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Treatment of Graves' Orbitopathy (Thyroid Eye Disease) to Reduce Proptosis With Teprotumumab Infusions in a Randomized, Placebo-Controlled, Clinical Study (OPTIC)

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ClinicalTrials.gov Identifier: NCT03298867
Recruitment Status : Completed
First Posted : October 2, 2017
Results First Posted : March 10, 2020
Last Update Posted : April 8, 2021
Sponsor:
Information provided by (Responsible Party):
Horizon Pharma USA, Inc.

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor);   Primary Purpose: Treatment
Conditions Thyroid Eye Disease
Graves' Orbitopathy
Interventions Biological: Teprotumumab
Other: Placebo
Enrollment 83
Recruitment Details  
Pre-assignment Details Results data presented corresponds to the completion of the Double-Masked Treatment Period (last patient last visit, 13 February 2019; data cut-off date, 19 February 2019).
Arm/Group Title Placebo Teprotumumab 20 mg/kg
Hide Arm/Group Description Eight infusions of placebo every 3 weeks (q3W) for a total of 21 weeks. Eight infusions of teprotumumab every q3W for a total of 21 weeks. Teprotumumab 10 mg/kg administered on Day 1 and teprotumumab 20 mg/kg administered q3W for the remaining 7 infusions.
Period Title: Overall Study
Started 42 41
Completed [1] 40 39
Not Completed 2 2
Reason Not Completed
Did not Continue in the Follow-Up Period             2             1
Continued in the Follow-Up Period             0             1
[1]
Completed Double-Masked Treatment Period
Arm/Group Title Placebo Teprotumumab 20 mg/kg Total
Hide Arm/Group Description Eight infusions of placebo q3W for a total of 21 weeks. Eight infusions of teprotumumab q3W for a total of 21 weeks. Teprotumumab 10 mg/kg administered on Day 1 and teprotumumab 20 mg/kg administered q3W for the remaining 7 infusions. Total of all reporting groups
Overall Number of Baseline Participants 42 41 83
Hide Baseline Analysis Population Description
[Not Specified]
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 42 participants 41 participants 83 participants
48.9  (12.96) 51.6  (12.63) 50.2  (12.79)
Age, Customized  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 42 participants 41 participants 83 participants
<65 years
38
  90.5%
32
  78.0%
70
  84.3%
≥65 years
4
   9.5%
9
  22.0%
13
  15.7%
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 42 participants 41 participants 83 participants
Female
31
  73.8%
29
  70.7%
60
  72.3%
Male
11
  26.2%
12
  29.3%
23
  27.7%
Ethnicity (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 42 participants 41 participants 83 participants
Hispanic or Latino
1
   2.4%
2
   4.9%
3
   3.6%
Not Hispanic or Latino
41
  97.6%
39
  95.1%
80
  96.4%
Unknown or Not Reported
0
   0.0%
0
   0.0%
0
   0.0%
Race/Ethnicity, Customized  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 42 participants 41 participants 83 participants
Asian
1
   2.4%
2
   4.9%
3
   3.6%
Black or African American
2
   4.8%
4
   9.8%
6
   7.2%
White
37
  88.1%
35
  85.4%
72
  86.7%
More Than 1 Race
2
   4.8%
0
   0.0%
2
   2.4%
Tobacco use status - as randomized  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 42 participants 41 participants 83 participants
Non-User
33
  78.6%
32
  78.0%
65
  78.3%
User
9
  21.4%
9
  22.0%
18
  21.7%
Tobacco use status - actual   [1] 
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 42 participants 41 participants 83 participants
Non-User
34
  81.0%
32
  78.0%
66
  79.5%
User
8
  19.0%
9
  22.0%
17
  20.5%
[1]
Measure Description: Actual tobacco use status reflects the status as reported on the substance use case report form. One participant was randomized in error to the tobacco user stratum as this subject was reported as a non-user (former tobacco use status) on the substance use case report form.
1.Primary Outcome
Title Percentage of Participants Who Were Proptosis Responders at Week 24
Hide Description Proptosis responders were defined as participants with a ≥2 mm reduction from Baseline in proptosis in the study eye, without deterioration (≥2 mm increase) of proptosis in the fellow eye at Week 24.
Time Frame Week 24
Hide Outcome Measure Data
Hide Analysis Population Description
Intent-to-treat population: all randomized participants.
Arm/Group Title Placebo Teprotumumab 20 mg/kg
Hide Arm/Group Description:
Eight infusions of placebo q3W for a total of 21 weeks.
Eight infusions of teprotumumab q3W for a total of 21 weeks. Teprotumumab 10 mg/kg administered on Day 1 and teprotumumab 20 mg/kg administered q3W for the remaining 7 infusions.
Overall Number of Participants Analyzed 42 41
Measure Type: Number
Unit of Measure: percentage of participants
9.5 82.9
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Teprotumumab 20 mg/kg
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments Two-sided p-value calculated assuming the test statistic was distributed as a standard normal random variable.
Method Cochran-Mantel-Haenszel
Comments [Not Specified]
Method of Estimation Estimation Parameter Stratified difference
Estimated Value 73.45
Confidence Interval (2-Sided) 95%
58.89 to 88.01
Parameter Dispersion
Type: Standard Error of the Mean
Value: 7.43
Estimation Comments Stratified difference (teprotumumab - placebo) is a weighted average of the difference within each stratum. Estimates from the 2 strata (tobacco user, tobacco non-user) were combined with Cochran-Mantel-Haenszel (CMH) weights.
Other Statistical Analysis Test statistic=9.889, calculated by dividing the stratified difference by the SE.
2.Secondary Outcome
Title Percentage of Participants Who Were Overall Responders at Week 24
Hide Description

