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Phase 3 Study of Deoxycholic Acid Injection (ATX-101) Versus Placebo for the Reduction of Localized Subcutaneous Fat in the Submental Area (REFINE-1)

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ClinicalTrials.gov Identifier: NCT01542034
Recruitment Status : Completed
First Posted : March 1, 2012
Results First Posted : June 15, 2015
Last Update Posted : June 15, 2015
Sponsor:
Information provided by (Responsible Party):
Kythera Biopharmaceuticals

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Double (Participant, Investigator);   Primary Purpose: Treatment
Condition Moderate or Severe Submental Fullness
Interventions Drug: Deoxycholic acid injection
Drug: Placebo
Enrollment 506
Recruitment Details The study was performed at 35 investigational centers in the United States (US) and Canada.
Pre-assignment Details  
Arm/Group Title Deoxycholic Acid Injection Placebo
Hide Arm/Group Description Participants received deoxycholic acid 2 mg/cm² administered in 0.2 mL injections, up to 10 mL per treatment session at intervals of approximately 1 month for up to a maximum of 6 treatments. Participants received placebo administered in 0.2 mL injections, up to 10 mL per treatment session at intervals of approximately 1 month for up to a maximum of 6 treatments.
Period Title: Overall Study
Started 256 250
Received Treatment 256 249
Completed 226 [1] 227 [1]
Not Completed 30 23
Reason Not Completed
Consent Withdrawn (Subject Convenience)             20             12
Administrative decision             0             3
Subject Noncompliance             1             0
Adverse Event             2             2
Lost to Follow-up             7             6
[1]
Participants who completed long-term follow-up 24 weeks after the last treatment
Arm/Group Title Deoxycholic Acid Injection Placebo Total
Hide Arm/Group Description Participants received deoxycholic acid 2 mg/cm² administered in 0.2 mL injections, up to 10 mL per treatment session at intervals of approximately 1 month for up to a maximum of 6 treatments. Participants received placebo administered in 0.2 mL injections, up to 10 mL per treatment session at intervals of approximately 1 month for up to a maximum of 6 treatments. Total of all reporting groups
Overall Number of Baseline Participants 256 250 506
Hide Baseline Analysis Population Description
Intention-to-treat population
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 256 participants 250 participants 506 participants
49.5  (9.30) 49.4  (9.33) 49.5  (9.30)
Age, Customized  
Measure Type: Number
Unit of measure:  Participants
 Number Analyzed 256 participants 250 participants 506 participants
18 - 50 years 122 121 243
51 - 65 years 134 129 263
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 256 participants 250 participants 506 participants
Female
213
  83.2%
208
  83.2%
421
  83.2%
Male
43
  16.8%
42
  16.8%
85
  16.8%
Race/Ethnicity, Customized  
Measure Type: Number
Unit of measure:  Participants
 Number Analyzed 256 participants 250 participants 506 participants
White 218 227 445
Black or African American 24 13 37
Asian 7 5 12
American Indian or Alaskan Native 0 2 2
Native Hawaiian or Pacific Islander 0 1 1
Multiple 2 0 2
Other 5 2 7
Race/Ethnicity, Customized  
Measure Type: Number
Unit of measure:  Participants
 Number Analyzed 256 participants 250 participants 506 participants
Hispanic or Latino 28 17 45
Non-Hispanic or Latino 228 233 461
Weight   [1] 
Mean (Standard Deviation)
Unit of measure:  Kg
Number Analyzed 256 participants 250 participants 506 participants
81.15  (14.549) 80.98  (14.296) 81.07  (14.411)
[1]
Measure Description: Data available for 256 and 249 participants in each treatment group respectively
Body Mass Index (BMI)   [1] 
Mean (Standard Deviation)
Unit of measure:  Kg/m²
Number Analyzed 256 participants 250 participants 506 participants
29.23  (4.406) 29.26  (4.281) 29.25  (4.340)
[1]
Measure Description: Data available for 256 and 249 participants in each treatment group respectively
Fitzpatrick Skin Type   [1] 
Measure Type: Number
Unit of measure:  Participants
 Number Analyzed 256 participants 250 participants 506 participants
I - III 180 187 367
IV - VI 76 63 139
[1]
Measure Description:

Fitzpatrick Skin Type is a numerical classification schema for human skin color and typical response to ultraviolet (UV) light:

  • Type I: Pale white skin, blue/hazel eyes, blond/red hair; Always burns, does not tan.
  • Type II: Fair skin, blue eyes; Burns easily, tans poorly.
  • Type III: Darker white skin; Tans after initial burn.
  • Type IV: Light brown skin; Burns minimally, tans easily.
  • Type V: Brown skin; Rarely burns, tans darkly easily.
  • Type VI: Dark brown or black skin; Never burns, always tans darkly.
1.Primary Outcome
Title Percentage of Participants Who Achieved a Composite 1-grade Response
Hide Description

A composite 1-grade response is defined as at least a 1-grade improvement from Baseline on both the Clinician-Reported Submental Fat Rating Scale (CR-SMFRS) and Patient-Reported Submental Fat Rating Scale (PR-SMFRS) 12 weeks after the last treatment.

