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A Combination Trial of Copaxone Plus Estriol in Relapsing Remitting Multiple Sclerosis (RRMS) (Estriol-MS)

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ClinicalTrials.gov Identifier: NCT00451204
Recruitment Status : Completed
First Posted : March 23, 2007
Results First Posted : June 16, 2016
Last Update Posted : June 16, 2016
Sponsor:
Collaborators:
Washington University School of Medicine
University of Texas Southwestern Medical Center
Ohio State University
University of Medicine and Dentistry of New Jersey
University of Chicago
University of Utah
Johns Hopkins University
University of Kansas Medical Center
University of Minnesota, MN
Mayo Clinic
University of Colorado, Aurora
University of New Mexico
University of Pennsylvania
Dartmouth-Hitchcock Medical Center
National Multiple Sclerosis Society
National Institutes of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Information provided by (Responsible Party):
Rhonda Voskuhl, University of California, Los Angeles

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Triple (Participant, Care Provider, Investigator);   Primary Purpose: Treatment
Condition Relapsing Remitting Multiple Sclerosis
Interventions Drug: Estriol
Drug: Placebo
Drug: Copaxone
Enrollment 158
Recruitment Details  
Pre-assignment Details  
Arm/Group Title Estriol Capsules Plus Copaxone Injections Placebo Capsules Plus Copaxone Injections
Hide Arm/Group Description Estriol: Estriol 8 mg capsule, once per day, duration of treatment is 2 years Placebo: Placebo capsule, once per day, treatment duration is 2 years
Period Title: Overall Study
Started 82 76
Completed 60 [1] 56
Not Completed 22 20
Reason Not Completed
Adverse Event             4             6
Lack of Efficacy             4             4
Lost to Follow-up             4             4
Protocol Violation             1             0
Patient refusal             8             4
Other             1             2
[1]
60 completed the study but 3 stopped study drug(s) early
Arm/Group Title Estriol Capsules Plus Copaxone Injections Placebo Capsules Plus Copaxone Injections Total
Hide Arm/Group Description Estriol: Estriol 8 mg capsule, once per day, duration of treatment is 2 years Placebo: Placebo capsule, once a day, treatment duration is 2 years Total of all reporting groups
Overall Number of Baseline Participants 82 76 158
Hide Baseline Analysis Population Description
Relapsing remitting multiple sclerosis women aged 18 to 50 years.
Age, Categorical  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 82 participants 76 participants 158 participants
<=18 years
0
   0.0%
0
   0.0%
0
   0.0%
Between 18 and 65 years
82
 100.0%
76
 100.0%
158
 100.0%
>=65 years
0
   0.0%
0
   0.0%
0
   0.0%
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 82 participants 76 participants 158 participants
37.7  (7.6) 37.1  (7.3) 37.4  (7.45)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 82 participants 76 participants 158 participants
Female
82
 100.0%
76
 100.0%
158
 100.0%
Male
0
   0.0%
0
   0.0%
0
   0.0%
Region of Enrollment  
Measure Type: Number
Unit of measure:  Participants
United States Number Analyzed 82 participants 76 participants 158 participants
82 76 158
1.Primary Outcome
Title Confirmed Relapse, Annualized Relapse Rate
Hide Description A confirmed relapse was defined as new neurological symptoms or worsening of pre-existing symptoms, lasting at least 48 hours in a subject who had been neurologically stable or improving in the previous 30 days, accompanied by objective change in the neurological examination (worsening of 0.5 points on the EDSS or worsening by 1.0 or more points on the pyramidal, cerebellar, brainstem or visual functional system scores), not due to fatigue alone and not associated with fever or infection.
Time Frame 24 months
Hide Outcome Measure Data
Hide Analysis Population Description
Included all as intention to treat
Arm/Group Title Estriol Capsules Plus Copaxone Injections Placebo Capsules Plus Copaxone Injections
Hide Arm/Group Description:
Estriol: Estriol 8 mg capsule, once per day, duration of treatment is 2 years
Placebo: Placebo capsule, once a day, treatment duration is 2 years
Overall Number of Participants Analyzed 82 76
Mean (95% Confidence Interval)
Unit of Measure: relapses per year
0.25
(0.17 to 0.37)
0.37
(0.25 to 0.53)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Estriol Capsules Plus Copaxone Injections, Placebo Capsules Plus Copaxone Injections
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.077
Comments [Not Specified]
Method negative binomial regression
Comments adjusted for age, BL EDSS score, # of relapses in previous 12 mo, time since dx, previous glatiramer acetate tx, and previous interferon beta tx.