Overall responders were defined as participants with a ≥2 mm reduction in proptosis AND a ≥2 point reduction in Clinical Activity Score (CAS) from Baseline in the study eye, without deterioration (≥2 mm increase in proptosis or ≥2 point increase in CAS) in the fellow eye at Week 24.

The CAS is a 7-item description of clinical activity, including: 1. Spontaneous orbital pain; 2. Gaze evoked orbital pain; 3. Eyelid swelling that is considered to be due to active (inflammatory phase) thyroid eye disease/ Graves' Ophthalmopathy or Orbitopathy (TED/GO); 4. Eyelid erythema; 5. Conjunctival redness that is considered to be due to active (inflammatory phase) TED/GO (ignore "equivocal" redness); 6. Chemosis; 7. Inflammation of caruncle or plica. Each item is scored (1=present; 0=absent) and scores for each item are summed for total score of 0 (no clinical activity) to 7 (most clinical activity).

Time Frame Week 24
Hide Outcome Measure Data
Hide Analysis Population Description
Intent-to-treat population: all randomized participants.
Arm/Group Title Placebo Teprotumumab 20 mg/kg
Hide Arm/Group Description:
Eight infusions of placebo q3W for a total of 21 weeks.
Eight infusions of teprotumumab q3W for a total of 21 weeks. Teprotumumab 10 mg/kg administered on Day 1 and teprotumumab 20 mg/kg administered q3W for the remaining 7 infusions.
Overall Number of Participants Analyzed 42 41
Measure Type: Number
Unit of Measure: percentage of participants
7.1 78.0
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Teprotumumab 20 mg/kg
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments Two-sided p-value calculated assuming the test statistic was distributed as a standard normal random variable.
Method Cochran-Mantel-Haenszel
Comments [Not Specified]
Method of Estimation Estimation Parameter Stratified difference
Estimated Value 70.82
Confidence Interval (2-Sided) 95%
55.89 to 85.75
Parameter Dispersion
Type: Standard Error of the Mean
Value: 7.62
Estimation Comments Stratified difference (teprotumumab - placebo) is a weighted average of the difference within each stratum. Estimates from the 2 strata (tobacco user, tobacco non-user) were combined with CMH weights.
Other Statistical Analysis Test statistic=9.298, calculated by dividing the stratified difference by the SE.
3.Secondary Outcome
Title Percentage of Participants Who Were CAS Categorical Responders at Week 24
Hide Description

CAS categorical responders were defined as participants with a reduction to a CAS of 0 or 1 (no or minimal inflammatory symptoms).

