Clinical Trial Results:
A Phase IIb, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Neutralization of the Interferon Gene Signature and the Clinical Efficacy of IFNα-Kinoid in Adult Subjects with Systemic Lupus Erythematosus
|
Summary
|
|
EudraCT number |
2015-001341-86 |
Trial protocol |
DE BE HR ES BG IT |
Global end of trial date |
|
|
Results information
|
|
Results version number |
v1(current) |
This version publication date |
31 Oct 2019
|
First version publication date |
31 Oct 2019
|
Other versions |
|
Summary report(s) |
IFN-K-002 CSR 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 |
IFN-K-002
|
||
|
Additional study identifiers
|
|||
ISRCTN number |
- | ||
US NCT number |
NCT02665364 | ||
WHO universal trial number (UTN) |
- | ||
|
Sponsors
|
|||
Sponsor organisation name |
Neovacs
|
||
Sponsor organisation address |
3-5 Impasse Reille, Paris, France, 75014
|
||
Public contact |
Valérie Salentey, Neovacs S.A., 33 15310 9300, vsalentey@neovacs.com
|
||
Scientific contact |
Valérie Salentey, Neovacs S.A., 33 15310 9300, vsalentey@neovacs.com
|
||
|
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 |
Interim
|
||
Date of interim/final analysis |
26 Jun 2019
|
||
Is this the analysis of the primary completion data? |
Yes
|
||
Primary completion date |
15 Mar 2018
|
||
Global end of trial reached? |
No
|
||
|
General information about the trial
|
|||
Main objective of the trial |
Primary Objective:
The primary objective of the main study (at week 36) is to evaluate the neutralization of the IFN gene signature following treatment with IFN-K, as measured by the change from baseline of the expression of IFN-induced genes and to evaluate the efficacy of treatment with IFN-K using the British Isles Lupus Assessment Group (BILAG)-based Composite Lupus Assessment (BICLA) response modified by mandatory CS tapering.
|
||
Protection of trial subjects |
The Phase IIb - IFN-K-002 study was conducted in accordance with the European Union Clinical Trial Directive, and local national laws as applicable, International Conference on Harmonization (ICH) E6 GCP guidelines, and the guidelines of the Declaration of Helsinki, revised form of 64th World Medical Association (WMA) General Assembly, Fortaleza, Brazil , 2013.
An independent data safety monitoring board (iDSMB) consisting of experts in the appropriate disciplines, has been set up to oversee the conduct of the study as well as the safety with specific attention on "Lupus flares" and "Infections". Data review meetings held by iDSMB were planned 6 months after randomization of the first subject and then on a 6-monthly basis unless unscheduled meetings are required to adress particular safety concerns.
|
||
Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
23 Sep 2015
|
||
Long term follow-up planned |
Yes
|
||
Long term follow-up rationale |
Safety | ||
Long term follow-up duration |
5 Years | ||
Independent data monitoring committee (IDMC) involvement? |
Yes
|
||
|
Population of trial subjects
|
|||
Number of subjects enrolled per country |
|||
Country: Number of subjects enrolled |
Taiwan: 2
|
||
Country: Number of subjects enrolled |
Thailand: 3
|
||
Country: Number of subjects enrolled |
Tunisia: 9
|
||
Country: Number of subjects enrolled |
United States: 6
|
||
Country: Number of subjects enrolled |
Argentina: 1
|
||
Country: Number of subjects enrolled |
Belgium: 1
|
||
Country: Number of subjects enrolled |
Chile: 6
|
||
Country: Number of subjects enrolled |
Colombia: 18
|
||
Country: Number of subjects enrolled |
Croatia: 2
|
||
Country: Number of subjects enrolled |
France: 1
|
||
Country: Number of subjects enrolled |
Georgia: 5
|
||
Country: Number of subjects enrolled |
Germany: 4
|
||
Country: Number of subjects enrolled |
Italy: 6
|
||
Country: Number of subjects enrolled |
