Clinical Trial Results:
Open-Label, Phase 4 Study, Investigating the Incidence of Extra-Articular Manifestations in Subjects With Ankylosing Spondylitis Treated With Golimumab; Protocol No. MK-8259-012
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Summary
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EudraCT number |
2012-002458-21 |
Trial protocol |
NL |
Global end of trial date |
30 Apr 2015
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Results information
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Results version number |
v2(current) |
This version publication date |
04 Aug 2016
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First version publication date |
04 May 2016
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Other versions |
v1 |
Version creation reason |
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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 |
MK-8259-012
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT01668004 | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
Merck Sharp & Dohme Corp.
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Sponsor organisation address |
2000 Galloping Hill Road, Kenilworth, NJ, United States, 07033
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Public contact |
Clinical Trials Disclosure, Merck Sharp & Dohme Corp., ClinicalTrialsDisclosure@merck.com
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Scientific contact |
Clinical Trials Disclosure, Merck Sharp & Dohme Corp., ClinicalTrialsDisclosure@merck.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 |
30 Apr 2015
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
30 Apr 2015
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Global end of trial reached? |
Yes
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Global end of trial date |
30 Apr 2015
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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 objective of this study is to determine the difference in the annual incidence rate of uveitis attacks in participants with ankylosing spondylitis (AS) before start initial anti-TNF therapy and after treatment with golimumab (GLM).
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Protection of trial subjects |
This study was conducted in conformance with Good Clinical Practice standards and applicable country and/or local statutes and regulations regarding ethical committee review, informed consent, and the protection of human subjects participating in biomedical research.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
03 Sep 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 |
Netherlands: 101
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Worldwide total number of subjects |
101
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EEA total number of subjects |
101
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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) |
94
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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 |
- | ||||||||||||||||||||
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Pre-assignment
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Screening details |
A total of 104 participants were screened; 3 participants were screen failures who did not enroll. | ||||||||||||||||||||
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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 | ||||||||||||||||||||
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Arms
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Arm title
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GLM 50 mg | ||||||||||||||||||||
Arm description |
GLM given subcutaneously at a dose of 50 mg once monthly for up to 12 months | ||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||
Investigational medicinal product name |
Golimumab
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Investigational medicinal product code |
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Other name |
Simponi®
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Pharmaceutical forms |
Solution for injection in pre-filled pen
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Routes of administration |
Subcutaneous use
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Dosage and administration details |
GLM 50 mg subcutaneously once monthly.
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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 |
GLM 50 mg
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Reporting group description |
GLM given subcutaneously at a dose of 50 mg once monthly for up to 12 months | ||
Subject analysis set title |
Before initial anti-TNF/GLM treatment
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Subject analysis set type |
Per protocol | ||
Subject analysis set description |
Historical observation period: Retrospective record review over the 12 months prior to the initial anti-TNF treatment (anti-TNF experienced participants) or the first GLM dose (anti-TNF naïve participants).
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Subject analysis set title |
After GLM treatment start
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Subject analysis set type |
Per protocol | ||
Subject analysis set description |
GLM observation period: Prospective follow-up of participants given GLM subcutaneously at a dose of 50 mg once monthly for up to 12 months
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End point title |
Occurence Rate of Uveitis Attacks in Participants Before Anti-TNF/GLM Treatment and After the Start of GLM Treatment | ||||||||||||
End point description |
Uveitis is an extra-articular manifestation of ankylosing spondylitis (AS) involving inflammation of the eye. The occurrence rate (assessed as present/absent) of uveitis attacks was determined over two 1-year long periods regardless of whether the event started during the assessed year: 1) the historical observation period consisting of the year before initial anti-TNF treatment (for anti-TNF experienced participants) or prior to first GLM dose (for anti-TNF naïve participants); and 2) the GLM observation period consisting of the year after first GLM dose. All participants who received at least 3 months of GLM in the study and at least 3 months of follow-up data available for analysis of the endpoint.
