Efficacy and Safety of Tirzepatide Versus Placebo or Lisdexamfetamine Dimesylate for Binge-Eating Disorder

Inclusion Criteria:

Disease Characteristics

1. Have a BMI ≥30 kg/m2 or ≥27 kg/m2

• previously diagnosed with at least one obesity-related comorbidity:

2. Have at least one self-reported unsuccessful dietary effort to lose body weight

3. Meet Diagnostic and Statistical Manual (DSM)-5 criteria for Binge Eating Disorder (BED) as diagnosed by the Eating Disorder Examination interview and confirmed bybinge-eating diaries that is moderate or greater in severity (4 or more episodes perweek) Participant Characteristics

4. Are 18 years of age or older

5. Participants assigned female at birth: (participants assigned female at birth whoare not of childbearing potential may participate and include those who are:

• infertile due to surgical sterilization (hysterectomy, bilateral oophorectomyor tubal ligation), congenital anomaly such as Mullerian agenesis

• postmenopausal, defined as either

• a female at least 40 years of age with an intact uterus, not on hormone therapyand who has cessation of menses for at least 1 year without an alternativemedical cause; women in this category must test negative in pregnancy testprior to study entry OR

• a female 55 or older not on hormone therapy, who has had at least 12 months ofspontaneous amenorrhea OR

• a female at least 55 years of age with a diagnosis of menopause prior tostarting hormone replacement therapy Participants assigned female at birth of child-bearing potential (not surgicallysterilized and between menarche and 1-year postmenopausal) must:

• test negative for pregnancy at Visit 1 based on a serum pregnancy test

• and if sexually active, agree in writing to use 2 forms of effectivecontraception, where at least 1 form is highly effective, for the duration ofthe trial

• not be breastfeeding Informed Consent

6. Understand and be willing to comply with all study-related procedures and agree toparticipate in the study by giving written informed consent in accordance with localregulations

7. In the investigator's opinion, are well-motivated, capable, and willing to:

• Learn how to self-inject study drug, as required for this protocol (personswith visual impairments or physical limitations who are not able to perform theinjections must have the assistance of an individual trained to inject studydrug)

• Inject study drug (or receive an injection from a trained individual ifvisually impaired or with physical limitations)

• Learn how to take oral capsules, be consistently able to swallow capsules, andwilling to take oral capsules daily as required for this protocol

• Follow study procedures for the duration of the study

Exclusion Criteria: Medical Conditions Eating disorder-related

8. Current diagnosis of bulimia nervosa or anorexia nervosa Diabetes-related

9. Have type 1 diabetes mellitus (T1DM) or Type 2 diabetes mellitus (T2DM), history ofketoacidosis, or hyperosmolar state/coma

10. Have laboratory evidence diagnostic of diabetes mellitus during screening, includingan HbA1c ≥6.5% or fasting glucose >126 mg/dL Obesity-related:

11. Have a self-reported change in body weight >5 kg within 3 months prior to screening

12. Have a prior or planned surgical treatment for obesity (excluding lap-band ifremoved >6 months prior to screening or liposuction or abdominoplasty if performed >1 year prior to screening)

13. Have or plan to have endoscopic and/or device-based therapy for obesity or have haddevice removal within the last 6 months prior to screening (for example, mucosalablation, gastric artery embolization, intragastric balloon and duodenal-jejunalbypass sleeve)

Other medical

• Have a family or personal history of medullary thyroid carcinoma (MTC) or MultipleEndocrine Neoplasia (MEN) Syndrome type 2

• Known serious hypersensitivity to tirzepatide or lisdexamfetamine dimesylate or anyof the excipients in the medications

• Have severe gastrointestinal disease

• Have known clinically significant renal impairment

• Have uncontrolled medical conditions or contraindications to tirzepatide orlisdexamfetamine dimesylate

• Have personal or family history of cardiovascular disease that could increasevulnerability to sympathomimetic effects of psychostimulants