Korea, Republic of: 2
|
||
Country: Number of subjects enrolled |
Mexico: 19
|
||
Country: Number of subjects enrolled |
Moldova, Republic of: 20
|
||
Country: Number of subjects enrolled |
Peru: 21
|
||
Country: Number of subjects enrolled |
Philippines: 19
|
||
Country: Number of subjects enrolled |
Poland: 18
|
||
Country: Number of subjects enrolled |
Russian Federation: 22
|
||
Worldwide total number of subjects |
185
|
||
EEA total number of subjects |
32
|
||
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) |
185
|
||
From 65 to 84 years |
0
|
||
85 years and over |
0
|
||
|
|||||||||||||||||||||||||
|
Recruitment
|
|||||||||||||||||||||||||
Recruitment details |
A total of 185 subjects positive for IFN gene signature were randomized (1:1) to IFN-K or placebo. One subject was randomized in the IFN-K group and did not receive IFN-K. 184 subjects were treated; 91 subjects received IFN-K; and 93 subjects received Placebo. | ||||||||||||||||||||||||
|
Pre-assignment
|
|||||||||||||||||||||||||
Screening details |
4-week screening period A total of 707 subjects were screened, 185 subjects were randomized. | ||||||||||||||||||||||||
|
Period 1
|
|||||||||||||||||||||||||
Period 1 title |
Main study Period (overall period)
|
||||||||||||||||||||||||
Is this the baseline period? |
Yes | ||||||||||||||||||||||||
Allocation method |
Randomised - controlled
|
||||||||||||||||||||||||
Blinding used |
Double blind | ||||||||||||||||||||||||
Roles blinded |
Subject, Investigator | ||||||||||||||||||||||||
Blinding implementation details |
The main study was conducted with a double-blind design (subjects and Investigators were blinded).
|
||||||||||||||||||||||||
|
Arms
|
|||||||||||||||||||||||||
Are arms mutually exclusive |
Yes
|
||||||||||||||||||||||||
|
Arm title
|
Placebo | ||||||||||||||||||||||||
Arm description |
Subjects received placebo normal saline (0.9% Sodium Chloride) adjuvanted with ISA 51 VG via intramuscular injection. 1 administration of 240 µg at week (W)0, W1, W4 and 1 administration of 120 µg at month 3 (W12) and month 6 (W24) in addition to standard of care treatment. | ||||||||||||||||||||||||
Arm type |
Placebo | ||||||||||||||||||||||||
Investigational medicinal product name |
Placebo
|
||||||||||||||||||||||||
Investigational medicinal product code |
|||||||||||||||||||||||||
Other name |
|||||||||||||||||||||||||
Pharmaceutical forms |
Solution for injection
|
||||||||||||||||||||||||
Routes of administration |
Intramuscular use
|
||||||||||||||||||||||||
Dosage and administration details |
Subjects received placebo normal saline (0.9% Sodium Chloride) adjuvanted with ISA 51 VG via intramuscular injection. 1 administration of 240 µg at W0, W1, W4 and 1 administration of 120 µg at month 3 (W12) and month 6 (W24) in addition to standard of care treatment.
|
||||||||||||||||||||||||
|
Arm title
|
IFN-K | ||||||||||||||||||||||||
Arm description |
Subjects received IFN-K adjuvanted with ISA 51 VG via intramuscular injection. 1 administration of 240 µg at W0, W1, W4 and 1 administration of 120 µg at month 3 (W12) and month 6 (W24) in addition to standard of care treatment. | ||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||
Investigational medicinal product name |
IFN-alpha Kinoid
|
||||||||||||||||||||||||
Investigational medicinal product code |
IFN-K
|
||||||||||||||||||||||||
Other name |
|||||||||||||||||||||||||
Pharmaceutical forms |
Solution for injection
|
||||||||||||||||||||||||
Routes of administration |
Intramuscular use
|
||||||||||||||||||||||||
Dosage and administration details |
Subjects received IFN-K adjuvanted with ISA 51 VG via intramuscular injection. 1 administration of 240 µg at W0, W1, W4 and 1 administration of 120 µg at month 3 (W12) and month 6 (W24) in addition to standard of care treatment.