Method of Estimation Estimation Parameter Rate ratio
Estimated Value 0.63
Confidence Interval (2-Sided) 95%
0.37 to 1.05
Estimation Comments [Not Specified]
2.Secondary Outcome
Title Relapse Event, Annualized Relapse Rate
Hide Description Met all criteria for relapse except not confirmed to have increase in EDSS by an independent examiner.
Time Frame 24 months
Hide Outcome Measure Data
Hide Analysis Population Description
Included all as intention to treat.
Arm/Group Title Estriol Capsules Plus Copaxone Injections Placebo Capsules Plus Copaxone Injections
Hide Arm/Group Description:
Estriol: Estriol 8 mg capsule, once per day, duration of treatment is 2 years
Placebo: Placebo capsule, once per day, treatment duration is 2 years
Overall Number of Participants Analyzed 82 76
Mean (95% Confidence Interval)
Unit of Measure: relapses per year
0.32
(0.22 to 0.46)
0.46
(0.32 to 0.65)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Estriol Capsules Plus Copaxone Injections, Placebo Capsules Plus Copaxone Injections
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.098
Comments [Not Specified]
Method negative binomial regression
Comments adjusted for age, BL EDSS score, # of relapses in previous 12 months, time since dx, previous GA treatment, and previous interferon beta treatment.
Method of Estimation Estimation Parameter Rate ratio
Estimated Value 0.65
Confidence Interval (2-Sided) 95%
0.39 to 1.08
Estimation Comments [Not Specified]
3.Secondary Outcome
Title Confirmed Relapse, Probability of First Relapse
Hide Description [Not Specified]
Time Frame 24 months
Hide Outcome Measure Data
Hide Analysis Population Description
All included as intention to treat
Arm/Group Title Estriol Capsules Plus Copaxone Injections Placebo Capsules Plus Copaxone Injections
Hide Arm/Group Description:
Estriol: Estriol 8 mg capsule, once per day, duration of treatment is 2 years
Placebo: Placebo capsule, once per day, treatment duration is 2 years
Overall Number of Participants Analyzed 82 76
Mean (95% Confidence Interval)
Unit of Measure: probability of relapse at 24 months
33.3
(23.8 to 45.4)
42.9
(32.1 to 55.5)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Estriol Capsules Plus Copaxone Injections, Placebo Capsules Plus Copaxone Injections
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.096
Comments [Not Specified]
Method negative binomial regression
Comments adjusted for age, BL EDSS score, # of relapses in previous 12 months, time since dx, previous GA treatment, and previous interferon beta treatment.
Method of Estimation Estimation Parameter Rate ratio
Estimated Value 0.63
Confidence Interval (2-Sided) 95%
0.36 to 1.09
Estimation Comments [Not Specified]
4.Secondary Outcome
Title Relapse Event, Probability of First Relapse Event
Hide Description [Not Specified]
Time Frame 24 months
Hide Outcome Measure Data
Hide Analysis Population Description
Included all as intention to treat
Arm/Group Title Estriol Capsules Plus Copaxone Injections Placebo Capsules Plus Copaxone Injections
Hide Arm/Group Description:
Estriol: Estriol 8 mg capsule, once per day, duration of treatment is 2 years
Placebo: Placebo capsule, once per day, treatment duration is 2 years
Overall Number of Participants Analyzed 82 76
Mean (95% Confidence Interval)
Unit of Measure: probability of relapse event at 24 mo
40.5
(30.0 to 53.0)
46.9
(35.9 to 59.3)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Estriol Capsules Plus Copaxone Injections, Placebo Capsules Plus Copaxone Injections
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.179
Comments [Not Specified]
Method negative binomial regression
Comments adjusted for age, BL EDSS score, # of relapses in previous 12 months, time since dx, previous GA treatment, and previous interferon beta treatment.
