Clinical Trial Results:
Double-blind, randomised, placebo-controlled, multicentre, Phase IIa study to investigate the effect of phosphorylcholine human monoclonal antibody (PC mAb) 3G10 on arterial inflammation, together with safety and tolerability, in subjects with elevated lipoprotein a (Lp[a])
|
Summary
|
|
EudraCT number |
2017-002106-13 |
Trial protocol |
SE NL |
Global end of trial date |
03 Jul 2018
|
|
Results information
|
|
Results version number |
v1(current) |
This version publication date |
29 Oct 2021
|
First version publication date |
29 Oct 2021
|
Other versions |
|
Summary report(s) |
Synopsis |
Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
|
|||
|
Trial identification
|
|||
Sponsor protocol code |
ATH3G10-005
|
||
|
Additional study identifiers
|
|||
ISRCTN number |
- | ||
US NCT number |
NCT03320265 | ||
WHO universal trial number (UTN) |
- | ||
|
Sponsors
|
|||
Sponsor organisation name |
Athera Biotechnologies AB
|
||
Sponsor organisation address |
c/o Business Center, level 4, Sankt Eriksgatan 117, Stockholm, Sweden, SE-113 43
|
||
Public contact |
James Hall, Athera Biotechnologies AB, 0046 87955555, j.hall@athera.se
|
||
Scientific contact |
James Hall, Athera Biotechnologies AB, 0046 87955555, j.hall@athera.se
|
||
|
Paediatric regulatory details
|
|||
Is trial part of an agreed paediatric investigation plan (PIP) |
No
|
||
Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
|
||
Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
|
||
|
Results analysis stage
|
|||
Analysis stage |
Final
|
||
Date of interim/final analysis |
05 Jul 2018
|
||
Is this the analysis of the primary completion data? |
Yes
|
||
Primary completion date |
19 Mar 2018
|
||
Global end of trial reached? |
Yes
|
||
Global end of trial date |
03 Jul 2018
|
||
Was the trial ended prematurely? |
Yes
|
||
|
General information about the trial
|
|||
Main objective of the trial |
The primary objective was to assess the effects of four 250 mg 3G10 once monthly intravenous injections on monocyte function ex vivo.
|
||
Protection of trial subjects |
The study was performed in accordance with the ethical principles that have their origin in the
Declaration of Helsinki that are consistent with International Council for Harmonisation of Technical
Requirements for Pharmaceuticals for Human Use (ICH)/Good Clinical Practice (GCP) and applicable
regulatory requirements.
|
||
Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
22 Sep 2017
|
||
Long term follow-up planned |
No
|
||
Independent data monitoring committee (IDMC) involvement? |
Yes
|
||
|
Population of trial subjects
|
|||
Number of subjects enrolled per country |
|||
Country: Number of subjects enrolled |
Netherlands: 1
|
||
Country: Number of subjects enrolled |
Sweden: 9
|
||
Worldwide total number of subjects |
10
|
||
EEA total number of subjects |
10
|
||
Number of subjects enrolled per age group |
|||
In utero |
0
|
||
Preterm newborn - gestational age < 37 wk |
0
|
||
Newborns (0-27 days) |
0
|
||
Infants and toddlers (28 days-23 months) |
0
|
||
Children (2-11 years) |
0
|
||
Adolescents (12-17 years) |
0
|
||
Adults (18-64 years) |
4
|
||
From 65 to 84 years |
6
|
||
85 years and over |
0
|
||
|
||||||||||
|
Recruitment
|
||||||||||
Recruitment details |
A total of 40 Male and female subjects, age above 50 years, with elevated Lp(a) (above 50 mg/dL) were planned for inclusion. Potential study subjects were identified by advertising in local media and by review of pre-existing databases at the study sites. The study was conducted in two countries–the Netherlands and Sweden. | |||||||||
|
Pre-assignment
|
||||||||||
Screening details |
Assessments included: informed consent; demographics, medications, and med./surg. history; eligibility; weight; height; physical exam.; vital signs (blood press. & body temp); ECG (incl. heart rate); pregnancy; FSH & oestradiol; HIV, Hepatitis B, C; Lp(a); Haematology, clin. chemistry, coagulation complement; urine analysis; and concomitant meds | |||||||||
|
Pre-assignment period milestones
|
||||||||||
Number of subjects started |
10 | |||||||||
Number of subjects completed |
10 | |||||||||
|
Period 1
|
||||||||||
Period 1 title |
overall trial (overall period)
|
|||||||||
Is this the baseline period? |
Yes | |||||||||
Allocation method |
Randomised - controlled
|
|||||||||
Blinding used |
Double blind | |||||||||
Roles blinded |
Subject, Investigator, Monitor, Data analyst, Carer, Assessor | |||||||||
Blinding implementation details |
This was a double-blinded study, the treatment was blinded to the subject, the investigators and the personnel administering IMP.