The CAS is a 7-item description of clinical activity, including: 1. Spontaneous orbital pain; 2. Gaze evoked orbital pain; 3. Eyelid swelling that is considered to be due to active (inflammatory phase) thyroid eye disease/ Graves' Ophthalmopathy or Orbitopathy (TED/GO); 4. Eyelid erythema; 5. Conjunctival redness that is considered to be due to active (inflammatory phase) TED/GO (ignore "equivocal" redness); 6. Chemosis; 7. Inflammation of caruncle or plica. Each item is scored (1=present; 0=absent) and scores for each item are summed for total score of 0 (no inflammatory symptoms) to 7 (most inflammatory symptoms).

Time Frame Week 24
Hide Outcome Measure Data
Hide Analysis Population Description
Intent-to-treat population: all randomized participants.
Arm/Group Title Placebo Teprotumumab 20 mg/kg
Hide Arm/Group Description:
Eight infusions of placebo q3W for a total of 21 weeks.
Eight infusions of teprotumumab q3W for a total of 21 weeks. Teprotumumab 10 mg/kg administered on Day 1 and teprotumumab 20 mg/kg administered q3W for the remaining 7 infusions.
Overall Number of Participants Analyzed 42 41
Measure Type: Number
Unit of Measure: percentage of participants
21.4 58.5
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Teprotumumab 20 mg/kg
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments Two-sided p-value calculated assuming the test statistic was distributed as a standard normal random variable.
Method Cochran-Mantel-Haenszel
Comments [Not Specified]
Method of Estimation Estimation Parameter Stratified difference
Estimated Value 36.03
Confidence Interval (2-Sided) 95%
17.39 to 54.67
Parameter Dispersion
Type: Standard Error of the Mean
Value: 9.51
Estimation Comments Stratified difference (teprotumumab - placebo) is a weighted average of the difference within each stratum. Estimates from the 2 strata (tobacco user, tobacco non-user) were combined with CMH weights.
Other Statistical Analysis Test statistic=3.788, calculated by dividing the stratified difference by the SE.
4.Secondary Outcome
Title Change From Baseline in Proptosis to Week 24
Hide Description [Not Specified]
Time Frame Baseline, up to Week 24
Hide Outcome Measure Data
Hide Analysis Population Description
Intent-to-treat population: all randomized participants.
Arm/Group Title Placebo Teprotumumab 20 mg/kg
Hide Arm/Group Description:
Eight infusions of placebo q3W for a total of 21 weeks.
Eight infusions of teprotumumab q3W for a total of 21 weeks. Teprotumumab 10 mg/kg administered on Day 1 and teprotumumab 20 mg/kg administered q3W for the remaining 7 infusions.
Overall Number of Participants Analyzed 42 41
Least Squares Mean (Standard Error)
Unit of Measure: mm
-0.54  (0.192) -2.82  (0.191)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Teprotumumab 20 mg/kg
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments Results obtained from an MMRM with an unstructured covariance matrix including the following terms: Baseline value, tobacco use status, treatment group, visit, visit-by-treatment interaction and visit-by-Baseline-value interaction.
Method mixed model repeated-measures (MMRM)
Comments [Not Specified]
Method of Estimation Estimation Parameter Difference in LS mean
Estimated Value -2.28
Confidence Interval (2-Sided) 95%
-2.77 to -1.80
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.244
Estimation Comments [Not Specified]
5.Secondary Outcome
Title Percentage of Participants Who Were Diplopia Responders at Week 24
Hide Description

Diplopia responders were defined as participants with Baseline diplopia Subjective Diplopia Score grade >0 in the study eye who had a reduction of ≥1 grade with no corresponding deterioration (≥1 grade worsening) in the fellow eye at Week 24. Denominator is the number of subjects with diplopia at Baseline.