Method of Estimation Estimation Parameter Rate ratio
Estimated Value 0.70
Confidence Interval (2-Sided) 95%
0.42 to 1.17
Estimation Comments [Not Specified]
5.Other Pre-specified Outcome
Title Confirmed Relapse, Annualized Relapse Rate
Hide Description A confirmed relapse was defined as new neurological symptoms or worsening of pre-existing symptoms, lasting at least 48 hours in a subject who had been neurologically stable or improving in the previous 30 days, accompanied by objective change in the neurological examination (worsening of 0.5 points on the EDSS or worsening by 1.0 or more points on the pyramidal, cerebellar, brainstem or visual functional system scores), not due to fatigue alone and not associated with fever or infection.
Time Frame 12 months
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Estriol Capsules Plus Copaxone Injections Placebo Capsules Plus Copaxone Injections
Hide Arm/Group Description:
Estriol 8 mg capsule, once per day, duration of treatment is 2 years
Placebo capsule, once a day, treatment duration is 2 years
Overall Number of Participants Analyzed 82 76
Mean (95% Confidence Interval)
Unit of Measure: relapses per year
0.25
(0.16 to 0.40)
0.48
(0.33 to 0.69)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Estriol Capsules Plus Copaxone Injections, Placebo Capsules Plus Copaxone Injections
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.016
Comments [Not Specified]
Method negative binomial regression
Comments adjusted for age, BL EDSS score, # of relapses in previous 12 months, time since dx, previous GA treatment, and previous interferon beta treatment.
Method of Estimation Estimation Parameter Rate ratio
Estimated Value 0.49
Confidence Interval (2-Sided) 95%
0.28 to 0.88
Estimation Comments [Not Specified]
6.Other Pre-specified Outcome
Title Relapse Event, Annualized Relapse Rate
Hide Description Met all criteria for relapse except not confirmed to have increase in EDSS by an independent examiner.
Time Frame 12 months
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Estriol Capsules Plus Copaxone Injections Placebo Capsules Plus Copaxone Injections
Hide Arm/Group Description:
Estriol 8 mg capsule, once per day, duration of treatment is 2 years
Placebo capsule, once a day, treatment duration is 2 years
Overall Number of Participants Analyzed 82 76
Mean (95% Confidence Interval)
Unit of Measure: relapses per year
0.33
(0.22 to 0.50)
0.61
(0.44 to 0.84)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Estriol Capsules Plus Copaxone Injections, Placebo Capsules Plus Copaxone Injections
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.012
Comments [Not Specified]
Method negative binomial regression
Comments adjusted for age, BL EDSS score, # of relapses in previous 12 months, time since dx, previous GA treatment, and previous interferon beta treatment.
Method of Estimation Estimation Parameter Rate ratio
Estimated Value 0.52
Confidence Interval (2-Sided) 95%
0.31 to 0.86
Estimation Comments [Not Specified]
Time Frame After enrollment, during the 24-month treatment period
Adverse Event Reporting Description An adverse event is any condition that occurs after enrollment, whether or not considered related to study treatment.
 
Arm/Group Title Estriol Capsules Plus Copaxone Injections Placebo Capsules Plus Copaxone Injections
Hide Arm/Group Description Estriol: Estriol 8 mg capsule, once per day, duration of treatment is 2 years Placebo: Placebo capsule, once a day, treatment duration is 2 years
All-Cause Mortality
Estriol Capsules Plus Copaxone Injections Placebo Capsules Plus Copaxone Injections
Affected / at Risk (%) Affected / at Risk (%)
Total   --/--      --/--    
Show Serious Adverse Events Hide Serious Adverse Events
Estriol Capsules Plus Copaxone Injections Placebo Capsules Plus Copaxone Injections
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   8/82 (9.76%)      10/76 (13.16%)    