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End point type |
Primary
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End point timeframe |
Twelve Months Prior to Enrollment to Study Month 12
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Statistical analysis title |
Treatment Comparison | ||||||||||||
Statistical analysis description |
Treatment comparison of uveitis occurrence rate assessed 1 year before initial anti-TNF/GLM treatment and 1 year after start of GLM treatment
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Comparison groups |
Before initial anti-TNF/GLM treatment v After GLM treatment start
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Number of subjects included in analysis |
186
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Analysis specification |
Pre-specified
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Analysis type |
other [1] | ||||||||||||
P-value |
= 1 | ||||||||||||
Method |
Mcnemar | ||||||||||||
Confidence interval |
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| Notes [1] - Number of subjects included in analysis: N=93 |
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End point title |
Annual Incidence Rate of New Uveitis Attacks in Participants Before Anti-TNF/GLM Treatment and After the Start of GLM Treatment | ||||||||||||
End point description |
Uveitis is an extra-articular manifestation of AS involving inflammation of the eye. The annual incidence rate of new uveitis attacks was determined over two 1-year long periods: 1) the historical observation period consisting of the year before initial anti-TNF treatment (for anti-TNF experienced participants) or prior to first GLM dose (for anti-TNF naïve participants); & 2) the GLM observation period consisting of the year after first GLM dose. All participants were counted as contributing a full year of GLM exposure even if discontinuing early. Due to ongoing uveitis cases at time of period entry, participants did not have the same risk of new events during the one year periods. Participants with ongoing uveitis at start of GLM who had the adverse event for the entire treatment period were counted as having the 'new attack' before & no “new attack” after GLM treatment start. All participants receiving at least 3 months of GLM with at least 3 months of follow-up data were included
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End point type |
Primary
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End point timeframe |
Twelve Months Prior to Enrollment to Study Month 12
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| Notes [2] - One participant for whom the timing of uveitis events could not be determined was excluded. [3] - One participant for whom the timing of uveitis events could not be determined was excluded. |
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Statistical analysis title |
Statistical Comparison | ||||||||||||
Statistical analysis description |
Treatment difference (expressed as ratio) in uveitis incidence rate assessed 1 year before initial anti-TNF/GLM treatment and 1 year after start of GLM treatment
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Comparison groups |
Before initial anti-TNF/GLM treatment v After GLM treatment start
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Number of subjects included in analysis |
184
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Analysis specification |
Pre-specified
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Analysis type |
other [4] | ||||||||||||
P-value |
< 0.0001 | ||||||||||||
Method |
Generalized estimating equation | ||||||||||||
Parameter type |
Treatment Ratio | ||||||||||||
Point estimate |
4.5
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
3.86 | ||||||||||||
upper limit |
5.25 | ||||||||||||
| Notes [4] - Number of subjects included in analysis: N=92 |
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End point title |
Annual Incidence Rate of New-Onset or Flares of Inflammatory Bowel Disease (IBD) and Psoriasis in Participants Before Anti-TNF/GLM Treatment and After the Start of GLM Treatment | |||||||||
End point description |
IBD (Crohn's disease or ulcerative colitis) and psoriaris are extra-articular manifestations of AS involving the intestinal tract and skin, respectively. The annual incidence rates of new-onset or flares of IBD and psoriasis were to be determined separately (i.e., for each condition) over two 1-year long periods: 1) the historical observation period consisting of the year before initial anti-TNF treatment (for anti-TNF experienced participants) or prior to first GLM dose (for anti-TNF naïve participants); and 2) the GLM observation period consisting of the year after first GLM dose. The incidence rates for new onset or flares of IBD and psoriasis could not be evaluated due to limitations of the data collected; occurrence of flares was not collected (specifically, history of IBD and/or psoriasis could not be distinguished from flares of IBD and/or psoriasis) and, therefore, results could not be determined.
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End point type |
Secondary
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End point timeframe |
Twelve Months Prior to Enrollment to Study Month 12
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| Notes [5] - Results not provided due to limitations of data collected. [6] - Results not provided due to limitations of data collected. |
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| No statistical analyses for this end point | ||||||||||
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End point title |
Percentage of Bath Ankylosing Spondylitis Disease Activity Index 50 (BASDAI 50) Responders Following Treatment With GLM | ||||||||
End point description |
The percentage of participants with a BASDAI 50 response (defined as a 50% improvement or as an absolute improvement of 2 points in their BASDAI physical function score) at three months was determined. The BASDAI consists of total of six visual analog scales (VAS): five VAS (0 to 10 cm; increasing severity) measuring severity of fatigue, spinal pain, peripheral joint pain or swelling, localized tenderness, and severity of morning stiffness and one VAS (0 to 10 cm; increasing duration up to 2 hours) measuring duration of morning stiffness. The morning stiffness scores are averaged and summed with the scores for the remaining four items resulting in a composite score (0-50); the final BASDAI score (0-10) is derived by dividing by 5. All participants who received at least 3 months of GLM in the study and at least 3 months of follow-up data available for analysis of the endpoint (BASDAI 50).
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End point type |
Secondary
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End point timeframe |
Baseline (BL), Study Month 3
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| No statistical analyses for this end point | |||||||||
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End point title |
Percentage of Ankylosing Spondylitis Disease Activity Score (ASDAS) Responders Following Treatment With GLM | ||||||||||||
End point description |
The percentage of participants with ASDAS clinically important improvement (ASDAS-CII; ≥ 1.1 units) & major improvement (ASDAS-MI; ≥ 2.0 units) at 3 months were determined. The ASDAS incorporates three items from the BASDAI (spinal pain, duration of morning stiffness, & peripheral joint pain or swelling) each assessed on a VAS (0 to 10 cm; increasing severity) as well as patient global assessment of disease activity (VAS; 0 to 10 cm; increasing severity) & a laboratory measure of inflammation (CRP level [mg/L] or ESR [mm/hr]). ASDAS was calculated using the formula: 0.12*Spinal Pain + 0.06*Duration of Morning Stiffness + 0.11*Patient Global + 0.07*Peripheral Pain/Swelling + 0.58*ln(CRP (mg/L) +1). A decrease in ASDAS at 3 months relative to BL signifies an improvement in physical function; ASDAS-MI signifies a comparatively greater improvement in physical function than ASDAS-CII. All participants receiving at least 3 months of GLM with at least 3 months of follow-up data included.
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End point type |
Secondary
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End point timeframe |
BL, Study Month 3
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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 |
Up to one year
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Adverse event reporting additional description |
All safety analyses were performed on the All Treated Set defined as all patients who received at least one dose of golimumab in the study. Only safety data during the GLM period was collected.
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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 |
GLM 50 mg
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Reporting group description |
GLM given subcutaneously at a dose of 50 mg once monthly for up to 12 months | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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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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14 Feb 2013 |
Amendment 1 included changes to procedure for collection of retrospective 12 month data, pregnancy test procedure, and Pain and Patient Global Disease Activity assessment procedure. |
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05 Aug 2013 |
Amendment 2 included changes to echocardiography and other heart-related procedures performed within two weeks after first study drug administration. |
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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 | |||