The CR-SMFRS score is based on the investigator’s clinical evaluation of the participant, where submental fullness is scored on a 5-point ordinal scale (0–4) with 0 = absent, 1 = mild, 2 = moderate, 3 = severe, and 4 = extreme.

The PR-SMFRS is based on the participant's response to the question "How much fat do you have under your chin right now?" answered on a 5-point ordinal scale (0–4) with 0 = no chin fat at all, 1 = a slight amount of chin fat, 2 = a moderate amount of chin fat, 3 = a large amount of chin fat, and 4 = a very large amount of chin fat.
Time Frame Baseline and 12 weeks after last treatment (up to 32 weeks after first treatment)
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Intent-to-treat (ITT) population; missing values were imputed using a multiple imputation process.
Arm/Group Title Deoxycholic Acid Injection Placebo
Hide Arm/Group Description:
Participants received deoxycholic acid 2 mg/cm² administered in 0.2 mL injections, up to 10 mL per treatment session at intervals of approximately 1 month for up to a maximum of 6 treatments.
Participants received placebo administered in 0.2 mL injections, up to 10 mL per treatment session at intervals of approximately 1 month for up to a maximum of 6 treatments.
Overall Number of Participants Analyzed 256 250
Measure Type: Number
Unit of Measure: percentage of participants
70.0 18.6
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Deoxycholic Acid Injection, Placebo
Comments The primary analysis was satisfied if both null hypotheses (there is no treatment difference in 1-grade or 2-grade response rate) were rejected in favor of the two-tailed alternative at the 0.05 level of significance for both primary efficacy endpoints, and the response rates were higher for the deoxycholic acid injection treatment group than the placebo group. Because both hypotheses must be rejected, the type I error was preserved when testing the primary endpoints.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments [Not Specified]
Method Cochran-Mantel-Haenszel
Comments Cochran-Mantel-Haenszel (CMH) method stratified by pooled study center.
Method of Estimation Estimation Parameter Risk Ratio (RR)
Estimated Value 3.702
Confidence Interval (2-Sided) 95%
2.808 to 4.880
Estimation Comments A risk ratio greater than 1 favors deoxycholic acid injection treatment, and between 0 and 1 favors placebo.
2.Primary Outcome
Title Percentage of Participants Who Achieved a Composite 2-grade Response
Hide Description

A composite 2-grade response is defined as at least a 2-grade improvement from Baseline on both the Clinician-Reported Submental Fat Rating Scale (CR-SMFRS) and Patient-Reported Submental Fat Rating Scale (PR-SMFRS) 12 weeks after the last treatment.

The CR-SMFRS score is based on the investigator’s clinical evaluation of the participant, where submental fullness is scored on a 5-point ordinal scale (0–4) with 0 = absent, 1 = mild, 2 = moderate, 3 = severe, and 4 = extreme.

