Clinical Trial Results:
A randomised, double-blind, placebo-controlled, parallel-group trial to assess clinical efficacy of NNC0114-0006 in subjects with active rheumatoid arthritis
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Summary
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EudraCT number |
2011-005376-42 |
Trial protocol |
LV ES HU BG |
Global end of trial date |
26 Aug 2013
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Results information
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Results version number |
v1(current) |
This version publication date |
15 Mar 2016
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First version publication date |
28 Jul 2015
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Other versions |
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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 |
NN8828-3842
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT01647451 | ||
WHO universal trial number (UTN) |
U1111-1125-6552 | ||
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Sponsors
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Sponsor organisation name |
Novo Nordisk A/S
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Sponsor organisation address |
Novo Allé, Bagsvaerd, Denmark, Bagsvaerd
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Public contact |
Global Clinical Registry (GCR, 1452), Novo Nordisk A/S , clinicaltrials@novonordisk.com
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Scientific contact |
Global Clinical Registry (GCR, 1452), Novo Nordisk A/S , clinicaltrials@novonordisk.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 |
03 Jul 2014
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
26 Aug 2013
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Global end of trial reached? |
Yes
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Global end of trial date |
26 Aug 2013
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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 |
To evaluate the change in disease activity following intravenous (i.v.) administration of two doses of NNC0114-0006 compared to placebo in subjects with active rheumatoid arthritis (RA) on background methotrexate (MTX) therapy.
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Protection of trial subjects |
The trial was conducted in accordance with the Declaration of Helsinki (amended 2008) and ICH Good Clinical Practice (1996) and 21 CFR 312.120.
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Background therapy |
The trial population included subjects with active rheumatoid arthritis on concomitant treatment with MTX ≥15 mg/week for at least 4 months prior to screening, with stable dose of ≥15 mg/week and ≤25 mg/week for at least 6 weeks prior to screening (MTX doses between 7.5 and 12.5 mg/week were allowed, if the patient had intolerance to 15 mg/week). | ||
Evidence for comparator |
not applicable | ||
Actual start date of recruitment |
20 Jul 2012
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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: 36
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Country: Number of subjects enrolled |
Spain: 3
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Country: Number of subjects enrolled |
Bulgaria: 9
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Country: Number of subjects enrolled |
Latvia: 1
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Country: Number of subjects enrolled |
Russian Federation: 8
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Country: Number of subjects enrolled |
Serbia: 5
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Worldwide total number of subjects |
62
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EEA total number of subjects |
49
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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) |
55
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From 65 to 84 years |
7
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85 years and over |
0
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Recruitment
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Recruitment details |
The trial was conducted at 18 sites in 6 countries, as follows: Bulgaria: 4 sites; Latvia: 1; Poland: 5; Russian Federation: 4; Serbia: 2; Spain: 2 sites. | ||||||||||||||||||
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Pre-assignment
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Screening details |
Subjects with active RA who were concomitantly treated with MTX for at least 4 months prior to screening were included in the trial. | ||||||||||||||||||
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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 |
Randomised - controlled
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Blinding used |
Double blind | ||||||||||||||||||
Roles blinded |
Subject, Investigator | ||||||||||||||||||
Blinding implementation details |
An unblinded monitor was responsible for monitoring the handling and preparation of the trial products during the conduct of the trial. The unblinded monitor arranged for destruction of used and unused trial products at the end of the trial.
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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NNC0114-0006 | ||||||||||||||||||
Arm description |
Subjects received two doses of 12 mg/kg NNC0114-0006, administered 6 weeks apart as an i.v. infusion over a period of 30 minutes using an automated infusion pump. | ||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||
Investigational medicinal product name |
NNC0114-0006
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Powder for solution for infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
Two doses of 12 mg/kg NNC0114-0006 were administered 6 weeks apart as an i.v. (intravenous) infusion over a period of 30 minutes using an automated infusion pump. The dose was based on body weight measured at Visit 1, and the injection volumes varied subsequently between subjects.
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Arm title
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Placebo | ||||||||||||||||||
Arm description |
Subjects received two doses of placebo, administered 6 weeks apart as an i.v. infusion, over a period of 30 minutes using an automated infusion pump. | ||||||||||||||||||
Arm type |
Placebo | ||||||||||||||||||
Investigational medicinal product name |
Placebo
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Powder for solution for infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
Two doses of placebo, corresponding to the same volume as active drug, were administered 6 weeks apart as an i.v. (intravenous) infusion over a period of 30 minutes using an automated infusion pump. The dose was based on body weight measured at Visit 1, and the injection volumes varied subsequently between subjects.
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Baseline characteristics reporting groups
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Reporting group title |
NNC0114-0006
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Reporting group description |
Subjects received two doses of 12 mg/kg NNC0114-0006, administered 6 weeks apart as an i.v. infusion over a period of 30 minutes using an automated infusion pump. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Placebo
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Reporting group description |
Subjects received two doses of placebo, administered 6 weeks apart as an i.v. infusion, over a period of 30 minutes using an automated infusion pump. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
NNC0114-0006
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Reporting group description |
Subjects received two doses of 12 mg/kg NNC0114-0006, administered 6 weeks apart as an i.v. infusion over a period of 30 minutes using an automated infusion pump. | ||
Reporting group title |
Placebo
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Reporting group description |
Subjects received two doses of placebo, administered 6 weeks apart as an i.v. infusion, over a period of 30 minutes using an automated infusion pump. | ||
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End point title |
Change in disease activity score based on 28 joints and c-reactive protein (DAS28-CRP) | ||||||||||||
End point description |
Change in disease activity score DAS28 (CRP).