|
||||||||||||||||||||||||
|
|||||||||||||||||||||||||
| Notes [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same. Justification: A total of 185 subjects were randomized. One subject was randomized in IFN-K group and did not receive IFN-K. 184 subjects were treated; 91 subjects received IFN-K and 93 subjects received placebo. |
|||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||
|
Baseline characteristics reporting groups
|
|||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Placebo
|
||||||||||||||||||||||||||||||||||||||||||||
Reporting group description |
Subjects received placebo normal saline (0.9% Sodium Chloride) adjuvanted with ISA 51 VG via intramuscular injection. 1 administration of 240 µg at week (W)0, W1, W4 and 1 administration of 120 µg at month 3 (W12) and month 6 (W24) in addition to standard of care treatment. | ||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
IFN-K
|
||||||||||||||||||||||||||||||||||||||||||||
Reporting group description |
Subjects received IFN-K adjuvanted with ISA 51 VG via intramuscular injection. 1 administration of 240 µg at W0, W1, W4 and 1 administration of 120 µg at month 3 (W12) and month 6 (W24) in addition to standard of care treatment. | ||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||
|
Subject analysis sets
|
|||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set title |
Placebo
|
||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set type |
Full analysis | ||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set description |
Subjects received placebo normal saline (0.9% Sodium Chloride) adjuvanted with ISA 51 VG via intramuscular injection. 1 administration of 240 µg at W0, W1, W4 and 1 administration of 120 µg at month 3 (W12) and month 6 (W24) in addition to standard of care treatment.
|
||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set title |
IFN-K
|
||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set type |
Full analysis | ||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set description |
Subjects received IFN-K adjuvanted with ISA 51 VG via intramuscular injection. 1 administration of 240 µg at W0, W1, W4 and 1 administration of 120 µg at month 3 (W12) and month 6 (W24) in addition to standard of care treatment.
|
||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||
|
|||
|
End points reporting groups
|
|||
Reporting group title |
Placebo
|
||
Reporting group description |
Subjects received placebo normal saline (0.9% Sodium Chloride) adjuvanted with ISA 51 VG via intramuscular injection. 1 administration of 240 µg at week (W)0, W1, W4 and 1 administration of 120 µg at month 3 (W12) and month 6 (W24) in addition to standard of care treatment. | ||
Reporting group title |
IFN-K
|
||
Reporting group description |
Subjects received IFN-K adjuvanted with ISA 51 VG via intramuscular injection. 1 administration of 240 µg at W0, W1, W4 and 1 administration of 120 µg at month 3 (W12) and month 6 (W24) in addition to standard of care treatment. | ||
Subject analysis set title |
Placebo
|
||
Subject analysis set type |
Full analysis | ||
Subject analysis set description |
Subjects received placebo normal saline (0.9% Sodium Chloride) adjuvanted with ISA 51 VG via intramuscular injection. 1 administration of 240 µg at W0, W1, W4 and 1 administration of 120 µg at month 3 (W12) and month 6 (W24) in addition to standard of care treatment.
|
||
Subject analysis set title |
IFN-K
|
||
Subject analysis set type |
Full analysis | ||
Subject analysis set description |
Subjects received IFN-K adjuvanted with ISA 51 VG via intramuscular injection. 1 administration of 240 µg at W0, W1, W4 and 1 administration of 120 µg at month 3 (W12) and month 6 (W24) in addition to standard of care treatment.
|
||
|
|||||||||||||
End point title |
percent change from baseline in IFN gene signature at W36 | ||||||||||||
End point description |
The biological endpoint aimed at evaluating the neutralization of the IFN gene signature following treatment with IFN-K compared to placebo, as measured by the % change from baseline of the expression of IFN-induced genes.
|
||||||||||||
End point type |
Primary
|
||||||||||||
End point timeframe |
Baseline and W36
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
Statistical Analysis 1 | ||||||||||||
Statistical analysis description |
The percent of change from baseline to last available value between W24 and W36 of treatment in the expression of IFN-induced genes was analyzed using an analysis of covariance (ANCOVA) model.
