Obesity
Conditions
Keywords
Overweight, Metabolism and Nutrition Disorder
Brief summary
The main purpose of this study is to investigate the efficacy and safety of oral orforglipron in participants with obesity disease with obesity-related health problems.
Interventions
DRUGOrforglipron
Administered orally
DRUGPlacebo
Administered orally
Sponsors
Eli Lilly and Company
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Participants with a BMI ≥27 kg/m² and \<35 kg/m² and at least 2 obesity-related health problems (treated or untreated), OR a BMI ≥35 kg/m² and at least 1 obesity-related health problem (treated or untreated). At least one obesity-related health problem should be hypertension, dyslipidemia or T2D (approximately 25% of participants). * Have a history of at least one self-reported unsuccessful dietary effort to lose body weight. * Males and females may participate in this trial. Female participants must not be pregnant, intending to be pregnant, breastfeeding, or intending to breastfeed. * Contraceptive use by participants should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies. * No male contraception is required except in compliance with specific local government study requirements.
Exclusion criteria
* For participants with Type 2 Diabetes (T2D): * Have Type 1 Diabetes (T1D), history of ketoacidosis or hyperosmolar state/coma, or any other types of diabetes except T2D. * Have had 1 or more episode of severe hypoglycemia and/or 1 or more episode of hypoglycemia unawareness within the 180 days prior to screening. * Have renal impairment measured as estimated glomerular filtration rate (eGFR) \<15 mL/min/1.73 m², calculated by Japanese Society of Nephrology coefficient-modified chronic kidney disease-epidemiology equation during screening. * Have a known clinically significant gastric emptying abnormality. * For participants without Type 2 diabetes (T2D): Have any type of diabetes with hemoglobin A1c (HbA1c) ≥6.5 %. * Have a self-reported change in body weight \>5 kg (11 pounds) within 90 days prior to screening. * Have chronic kidney disease. * Have lupus or rheumatoid arthritis. * Have the following cardiovascular conditions within 90 days prior to screening. * Have acute or chronic hepatitis.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percent Change From Baseline in Body Weight at Week 72 | Baseline, Week 72 | Values reported as "LS Mean" are model-based estimates (MBE) of the adjusted (unconditional) treatment effect. MBEs was calculated using an analysis of covariance (ANCOVA) model with the following variables: treatment group, baseline value, baseline Body Mass Index (BMI) category (\<35 kilogram per meter square \[kg/m²\] or ≥35 kg/m²), and stratification factors (sex and baseline type 2 diabetes status). Strata were defined by joint levels of sex (female, male) and baseline type 2 diabetes status (yes, no). |
| Percentage of Participants Who Achieved With Greater Than or Equal to (≥) 5% Body Weight Reduction From Baseline | Baseline to Week 72 | Percentage of participants with ≥5% body weight reduction was analysed by Logistic regression with the following variables: treatment group, baseline value, baseline BMI category (\<35 kg/m² or ≥35 kg/m²), and stratification factors (sex and baseline type 2 diabetes status). Stratification factors were defined by the combination of sex (female, male) and baseline type 2 diabetes status (yes, no). The model also allowed the treatment effect to vary across baseline values and stratification factors. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Who Achieved ≥10% Body Weight Reduction From Baseline | Baseline to Week 72 | Percentage of participants with ≥10% body weight reduction was analysed by Logistic regression with the following variables: treatment group, baseline value, baseline BMI category (\<35 kg/m² or ≥35 kg/m²), and stratification factors (sex and baseline type 2 diabetes status). Stratification factors were defined by the combination of sex (female, male) and baseline type 2 diabetes status (yes, no). The model also allowed the treatment effect to vary across baseline values and stratification factors. |
| Percentage of Participants Who Achieved ≥15% Body Weight Reduction From Baseline | Baseline to Week 72 | Percentage of participants with ≥15% body weight reduction was analysed by Logistic regression with the following variables: treatment group, baseline value, baseline BMI category (\<35 kg/m² or ≥35 kg/m²), and stratification factors (sex and baseline type 2 diabetes status). Stratification factors were defined by the combination of sex (female, male) and baseline type 2 diabetes status (yes, no). The model also allowed the treatment effect to vary across baseline values and stratification factors. |
| Percentage of Participants Who Achieved ≥20% Body Weight Reduction From Baseline | Baseline to Week 72 | Percentage of participants with ≥20% body weight reduction was analysed by Logistic regression with the following variables: treatment group, baseline value, baseline BMI category (\<35 kg/m² or ≥35 kg/m²), and stratification factors (sex and baseline type 2 diabetes status). Stratification factors were defined by the combination of sex (female, male) and baseline type 2 diabetes status (yes, no). The model also allowed the treatment effect to vary across baseline values and stratification factors. |
