Moderate or Severe Submental Fullness
Conditions
Brief summary
To evaluate the safety and efficacy of deoxycholic acid injection in the reduction of submental fat (fat below the chin).
Interventions
Formulated as an injectable solution containing deoxycholic acid at a concentration of 10 mg/mL.
DRUGPlacebo
Phosphate buffered saline placebo for injection
Sponsors
Kythera Biopharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
Yes
Inclusion criteria
1. Submental fat graded by the investigator as 2 or 3 using the Clinician-Reported Submental Fat Rating Scale (CR-SMFRS) and graded by the subject as 2 or 3 using the Patient-Reported Submental Fat Rating Scale (PR-SMFRS) as determined on Visit 1 (within 28 days before randomization). 2. Dissatisfaction with the submental area expressed by the subject as a rating of 0, 1, or 2 using the Subject Self Rating Scale (SSRS) as determined on Visit 1 (within 28 days before randomization). 3. Males and nonpregnant, nonlactating females 18 to 65 years of age, inclusive, on the day of randomization (Visit 2). Females of childbearing potential must have a negative human chorionic gonadotropin (hCG) test result within 28 days before Visit 2 and agree to practice adequate contraception, in the judgment of the investigator, during the course of the study. Females of childbearing potential who are not sexually active need not practice contraception. 4. History of stable body weight, in the judgment of the investigator, for at least 6 months before randomization. 5. Expected to understand and agree to comply with the visit schedule and all protocol-specified tests and procedures and agreement by the subject to refrain from making significant changes, in the judgment of the investigator, to his or her dietary or exercise habits during the course of the subject's participation. 6. Agreement to forego any treatment or behavior (e.g., unshaven facial hair) during the subject's participation in the study that may affect the assessments of the submental area. 7. Medically able to undergo the administration of study material determined by clinical and laboratory tests obtained within 28 days before randomization for which the investigator identified no clinically significant abnormality. 8. Signed informed consent obtained before any study-specific procedure is performed.
Exclusion criteria
1. History of any intervention to treat submental fat (e.g., liposuction, surgery, or lipolytic agents). 2. History of trauma associated with the chin or neck areas that in the judgment of the investigator may affect evaluation of safety or efficacy of treatment. 3. A Submental Skin Laxity Grade (SMSLG) of 4 or other anatomical feature (e.g., predominant subplatysmal fat, loose skin in the neck or chin area, prominent platysmal bands), as assessed within 28 days before randomization, for which reduction in submental fat may, in the judgment of the investigator, result in an aesthetically unacceptable outcome. 4. Evidence of any cause of enlargement in the submental area (e.g., thyroid enlargement, cervical adenopathy) other than localized submental fat. 5. Body mass index of \> 40.0 as determined on Visit 1. 6. History or current symptoms of dysphagia. 7. A result on coagulation tests (PT, PTT) obtained within 28 days before randomization that indicates the presence of any clinically significant bleeding disorder. 8. Any medical condition (e.g., respiratory, cardiovascular, hepatic, neurological disease, or thyroid dysfunction) that would interfere with assessment of safety or efficacy or compromise the subject's ability to undergo study procedures or give informed consent. 9. Treatment with radio frequency, laser procedures, chemical peels, or dermal fillers in the neck or chin area within 12 months before randomization. 10. Treatment with botulinum toxin injections in the neck or chin area within 6 months before randomization. 11. History of sensitivity to any components of the study material 12. History of sensitivity to topical or local anesthetics (e.g., lidocaine, benzocaine, procaine). 13. Previous randomization in this study or previous participation in a Kythera-sponsored ATX 101 trial. 14. Treatment with an investigational device or agent within 30 days before randomization. 15. For centers selected to conduct magnetic resonance imaging (MRI) evaluations, any subject with the presence of any condition that would render a subject unsuitable for MRI evaluation (e.g., claustrophobia), or metals in the body that would interfere with MRI acquisition (e.g., nonremovable metal appliances in the mouth such as silver or gold caps, pacemakers, metal joints).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Who Achieved a Composite 1-grade Response | Baseline and 12 weeks after last treatment (up to 32 weeks after first treatment) | 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. |
| Percentage of Participants Who Achieved a Composite 2-grade Response | Baseline and 12 weeks after last treatment (up to 32 weeks after first treatment) | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With a Magnetic Resonance Imaging (MRI) Response | Baseline and 12 weeks after last treatment (up to 32 weeks after first treatment) | 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. |
| Change From Baseline in Patient-Reported Submental Fat Impact Scale (PR-SMFIS) | Baseline and 12 weeks after last treatment (up to 32 weeks after first treatment) | 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. |
Countries
Canada, United States
Participant flow
Recruitment details
The study was performed at 35 investigational centers in the United States (US) and Canada.