The PR-SMFRS is based on the participant's response to the question "How much fat do you have under your chin right now?" answered on a 5-point ordinal scale (0–4) with 0 = no chin fat at all, 1 = a slight amount of chin fat, 2 = a moderate amount of chin fat, 3 = a large amount of chin fat, and 4 = a very large amount of chin fat.
Time Frame Baseline and 12 weeks after last treatment (up to 32 weeks after first treatment)
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Intent-to-treat population; missing values were imputed using a multiple imputation process.
Arm/Group Title Deoxycholic Acid Injection Placebo
Hide Arm/Group Description:
Participants received deoxycholic acid 2 mg/cm² administered in 0.2 mL injections, up to 10 mL per treatment session at intervals of approximately 1 month for up to a maximum of 6 treatments.
Participants received placebo administered in 0.2 mL injections, up to 10 mL per treatment session at intervals of approximately 1 month for up to a maximum of 6 treatments.
Overall Number of Participants Analyzed 256 250
Measure Type: Number
Unit of Measure: percentage of participants
13.4 0.0
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Deoxycholic Acid Injection, Placebo
Comments The primary analysis was satisfied if both null hypotheses (there is no treatment difference in 1-grade or 2-grade response rate) were rejected in favor of the two-tailed alternative at the 0.05 level of significance for both primary efficacy endpoints, and the response rates were higher for the deoxycholic acid injection treatment group than the placebo group. Because both hypotheses must be rejected, the type I error was preserved when testing the primary endpoints.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments [Not Specified]
Method Cochran-Mantel-Haenszel
Comments CMH method stratified by pooled study center.
3.Secondary Outcome
Title Percentage of Participants With a Magnetic Resonance Imaging (MRI) Response
Hide Description An MRI responder is a participant who exhibited at least a 10% reduction in submental fat volume as measured by MRI from Baseline to 12 weeks after last treatment. Magnetic resonance imaging was evaluated in a subset of participants at selected centers.
Time Frame Baseline and 12 weeks after last treatment (up to 32 weeks after first treatment)
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
The ITT-MRI population consisted of all randomized participants who participated in the MRI cohort and had evaluable Baseline MRI data. A multiple imputation process was used.
Arm/Group Title Deoxycholic Acid Injection Placebo
Hide Arm/Group Description:
Participants received deoxycholic acid 2 mg/cm² administered in 0.2 mL injections, up to 10 mL per treatment session at intervals of approximately 1 month for up to a maximum of 6 treatments.
Participants received placebo administered in 0.2 mL injections, up to 10 mL per treatment session at intervals of approximately 1 month for up to a maximum of 6 treatments.
Overall Number of Participants Analyzed 113 111
Measure Type: Number
Unit of Measure: percentage of participants
46.3 5.3
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Deoxycholic Acid Injection, Placebo
Comments If both primary endpoints were statistically significant, testing continued to the 2 secondary endpoints using the Bonferroni-Holm method. The smaller of the 2 p-values for the treatment difference was tested at the 0.025 level. If significant, testing proceeded for the remaining secondary endpoint at the 0.05 level. If the smaller p-value was > 0.025, the null hypothesis for the associated variable would not be rejected, and testing of the second endpoint would not proceed.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments [Not Specified]
Method Cochran-Mantel-Haenszel
Comments CMH method stratified by pooled study center
Method of Estimation Estimation Parameter Risk Ratio (RR)
Estimated Value 8.541
Confidence Interval (2-Sided) 95%
3.620 to 20.148
Estimation Comments A risk ratio greater than 1 favors deoxycholic acid injection treatment, and between 0 and 1 favors placebo.
4.Secondary Outcome
Title Change From Baseline in Patient-Reported Submental Fat Impact Scale (PR-SMFIS)
Hide Description The PR-SMFIS assesses the impact of submental fat on self-perception of 6 emotional and visual characteristics related to the appearance of submental fullness (unhappy, bothered, self-conscious, embarrassed, look older, and look overweight) as evaluated by the participant. Each item is rated on an 11-point numeric scale from 0 to 10. Scores for the 6 items were averaged to generate a PR-SMFIS total scale score ranging from 0 to 10 where 0 is a positive outcome and 10 is a negative outcome. A negative change from Baseline indicates improvement.
Time Frame Baseline and 12 weeks after last treatment (up to 32 weeks after first treatment)
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Intent-to-treat population; missing values were imputed using a multiple imputation process.
Arm/Group Title Deoxycholic Acid Injection Placebo
Hide Arm/Group Description:
Participants received deoxycholic acid 2 mg/cm² administered in 0.2 mL injections, up to 10 mL per treatment session at intervals of approximately 1 month for up to a maximum of 6 treatments.
Participants received placebo administered in 0.2 mL injections, up to 10 mL per treatment session at intervals of approximately 1 month for up to a maximum of 6 treatments.
Overall Number of Participants Analyzed 256 250
Mean (Standard Deviation)
Unit of Measure: units on a scale
-3.56  (2.793) -1.16  (2.064)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Deoxycholic Acid Injection, Placebo
Comments If both primary endpoints were statistically significant, testing continued to the 2 secondary endpoints using the Bonferroni-Holm method. The smaller of the 2 p-values for the treatment difference was tested at the 0.025 level. If significant, testing proceeded for the remaining secondary endpoint at the 0.05 level. If the smaller p-value was > 0.025, the null hypothesis for the associated variable would not be rejected, and testing of the second endpoint would not proceed.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments [Not Specified]
Method ANCOVA
Comments Analysis of covariance (ANCOVA) model included treatment and Baseline PR-SMFIS total scale score.
Time Frame From the first dose of study drug until 24 weeks after the last dose (up to 44 weeks after first treatment).
Adverse Event Reporting Description The safety population consisted of all participants who received at least 1 injection of study drug. One participant was randomized to placebo, received deoxycholic acid injection at Visit 4 (Week 8), and was included in the deoxycholic acid injection arm for safety analyses.
 