The code envelopes were to be kept in a secure place with limited access. In case of emergency or other situation that it was crucial for the Investigator to know which treatment the subject had received, the code envelope might be opened. If the code was broken, this was to be documented on the treatment code envelope and in the subject’s hospital records.
|
|||||||||
|
Arms
|
||||||||||
Are arms mutually exclusive |
Yes
|
|||||||||
|
Arm title
|
3G10 | |||||||||
Arm description |
PC-mAb 3G10 (referred to as 3G10), 250 mg, intravenous injections/infusions. Batch numbers: 8047563 (Apotek Produktion & Laboratorier [APL], expiry date: 2018-03-31), 8047627 (APL, expiry date: 2018-03-31) | |||||||||
Arm type |
Experimental | |||||||||
Investigational medicinal product name |
PC-mAb 3G10
|
|||||||||
Investigational medicinal product code |
||||||||||
Other name |
3G10
|
|||||||||
Pharmaceutical forms |
Concentrate for solution for infusion
|
|||||||||
Routes of administration |
Intravenous use
|
|||||||||
Dosage and administration details |
Subjects were allocated to receive either 250 mg of the test product 3G10 or the reference product,
matching placebo. Each subject was to receive once monthly intravenous injections for four months.
At the dosing day, subjects received each dose of IMP as an intravenous infusion for 30 minutes and
remained in the clinic for supervision for 1 hour after each dosing.
|
|||||||||
|
Arm title
|
Placebo | |||||||||
Arm description |
The reference product/placebo was commercially available acquired at the local hospital pharmacies and contained sterile sodium chloride 0.9% solution for infusion compliant to the European Pharmacopoeia (Ph.Eur). | |||||||||
Arm type |
Placebo | |||||||||
Investigational medicinal product name |
Placebo
|
|||||||||
Investigational medicinal product code |
||||||||||
Other name |
Placebo
|
|||||||||
Pharmaceutical forms |
Concentrate for solution for infusion
|
|||||||||
Routes of administration |
Intravenous use
|
|||||||||
Dosage and administration details |
Subjects were allocated to receive either 250 mg of the test product 3G10 or the reference product,
matching placebo. Each subject was to receive once monthly intravenous injections for four months.
At the dosing day, subjects received each dose of IMP as an intravenous infusion for 30 minutes and
remained in the clinic for supervision for 1 hour after each dosing.