|
||||||||||||
Comparison groups |
IFN-K v Placebo
|
||||||||||||
Number of subjects included in analysis |
171
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority | ||||||||||||
P-value |
< 0.0001 | ||||||||||||
Method |
ANCOVA | ||||||||||||
Parameter type |
LS mean difference | ||||||||||||
Point estimate |
-30.2802
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
-40.6653 | ||||||||||||
upper limit |
-19.8951 | ||||||||||||
Variability estimate |
Standard error of the mean
|
||||||||||||
Dispersion value |
5.2588
|
||||||||||||
|
||||||||||
End point title |
BICLA Response with superimposed CS Tapering at Week 36 | |||||||||
End point description |
BICLA responder was defined as a subject who had the following criteria at week 36:
- All BILAG A scores at baseline improve to B/C/D and all BILAG B scores improve to C/D at W36, and
- No BILAG worsening in other body systems: no new BILAG A or ≥ 2 new BILAG B scores at W36, and
- No worsening in SLEDAI-2K total score at W36 compared with baseline, and
- No deterioration in Physician Global Assessment (PGA) (< 10% worsening) on Visual Analog Scale (VAS) 100 mm at W36 compared with baseline, and
- No addition or increased dose level of anti-malarial drugs or immunosuppressive drugs or CS* between W24 and W36 (*≤5 mg prednisolone or equivalent /day at W24 and no increase until W36).
|
|||||||||
End point type |
Primary
|
|||||||||
End point timeframe |
At Week 36
|
|||||||||
|
||||||||||
Statistical analysis title |
Statistical Analysis 1 | |||||||||
Statistical analysis description |
Descriptive statistics for the response to treatment according to BICLA at week 36 were presented by treatment group. The response to treatment according to BICLA was analyzed using a logistic regression with the response rate as dependent variable and treatment as independent variable, while adjusting for the minimization factors used for randomization.
|
|||||||||
Comparison groups |
Placebo v IFN-K
|
|||||||||
Number of subjects included in analysis |
169
|
|||||||||
Analysis specification |
Pre-specified
|
|||||||||
Analysis type |
superiority | |||||||||
P-value |
= 0.34 | |||||||||
Method |
Regression, Logistic | |||||||||
Parameter type |
Odds ratio (OR) | |||||||||
Point estimate |
1.38
|
|||||||||
Confidence interval |
||||||||||
level |
95% | |||||||||
sides |
2-sided
|
|||||||||
lower limit |
0.716 | |||||||||
upper limit |
2.657 | |||||||||
|
||||||||||
End point title |
SRI-4 response at Week 36 | |||||||||
End point description |
SLE Responder Index (SRI); SRI-4 responder was defined as a subject who had the following criteria at week 36:
- reduction ≥4 points in SELENA-SLEDAI at week 36 compared with baseline, and
- no new BILAG A at week 36, and
- no more than 1 new BILAG B at week 36, and
- no deterioration in PGA (<10% worsening) on 100-mm VAS compared with baseline
|
|||||||||
End point type |
Secondary
|
|||||||||
End point timeframe |
At Week 36
|
|||||||||
|
||||||||||
Statistical analysis title |
Statistical Analysis 1 | |||||||||
Statistical analysis description |
The SRI-4 response was analyzed using a logistic regression using the response rate as dependent variable and treatment as independent variable, while adjusting for the minimization factors used for randomization.
|
|||||||||
Comparison groups |
Placebo v IFN-K
|
|||||||||
Number of subjects included in analysis |
167
|
|||||||||
Analysis specification |
Pre-specified
|
|||||||||
Analysis type |
superiority | |||||||||
P-value |
= 0.6243 | |||||||||
Method |
Regression, Logistic | |||||||||
Parameter type |
Odds ratio (OR) | |||||||||
Point estimate |
1.18
|
|||||||||
Confidence interval |
||||||||||
level |
95% | |||||||||
sides |
2-sided
|
|||||||||
lower limit |
0.602 | |||||||||
upper limit |
2.329 | |||||||||
|
||||||||||
End point title |
Composite SRI-4 including CS ≤5mg/day response at Week 36 | |||||||||
End point description |
SRI-4 plus CS ≤ 5mg/day responder was defined as a participant who had the following criteria at week 36:
- reduction ≥4 points in SELENA-SLEDAI at week 36 compared with baseline, and
- no new BILAG A at week 36, and
- no more than 1 new BILAG B at week 36, and
- no deterioration in PGA (<10% worsening) on 100-mm VAS compared with baseline
plus corticosteroids (CS) ≤5mg equivalent prednisolone per day at week 36
|
|||||||||
End point type |
Secondary
|
|||||||||
End point timeframe |
At Week 36
|
|||||||||
|
||||||||||
Statistical analysis title |
Statistical Analysis 1 | |||||||||
Comparison groups |
Placebo v IFN-K
|
|||||||||
Number of subjects included in analysis |
156
|
|||||||||
Analysis specification |
Pre-specified
|
|||||||||
Analysis type |
superiority | |||||||||
P-value |
= 0.0762 | |||||||||
Method |
Regression, Logistic | |||||||||
Parameter type |
Odds ratio (OR) | |||||||||
Point estimate |
1.83
|
|||||||||
Confidence interval |
||||||||||
level |
95% | |||||||||
sides |
2-sided
|
|||||||||
lower limit |
0.938 | |||||||||
upper limit |
3.574 | |||||||||
|
||||||||||
End point title |
SLEDAI response at Week 36 | |||||||||
End point description |
SLE Disease Activity Index (SLEDAI)-2K is an activity index that measures disease activity and records feature of active Lupus as present or not present. There are 24 items in a total of 9 organs/systems; total scores range from 0 (non-active disease) – 105 points. Scores were attributed taking into account disease activity over the previous 10 days.
