Clinical Trial Results:
COBALT: Coversin Global Study: An Open-Label, Safety and Efficacy Trial in PNH Patients
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Summary
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EudraCT number |
2016-002067-33 |
Trial protocol |
GB |
Global end of trial date |
21 Dec 2017
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Results information
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Results version number |
v1(current) |
This version publication date |
06 Jan 2019
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First version publication date |
06 Jan 2019
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Other versions |
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Summary report(s) |
AK579 Synopsis |
Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
AK579
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
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WHO universal trial number (UTN) |
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Sponsors
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Sponsor organisation name |
Akari Therapeutics plc
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Sponsor organisation address |
75-75 Wimpole Street, London, United Kingdom, W1G 9RT
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Public contact |
Medical Director, Akari Therapeutics Plc, +44 0208004 0261, wwd@akaritx.com
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Scientific contact |
Medical Director, Akari Therapeutics Plc, +44 0208004 0261, wwd@akaritx.com
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
13 Aug 2018
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
21 Dec 2017
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Global end of trial reached? |
Yes
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Global end of trial date |
21 Dec 2017
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Was the trial ended prematurely? |
No
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General information about the trial
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Main objective of the trial |
The objectives of the study are:
• To assess the safety and tolerability of Coversin for all patients for the duration of the study.
• To assess efficacy of the dosage regimen to reduce haemolysis and control the signs and symptoms thereof, in PNH subjects as manifested by:
i. Serum lactic dehydrogenase (LDH) change from baseline (day 1) to day 28
ii. Haemoglobin (Hb) at day 28 and day 90, absolute and change from baseline
iii. Number of blood transfusions
iv. Quality of Life - EORTC QLQ-C30 at day 1 (baseline), 7, 14, 21, 29, 60 and 90 days
v. Quality of Life – EQ-5D-5L at baseline day 1 (baseline) up to day 60 and then at day 90.
• To determine whether self-injection by subjects with PNH is well-accepted and the home care nursing supervision period sufficient using a (non validated) questionnaire at day 29 and day 90.
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Protection of trial subjects |
There were no specific measures put in place for the protection of trial subjects - normal GCP procedures were utilised
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Background therapy |
Normal standard of care excluding treatment with other complement C5 inhibitors | ||
Evidence for comparator |
No comparator | ||
Actual start date of recruitment |
25 Aug 2016
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
No
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
Poland: 5
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Country: Number of subjects enrolled |
United Kingdom: 3
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Worldwide total number of subjects |
8
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EEA total number of subjects |
8
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
5
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From 65 to 84 years |
3
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85 years and over |
0
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Recruitment
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Recruitment details |
Patients were recruited between 13 December 2016 and last patient last visit was 21 December 2017. The study was opened up for recruitment in both UK and Poland with the first patient being recruited in the UK and also the last patient. | ||||||||||
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Pre-assignment
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Screening details |
Nine patients were screened with 8 being recruited. One patient was screened but withdrew consent at this point. They subsequently decided to take part in the study, | ||||||||||
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Period 1
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Period 1 title |
Overall Study (overall period)
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Is this the baseline period? |
Yes | ||||||||||
Allocation method |
Not applicable
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Blinding used |
Not blinded | ||||||||||
Blinding implementation details |
Not applicable
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Arms
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Arm title
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Intent to Treat | ||||||||||
Arm description |
All patients received the IMP treatment | ||||||||||
Arm type |
Experimental | ||||||||||
Investigational medicinal product name |
rVA576 (Coversin)
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Investigational medicinal product code |
rVA576
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Other name |
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Pharmaceutical forms |
Powder for solution for injection
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Routes of administration |
Subcutaneous use
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Dosage and administration details |
The product is packaged as a lyophilised powder for solution for injection in a vail containing 18 mg/Vial. The product is reconstituted prior to use with 0.6mL WFI giving a concentration of 30mg/mL.
Protocol version 3 used an ablating dosage scheme of 60 mg followed by three times 30 mg every 12 hours. Patients then received 15 mg every 12 hours up to Day 28 and then 30 mg once daily every 24 hours to the end of the study. Patients doses could be amended on response and patients would be dosed either every 24 hours or every 12 hours.