|
|||||||||
|
||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
Baseline characteristics reporting groups
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
3G10
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group description |
PC-mAb 3G10 (referred to as 3G10), 250 mg, intravenous injections/infusions. Batch numbers: 8047563 (Apotek Produktion & Laboratorier [APL], expiry date: 2018-03-31), 8047627 (APL, expiry date: 2018-03-31) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Placebo
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group description |
The reference product/placebo was commercially available acquired at the local hospital pharmacies and contained sterile sodium chloride 0.9% solution for infusion compliant to the European Pharmacopoeia (Ph.Eur). | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||
|
End points reporting groups
|
|||
Reporting group title |
3G10
|
||
Reporting group description |
PC-mAb 3G10 (referred to as 3G10), 250 mg, intravenous injections/infusions. Batch numbers: 8047563 (Apotek Produktion & Laboratorier [APL], expiry date: 2018-03-31), 8047627 (APL, expiry date: 2018-03-31) | ||
Reporting group title |
Placebo
|
||
Reporting group description |
The reference product/placebo was commercially available acquired at the local hospital pharmacies and contained sterile sodium chloride 0.9% solution for infusion compliant to the European Pharmacopoeia (Ph.Eur). | ||
|
||||||||||
End point title |
Trans-endothelial migration [1] | |||||||||
End point description |
Blood sampling for assessment of the primary endpoint, TEM in monocytes isolated from treated
subjects, was performed pre-dose at Visit 4 (1st dose) and at follow-up (Visit 11). The ex vivo
measurement of monocyte function was performed using the TEM assay. The total number of monocytes
and the number of transmigrated monocytes were counted using images obtained with a confocal laser
microscope and results were presented as % of migrated monocytes.
|
|||||||||
End point type |
Primary
|
|||||||||
End point timeframe |
From Visit 4 to Visit 11
|
|||||||||
| 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: No formal statistical analysis (statistical tests etc.) was performed, efficacy data are presented descriptively in subject data listings. |
||||||||||
|
||||||||||
Attachments |
Trans-endothelial migration |
|||||||||
| Notes [2] - Only listings available, see attachment. [3] - Only listings available, see attachment. |
||||||||||
| No statistical analyses for this end point | ||||||||||
|
||||||||||
End point title |
Change in tissue to background ratio in common carotid arteries | |||||||||
End point description |
The PET/CT examinations were to be performed at Visit 3 and at follow-up (Visit 11). No PET/CT assessments were performed at Visit 11 as judged to be of little value for the evaluation of the study
compared to the radiation dose received, as the study was on hold
|
|||||||||
End point type |
Secondary
|
|||||||||
End point timeframe |
Visit 3 to Visit 11
|
|||||||||
|
||||||||||
| Notes [4] - No PET/CT assessments were performed at Visit 11. [5] - No PET/CT assessments were performed at Visit 11. |
||||||||||
| No statistical analyses for this end point | ||||||||||
|
||||||||||
End point title |
Change in pulse wave velocity | |||||||||
End point description |
Assessment of arterial stiffness were to be performed at the dosing visits (pre-dose at Visit 4 and postdose at Visit 6, Visit 8 and Visit 10), at follow-up (Visit 11) and at the end of study visit (Visit 12)
|
|||||||||
End point type |
Secondary
|
|||||||||
End point timeframe |
Visit 4 to Visit 11
|
|||||||||
|
||||||||||
Attachments |
Pulse way velocity (m/sec) Aortic augmentation index (AIx [AP/PP]) (%) |
|||||||||
| Notes [6] - Only listings available, see attachment. [7] - Only listings available, see attachment. |
||||||||||
| No statistical analyses for this end point | ||||||||||
|
||||||||||
End point title |
Magnetic resonance imaging | |||||||||
End point description |
Magnetic resonance imaging (MRI) examinations were performed in a subgroup of the population prior to randomisation at Visit 3 and
at follow-up (Visit 11). MRI scans were assessed for cardiac function (cardiac MRI variables) and limb flow reserve (LFR).
