Clinical Trial Results:
A Phase 2, Open-Label, Multicenter Study to Explore the Efficacy and Safety of Mongersen (GED-0301) in Subjects with Active Ulcerative Colitis (UC)
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Summary
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EudraCT number |
2015-003364-36 |
Trial protocol |
HU SK BG |
Global end of trial date |
08 Aug 2017
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Results information
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Results version number |
v1(current) |
This version publication date |
22 Aug 2018
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First version publication date |
22 Aug 2018
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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 |
GED-0301-UC-002
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT02601300 | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
Celgene Corporation
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Sponsor organisation address |
86 Morris Avenue, Summit, United States, 07901
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Public contact |
Clinical Trial Disclosure, Celgene Corporation, 01 888-260-1599, ClinicalTrialDisclosure@Celgene.com
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Scientific contact |
Guillermo Rossiter, Celgene Corporation, 01 9088976467, GRossiter@Celgene.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 Oct 2017
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Is this the analysis of the primary completion data? |
No
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Global end of trial reached? |
Yes
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Global end of trial date |
08 Aug 2017
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Was the trial ended prematurely? |
No
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General information about the trial
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Main objective of the trial |
The primary objective of the study was to explore the effect of mongersen (GED-0301) on clinical activity, as measured by the modified Mayo score (MMS) in subjects with active ulcerative colitis (UC).
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Protection of trial subjects |
This study was conducted in accordance with the guidelines of current Good Clinical Practice including the archiving of essential documents.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
09 Dec 2015
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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 |
Slovakia: 10
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Country: Number of subjects enrolled |
United States: 22
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Country: Number of subjects enrolled |
Bulgaria: 1
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Country: Number of subjects enrolled |
Canada: 6
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Country: Number of subjects enrolled |
Poland: 2
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Worldwide total number of subjects |
41
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EEA total number of subjects |
13
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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) |
40
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From 65 to 84 years |
1
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85 years and over |
0
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Recruitment
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Recruitment details |
Participants were enrolled at 21 study centers within the United States, Bulgaria, Poland, Slovakia and Canada. | ||||||||||||||||
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Pre-assignment
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Screening details |
Participants were 18 years of age and older with active ulcerative colitis for 3 months prior to screening, had a modified Mayo score (MMS) ≥ 4 to ≤ 9 absolute rectal bleeding (RBS) subscore ≥ 1 at screening, a mayo endoscopic subscore ≥ 2 at screening and must have had a therapeutic failure or been intolerant to other therapies. | ||||||||||||||||
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Period 1
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Period 1 title |
Induction Phase
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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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Mongersen (Weeks 0-8) | ||||||||||||||||
Arm description |
Participants received oral mongersen 160 mg tablets daily for 8 weeks during the induction phase. | ||||||||||||||||
Arm type |
Experimental | ||||||||||||||||
Investigational medicinal product name |
Mongersen
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Investigational medicinal product code |
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Other name |
GED-0301
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Pharmaceutical forms |
Film-coated tablet
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Routes of administration |
Oral use
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Dosage and administration details |
Mongersen 160 mg tablets by mouth daily for 8 weeks.
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Period 2
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Period 2 title |
Extension Phase
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Is this the baseline period? |
No | ||||||||||||||||
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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Mongersen (Weeks 8-52) | ||||||||||||||||
Arm description |
Participants received oral mongersen 160 mg tablets daily on an alternating dosing schedule for 4 weeks, followed by a 4 week break, (4 weeks on investigational product (IP) followed by 4 weeks off) for an additional 44 weeks. Participants who did not achieve at least a 20% decrease in partial Mayo score (PMS) from baseline at Week 12 were discontinued from the study. | ||||||||||||||||
Arm type |
Experimental | ||||||||||||||||
Investigational medicinal product name |
Mongersen
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Investigational medicinal product code |
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Other name |
GED-0301
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Pharmaceutical forms |
Film-coated tablet
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Routes of administration |
Oral use
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Dosage and administration details |
Mongersen 160 mg tablets daily on an alternating dosing schedule for 4 weeks, followed by a 4 week break, (4 weeks on investigational product followed by 4 weeks off) for an additional 44 weeks.