| Change From Baseline in Body Mass Index (BMI) at Week 72 | Baseline, Week 72 | Values reported as "LS Mean" are model-based estimates (MBE) of the adjusted (unconditional) treatment effect. MBE was calculated using an ANCOVA model with the following variables: baseline, treatment, baseline BMI group, and strata in the model, including treatment-by-baseline and treatment-by-strata interaction terms. Strata were defined by joint levels of sex (female, male) and baseline type 2 diabetes status (yes, no). The model also allowed the treatment effect to vary across baseline values and stratification factors. |
| Percentage of Participants Who Had Improvements in Hypertension | Baseline to Week 72 | Percentage of participants achieving hypertension improvement ((Systolic blood pressure \<130 mmHg and diastolic blood pressure \<80 mmHg) was analysed using logistic regression with the following variables: treatment, baseline BMI group, and strata in the model. Strata were defined by joint levels of sex (female, male) and baseline type 2 diabetes status (yes, no). The estimates (odds ratio and corresponding confidence intervals) were derived using observed data. |
| Percentage of Participants Who Had Improvements in Dyslipidemia | Baseline to Week 72 | Percentage of participants achieving dyslipidemia improvement (Low-density lipoprotein cholesterol \<140 milligrams per deciliter (mg/dL), triglycerides \<150 mg/dL, and high-density lipoprotein cholesterol ≥40 mg/dL) was analysed using logistic regression with the following variables: treatment, baseline BMI group, and strata in the model. Strata were defined by joint levels of sex (female, male) and baseline type 2 diabetes status (yes, no). The estimates (odds ratio and corresponding confidence intervals) were derived using observed data. |
| Percentage of Participants Who Achieve Hemoglobin A1c (HbA1c) Target Value (<6.5% [48 mmol/Mol]) | Baseline to Week 72 | Percentage of participants achieving HbA1c \<6.5% was analysed using logistic regression with the following variables: baseline, treatment, baseline BMI group, and sex in the model, including treatment-by-baseline and treatment-by-sex interaction terms. |
| Mean Change From Baseline in Visceral Adipose Tissue (VAT) at Week 72 | Baseline, Week 72 | Values represented under "LS Mean" are model-based estimates (MBE) of the unconditional average treatment effect. MBE was calculated using an ANCOVA model with the following variables: baseline, treatment, baseline BMI group, and strata in the model, including treatment-by-baseline and treatment-by-strata interaction terms. Strata were defined by joint levels of sex (female, male) and baseline type 2 diabetes status (yes, no). |
| Mean Change From Baseline in Waist Circumference at Umbilical Level at Week 72 | Baseline, Week 72 | Values represented under "LS Mean" are model-based estimates (MBE) of the unconditional average treatment effect. MBE was calculated using an ANCOVA model with the following variables: baseline, treatment, baseline BMI group, and strata in the model, including treatment-by-baseline and treatment-by-strata interaction terms. Strata were defined by joint levels of sex (female, male) and baseline type 2 diabetes status (yes, no). |
| Mean Change From Baseline in Systolic Blood Pressure (SBP) at Week 72 | Baseline, Week 72 | Values represented under "LS Mean" are model-based estimates (MBE) of the unconditional average treatment effect. MBE was calculated using an ANCOVA model with the following variables: baseline, treatment, baseline BMI group, and strata in the model, including treatment-by-baseline and treatment-by-strata interaction terms. Strata were defined by joint levels of sex (female, male) and baseline type 2 diabetes status (yes, no). |
| Percent Change From Baseline in Non-High Density Lipoprotein (Non-HDL) at Week 72 | Baseline, Week 72 | Values represented as LS means are model-based estimates (MBE) of the unconditional average treatment effect on the log-transformed scale. MBE was calculated using an ANCOVA model for log(Actual Value/Baseline), including log-transformed baseline, treatment, baseline BMI group, and strata (defined by joint levels of sex \[female, male\] and baseline type 2 diabetes status \[yes, no\]) as covariates, with treatment-by-log(baseline) and treatment-by-strata interaction terms included in the model. |
| Percent Change From Baseline in High Density Lipoprotein (HDL) at Week 72 | Baseline, Week 72 | Values represented as LS means are model-based estimates (MBE) of the unconditional average treatment effect on the log-transformed scale. MBE was calculated using an ANCOVA model for log(Actual Value/Baseline), including log-transformed baseline, treatment, baseline BMI group, and strata (defined by joint levels of sex \[female, male\] and baseline type 2 diabetes status \[yes, no\]) as covariates, with treatment-by-log(baseline) and treatment-by-strata interaction terms included in the model. |
| Percent Change From Baseline in Triglycerides at Week 72 | Baseline, Week 72 | Values represented as LS means are model-based estimates (MBE) of the unconditional average treatment effect on the log-transformed scale. MBE was calculated using an ANCOVA model for log(Actual Value/Baseline), including log-transformed baseline, treatment, baseline BMI group, and strata (defined by joint levels of sex \[female, male\] and baseline type 2 diabetes status \[yes, no\]) as covariates, with treatment-by-log(baseline) and treatment-by-strata interaction terms included in the model. |