Cardiac disorders     
Heart Failure/ pace maker implantation   1/82 (1.22%)  1 0/76 (0.00%)  0
Eye disorders     
Migraine headache related eye pain   1/82 (1.22%)  1 0/76 (0.00%)  0
Infections and infestations     
Urinary Tract Infection   1/82 (1.22%)  1 1/76 (1.32%)  1
Acute appendicitis   0/82 (0.00%)  0 1/76 (1.32%)  1
Injury, poisoning and procedural complications     
car accident related body numbness   0/82 (0.00%)  0 1/76 (1.32%)  1
Investigations     
Accidentally took other's drug   0/82 (0.00%)  0 1/76 (1.32%)  1
Musculoskeletal and connective tissue disorders     
Right Knee Replacemebt   0/82 (0.00%)  0 1/76 (1.32%)  1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)     
B-cell lymphoma   0/82 (0.00%)  0 1/76 (1.32%)  1
Nervous system disorders     
MS Relapse (hospitalization)   2/82 (2.44%)  2 5/76 (6.58%)  6
Pregnancy, puerperium and perinatal conditions     
Pregnancy   2/82 (2.44%)  2 0/76 (0.00%)  0
Renal and urinary disorders     
Pyelonephritis   1/82 (1.22%)  1 0/76 (0.00%)  0
Indicates events were collected by systematic assessment
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 0%
Estriol Capsules Plus Copaxone Injections Placebo Capsules Plus Copaxone Injections
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   76/82 (92.68%)      67/76 (88.16%)    
Cardiac disorders     
Heart palpitation   2/82 (2.44%)  2 4/76 (5.26%)  4
Eye disorders     
Vision problem (blurry, double)   4/82 (4.88%)  6 7/76 (9.21%)  7
Gastrointestinal disorders     
Nausea/ vomitting   7/82 (8.54%)  9 5/76 (6.58%)  5
Gastroenteritis   5/82 (6.10%)  7 3/76 (3.95%)  4
General disorders     
Fatigue   13/82 (15.85%)  15 8/76 (10.53%)  10
Headache   9/82 (10.98%)  11 11/76 (14.47%)  12
GA injection systemic reaction (SOB, hot flashes)   7/82 (8.54%)  7 2/76 (2.63%)  2
Back Pain   4/82 (4.88%)  5 5/76 (6.58%)  5
Insomnia   4/82 (4.88%)  4 4/76 (5.26%)  4
Infections and infestations     
Upper respiratory Infection   22/82 (26.83%)  33 26/76 (34.21%)  38
Nervous system disorders     
Arm/ leg numbness, tingling   6/82 (7.32%)  7 7/76 (9.21%)  10
Dizziness   4/82 (4.88%)  5 7/76 (9.21%)  10
Psychiatric disorders     
Depression/ Anxiety   12/82 (14.63%)  14 9/76 (11.84%)  10
Renal and urinary disorders     
Urinary tract infection   15/82 (18.29%)  23 10/76 (13.16%)  16
Reproductive system and breast disorders     
Irregular menses/ spotting   19/82 (23.17%)  26 3/76 (3.95%)  4
Menstrual flow amount increased   11/82 (13.41%)  12 6/76 (7.89%)  8
Menstrual cramp   4/82 (4.88%)  4 4/76 (5.26%)  5
Vaginal infection   1/82 (1.22%)  1 8/76 (10.53%)  9
Uterus, endometrial thickness > 8mm (ultrasound)   24/82 (29.27%)  29 27/76 (35.53%)  36
Uterus, endometrial biopsies performed   9/82 (10.98%)  11 6/76 (7.89%)  8
Uterus, fibroibds (ultrasound)   8/82 (9.76%)  10 8/76 (10.53%)  11
Fibrocystic disease on clinical exam   5/82 (6.10%)  6 4/76 (5.26%)  5
Respiratory, thoracic and mediastinal disorders     
Sinusitis   6/82 (7.32%)  6 10/76 (13.16%)  14
Skin and subcutaneous tissue disorders     
GA injection area abnormalities   21/82 (25.61%)  25 12/76 (15.79%)  15
Shingles   2/82 (2.44%)  2 4/76 (5.26%)  4
Indicates events were collected by systematic assessment
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Dr. Rhonda Voskuhl
Organization: University of California Los Angeles
Phone: 310-206-4636
EMail: rvoskuhl@mednet.ucla.edu
Other Publications:
Layout table for additonal information
Responsible Party: Rhonda Voskuhl, University of California, Los Angeles
ClinicalTrials.gov Identifier: NCT00451204     History of Changes
Other Study ID Numbers: R01NS051591 ( U.S. NIH Grant/Contract )
R01NS051591 ( U.S. NIH Grant/Contract )
RG3915 ( Other Grant/Funding Number: NMSS )
First Submitted: March 22, 2007
First Posted: March 23, 2007
Results First Submitted: January 20, 2016
Results First Posted: June 16, 2016
Last Update Posted: June 16, 2016