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| Notes [1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period. Justification: Three subjects did not enter the Extension Phase: 2 subjects due to lack of efficacy (these subjects experienced treatment-emergent SAEs of worsening of UC a few days after completing the Induction Phase and 1 subject due to withdrawal. |
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Baseline characteristics reporting groups
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Reporting group title |
Mongersen (Weeks 0-8)
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Reporting group description |
Participants received oral mongersen 160 mg tablets daily for 8 weeks during the induction phase. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Mongersen (Weeks 0-8)
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Reporting group description |
Participants received oral mongersen 160 mg tablets daily for 8 weeks during the induction phase. | ||
Reporting group title |
Mongersen (Weeks 8-52)
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Reporting group description |
Participants received oral mongersen 160 mg tablets daily on an alternating dosing schedule for 4 weeks, followed by a 4 week break, (4 weeks on investigational product (IP) followed by 4 weeks off) for an additional 44 weeks. Participants who did not achieve at least a 20% decrease in partial Mayo score (PMS) from baseline at Week 12 were discontinued from the study. | ||
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End point title |
Percentage of Participants Who Achieved Clinical Remission in the Modified Mayo Score (MMS) at Week 8 [1] | ||||||||
End point description |
Clinical remission was defined as a modified Mayo score of ≤ 2, with no individual subscore > 1, at Week 8. The MMS was based on a modification of the total Mayo score (TMS) which included the stool frequency, rectal bleeding, and endoscopic subscores of the TMS and excluded the Physician's Global Assessment (PGA) subscore, since this was a global measure that is subjective in nature. The MMS ranges from 0 to 9 points. The endoscopy subscores was centrally reviewed. Two-sided confidence intervals for the within-group percentage were based on the Wilson score method. The intent to treat (ITT) population included all subjects who received at least one dose of IP. The primary approach to handling missing data was non-responder imputation (NRI), where subjects who had insufficient data for response determination at Week 8 were considered non-responders for clinical remission.
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End point type |
Primary
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End point timeframe |
Baseline to Week 8
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| Notes [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: This is a one arm, open-label, Phase 2 study with only 41 subjects. No statistical analysis could be conducted for the treatment effect. |
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| No statistical analyses for this end point | |||||||||
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End point title |
Percentage of Participants Who Achieved a Modified Mayo Score of ≤ 2, with Rectal Bleeding Subscore of 0 and Stool Frequency Subscore and Mayo Endoscopic Subscore ≤ 1 at Week 8. | ||||||||
End point description |
A MMS was used to evaluate disease activity using 3 components: stool frequency, rectal bleeding and endoscopy; the MMS ranges from 0-9 with higher scores indicating greater disease severity.
SFS was defined as 0-3:
0 = Normal number of stools for patient
1 = 1-2 stools per day more than normal
2 = 3-4 stools more than normal
3 = ≥5 stools more than normal
RBS subscore (0-3) was defined as:
0 = No blood seen
1 = Streaks of blood in stool less than half time
2 = Obvious blood with stool most of the time
3 = Blood alone passes
Endoscopic subscore defined as:
0 = Normal or inactive disease
1 = Mild Disease (erythema, decreased vascular pattern, mild friability)
2 = Moderate Disease (marked erythema, lack of vascular pattern, friability erosions) 3 = Severe Disease (spontaneous bleeding, ulceration)
ITT population = subjects who received one dose of IP. NRI method was used where subjects who had insufficient data for response determination were considered non-responders
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End point type |
Secondary
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End point timeframe |
Baseline to Week 8
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| No statistical analyses for this end point | |||||||||
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End point title |
Percentage of Participants Who Achieved a Mayo Endoscopic Subscore of ≤ 1 at Week 8. | ||||||||
End point description |
A Mayo endoscopic subscore of ≤ 1 was assessed and evaluated in participants who achieved a Mayo endoscopic subscore at Week 8. The endoscopy subscore findings are defined as:
0 = Normal or inactive disease
1 = Mild Disease (erythema, decreased vascular pattern, mild friability)
2 = Moderate Disease (marked erythema, lack of vascular pattern, friability erosions)
3 = Severe Disease (spontaneous bleeding, ulceration)
The endoscopy scores were centrally reviewed. Two-sided 95% CIs for the within-group percentage were based on the Wilson score method. The ITT population included all participants who received at least one dose of IP. The primary approach to handling missing data was NRI method, where subjects who had insufficient data for response determination at Week 8 were considered non-responders for the Mayo endoscopic subscore.
