Clinical Trial Results:
A Phase 3 Randomized, Double-Blind, Placebo-Controlled Trial to Study the Efficacy and Safety of MK-8342B (ENG-E2 Vaginal Ring) in Women with Moderate to Severe Primary Dysmenorrhea (with Optional Extension)
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Summary
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EudraCT number |
2015-004325-14 |
Trial protocol |
DE FI |
Global end of trial date |
07 Sep 2016
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Results information
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Results version number |
v1(current) |
This version publication date |
18 May 2018
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First version publication date |
18 May 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 |
8342B-059
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT02668783 | ||
WHO universal trial number (UTN) |
- | ||
Other trial identifiers |
Merck Protocol Number: MK-8342B-059 | ||
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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 |
07 Sep 2016
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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 |
07 Sep 2016
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Was the trial ended prematurely? |
Yes
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General information about the trial
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Main objective of the trial |
The purpose of this study is to assess the etonogestrel (ENG) + 17β-estradiol (E2) vaginal ring's efficacy compared to a placebo vaginal ring in the treatment of dysmenorrhea at Treatment Cycle 2. In addition, this study will assess the safety and tolerability of the ENG-E2 vaginal rings. Primary hypothesis: Relative to the placebo ring, the ENG-E2 vaginal ring results in a greater proportion of participants with a ≥3 point reduction in peak pelvic pain score and no increase in the number of rescue pain relief (ibuprofen) tablets taken at Treatment Cycle 2 as compared to baseline.
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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 |
11 Feb 2016
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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 |
Finland: 2
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Country: Number of subjects enrolled |
Russian Federation: 5
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Country: Number of subjects enrolled |
United States: 18
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Worldwide total number of subjects |
25
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EEA total number of subjects |
2
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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) |
25
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From 65 to 84 years |
0
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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 25 participants were randomized, with 24 participants receiving study treatment. | ||||||||||||||||||||||||||||||
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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 | ||||||||||||||||||||||||||||||
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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ENG-E2 125 μg/300 μg | ||||||||||||||||||||||||||||||
Arm description |
Participants received 4 cycles (or 6 cycles if also participating in the extension) of ENG-E2 125 μg/300 μg. Each cycle consisted of 21 days of vaginal ring use followed by 7 ring-free days. | ||||||||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||||||||
Investigational medicinal product name |
Etonogestrel (ENG) 125μg + 17β-estradiol (E2) 300 μg vaginal ring
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Vaginal delivery system
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Routes of administration |
Vaginal use
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Dosage and administration details |
Up to 4 cycles (or 6 cycles if also participating in the extension) of ENG-E2 125 μg/300 μg administered intravaginally. Each cycle will consist of 21 days of vaginal ring use followed by 7 ring-free days.
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Investigational medicinal product name |
Ibuprofen
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Tablet
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Routes of administration |
Oral use
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Dosage and administration details |
Ibuprofen tablets, to be taken orally, will be provided for use as rescue medication for dysmenorrhea treatment throughout the study. Participants may take 400 mg every 4 hours as needed for pelvic pain/cramping, or as instructed by their physician according to local labeling for relief of menstrual pain.
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Arm title
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Placebo | ||||||||||||||||||||||||||||||
Arm description |
Participants received 4 cycles (or 6 cycles if also participating in the extension) of placebo. Each cycle consisted of 21 days of placebo vaginal ring use followed by 7 ring-free days. | ||||||||||||||||||||||||||||||
Arm type |
Placebo | ||||||||||||||||||||||||||||||
Investigational medicinal product name |
Placebo vaginal ring
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Vaginal delivery system
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Routes of administration |
Vaginal use
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Dosage and administration details |
Up to 4 cycles (or 6 cycles if also participating in the extension) of placebo administered intravaginally. Each cycle will consist of 21 days of vaginal ring use followed by 7 ring-free days.
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Investigational medicinal product name |
Ibuprofen
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Tablet
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Routes of administration |
Oral use
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Dosage and administration details |
Ibuprofen tablets, to be taken orally, will be provided for use as rescue medication for dysmenorrhea treatment throughout the study. Participants may take 400 mg every 4 hours as needed for pelvic pain/cramping, or as instructed by their physician according to local labeling for relief of menstrual pain.