The Subjective Diplopia Score is a clinical measure of diplopia severity on a grade scale of 0 to 3: 0=no diplopia; 1=intermittent (diplopia in primary position of gaze, when tired or when first awakening); 2=inconstant (diplopia at extremes of gaze); 3=constant (continuous diplopia in primary or reading position).

Time Frame Week 24
Hide Outcome Measure Data
Hide Analysis Population Description
Intent-to-treat population: all randomized participants with diplopia at baseline.
Arm/Group Title Placebo Teprotumumab 20 mg/kg
Hide Arm/Group Description:
Eight infusions of placebo q3W for a total of 21 weeks.
Eight infusions of teprotumumab q3W for a total of 21 weeks. Teprotumumab 10 mg/kg administered on Day 1 and teprotumumab 20 mg/kg administered q3W for the remaining 7 infusions.
Overall Number of Participants Analyzed 28 28
Measure Type: Number
Unit of Measure: percentage of participants
28.6 67.9
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Teprotumumab 20 mg/kg
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.001
Comments Two-sided p-value calculated assuming the test statistic was distributed as a standard normal random variable.
Method Cochran-Mantel-Haenszel
Comments [Not Specified]
Method of Estimation Estimation Parameter Stratified difference
Estimated Value 39.29
Confidence Interval (2-Sided) 95%
15.55 to 63.02
Parameter Dispersion
Type: Standard Error of the Mean
Value: 12.11
Estimation Comments Stratified difference is a weighted average of the difference within each stratum. Estimates from the 2 strata (tobacco user, tobacco non-user) were combined with CMH weights.
Other Statistical Analysis Test statistic=3.244, calculated by dividing the stratified difference by the SE.
6.Secondary Outcome
Title Change From Baseline in the Graves' Ophthalmopathy Quality of Life (GO-QoL) Questionnaire Overall Score to Week 24
Hide Description The GO-QoL is a 16-item self-administered questionnaire divided into 2 subsets and used to assess the perceived effects of TED by the subjects on (i) their daily physical activity as it relates to visual function, and (ii) psychosocial functioning. The range of the GO-QoL overall transformed scores is 0 to 100, where higher values correspond to better quality of life.
Time Frame Baseline, up to Week 24
Hide Outcome Measure Data
Hide Analysis Population Description
Intent-to-treat population: all randomized participants.
Arm/Group Title Placebo Teprotumumab 20 mg/kg
Hide Arm/Group Description:
Eight infusions of placebo q3W for a total of 21 weeks.
Eight infusions of teprotumumab q3W for a total of 21 weeks. Teprotumumab 10 mg/kg administered on Day 1 and teprotumumab 20 mg/kg administered q3W for the remaining 7 infusions.
Overall Number of Participants Analyzed 42 41
Least Squares Mean (Standard Error)
Unit of Measure: score on a scale
4.43  (2.102) 13.79  (2.074)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Teprotumumab 20 mg/kg
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments Results obtained from an MMRM with an unstructured covariance matrix including the following terms: Baseline value, tobacco use status, treatment group, visit, visit-by-treatment interaction and visit-by-Baseline-value interaction.
Method mixed-effect model repeated measure
Comments [Not Specified]
Method of Estimation Estimation Parameter Difference in LS mean
Estimated Value 9.36
Confidence Interval (2-Sided) 95%
4.08 to 14.64
Parameter Dispersion