Protocol version 4 used an refined ablating scheme of 60 mg followed by 30 mg 12 hours later and then from Days 2 -28 a dose of 22.5 mg every 12 hours. From Day 29 to the end of the study patients received 45 mg once daily. If control of CH50 was not maintained patients could have their 45 mg dose split into 22.5 mg every 12 hours.
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Baseline characteristics reporting groups
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Reporting group title |
Overall Study
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Reporting group description |
- | ||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Intent to Treat
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Reporting group description |
All patients received the IMP treatment | ||
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End point title |
Reduction in serum LDH to <=1.8 x upper limit of Normal from Day 1 to Day 29 [1] | ||||||
End point description |
The number of patients who achieved a reduction in serum LDH to <= to 1.8 times the upper limit of normal (ULN) by Day 29. There was a drop in LDH over time with median LDH <= 1.8 x ULN reached by Day 29 and maintained throughout the remainder of the study. The number of patients who successfully achieved the primary endpoint was five out of eight.
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End point type |
Primary
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End point timeframe |
Day 1 to Day 29
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| Notes [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Descriptive statistics were the only statistics performed on the results |
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| No statistical analyses for this end point | |||||||
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End point title |
Reduction in LDH at Day 29 to 50% or less of mean of all pre-dose measurements | |||
End point description |
Reduction of LDH at Day 29 to 50% or less of the mean of all pre-dose measurements taken within 14 days of commencing Coversin treatment
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End point type |
Secondary
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End point timeframe |
Day 29
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| No statistical analyses for this end point | ||||
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End point title |
Reduction in CH50 from Day 1 pre-dose to Days 7, 14, 21, 29, 60 and 90 | ||||||
End point description |
The derived average CH50 level obtained from the Day 1 pre-dose evaluation will be regarded as baseline. Changes and percentage changes from baseline to each post-baseline CH50 average assessment will be derived.
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End point type |
Secondary
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End point timeframe |
Day 1 pre-dose to Day 7, 14, 21, 29, 60 and 90
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| Notes [2] - One patient was withdrawn at Day 43 so no Day 60 and 90 values available |
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| No statistical analyses for this end point | |||||||
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End point title |
Reduction in serum LDH to <= 1.8 times the ULN for the Investigators' Reference Laboratory at Day 60 | ||||||
End point description |
The number of patients who achieved a reduction in serum LDH to <= 1.8 times the ULN for the Investigator's reference laboratory at Day 60 and Day 90
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End point type |
Secondary
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End point timeframe |
From Day 1 pre-dose to Day 60
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| Notes [3] - One patient was withdrawn at Day 43 |
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| No statistical analyses for this end point | |||||||
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End point title |
Reduction in serum LDH to < = 1.8 times the ULN for the Investigator's reference laboratory at Day 90 | ||||||
End point description |
The number of patients with a reduction in serum LDH to <=1.8 times the ULN for the Investigator's reference laboratory at Day 90
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End point type |
Secondary
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End point timeframe |
From Day 1 pre-dose to Day 90
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| Notes [4] - One patient was withdrawn at Day 43 |
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| No statistical analyses for this end point | |||||||
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End point title |
Increase in haemoglobin from Day 1 to Day 29 to Day 90 | ||||||
End point description |
Mean Hb started at approximately 0.8x the LLN and remained at a mean of 0.8 x the LLN though out the trial
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End point type |
Secondary
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End point timeframe |
Day 1 predose to Day 90
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| Notes [5] - One patient was withdrawn at Day 43 |
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| No statistical analyses for this end point | |||||||
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End point title |
Number of blood transfusions during study period | ||||||
End point description |
The number of patients who did not require transfusions by the end of the study
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End point type |
Secondary
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End point timeframe |
Day 1 pre-dose to Day 90
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| Notes [6] - Only 6 received transfusions prior to joining the study |
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| No statistical analyses for this end point | |||||||
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End point title |
Change in EORTC QLQ-C30 Score from Day 1 (baseline) to Days 7, 14, 21, 29, 60 and 90 | ||||||
End point description |
Patients were to complete the EORTC QLQ-C30 prior to start of Coversin Administration on Day 1 and repeat on Day 7 (+/- 1), Days 14, 21, 29, 36, 60 and Days 90 (+/- 2).