Arm/Group Title Deoxycholic Acid Injection Placebo
Hide Arm/Group Description Participants received deoxycholic acid 2 mg/cm² administered in 0.2 mL injections, up to 10 mL per treatment session at intervals of approximately 1 month for up to a maximum of 6 treatments. Participants received placebo administered in 0.2 mL injections, up to 10 mL per treatment session at intervals of approximately 1 month for up to a maximum of 6 treatments.
All-Cause Mortality
Deoxycholic Acid Injection Placebo
Affected / at Risk (%) Affected / at Risk (%)
Total   --/--   --/-- 
Show Serious Adverse Events Hide Serious Adverse Events
Deoxycholic Acid Injection Placebo
Affected / at Risk (%) Affected / at Risk (%)
Total   6/257 (2.33%)   12/248 (4.84%) 
Cardiac disorders     
Cardiac arrest † 1  0/257 (0.00%)  1/248 (0.40%) 
Gastrointestinal disorders     
Colitis microscopic † 1  1/257 (0.39%)  0/248 (0.00%) 
Gastrointestinal haemorrhage † 1  0/257 (0.00%)  1/248 (0.40%) 
Gastrooesophageal reflux disease † 1  0/257 (0.00%)  1/248 (0.40%) 
Hiatus hernia † 1  0/257 (0.00%)  1/248 (0.40%) 
Infections and infestations     
Abdominal abscess † 1  1/257 (0.39%)  0/248 (0.00%) 
Abscess oral † 1  0/257 (0.00%)  1/248 (0.40%) 
Diverticulitis † 1  0/257 (0.00%)  1/248 (0.40%) 
Injury, poisoning and procedural complications     
Concussion † 1  1/257 (0.39%)  0/248 (0.00%) 
Contusion † 1  1/257 (0.39%)  0/248 (0.00%) 
Head injury † 1  1/257 (0.39%)  0/248 (0.00%) 
Humerus fracture † 1  0/257 (0.00%)  1/248 (0.40%) 
Skull fracture † 1  1/257 (0.39%)  0/248 (0.00%) 
Metabolism and nutrition disorders     
Dehydration † 1  0/257 (0.00%)  1/248 (0.40%) 
Musculoskeletal and connective tissue disorders     
Osteoarthritis † 1  1/257 (0.39%)  1/248 (0.40%) 
Intervertebral disc protrusion † 1  0/257 (0.00%)  1/248 (0.40%) 
Spinal column stenosis † 1  1/257 (0.39%)  0/248 (0.00%) 
Neoplasms benign, malignant and unspecified (incl cysts and polyps)     
Breast cancer † 1  0/257 (0.00%)  1/248 (0.40%) 
Multiple myeloma † 1  0/257 (0.00%)  1/248 (0.40%) 
Nervous system disorders     
Meningism † 1  1/257 (0.39%)  0/248 (0.00%) 
Renal and urinary disorders     
Urethral disorder † 1  0/257 (0.00%)  1/248 (0.40%) 
Respiratory, thoracic and mediastinal disorders     
Respiratory distress † 1  0/257 (0.00%)  1/248 (0.40%) 
Respiratory failure † 1  1/257 (0.39%)  0/248 (0.00%) 
Surgical and medical procedures     
Hip arthroplasty † 1  0/257 (0.00%)  1/248 (0.40%) 
†
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA (14.1)
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Deoxycholic Acid Injection Placebo
Affected / at Risk (%) Affected / at Risk (%)
Total   246/257 (95.72%)   196/248 (79.03%) 
General disorders     
Injection site haematoma † 1  180/257 (70.04%)  167/248 (67.34%) 
Injection site pain † 1  168/257 (65.37%)  58/248 (23.39%) 
Injection site oedema † 1  136/257 (52.92%)  54/248 (21.77%) 
Injection site anaesthesia † 1  172/257 (66.93%)  11/248 (4.44%) 
Injection site swelling † 1  96/257 (37.35%)  39/248 (15.73%) 
Injection site erythema † 1  46/257 (17.90%)  25/248 (10.08%) 
Injection site induration † 1  47/257 (18.29%)  4/248 (1.61%) 
Injection site paraesthesia † 1  33/257 (12.84%)  8/248 (3.23%) 
Injection site nodule † 1  32/257 (12.45%)  2/248 (0.81%) 
Injection site pruritus † 1  22/257 (8.56%)  9/248 (3.63%) 
Infections and infestations     
Nasopharyngitis † 1  23/257 (8.95%)  26/248 (10.48%) 
Nervous system disorders     
Headache † 1  19/257 (7.39%)  11/248 (4.44%) 
†
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA (14.1)
[Not Specified]
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.
The Clinical Study Agreement requires that the investigator or institution obtain written consent from Kythera prior to presenting and/or publishing results of this study.
Results Point of Contact
Name/Title: Clinical Trial Disclosure
Organization: Kythera
Responsible Party: Kythera Biopharmaceuticals
ClinicalTrials.gov Identifier: NCT01542034     History of Changes
Other Study ID Numbers: ATX-101-11-22
First Submitted: February 24, 2012
First Posted: March 1, 2012
Results First Submitted: May 28, 2015
Results First Posted: June 15, 2015
Last Update Posted: June 15, 2015