E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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E.1.1.1 | Medical condition in easily understood language |
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E.1.1.2 | Therapeutic area | Diseases [C] - Nutritional and Metabolic Diseases [C18] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10029883 |
E.1.2 | Term | Obesity |
E.1.2 | System Organ Class | 10027433 - Metabolism and nutrition disorders |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 24.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10033307 |
E.1.2 | Term | Overweight |
E.1.2 | System Organ Class | 10027433 - Metabolism and nutrition disorders |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To compare and assess the dose-response of 3 selected doses of AMG 133 compared with placebo, on inducing and maintaining weight loss from baseline at week 52 in subjects with overweight or obesity without diabetes mellitus (cohort A) and in subjects with overweight or obesity with type 2 diabetes mellitus (cohort B). |
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E.2.2 | Secondary objectives of the trial |
Key Secondary • To evaluate the effect of AMG 133 on achieving specific categories of body weight loss from baseline at week 52 in cohorts A and B • To evaluate the effect of AMG 133 on glucose metabolism in cohorts A and B • To characterize the pharmacokinetics (PK) properties of AMG 133 Secondary • To evaluate the effect of AMG 133 on waist circumference • To assess the treatment effect of dose-escalation regimens • To evaluate the effect of AMG 133 on systolic blood pressure (SBP) • To evaluate the effect of AMG 133 on diastolic blood pressure (DBP) • To evaluate the effect of AMG 133 on body composition in a subpopulation • To evaluate the effect of AMG 133 on a marker of inflammation • To evaluate the effect of AMG 133 on body mass index (BMI) • To evaluate the effect of AMG 133 on lipid parameters |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Subjects are eligible to be included in the study only if all of the following criteria apply: - The subject has provided informed consent prior to initiation of any study-specific activities/procedures. - Age ≥ 18 years (or ≥ legal age within the country if it is older than 18 years). - Subject has a BMI ≥ 27 kg/m2 at screening. - Subject has had at least 1 unsuccessful attempt at weight loss by diet and exercise in the opinion of the investigator. - For subjects in cohort A only, the presence of at least 1 of the following weight-related complications: hypertension, dyslipidemia, obstructive sleep apnea or cardiovascular disease; or BMI ≥ 30 kg/m2. - For subjects in cohort A only, HbA1c < 6.5% (< 48 mmol/mol) at screening without a diagnosis of type 1 or 2 diabetes mellitus. - For subjects in cohort B only, HbA1c ≥ 7% and ≤ 10% (53 to 86 mmol/mol) at screening with an established diagnosis of type 2 diabetes mellitus for ≥ 180 days prior to screening. - For subjects in cohort B only, either treated with diet and exercise alone or on stable (at least 90 days prior to screening) treatment with metformin, a sulfonylurea, or a sodium-glucose cotransporter 2 (SGLT2) inhibitor as monotherapy or combination therapy, per approved local label. |
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E.4 | Principal exclusion criteria |
Subjects are excluded from the study if any of the following criteria apply: Disease Related •Subjects with type 1 diabetes mellitus, history of ketoacidosis or hyperosmolar state/coma, or any other types of diabetes except type 2 diabetes mellitus (for cohort B only). •History of proliferative diabetic retinopathy, diabetic macular edema, or nonproliferative diabetic retinopathy that requires acute treatment. •For the subjects in the DXA substudy only, body weight greater than the local DXA scanner capacity at screening. •Change in body weight > 5 kg within 90 days before screening per subject report or medical records. •For subjects in cohort B only, fasting glucose > 270 mg/dL (15.0 mmol/L) at screening. Other Medical Conditions •Any of the following within the last 6 months prior to screening: myocardial infarction, unstable angina, coronary artery bypass graft, percutaneous coronary intervention (diagnostic angiograms are permitted), transient ischemic attack, cerebrovascular accident, or decompensated congestive heart failure; or currently have New York Health Association Class III or IV heart failure •Malignancy except nonmelanoma skin cancers, cervical or breast ductal carcinoma in situ within the last 5 years. •Uncontrolled thyroid disease, defined as TSH > 6.0 mIU/L or < 0.4 mIU/L as measured by central laboratory at screening. Subjects who received treatment for hypothyroidism are permitted in the study, if their thyroid hormone replacement dose has been stable for at least 90 days and their TSH at screening is within the above range. •Obesity induced by other endocrine disorders (eg, Cushing syndrome). •History of severe or symptomatic gastroparesis. •A corrected QT interval (QTc) of > 450 msec in