QLQ-C30 comprises of 30 questions on daily quality of life with each question having a response score on a scale of 1-4 or 1-7. QLQ-C30 incorporates a global health status, five functional scales, three symptom scales and six single items.
THE EORTC-QLQ-C30 showed a general improvement in most aspects.
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End point type |
Secondary
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End point timeframe |
Day 1 baseline to Days 7, 14, 21, 29,, 60 and 90
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| Notes [7] - One patient was withdrawn on Day 43 |
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| No statistical analyses for this end point | |||||||
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End point title |
Change in EQ-5D-5L from Baseline Day 1 to Day 60 and Day 90 | ||||||
End point description |
Patients were to complete the EQ-5D-5L prior to start of Coversin administration on Day 1 and every day up to Day 60 then at Day 90. EQ-5D-5L comprises of 5 questions (mobility, self-care, usual activities, pain/discomfort, anxiety/depression), each with five levels plus the EQ Visual Analogue scale.
A general improvement in all five scales was observed in all EQ-5D-5L.
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End point type |
Secondary
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End point timeframe |
From Day 1 predose to Day 60 and Day 90
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| Notes [8] - One patient was withdrawn at Day 43 |
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| No statistical analyses for this end point | |||||||
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Adverse events information
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Timeframe for reporting adverse events |
From first dose of study medication to end of study (approximately 90 days of treatment). All patients except one entered the separate long-term safety study
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Adverse event reporting additional description |
Reporting was a mixture of systematic and non-systematic through the use of diary cards
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Assessment type |
Non-systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
19
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Reporting groups
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Reporting group title |
Safety Analysis Set
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Reporting group description |
All subjects who received at least one dose of Coversin | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Frequency threshold for reporting non-serious adverse events: 0% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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| Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
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08 Jul 2016 |
Protocol amendment 2 dated 27 June 2016 was updated at the request of the MHRA during their assessment of the initial CTA. The changes included the addition of a discussion on C5 polymorphisms and the need to monitor patients for complete inhibition of CH50 in accordance with the information in the IB. To include information on the fact that the phototoxicity potential of Coversin was unknown and that patients should avoid excessive exposure to sunlight or UV light. The addition of a new exclusion criteria to exclude patients with a known sensitivity to the excipients of meningococcal vaccines, ciprofloxacin or any other antibiotic being administered for the purpose of meningococcal prophylaxis. |
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12 Sep 2016 |
Change in ablating dose from four times 30 mg every 12 hours over to days to an initial ablating dose of 60 mg followed by three times 30 mg every 12 hours for 2 days. There was also a change in the proposed dosing scheme from 30 mg every 24 hours from Day 3 to Day 88 to the initial ablating dose would be followed by 15 mg every 12 hours from Day 3 to Day 28 and then a switch to 30 mg once daily until the end of the trial. The addition of text to state that the dose could be changed from Day 7 onwards in the case of an ineffective dose (e.g. 30 mg once daily) to either an increased dose of 45 mg once daily for example or by dividing the single dose into two doses administered 12 hours apart (e.g. 15 mg or 22.5 mg). An additional secondary endpoint was added to capture the reduction in serum LDH to <= 1.8 times the upper limit of normal (ULN) for the Investigator's reference laboratory or 500 I U/L whichever is the lower at Day 60 and at Day 90.
There were other changes made throughout the protocol to reflect these updates to the dosing schedule including the frequency of blood draws and visits. |
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28 Jul 2017 |
The main changes to protocol amendment 4 dated 19 June 2017 was a change to the ablating dose from 60 mg followed by three times 30 mg over 12 hours for 2 days to 60 mg followed by 30 mg 12 hours later all in the first day. The initiation phase dosing was changed from 15 mg every 12 hours for 26 days to 22.5 mg every 12 hours for 27 days. The maintenance phase dosing was changed from a single dose of 30 mg every 24 hours to a single dose of 45 mg every 24 hours. Dose increases were no longer permitted but the dose could be split to 12 hourly. There was the removal of some of the homecare visits. Additional safety assessments were added. |
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Interruptions (globally) |
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| Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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| Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
| None reported | |||