• Have a history of suspected substance abuse within the past 5 years

• Have a lifetime history of psychostimulant abuse and/or dependence

• Have glaucoma

• Have had a history of chronic or acute pancreatitis

• Have obesity induced by other endocrinologic disorders (for example, CushingSyndrome) or diagnosed monogenetic or syndromic forms of obesity (for example,Melanocortin 4 Receptor deficiency or Prader Willi Syndrome)

• Have a current diagnosis of attention-deficit/hyperactivity disorder

• Have a history of significant active or unstable Major Depressive Disorder (MDD;within the last 2 years) or other severe psychiatric disorder (for example,schizophrenia, bipolar disorder, psychosis, mania, hypomania, or other serious moodor anxiety disorder) Note: Patients with MDD or generalized anxiety disorder whosedisease state is considered stable and expected to remain stable throughout thecourse of the study, in the opinion of the investigator, may be considered forinclusion if not on excluded medications

• Have a Patient Health Questionnaire-9 (PHQ-9) score of 15 or more at Visit 1 or 2,prior to randomization

• Have any lifetime history of a suicide attempt

• Individual is considered a suicide risk in the opinion of the investigator; orendorsement of current, active suicidal ideation at screening or randomization. Onthe Columbia-Suicide Severity Rating Scale (C-SSRS) at Visits 1 or 2, prior torandomization:

• a "yes" answer to either Question 4 (Active Suicidal Ideation with Some Intentto Act, Without Specific Plan) or

• a "yes" answer to Question 5 (Active Suicidal Ideation with Specific Plan andIntent) on the "Suicidal Ideation" portion of the C-SSRS or

• a "yes" answer to any of the suicide-related behaviors (Actual Attempt,Interrupted Attempt, Aborted Attempt, Preparatory Act or Behavior) on the "Suicidal Behavior" portion of the C-SSRS and

• the ideation or behavior occurred within the past month

• Have taken monoamine oxidate inhibitors (MAOI), or within 14 days of stopping MAOIs

• Have uncontrolled hypertension (SBP above or equal to 160 mmHg and/or diastolicblood pressure above or equal to 100 mmHg)

• Have any of the following cardiovascular conditions within 3 months prior torandomization: acute myocardial infarction (MI), cerebrovascular accident (stroke),unstable angina

• Have a history of an active or untreated malignancy or are in remission from aclinically significant malignancy (other than basal- or squamous-cell skin cancer,in situ carcinomas of the cervix, or in situ prostate cancer) for less than 5 years

• History of seizures (other than infantile febrile seizures), any tic disorder, or acurrent diagnosis and/or known family history of Tourette's Disorder, seriousneurological disease, history of significant head trauma, dementia, Parkinson'sdisease, or intracranial lesions

• Participant has known history of symptomatic cardiovascular disease, advancedarteriosclerosis, structural cardiac abnormality, cardiomyopathy, serious heartrhythm abnormalities, coronary artery disease, or other serious cardiac problemsthat may place the participant at increased vulnerability to the sympathomimeticeffects of a stimulant medication

• Have a history of any other condition that, in the opinion of the investigator, maypreclude the participant from following and completing the protocol

Prior/Concomitant Therapy

• Are receiving concurrent treatment for eating or weight disorders

• Use of a psychostimulant within the past 6 months

• Have taken within 3 months prior to screening, medications (prescribed or over-thecounter) intended to promote weight loss. Examples include, but are not limited to

• Saxenda® (liraglutide 3.0 mg)

• Xenical®/Alli® (orlistat)

• Meridia® (sibutramine)

• Adipex® (phentermine)

• BELVIQ® (lorcaserin)

• Qsymia® (phentermine/topiramate combination)

• Contrave® (naltrexone/bupropion)

• Ozempic or Wegovy (semaglutide)

• Mounjaro or Zepbound (tirzepatide)

• Rybelsus (semaglutide)

Prior/Concurrent Clinical Study Experience

• Are currently enrolled in any other clinical study involving an investigationalproduct (IP) or any other type of medical research judged not to be scientificallyor medically compatible with this study