|
|||||||||
End point type |
Other pre-specified
|
|||||||||
End point timeframe |
Visit 3 and Visit 11
|
|||||||||
|
||||||||||
Attachments |
Left vent. global diast. circ. Left ventr. global long. strain Limb flow reserve T2* grad. dur. reac. hyperaemia |
|||||||||
| Notes [8] - Only listings available, see attachment. [9] - Only listings available, see attachment. |
||||||||||
| No statistical analyses for this end point | ||||||||||
|
||||||||||
End point title |
Biomarker analysis | |||||||||
End point description |
Blood sampling for biomarker analysis (including IgM anti-PC, Lp(a) and proteomic biomarkers) were to
be performed at the dosing visits (pre-dose at Visit 4 and post-dose at Visit 4, Visit 6, Visit 8 and Visit
10), at follow-up (Visit 11) and at end of study (Visit 12). The biomarkers related to monocyte function
were assessed by FACS analysis. The proteomic biomarkers were analysed using Proximity Extension
Assay (PEA; OLINK kits CVDII, CVDIII and Inflammation).
|
|||||||||
End point type |
Other pre-specified
|
|||||||||
End point timeframe |
At dosing visits
|
|||||||||
|
||||||||||
Attachments |
IgM anti-PC (U/mL) Lipoprotein (a) levels (mg/dL) |
|||||||||
| Notes [10] - Only listings available, see attachment. [11] - Only listings available, see attachment. |
||||||||||
| No statistical analyses for this end point | ||||||||||
|
||||||||||
End point title |
Pharmacokinetics | |||||||||
End point description |
Blood sampling for pharmacokinetic analysis of 3G10 concentration in serum was to be performed predose, and at 5 minutes and at 1-hour post-dose at the dosing visits (Visit 4, Visit 6, Visit 8 and Visit 10), at follow-up (Visit 11) and at end of study (Visit 12).
|
|||||||||
End point type |
Other pre-specified
|
|||||||||
End point timeframe |
Pre-dose and at dosing visits
|
|||||||||
|
||||||||||
Attachments |
3G10 concentration (ng/mL) |
|||||||||
| Notes [12] - Only listings available, see attachment. [13] - Only listings available, see attachment. |
||||||||||
| No statistical analyses for this end point | ||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
Adverse events information
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Timeframe for reporting adverse events |
Adverse events and SAEs were to be reported from the first dose of IMP (Visit 4) until the end of study visit (Visit 12).
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
Dictionary used for adverse event reporting
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
21.0
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
Reporting groups
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
3G10
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group description |
PC-mAb 3G10 (referred to as 3G10), 250 mg, intravenous injections/infusions. Batch numbers: 8047563 (Apotek Produktion & Laboratorier [APL], expiry date: 2018-03-31), 8047627 (APL, expiry date: 2018-03-31) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Placebo
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group description |
The reference product/placebo was commercially available acquired at the local hospital pharmacies and contained sterile sodium chloride 0.9% solution for infusion compliant to the European Pharmacopoeia (Ph.Eur). | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Frequency threshold for reporting non-serious adverse events: 0% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
||||||||||
Substantial protocol amendments (globally) |
||||||||||
| Were there any global substantial amendments to the protocol? Yes | ||||||||||
Date |
Amendment |
|||||||||
19 Sep 2017 |
Clarification of exclusion criterion 2 to ensure exclusion of subjects having
illnesses between the screening visit and the randomization visit.
Clarification of exclusion criterion 8.
A majority of patients with Lp(a) >50 mg/dL, which is required to be included in
the study, have ongoing treatment with statins or other lipid lowering
medications. New data indicates that the added population is equally treatment
sensitive as statin/PCSK9 naïve patients with Lp(a) >50 mg/dL. Excluding these
patients will also greatly prolong the inclusion time and exceptions are therefore
needed.
Correction of study schedule. |
|||||||||
Interruptions (globally) |
||||||||||
| Were there any global interruptions to the trial? Yes | ||||||||||
|
||||||||||
Limitations and caveats |
||||||||||
| Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | ||||||||||
| Due to the early termination of the study, it was decided by the Sponsor that the formal statistical analysis planned in the CSP was not to be performed. Only subject listings were created. | ||||||||||