SLEDAI-2K responder was defined as a participant who had reduction of the SLEDAI-2K score of at least 4 points at week 36 compared to baseline.
|
|||||||||
End point type |
Secondary
|
|||||||||
End point timeframe |
At Week 36
|
|||||||||
|
||||||||||
| No statistical analyses for this end point | ||||||||||
|
|||||||||||||
End point title |
BILAG global score change from baseline at Week 36 | ||||||||||||
End point description |
British Isles Lupus Assessment Group (BILAG)-2004 index, it categorizes disease activity into 5 different levels from A to E, with Grade A representing very active disease and Grade E indicating no current or previous disease activity. Scoring was based on a total of 101 items, grouped into 9 organ/systems.
The BILAG global score change from baseline to Last Available Value (LVA) week 24 and week 36 were presented analyzed.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
At Week 36
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
Statistical Analysis 1 | ||||||||||||
Statistical analysis description |
Baseline to last available value between W24 and W36
|
||||||||||||
Comparison groups |
Placebo v IFN-K
|
||||||||||||
Number of subjects included in analysis |
171
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority | ||||||||||||
P-value |
= 0.7946 | ||||||||||||
Method |
Wilcoxon (Mann-Whitney) | ||||||||||||
Confidence interval |
|||||||||||||
|
|||||||||||||
End point title |
SELENA-SLEDAI - change from baseline to Week 36 | ||||||||||||
End point description |
Safety of Estrogens in Systemic Lupus Erythematosus National Assessment (SELENA)-SLEDAI, is a slightly modified version of the SLEDAI. This is a weighted index in which signs and symptoms, laboratory tests, and Physician’s Global Assessment (PGA) for each of nine organ systems are given a weighted score and summed up if present at the time of the visit or in the preceding 10 days. The maximum theoretical score for the SELENA SLEDAI is 105 (all 24 descriptors present simultaneously) with 0 indicating inactive disease.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Baseline and Week 36
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
Statistical Analysis 1 | ||||||||||||
Comparison groups |
Placebo v IFN-K
|
||||||||||||
Number of subjects included in analysis |
167
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority | ||||||||||||
P-value |
= 0.9224 | ||||||||||||
Method |
student - pooled | ||||||||||||
Confidence interval |
|||||||||||||
|
|||||||||||||
End point title |
SLICC/ACR-DI change from baseline at Week 36 | ||||||||||||
End point description |
Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index for systemic lupus erythematosus (SLICC/ACR-DI) captures permanent changes which have occurred in patients with SLE, regardless of causality. The questionnaire contains 41 items covering 12 different organ systems.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Baseline and Week 36
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
Statistical Analysis 1 | ||||||||||||
Statistical analysis description |
SLICC/ACR-DI was analyzed using Student-pooled
|
||||||||||||
Comparison groups |
Placebo v IFN-K
|
||||||||||||
Number of subjects included in analysis |
165
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority | ||||||||||||
P-value |
= 0.3258 | ||||||||||||
Method |
student - pooled | ||||||||||||
Confidence interval |
|||||||||||||
|
|||||||||||||
End point title |
CLASI total activity change from baseline at Week 36 | ||||||||||||
End point description |
Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI) was specifically developed to assess the cutaneous manifestations of SLE. It measures both disease activity and permanent damage (e.g. dyspigmentation and scarring) over the entire body surface.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Baseline and Week 36
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
Statistical Analysis 1 | ||||||||||||
Comparison groups |
Placebo v IFN-K
|
||||||||||||
Number of subjects included in analysis |
169
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority | ||||||||||||
P-value |
= 0.6169 | ||||||||||||
Method |
Student - Satterthwaite | ||||||||||||
Confidence interval |
|||||||||||||
|
||||||||||