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End point type |
Secondary
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End point timeframe |
Baseline to Week 8
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| No statistical analyses for this end point | |||||||||
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End point title |
Percentage of Participants Who Achieved a Mayo Endoscopic Subscore of ≤ 1 by Individual Segment at Week 8. | ||||||||||||||||||
End point description |
A Mayo endoscopic subscore by individual segment (rectum, sigmoid, descending colon, transverse colon, ascending colon/cecum) of ≤ 1 was evaluated at week 8.
The endoscopy subscore findings are defined as:
0 = Normal or inactive disease
1 = Mild Disease (erythema, decreased vascular pattern, mild friability)
2 = Moderate Disease (marked erythema, lack of vascular pattern, friability erosions)
3 = Severe Disease (spontaneous bleeding, ulceration)
The endoscopy scores were centrally reviewed. Two-sided 95% CIs for the within-group percentage were based on the Wilson score method. The ITT population included all participants who received at least one dose of IP. Only participants with sufficient data for response determination in each segment
were included in the analysis.
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End point type |
Secondary
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End point timeframe |
Baseline to Week 8
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| No statistical analyses for this end point | |||||||||||||||||||
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End point title |
Percentage of Participants Who Achieved a Clinical Response in the Modified Mayo Score at Week 8 | ||||||||
End point description |
Clinical response in the MMS was defined as a decrease from baseline in the MMS of at least 2 points and at least 25%, along with a reduction in the RBS of at least 1 point or an absolute RBS ≤ 1. The MMS was based on the stool frequency, rectal bleeding, and endoscopic subscores of the TMS and excluded the PGA subscore. The MMS ranges from 0 to 9 points. See endpoint #2. The RBS was defined as:
0 = No blood seen
1 = Streaks of blood with stool less than half the time
2 = Obvious blood with stool most of the time
3 = Blood alone passes
The daily bleeding score represents the most severe bleeding score represents the most severe bleeding of the day. The ITT population included all participants who received at least one dose of IP. The primary approach to handling missing data was NRI method, where subjects who had insufficient data for response determination at Week 8 were considered non-responders for clinical response in the MMS.
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End point type |
Secondary
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End point timeframe |
Baseline to Week 8
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| No statistical analyses for this end point | |||||||||
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End point title |
Percentage of Participants Who Achieved a Mayo Endoscopic Response at Week 8. | ||||||||
End point description |
Endoscopic response was defined as a decrease from baseline of at least 1 point in the Mayo endoscopic subscore. The Mayo endoscopy subscore findings are defined as:
0 = Normal or inactive disease
1 = Mild Disease (erythema, decreased vascular pattern, mild friability)
2 = Moderate Disease (marked erythema, lack of vascular pattern, friability erosions) 3 = Severe Disease (spontaneous bleeding, ulceration)
The endoscopy subscores were centrally reviewed. Two-sided 95% CIs for the within- group percentage were based on the Wilson score method. The ITT population included all participants who received at least one dose of IP. The primary approach to handling missing data was NRI method, where subjects who had insufficient data for response determination at Week 8 were considered non-responders for endoscopic response.
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End point type |
Secondary
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End point timeframe |
Baseline to Week 8
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| No statistical analyses for this end point | |||||||||
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End point title |
Percentage of Participants Who Achieved a Clinical Remission in the Total Mayo Score (TMS) at Week 8 | ||||||||
End point description |
Clinical remission in total mayo score was defined as a total mayo score of ≤ 2, with no individual subscore >1. The TMS is an instrument designed to measure disease activity of ulcerative colitis. The TMS ranges from 0 to 12 points. It consists of 4 subscores, each graded from 0 to 3 with higher scores indicating more severe disease.
