
7. Failure to satisfy the Investigator of fitness to participate for any other reason or any other condition which, in the opinion of the investigator, could increase the subject's risk by participating in the study or confound the outcome of the study.
8. Use of prohibited medication
9. The subject has a history of drug abuse (defined as any illicit drug use) or a history of alcohol abuse.
10. Participation in other clinical trials with investigational product.

Participant flow

Outcome results

• Long Term Safety and Efficacy of rVA576 (Coversin) Therapy Assessed by AEs, SAEs, Standard Lab Tests and ECG Results. (Primary), Count of participants, Participants: rVA576 14
• Proportion of Subjects With Thrombotic and Haemolytic Event Free Status During Each 3month Time Period Since the Start of the Study. (Secondary), Count of participants, Participants: rVA576 15
• Time to Thrombotic or Haemolytic Event Since Joining This Study. (Secondary), Mean, days since first dose: rVA576 Coversin 113.0 +/- 80.61
• Proportion of Subjects Who Require PRBC Transfusion During Each 3-month Period Since the Start of the Study and Over the Entire Period of the Study (Secondary), Count of participants, Participants: rVA576 Coversin 3
• Time to First Transfusion Since Joining the Study. (Secondary), Median, days: rVA576 Coversin 30.5 (1 to 284)
• Proportion of Subjects With no Adverse Change in Overall Scores of Quality of Life Using the EORTC QLQ-C30, the EQ-5D-5L and FACIT-F Instruments at Each 3-month Time Period Since the Start of the Study. (Secondary), Count of participants, Participants: rVA576 Coversin 9
• Proportion of Subjects With Serum Lactate Dehydrogenase (LDH) <1.8, >1.8 to 2.4, >2.4 to 3, and >3 Times the Upper Limit of Normal (ULN) at Each 3-month Time Period Since the Start of the Study. (Secondary), Number, Participants: rVA576 3
• Proportion of Subjects With Median Serum Lactate Dehydrogenase (LDH) <1.8, >1.8 to 2.4, >2.4 to 3, and >3 Times the Upper Limit of Normal (ULN) Over the Entire Duration of the Study. (Secondary), Number, Participants: rVA576 4
• Proportion of Transfusion-independent Subjects at Each 3-month Time Point, With Haemoglobin (g/L) Above the Baseline Haemoglobin Value They Had at the Start of the Trial From Which They Entered CONSERVE (Secondary), Count of participants, Participants: rVA576 Coversin 11
• Proportion of Transfusion-independent Subjects Over the Entire Duration of the Study With Mean Haemoglobin (g/L) Above the Baseline Haemoglobin Value They Had at the Start of the Trial From Which They Entered CONSERVE (Secondary), Count of participants, Participants: rVA576 Coversin 11
• Proportion of Patients Experiencing Major Adverse Vascular Events (MAVE) Over the Entire Period of the Study. (Secondary), Count of participants, Participants: rVA576 Coversin 0
• Time to First Major Adverse Vascular Event (MAVE) for Each Subject Since Joining the Study. (Secondary)
• Number of Major Adverse Vascular Events (MAVE) Over the Entire Period of the Study. (Secondary), Number, events: rVA576 Coversin 0

Adverse events

Time frame: Approximately 3 years and 5 months

Serious adverse events by term

Other adverse events by term

Limitations and caveats: Due to the early termination of this study, only a subset of the outputs planned were produced. Parent trial locked databases were not pooled with the AK581 database, limiting the scope of the analyses that could be produced. The 'parent trial baseline' could not be used in calculations.

• Study Protocol (PDF, 2019-01-11)
• Statistical Analysis Plan (PDF, 2019-01-11)

• Wynne Weston Davies, Study director, AKARI Therapeutics