End point title |
LLDAS at Week 36 | |||||||||
End point description |
Lupus low disease activity state (LLDAS) was conceptually defined as ‘a state which, if sustained, is associated with a low likelihood of adverse outcome, considering disease activity and medication safety’. Subsequently defined using consensus methodology, LLDAS is attained if all the following items are met:
- SLEDAI-2K ≤4, with no activity in major organ systems (renal, CNS, cardiopulmonary, vasculitis, fever) and no hemolytic anemia or gastrointestinal activity
- No new features of lupus disease activity compared with the previous assessment
- SELENA-SLEDAI physician global assessment (PGA, scale 0–3) ≤1
- Current prednisolone (or equivalent) dose ≤7.5 mg daily
- Well tolerated standard maintenance doses of immunosuppressive drugs and approved biological agents, excluding investigational drugs
|
|||||||||
End point type |
Secondary
|
|||||||||
End point timeframe |
At Week 36
|
|||||||||
|
||||||||||
Statistical analysis title |
Statistical Analysis 1 | |||||||||
Comparison groups |
IFN-K v Placebo
|
|||||||||
Number of subjects included in analysis |
169
|
|||||||||
Analysis specification |
Pre-specified
|
|||||||||
Analysis type |
superiority | |||||||||
P-value |
= 0.0022 | |||||||||
Method |
Pearson's Chi-squared | |||||||||
Confidence interval |
||||||||||
|
||||||||||
End point title |
Neutralizing Anti-IFN-alpha antibodies response at W36 | |||||||||
End point description |
Individual serum antibody neutralizing capacity against recombinant IFN-alpha2b was measured by reporter gene assay using Interferon Sensitive Response Element (ISRE) reporter.
|
|||||||||
End point type |
Secondary
|
|||||||||
End point timeframe |
At week 36
|
|||||||||
|
||||||||||
| Notes [1] - No Neutralizing Anti-IFN-alpha antibodies were performed on placebo subjects |
||||||||||
| No statistical analyses for this end point | ||||||||||
|
||||||||||
End point title |
Composite SRI-4 including CS ≤7,5mg/day response at Week 36 | |||||||||
End point description |
SRI (4) plus CS ≤ 7.5 mg/day responder was defined as a participant who had the following criteria at week 36:
- reduction ≥4 points in SELENA-SLEDAI at week 36 compared with baseline, and
- no new BILAG A at week 36, and
- no more than 1 new BILAG B at week 36, and
- no deterioration in PGA (<10% worsening) on 100-mm VAS compared with baseline
plus CS ≤7.5mg equivalent prednisolone per day at week 36
|
|||||||||
End point type |
Secondary
|
|||||||||
End point timeframe |
At Week 36
|
|||||||||
|
||||||||||
Statistical analysis title |
Statistical Analysis 1 | |||||||||
Comparison groups |
Placebo v IFN-K
|
|||||||||
Number of subjects included in analysis |
156
|
|||||||||
Analysis specification |
Pre-specified
|
|||||||||
Analysis type |
superiority | |||||||||
P-value |
= 0.0796 | |||||||||
Method |
Regression, Logistic | |||||||||
Parameter type |
Odds ratio (OR) | |||||||||
Point estimate |
1.81
|
|||||||||
Confidence interval |
||||||||||
level |
95% | |||||||||
sides |
2-sided
|
|||||||||
lower limit |
0.932 | |||||||||
upper limit |
3.524 | |||||||||
|
|||||||||||||
End point title |
CS mean daily dose at W36 | ||||||||||||
End point description |
mean daily dose of corticosteroid (CS) (prednisone equivalent)
|
||||||||||||
End point type |
Other pre-specified
|
||||||||||||
End point timeframe |
W36
|
||||||||||||
|
|||||||||||||
Attachments |
Figure - Corticosteroids-IFN-K-002 |
||||||||||||
Statistical analysis title |
Statistical Analysis 1 | ||||||||||||
Comparison groups |
Placebo v IFN-K
|
||||||||||||
Number of subjects included in analysis |
169
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority | ||||||||||||
P-value |
= 0.0097 | ||||||||||||
Method |
Student - Satterthwaite | ||||||||||||
Confidence interval |
|||||||||||||
|
||||||||||
End point title |
Composite SRI-4 (CS ≤5mg/day) response excluding IFN-K subjects without positive anti-IFNalpha neutralizing antibodies at Week 36 | |||||||||
End point description |
Subjects who had the following criteria defined as : SRI-4 plus CS ≤5mg/day -excluding IFN-K subjects without positive anti-IFN-alpha neutralizing antibodies
|
|||||||||
End point type |
Post-hoc
|
|||||||||
End point timeframe |
At week 36
|