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Baseline characteristics reporting groups
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Reporting group title |
ENG-E2 125 μg/300 μg
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Reporting group description |
Participants received 4 cycles (or 6 cycles if also participating in the extension) of ENG-E2 125 μg/300 μg. Each cycle consisted of 21 days of vaginal ring use followed by 7 ring-free days. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Placebo
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Reporting group description |
Participants received 4 cycles (or 6 cycles if also participating in the extension) of placebo. Each cycle consisted of 21 days of placebo vaginal ring use followed by 7 ring-free days. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
ENG-E2 125 μg/300 μg
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Reporting group description |
Participants received 4 cycles (or 6 cycles if also participating in the extension) of ENG-E2 125 μg/300 μg. Each cycle consisted of 21 days of vaginal ring use followed by 7 ring-free days. | ||
Reporting group title |
Placebo
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Reporting group description |
Participants received 4 cycles (or 6 cycles if also participating in the extension) of placebo. Each cycle consisted of 21 days of placebo vaginal ring use followed by 7 ring-free days. | ||
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End point title |
Percentage of participants with ≥3 point reduction in peak pelvic pain score and no increase in number of ibuprofen tablets taken at Treatment Cycle 2, compared to baseline. [1] | |||||||||
End point description |
Participants rated pain/cramps in past 24 hours from 0 (none) to 10 (extreme) and reported number of ibuprofen tablets taken during 4-day cramping window. Peak pelvic pain score was defined as highest daily score in cycle cramping window. Baseline peak pelvic pain score (average of 2 scores) and baseline number (average) of ibuprofen tablets taken were defined during the cramping windows of 2 menstruations in screening period. Percentage of participants with reduction in peak pelvic pain score of ≥3 points and no increase in the use of ibuprofen at Cycle 2 compared to baseline was to be presented. Analysis Population: was to include all participants in whom a vaginal ring was inserted, with ≥1 day of diary entry in a 4-day cramping window during both a baseline & treatment cycle. Due to termination, a blinded independent committee to set cramping windows was not assembled, cramping windows were not determined & efficacy data could not be analyzed.
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End point type |
Primary
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End point timeframe |
Baseline 4-day cramping window and Treatment Cycle 2 4-day cramping window, as determined by committee for each participant
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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: Efficacy data could not be analyzed as cramping windows were not determined due to early trial termination. |
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| Notes [2] - Trial terminated before determination of cramping windows; efficacy data could not be analyzed. [3] - Trial terminated before determination of cramping windows; efficacy data could not be analyzed. |
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| No statistical analyses for this end point | ||||||||||
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End point title |
Number of participants who experienced an adverse event (AE) [4] | |||||||||
End point description |
An AE was defined as any unfavorable and unintended change in the structure, function, or chemistry of the body temporally associated with the use of the study treatment, whether or not considered related to the use of study treatment. The number of participants who experienced an AE is presented. Analysis Population: all randomized participants in whom a vaginal ring was inserted.
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End point type |
Primary
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End point timeframe |
Up to approximately 158 days
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| Notes [4] - 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: Statistical analyses were not conducted for this safety endpoint due to early trial termination. |
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| No statistical analyses for this end point | ||||||||||
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End point title |
Number of participants who discontinued treatment due to an AE [5] | |||||||||
End point description |
An AE was defined as any unfavorable and unintended change in the structure, function, or chemistry of the body temporally associated with the use of the study treatment, whether or not considered related to the use of study treatment. The number of participants who discontinued study treatment due to an AE is presented. Analysis Population: all randomized participants in whom a vaginal ring was inserted.
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End point type |
Primary
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End point timeframe |
Up to approximately 128 days
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| Notes [5] - 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: Statistical analyses were not conducted for this safety endpoint due to early trial termination. |
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| No statistical analyses for this end point | ||||||||||
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End point title |
Change from baseline in peak pelvic pain score at Treatment Cycle 2 | ||||||||||||
End point description |
Participants were asked to rate their worst pain or cramps in the past 24 hours on a scale of 0 to 10 (0=No pain or cramps to 10=Extreme pain or cramps). The peak pelvic pain score was to be calculated as the highest (daily) pelvic pain score observed within the 4-day cramping window of the cycle. The baseline peak pelvic pain score was to be defined as the mean value of the 2 peak pelvic pain scores during the cramping window of each of the 2 menstruations during the screening period. The change from baseline in peak pelvic pain score at Treatment Cycle 2 was to be presented. Analysis Population: was to consist of all participants in whom a vaginal ring was inserted & who had ≥1 day of diary entry each within 4-day cramping window during a baseline & a treatment cycle. Due to termination, a blinded independent committee to determine cramping windows was not assembled, cramping windows were not determined & efficacy data could not be analyzed.
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End point type |
Secondary
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End point timeframe |
Baseline 4-day cramping window and Treatment Cycle 2 4-day cramping window, as determined by committee for each participant
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| Notes [6] - Trial terminated before determination of cramping windows; efficacy data could not be analyzed. [7] - Trial terminated before determination of cramping windows; efficacy data could not be analyzed. |
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Change from baseline in the number of days with no impact on items of Physical, Work/School and Social/Leisure Activities at Treatment Cycle 2 | ||||||||||||
End point description |
Participants indicated how much pain/cramps limited their physical, work/school and social/leisure activities over the previous 24 hours. The level of negative impact of dysmenorrhea on daily life was scored on a 5-point scale (0=Not at all to 4=Extremely impacted). For each of the 3 items, baseline was defined as mean value obtained from the 2 menstruations during the screening period. Change from baseline to Treatment Cycle 2 in the number of days during the cramping window with no impact of dysmenorrhea (score = 0) on each of the following items was to be presented: work/school, physical, and leisure/social activities. Analysis Population: was to include all participants in whom a vaginal ring was inserted & who had ≥1 day of diary entry each in a 4-day cramping window during a baseline & a treatment cycle. Due to termination, a blinded independent committee to determine cramping windows was not assembled, cramping windows were not determined & efficacy data could not be analyzed.