| Mean Change From Baseline in Fasting Glucose at Week 72 | Baseline, Week 72 | Values represented under "LS Mean" are model-based estimates (MBE) of the unconditional average treatment effect. MBE was calculated using an ANCOVA model with the following variables: baseline, treatment, baseline BMI group, and strata in the model, including treatment-by-baseline and treatment-by-strata interaction terms. Strata were defined by joint levels of sex (female, male) and baseline type 2 diabetes status (yes, no). |
| Mean Change From Baseline in Hemoglobin A1c (HbA1c) at Week 72 | Baseline, Week 72 | * Hemoglobin A1c (HbA1c) is the glycosylated fraction of hemoglobin A, measured to reflect average plasma glucose concentration over prolonged periods of time. * Values represented under "LS Mean" are model-based estimates (MBE) of the unconditional average treatment effect. MBE was calculated using an ANCOVA model with the following variables: baseline, treatment, baseline BMI group, and strata in the model, including treatment-by-baseline and treatment-by-strata interaction terms. Strata were defined by joint levels of sex (female, male) and baseline type 2 diabetes status (yes, no). |
| Mean Change From Baseline in High-sensitivity C-reactive Protein at Week 72 | Baseline, Week 72 | Values represented under "LS Mean" are model-based estimates (MBE) of the unconditional average treatment effect. MBE was calculated using a mixed model for repeated measures (MMRM) with the following variables: baseline BMI group, baseline-by-time-by-treatment, and strata-by-time-by-treatment interaction terms in the model. Strata were defined by joint levels of sex (female, male) and baseline type 2 diabetes status (yes, no). An unstructured variance-covariance matrix was used. |
| Time to Onset of Type 2 Diabetes (T2D) | Up to Week 72 | Time to event was defined as the duration from randomization to adjudication committee-confirmed diagnosis of type 2 diabetes mellitus (T2D). Descriptive statistics are presented as Kaplan-Meier estimates of time to onset of T2D (in weeks). Time to onset of T2D was also analyzed using a Cox proportional hazards model, with treatment (pooled orforglipron dose groups) and sex as factors and baseline fasting serum glucose as a covariate. Hazard ratios with corresponding confidence intervals were estimated and reported in statistical analysis. Statistical significance between treatment groups was assessed using a two-sided log-rank test. |
| Mean Change From Baseline in Short Form 36 Version 2 (SF-36v2) Acute Form For Domain and Component Scores at Week 72 | Baseline, Week 72 | The SF-36v2 acute form, 1-week recall assesses participants' health-related quality of life on 8 domains: Physical Functioning, Role-Physical, Bodily Pain, General Health, Vitality, Social Functioning, Role-Emotional, and Mental Health. Each domain is scored individually and information from these 8 domains is further aggregated into 2 health component summary scores, a Physical Component Summary, and a Mental Component Summary. Items are answered on Likert scales of varying lengths (3-point, 5-point, or 6-point scales). Scoring of each domain and both summary scores are norm based and presented in the form of T scores, with mean of 50 and standard deviation of 10; higher scores indicate better levels of function and/or better health. Range cannot be specified in norm-based scores. |
| Mean Change From Baseline in Impact of Weight on Quality-of-Life Lite Clinical Trials Version (IWQOL-Lite-CT) of Physical Function, Physical, and Psychosocial Composite Score at Week 72 | Baseline, Week 72 | The IWQOL-Lite-CT is a 20-item, obesity-specific patient reported outcome instrument developed for use in obesity clinical trials. It assesses 2 primary domains of obesity-related health-related quality of life: physical (7 items), and psychosocial (13 items). A 5-item subset of the physical domain, the physical-function composite is also supported. Items in the physical-function composite describe physical impacts related to general and specific physical activities. All items are rated on either a 5-point frequency ("never" to "always") scale or a 5-point truth ("not at all true" to "completely true") scale. The two domain scores (Physical and Psychosocial) and composite score (Physical function) range from 0 to 100 with higher scores indicating greater functioning. Raw scores are then linearly transformed to a 0 (worst) -100 (best) scale using: 100×(average item score-1)/4. Higher scores indicate better quality of life/function; lower scores indicate greater impairment. |
| Pharmacokinetics (PK): Mean Plasma Concentration of Orforglipron | Pre-dose at Weeks 8, 24, and 48; post-dose at Week 16 (4 to 12 hours) and Week 36 (1 to 4 hours) | Plasma concentrations of orforglipron were measured at predefined pre-dose and post-dose sampling time points. |
Countries
Japan
Contacts
STUDY_DIRECTORCall 1-877-CTLILLY (1-877-285-4559) or 1-317-615-4559 Mon - Fri 9 AM - 5 PM Eastern time (UTC/GMT - 5 hours, EST)
Eli Lilly and Company
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Continuous | 54.1 years STANDARD_DEVIATION 11.17 |
| Body Weight | 87.78 Kilogram (Kg) STANDARD_DEVIATION 14.58 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 60 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 238 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 0 Participants |
| Region of Enrollment Japan | 61 Participants |
| Sex: Female, Male Female | 94 Participants |
| Sex: Female, Male Male | 37 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 60 | 0 / 61 | 0 / 57 | 1 / 60 |
| other Total, other adverse events | 47 / 60 | 51 / 61 | 48 / 57 | 51 / 60 |
| serious Total, serious adverse events | 5 / 60 | 1 / 61 | 3 / 57 | 6 / 60 |
Outcome results
None listed