Type: Standard Error of the Mean
Value: 2.651
Estimation Comments [Not Specified]
Time Frame From first dose of study drug through the end of the Double-Masked Treatment Period (up to 24 weeks). Mean (SD) number of days on study: Placebo 166.5 (19.47) vs Teprotumumab 166.8 (27.08).
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title Placebo Teprotumumab 20 mg/kg
Hide Arm/Group Description Eight infusions of placebo q3W for a total of 21 weeks. Eight infusions of teprotumumab q3W for a total of 21 weeks. Teprotumumab 10 mg/kg administered on Day 1 and teprotumumab 20 mg/kg administered q3W for the remaining 7 infusions.
All-Cause Mortality
Placebo Teprotumumab 20 mg/kg
Affected / at Risk (%) Affected / at Risk (%)
Total   0/42 (0.00%)   0/41 (0.00%) 
Hide Serious Adverse Events
Placebo Teprotumumab 20 mg/kg
Affected / at Risk (%) Affected / at Risk (%)
Total   1/42 (2.38%)   2/41 (4.88%) 
Eye disorders     
Visual field defect  1  1/42 (2.38%)  0/41 (0.00%) 
Injury, poisoning and procedural complications     
Infusion related reaction  1  0/42 (0.00%)  1/41 (2.44%) 
Respiratory, thoracic and mediastinal disorders     
Pneumothorax  1  0/42 (0.00%)  1/41 (2.44%) 
1
Term from vocabulary, MedDRA 20.1
Indicates events were collected by systematic assessment
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Placebo Teprotumumab 20 mg/kg
Affected / at Risk (%) Affected / at Risk (%)
Total   29/42 (69.05%)   35/41 (85.37%) 
Gastrointestinal disorders     
Abdominal Pain Upper  1  3/42 (7.14%)  2/41 (4.88%) 
Diarrhoea  1  5/42 (11.90%)  4/41 (9.76%) 
Nausea  1  4/42 (9.52%)  6/41 (14.63%) 
Stomatitis  1  1/42 (2.38%)  3/41 (7.32%) 
General disorders     
Fatigue  1  1/42 (2.38%)  5/41 (12.20%) 
Infections and infestations     
Influenza  1  3/42 (7.14%)  1/41 (2.44%) 
Musculoskeletal and connective tissue disorders     
Muscle Spasms  1  4/42 (9.52%)  13/41 (31.71%) 
Nervous system disorders     
Dizziness  1  0/42 (0.00%)  3/41 (7.32%) 
Dysgeusia  1  0/42 (0.00%)  4/41 (9.76%) 
Headache  1  4/42 (9.52%)  4/41 (9.76%) 
Reproductive system and breast disorders     
Amenorrhoea  1  0/42 (0.00%)  3/41 (7.32%) 
Respiratory, thoracic and mediastinal disorders     
Cough  1  3/42 (7.14%)  2/41 (4.88%) 
Skin and subcutaneous tissue disorders     
Alopecia  1  5/42 (11.90%)  8/41 (19.51%) 
Dry Skin  1  0/42 (0.00%)  4/41 (9.76%) 
1
Term from vocabulary, MedDRA 20.1
Indicates events were collected by systematic assessment
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS 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.
Horizon requests that any Investigator/institution that plans on presenting or publishing results provide written notification of their request a minimum of 60 days prior to presentation or publication. The Sponsor may request that Confidential Information be deleted and/or the publication be postponed in order to protect the Sponsors' Intellectual Property rights.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Suzy Hammel
Organization: Horizon Pharma USA, Inc.
Phone: 866-479-6742
EMail: clinicaltrials@horizontherapeutics.com
Layout table for additonal information
Responsible Party: Horizon Pharma USA, Inc.
ClinicalTrials.gov Identifier: NCT03298867    
Other Study ID Numbers: HZNP-TEP-301
2017-002763-18 ( EudraCT Number )
First Submitted: September 27, 2017
First Posted: October 2, 2017
Results First Submitted: February 14, 2020
Results First Posted: March 10, 2020
Last Update Posted: April 8, 2021