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End point type |
Secondary
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End point timeframe |
Baseline 4-day cramping window and Treatment Cycle 2 4-day cramping window, as determined by committee for each participant
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| Notes [8] - Trial terminated before determination of cramping windows; efficacy data could not be analyzed. [9] - Trial terminated before determination of cramping windows; efficacy data could not be analyzed. |
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Percentage of participants with pelvic pain score of "0" or "1" and no use of ibuprofen tablets at Treatment Cycle 2 | |||||||||
End point description |
Participants were asked to rate their worst pain or cramps on a scale of 0 to 10 (0=No pain or cramps to 10=Extreme pain or cramps) and to indicate the number of ibuprofen tablets they took during the 4-day cramping window. The percentage of participants with no or minimal pelvic pain (score of “0” or “1”) and no use of ibuprofen at Treatment Cycle 2 was to be presented. Analysis Population: was to consist of all participants in whom a vaginal ring was inserted & who had ≥1 day of diary entry each within a 4-day cramping window during Treatment Cycle 2. Due to termination, a blinded independent committee to determine cramping windows was not assembled, cramping windows were not determined & efficacy data could not be analyzed.
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End point type |
Secondary
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End point timeframe |
Treatment Cycle 2 4-day cramping window, as determined by committee for each participant
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| Notes [10] - Trial terminated before determination of cramping windows; efficacy data could not be analyzed. [11] - Trial terminated before determination of cramping windows; efficacy data could not be analyzed. |
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| No statistical analyses for this end point | ||||||||||
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End point title |
Percentage of participants with ≥3 point reduction in peak pelvic pain score and a decrease in ibuprofen tablet intake at Treatment Cycle 2, compared to baseline | |||||||||
End point description |
Participants rated worst pain/cramps in past 24 hours from 0 (None) to 10 (Extreme) and indicated the number of ibuprofen tablets taken during the 4-day cramping window. Baseline peak pelvic pain score and number of ibuprofen tablets taken were respectively defined as mean value of the 2 peak pelvic pain scores and mean number of ibuprofen tablets taken during the cramping window of each of the 2 menstruations during screening period. Percentage of participants with a reduction in peak pelvic pain score of ≥3 points and a decrease in the use of ibuprofen at Treatment Cycle 2 as compared to baseline was to be presented. Analysis Population: was to include all participants in whom a vaginal ring was inserted & who had ≥1 day of diary entry each within a 4-day cramping window during a baseline & treatment cycle. Due to termination, a blinded independent committee to determine cramping windows was not assembled, cramping windows were not determined & efficacy data could not be analyzed.
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End point type |
Secondary
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End point timeframe |
Baseline 4-day cramping window and Treatment Cycle 2 4-day cramping window, as determined by committee for each participant
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| Notes [12] - Trial terminated before determination of cramping windows; efficacy data could not be analyzed. [13] - Trial terminated before determination of cramping windows; efficacy data could not be analyzed. |
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| No statistical analyses for this end point | ||||||||||
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End point title |
Change from baseline in mean pelvic pain score at Treatment Cycle 2 | ||||||||||||
End point description |
The mean pelvic pain score was to be calculated as the mean of the highest scores for pelvic pain observed within the 4-day cramping window of the screening or treatment cycle. The baseline mean pelvic pain score was to be defined as the mean value of the 2 mean pelvic pain scores of the 2 menstruations during the screening period. The change from baseline in mean pelvic pain score at Treatment Cycle 2 was to be presented. Analysis Population: was to consist of all participants in whom a vaginal ring was inserted & who had ≥1 day of diary entry each within a 4-day cramping window during a baseline & a treatment cycle. Due to termination, a blinded independent committee to determine cramping windows was not assembled, cramping windows were not determined & efficacy data could not be analyzed.
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End point type |
Secondary
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End point timeframe |
Baseline 4-day cramping window and Treatment Cycle 2 4-day cramping window, as determined by committee for each participant
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| Notes [14] - Trial terminated before determination of cramping windows; efficacy data could not be analyzed. [15] - Trial terminated before determination of cramping windows; efficacy data could not be analyzed. |
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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 approximately 158 days
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Adverse event reporting additional description |
All randomized participants in whom a vaginal ring was inserted.
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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 |
19.0
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Reporting groups
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Reporting group title |
Placebo
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Reporting group description |
Participants received 4 cycles (or 6 cycles if also participating in the extension) of placebo. Each cycle consisted of 21 days of placebo vaginal ring use followed by 7 ring-free days. | |||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
ENG-E2 125 microgram/300 microgram
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Reporting group description |
Participants received 4 cycles (or 6 cycles if also participating in the extension) of ENG-E2 125 μg/300 μg. Each cycle consisted of 21 days of vaginal ring use followed by 7 ring-free days. | |||||||||||||||||||||||||||||||||||||||||||||
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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? No | |||||||
Interruptions (globally) |
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| Were there any global interruptions to the trial? Yes | |||||||
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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. | |||||||
| Study terminated by Sponsor as a result of a business decision to discontinue the development program for MK-8342B for reasons unrelated to safety or efficacy. | |||||||