|||||||||
|
||||||||||
Statistical analysis title |
Statistical Analysis 1 | |||||||||
Comparison groups |
Placebo v IFN-K
|
|||||||||
Number of subjects included in analysis |
149
|
|||||||||
Analysis specification |
Post-hoc
|
|||||||||
Analysis type |
superiority | |||||||||
P-value |
= 0.0425 | |||||||||
Method |
Pearson's Chi-squared | |||||||||
Confidence interval |
||||||||||
|
||||||||||
End point title |
Composite SRI-4 (CS ≤7.5mg/day) response excluding IFN-K subjects without positive anti-IFNalpha neutralizing antibodies at Week 36 | |||||||||
End point description |
participant who had the following criteria defined as : SRI-4 plus CS ≤7.5mg/day -excluding IFN-K Patients without positive anti-IFN-alpha neutralizing antibodies
|
|||||||||
End point type |
Post-hoc
|
|||||||||
End point timeframe |
At week 36
|
|||||||||
|
||||||||||
Statistical analysis title |
Statistical Analysis 1 | |||||||||
Comparison groups |
Placebo v IFN-K
|
|||||||||
Number of subjects included in analysis |
149
|
|||||||||
Analysis specification |
Post-hoc
|
|||||||||
Analysis type |
superiority | |||||||||
P-value |
= 0.0396 | |||||||||
Method |
Pearson's Chi-squared | |||||||||
Confidence interval |
||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
Adverse events information
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Timeframe for reporting adverse events |
Adverse Events (AEs) non serious and serious (SAEs) were collected from the start of study medication to Week 36.
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Adverse event reporting additional description |
Due to IFN-K mechanism of action, i.e. immunization, and the administration route, i.e. intramuscular (IM), some AEs, local and/or systemic AEs, were expected and solicited within 7 days after study Investigational Medicinal Product (IMP) administration.
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
Dictionary used for adverse event reporting
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
18
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
Reporting groups
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Placebo
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group description |
Subjects received placebo normal saline (0.9% Sodium Chloride) adjuvanted with ISA 51 VG via intramuscular injection. 1 administration of 240 µg at W0, W1, W4 and 1 administration of 120 µg at month 3 (W12) and month 6 (W24) in addition to standard of care treatment. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
IFN-K
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group description |
Subjects received IFN-K adjuvanted with ISA 51 VG via intramuscular injection. 1 administration of 240 µg at W0, W1, W4 and 1 administration of 120 µg at month 3 (W12) and month 6 (W24) in addition to standard of care treatment. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Frequency threshold for reporting non-serious adverse events: 5% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||
Substantial protocol amendments (globally) |
|||
| Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
||
11 Aug 2015 |
Amendment #1 (dated 11 August 2015): it amended the protocol Version 2.0 into protocol Version 3.0 as per request of the European Health Authorities. This amendment introduced and update of the promary objective to:
- The primary objective of this study is to evaluate the neutralization of the IFN gene signature following treatment with IFN-K, as measured by the change from baseline of the expression of IFN-induced genes and to evaluate the efficacy of treatment with IFN-K using the British Isles Lupus Assessment Group (BILAG)-based Composite Lupus Assessment (BICLA) response criteria. |
||
08 Dec 2015 |
Amendment #2 (dated 08 December 2015), amending the protocol Version 3.0 into protocol Version 4.0, introduced the following modifications:
- Addition of the extended follow-up within the IFN-K-002 protocol rather than in a separate protocol: the protocol Version 4.0 therefore integrated an extended follow up period up to a total duration of 5 years (60 months, i.e. 240 weeks) after the last visit of the main study (Visit 12 at week 36). The visit at week 276 (Month 69), i.e. FU10, was then considered as the last planned visit.