Participants by arm
| Arm | Count |
|---|---|
| Deoxycholic Acid Injection 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. | 256 |
| Placebo 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. | 250 |
| Total | 506 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Administrative decision | 0 | 3 |
| Overall Study | Adverse Event | 2 | 2 |
| Overall Study | Consent Withdrawn (Subject Convenience) | 20 | 12 |
| Overall Study | Lost to Follow-up | 7 | 6 |
| Overall Study | Subject Noncompliance | 1 | 0 |
Baseline characteristics
| Characteristic | Deoxycholic Acid Injection | Placebo | Total |
|---|---|---|---|
| Age, Continuous | 49.5 years STANDARD_DEVIATION 9.3 | 49.4 years STANDARD_DEVIATION 9.33 | 49.5 years STANDARD_DEVIATION 9.3 |
| Age, Customized 18 - 50 years | 122 participants | 121 participants | 243 participants |
| Age, Customized 51 - 65 years | 134 participants | 129 participants | 263 participants |
| Body Mass Index (BMI) | 29.23 kg/m² STANDARD_DEVIATION 4.406 | 29.26 kg/m² STANDARD_DEVIATION 4.281 | 29.25 kg/m² STANDARD_DEVIATION 4.34 |
| Fitzpatrick Skin Type I - III | 180 participants | 187 participants | 367 participants |
| Fitzpatrick Skin Type IV - VI | 76 participants | 63 participants | 139 participants |
| Race/Ethnicity, Customized American Indian or Alaskan Native | 0 participants | 2 participants | 2 participants |
| Race/Ethnicity, Customized Asian | 7 participants | 5 participants | 12 participants |
| Race/Ethnicity, Customized Black or African American | 24 participants | 13 participants | 37 participants |
| Race/Ethnicity, Customized Hispanic or Latino | 28 participants | 17 participants | 45 participants |
| Race/Ethnicity, Customized Multiple | 2 participants | 0 participants | 2 participants |
| Race/Ethnicity, Customized Native Hawaiian or Pacific Islander | 0 participants | 1 participants | 1 participants |
| Race/Ethnicity, Customized Non-Hispanic or Latino | 228 participants | 233 participants | 461 participants |
| Race/Ethnicity, Customized Other | 5 participants | 2 participants | 7 participants |
| Race/Ethnicity, Customized White | 218 participants | 227 participants | 445 participants |
| Sex: Female, Male Female | 213 Participants | 208 Participants | 421 Participants |
| Sex: Female, Male Male | 43 Participants | 42 Participants | 85 Participants |
| Weight | 81.15 kg STANDARD_DEVIATION 14.549 | 80.98 kg STANDARD_DEVIATION 14.296 | 81.07 kg STANDARD_DEVIATION 14.411 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 246 / 257 | 196 / 248 |
| serious Total, serious adverse events | 6 / 257 | 12 / 248 |
Outcome results
Primary
Percentage of Participants Who Achieved a Composite 1-grade Response
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)
Population: Intent-to-treat (ITT) population; missing values were imputed using a multiple imputation process.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Deoxycholic Acid Injection | Percentage of Participants Who Achieved a Composite 1-grade Response | 70.0 percentage of participants |
| Placebo | Percentage of Participants Who Achieved a Composite 1-grade Response | 18.6 percentage of participants |
Comparison: 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.p-value: <0.00195% CI: [2.808, 4.88]Cochran-Mantel-Haenszel
Primary
Percentage of Participants Who Achieved a Composite 2-grade Response
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)
Population: Intent-to-treat population; missing values were imputed using a multiple imputation process.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Deoxycholic Acid Injection | Percentage of Participants Who Achieved a Composite 2-grade Response | 13.4 percentage of participants |
| Placebo | Percentage of Participants Who Achieved a Composite 2-grade Response | 0.0 percentage of participants |
Comparison: 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.p-value: <0.001Cochran-Mantel-Haenszel
Secondary
Change From Baseline in Patient-Reported Submental Fat Impact Scale (PR-SMFIS)
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)
Population: Intent-to-treat population; missing values were imputed using a multiple imputation process.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Deoxycholic Acid Injection | Change From Baseline in Patient-Reported Submental Fat Impact Scale (PR-SMFIS) | -3.56 units on a scale | Standard Deviation 2.793 |
| Placebo | Change From Baseline in Patient-Reported Submental Fat Impact Scale (PR-SMFIS) | -1.16 units on a scale | Standard Deviation 2.064 |
Comparison: 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.p-value: <0.001ANCOVA
Secondary
Percentage of Participants With a Magnetic Resonance Imaging (MRI) Response
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)
Population: 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 | Measure | Value (NUMBER) |
|---|---|---|
| Deoxycholic Acid Injection | Percentage of Participants With a Magnetic Resonance Imaging (MRI) Response | 46.3 percentage of participants |
| Placebo | Percentage of Participants With a Magnetic Resonance Imaging (MRI) Response | 5.3 percentage of participants |
Comparison: 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.p-value: <0.00195% CI: [3.62, 20.148]Cochran-Mantel-Haenszel