• Stool frequency subscore
• Rectal bleeding subscore
• Endoscopic subscore
• Physician’s Global Assessment
The ITT population included all participants who received at least one dose of IP. The primary approach to handling missing data was NRI method, where subjects who had insufficient data for response determination at Week 8 were considered non-responders for clinical remission in the TMS.
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End point type |
Secondary
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End point timeframe |
Baseline to Week 8
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| No statistical analyses for this end point | |||||||||
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End point title |
Percentage of Participants Who Achieved a Clinical Response in the Total Mayo Score at Week 8 | ||||||||
End point description |
Clinical response in the TMS was defined as a decrease from baseline in the TMS of ≥ 3 points and ≥ 30%, along with a reduction in the RBS of ≥ 1 point or an absolute RBS of ≤ 1 at Week 8. The TMS is an instrument designed to measure disease activity of ulcerative colitis. The TMS ranges from 0 to 12 points. It consists of 4 subscores, each graded from 0 to 3 with higher scores indicating more severe disease.
• Stool frequency subscore
• Rectal bleeding subscore
• Endoscopic subscore
• Physician’s Global Assessment
The ITT population included all participants who received at least one dose of IP. The primary approach to handling missing data was NRI method, where subjects who had insufficient data for response determination at Week 8 were considered non-responders for clinical response in the TMS.
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End point type |
Secondary
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End point timeframe |
Baseline to Week 8
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| No statistical analyses for this end point | |||||||||
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End point title |
The Number of Participants Who Experienced Treatment Emergent Adverse Events (TEAE) | ||||||||||||||||||||||
End point description |
A TEAE was defined as any adverse event (AE) occurring or worsening on or after the first treatment of mongersen and up to 28 days after the last mongersen dose or the last follow-up date, whichever occurred earlier. A serious AE = any AE which results in death; is life-threatening; requires inpatient hospitalization or prolongation of existing hospitalization; results in persistent or significant disability/incapacity; is a congenital anomaly/birth defect; constitutes an important medical event. The severity of AEs was assessed by the investigator and based on the following scale: Mild = asymptomatic or mild symptoms; clinical or diagnostic observations only; Moderate = Symptoms cause moderate discomfort; Severe (could be non-serious or serious) = symptoms causing severe discomfort/pain. Safety population included all participants who were enrolled and received at least 1 dose of IP.
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End point type |
Secondary
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End point timeframe |
From the first day of mongersen until 28 days after the last dose of IP or follow-up visit, whichever occurred earlier; maximum duration of treatment was 56 weeks.
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| No statistical analyses for this end point | |||||||||||||||||||||||
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Adverse events information
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Timeframe for reporting adverse events |
From the first day of mongersen until 28 days after the last dose of IP or follow-up visit, whichever occurred earlier; maximum duration of treatment was 56 weeks.
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Assessment type |
Non-systematic | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
20.0
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Reporting groups
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Reporting group title |
Mongersen (Induction Phase: Weeks 0-8)
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Reporting group description |
Participants received oral mongersen 160 mg tablets daily for 8 weeks during the induction phase. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Mongersen (Extension Phase: Weeks 8-52)
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Reporting group description |
Participants received oral mongersen 160 mg tablets daily on an alternating dosing schedule for 4 weeks, followed by a 4-week break (4 weeks on investigational product (IP), followed by 4 weeks off) for an additional 44 weeks during the extension phase. Participants who did not achieve at least a 20% decrease in a partial Mayo score (PMS) from baseline at Week 12 were discontinued from the study. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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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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05 Oct 2015 |
• Optional intensive PK sampling was added.
Intensive PK data have shown negligible absorption in subjects with CD but no PK data are available in subjects with active UC. Intensive PK sampling was conducted at Week 4 in a subset of subjects in addition to sparse PK sampling to monitor systemic absorption of GED-0301 in the UC population.
• Individual subject and overall study stopping criteria were added.
The primary purpose of this protocol amendment was to add individual subject and overall study stopping criteria based on the known safety profile of GED-0301 and potential AEs known to be associated with antisense deoxynucleotides that would result in withdrawal of a subject from the study or in study termination.
• The definition of UC treatment failure and intolerance was modified.
The definition of treatment failure for TNF-α blockers was revised to be consistent with the approved dosing regimen in the product labeling. |
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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 | |||