- complete extended follow-up only for some subjects receiving the active treatment: due to the double-blind study design, all subjects who had completed the main study (up to Visit 12 at week 36) would enter into the extended follow-up period. When the results would be available, only subjects having received IFN-K and having produced anti-IFN-alpha antibodies (neutralizing) would continue the extended follow up. Subjects would remain into the extended follow-up period until they become negative for anti-IFN-alpha neutralizing antibodies or for up to 5 years (60 months, i.e. 240 weeks) after Visit 12, whichever comes first.
- frequency of visits during the extended follow-up: subjects would be followed every 6 months, as in the IFN-K-001 study.
- regular analyses: for safety purpose, a descriptive analysis would be performed at regular intervals, according to DSUR timelines.
|
||
28 Jan 2016 |
Amendment #3 (dated 28 January 2016), amending the protocol Version 4.0 into protocol Version 5.0, introduced the following modifications:
- Expansion of geographic areas for the study conduct: worldwide epidemiology studies reported large variations in incidence and prevalence of SLE, reflecting influences of race, ethnicity and socio-economic status; in addition, several studies have demonstrated an overexpression of IFN-alpha inducible genes in SLE subjects and a possible correlation between their expression and the disease activity notably the serological markers. The study being originally planned to be conducted in 3 geographic areas (Europe, Asia-Pacific and Latin-America), the protocol was amended to expand the study to the USA to provide results on an overall population and better cover the specificities of the different ethnicities.
- The relationship between the ethnicity and the expression of the IFN gene signature was taken into account in the randomization (minimization factor) and the sample size calculation was revised to ensure statistical power on the primary endpoints.
|
||
11 Apr 2016 |
Amendment #4 (dated 11 April 2016), amending the protocol Version 5.0 into protocol Version 6.0, introduced the following modifications:
- Complete extended follow-up only for all subjects receiving the active treatment: as requested by Food and Drug Administration (FDA), all subjects having received IFN-K would be followed up for up to 60 months, irrespective of the production of anti-IFN-alpha antibodies at Visit 12 (Week 36) and during the whole extended follow up period.
- Modification of inclusion criterion #8: as requested by FDA, the time on treatment and time on stable dose has been increased to 12 weeks prior to study product injection for subjects taking Methotrexate (MTX), Azathioprine (AZA) and Mycophenolate Mofetil (MMF).
- Modification of exclusion criterion #11 for US subjects only: as requested by FDA, only subjects with negative screening tests for malignancy according to the American Cancer Society (ACS) guidelines within 12 months before screening Visit could be enrolled; in addition, for subjects with history of treated cancers, only treated basal cell carcinoma was not preventing enrollment.
- Modification of an event leading to study product dicontinuation: as requested by FDA, “the occurrence of bronchospasm after administration of study product must be considered as a criterion for study product discontinuation” was revised as “bronchospasm or anaphylactic reaction following the administration of the study product”.
- Modification is AE reporting: since not all countries have the same requirements for reporting of fatal, life-threatening events and all other SAEs to Regulatory Health Authorities, the possibility to follow local requirements was added.
|
||
15 May 2017 |
Local amendment (amendment #5) for Argentina (dated 15 May 2017), amending the protocol Version 5.0 into protocol Version 6.1: per request of the Argentinian Health Authority, the following modifications have been made:
- Modification of exclusion criterion #11 for: “history of malignant cancer, except the following treated cancers: basal cell carcinoma or dermatological squamous cell carcinoma”.
- Modification of exclusion criterion #23 for: “cytological abnormalities ≥LSIL (low grade squamous intraepithelial lesions) on a cervical swab at Screening or within 3 months prior to the first planned study product administration”.
- Addition of clarification to inclusion criterion #9.
- Addition of clarification to exclusion criterion #1.
|
||
Interruptions (globally) |
|||
| Were there any global interruptions to the trial? No | |||
Limitations and caveats |
|||
| Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
| None reported | |||