DAS28 (CRP) was derived from the following formula:
DAS28 (CRP) = 0.56 × sqrt(tender joint count [TJC28]) + 0.28 × sqrt(swollen joint count [SJC28]) + 0.36 × ln(CRP+1) + 0.014 × PtGA + 0.96
TJC28 = 28 joint count for tenderness, SJC28 = 28 joint count for swelling, ln(CRP+1) = natural, logarithm of CRP+1 (mg/L), PtGA = subject’s global assessment of disease activity on a visual analogue scale (VAS) recorded on a 100 mm scale.
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End point type |
Primary
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End point timeframe |
From baseline to week 12.
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Statistical analysis title |
Analysis 1 | ||||||||||||
Statistical analysis description |
The primary model used to analyse the primary endpoint was an analysis of variance (ANOVA) model including treatment as fixed factor and the baseline level of DAS28 (CRP) as a continuous covariateThe effect at Week 12 (active – placebo) was estimated from this model and presented together with the 95% confidence interval and the p-value for no treatment effect.
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Comparison groups |
NNC0114-0006 v Placebo
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Number of subjects included in analysis |
61
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Analysis specification |
Pre-specified
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Analysis type |
other | ||||||||||||
P-value |
= 0.0403 | ||||||||||||
Method |
ANOVA | ||||||||||||
Parameter type |
Treatment difference | ||||||||||||
Point estimate |
-0.65
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Confidence interval |
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95% | ||||||||||||
sides |
2-sided
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lower limit |
-1.26 | ||||||||||||
upper limit |
-0.03 | ||||||||||||
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End point title |
ACR20/50/70. | |||||||||||||||||||||
End point description |
Percentage of subjects that fulfil ACR response at week 12.
To calculate the ACR responses, ACR20/50/70 and ACR-N, the following were assessed: Improvement in the swollen joint count (66 joints); Improvement in the tender joint count (68 joints); Improvement in at least 3 of the following 5 assessments;
Subject’s assessment of pain (VAS); Subject’s global assessment of disease activity (PtGA) (VAS); Physician’s global assessment of disease activity (PhGA) (VAS); Subject self-assessed disability (corresponding to health assessment questionnaire-disability; index [HAQ-DI]); CRP
Given that all three improvements occurred, patients were reported to have an ACR20, ACR50 or ACR70 response if the improvement from baseline was 20%, 50% or 70% or more, respectively.
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End point type |
Secondary
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End point timeframe |
At week 12.
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| No statistical analyses for this end point | ||||||||||||||||||||||
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End point title |
Incidence of adverse events (AEs) | |||||||||
End point description |
The number of adverse events from the first trial-related activity, after the subject had signed the informed consent and until post treatment follow-up period (up to week 24).
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End point type |
Secondary
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End point timeframe |
Up to week 24.
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| No statistical analyses for this end point | ||||||||||
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End point title |
Incidence of antibodies against NNC0114-0006. | ||||||||||||
End point description |
Percentage of subjects with anti-NNC0114-0006 antibodies at week 12.
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End point type |
Secondary
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End point timeframe |
Up to week 24.
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Terminal serum half-life (t½). [1] | ||||||||
End point description |
Mean terminal serum t½ after the second dose administration.
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End point type |
Secondary
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End point timeframe |
After second dose administration at Week 6.
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| Notes [1] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: Pharmacokinetic properties are not tested for subjects in the placebo arm. Therefore the results are presented only for the treatment arm. |
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| No statistical analyses for this end point | |||||||||
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End point title |
Change in serum levels of total IL-21. | ||||||||||||
End point description |
Total IL-21 relative to baseline at week 12 (85 days).
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End point type |
Secondary
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End point timeframe |
Up to Week 12.
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Change in Health Assessment Questionnaire – Disability Index score (HAQ-DI) | ||||||||||||
End point description |
Change in HAQ-DI score from baseline to Week 12.
The HAQ-DI assesses the functional status for performing activities of daily living and includes questions of fine movements of the upper extremity, locomotor activities of the lower extremity, and activities that involve both upper and lower extremities.
The HAQ-DI score ranged from 0 (0 = without any difficulty) to 3 (3 = worst functioning) and was calculated according to the HAQ manual based on the eight category scores and the use of aids/devices and/or help from another person when indicated.
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End point type |
Secondary
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End point timeframe |
From baseline to Week 12.
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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 |
Adverse events from the first trial-related activity, after the subject had signed the informed consent and until post treatment follow-up period.
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Assessment type |
Systematic | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
16.1
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Reporting groups
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Reporting group title |
NNC0114-0006
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Reporting group description |
Subjects received two doses of 12 mg/kg NNC0114-0006, 6 weeks apart as an i.v. infusion over a period of 30 minutes using an automated infusion pump. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Placebo
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Reporting group description |
Subjects received two doses of placebo 6 weeks apart as an i.v. infusion over a period of 30 minutes using an automated infusion pump. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Frequency threshold for reporting non-serious adverse events: 5% | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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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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22 May 2012 |
1. To remove tetanus toxoid immunisations as part of this trial due to sample size limitations for this pharmacodynamic assessment and logistical challenges of implementation. Sections and sentences related to the tetanus toxoid immunisation (non-investigational medical
product) have been deleted. 2. Other minor editorial revisions/changes. |
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04 Sep 2012 |
Included additional monitoring:
1. For tuberculosis at the end of trial.
2. For pregnancy at the second dosing visit (V5).
3. By increasing the minimum requirement post dosing follow-up at site to 4 hours, ensuring sufficient time to identify any acute reactions associated with trial product administration.
A change in International Trial Manager was also updated. |
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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. | |||
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