males or > 470 msec in females at screening as assessed by the investigator, or history of long QT syndrome. •Any of the following laboratory abnormalities at screening: i.An eGFR < 30 mL/min/1.73 m2 estimated according to chronic kidney disease epidemiology collaboration (CKD-EPI) equation. ii.Aspartate aminotransferase (AST) or alanine aminotransferase (ALT): ≥ 2.5 times the upper limit of normal (ULN). iii.Other laboratory abnormalities that may affect the completion or evaluation of the study, as judged by the investigator. •Calcitonin ≥ 50 ng/L (pg/mL) at screening. •Lifetime history of acute or chronic pancreatitis, or elevation in serum lipase/amylase (> 2x ULN) at screening, or fasting serum triglyceride level of > 500 mg/dL at screening. •Personal or family history of medullary thyroid carcinoma or multiple endocrine neoplasia type 2. •History of major depressive disorder within 2 years before randomization. •Lifetime history of other severe psychiatric disorders (eg, schizophrenia, bipolar disorder). •A PHQ-9 score of ≥ 15 at screening or day 1 before randomization. •Any lifetime history of a suicidal attempt. •Any suicidal behavior within 2 years before randomization. •Any suicidal ideation of type 4 or 5 on the C-SSRS at screening or day 1 before randomization. Prior/Concomitant Therapy •Treatment within 90 days before screening with any medication for obesity or that may cause significant weight change per the investigator's judgment, including but not limited to: phentermine, topiramate, zonisamide, lorcaserin, bupropion, naltrexone, orlistat, diethylpropion, exenatide, liraglutide, dulaglutide, semaglutide, tirzepatide, setmelanotide, pramlintide, leptin, or SGLT2 inhibitors (except for cohort B). •Previous or planned (during the study) obesity treatment with surgery or a weight loss device except for the following: iv.Liposuction and/or abdominoplasty that was performed > 1 year before screening v.Laparoscopic gastric band that was removed > 1 year before screening vi.Intragastric balloon that was removed > 1 year before screening vii.Duodenal-jejunal bypass sleeve that was removed > 1 year before screening •Treatment within 90 days before screening with medications that may cause significant weight gain, including systemic corticosteroids (except for a short course of treatment, ie, ≤ 10 days), tricyclic antidepressants, atypical antipsychotic, and mood stabilizers (eg, imipramine, amitryptiline, mirtazapin, paroxetine, phenelzine, clorpromazine, thioridazine, clozapine, olanzapine, valproic acid and its derivatives, and lithium). • Treatment within 90 days before screening with a central nervous system stimulant, eg, methylphenidate hydrochloride (Ritalin-SR®), amphetamine/dextroamphetamine mixed salts (Adderall XR®), and lisdexamfetamine (Vyvanse®), with the exception of caffeinated beverages. • Use within 90 days before screening of herbal supplements or overthe- counter medications taken for the purpose of weight loss. • Participation within 90 days before screening in an organized weight reduction program (eg, WeightWatchers®). See protocol for additional exclusion criteria. |
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E.5 End points |
E.5.1 | Primary end point(s) |
• Percent change from baseline to week 52 in body weight |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
Key Secondary: • Achieving ≥ 5% reduction in body weight from baseline at week 52 (yes/no) • Achieving ≥ 10% reduction in body weight from baseline at week 52 (yes/no) • Achieving ≥ 15% reduction in body weight from baseline at week 52 (yes/no) • Achieving ≥ 20% reduction in body weight from baseline at week 52 (yes/no) • Change from baseline to week 52 in hemoglobin A1c (HbA1c) (%, mmol/mol) • Change from baseline to week 52 in fasting serum insulin • Change from baseline to week 52 in fasting plasma glucose • Change from baseline to week 52 in Homeostasis Model Assessment for insulin resistance (HOMA2-IR) • Change from baseline to week 52 in Homeostasis Model Assessment for steady state beta cell function (HOMA2-%B) • PK parameters for AMG 133 including, but not limited to maximum observed plasma concentration (Cmax), and area under the concentration-time curve (AUC) Secondary • Change from baseline to week 52 in waist circumference • Change from baseline to week 52 in body weight • Change from baseline to week 52 in SBP • Change from baseline to week 52 in DBP • Change from baseline to week 52 in body composition (eg, fat mass, lean mass) using dual energy X ray absorptiometry (DXA) for a subset of subjects • Percent change from baseline to week 52 in high-sensitivity Creactive protein (hs-CRP) • Change from baseline to week 52 in BMI • Percent change from baseline to week 52 in low density lipoprotein cholesterol (LDL-C) • Percent change from baseline to week 52 in total cholesterol • Percent change from baseline to week 52 in high density lipoprotein cholesterol (HDL-C) • Percent change from baseline to week 52 in non-HDL-C • Percent change from baseline to week 52 in very low-density lipoprotein cholesterol (VLDL-C) • Percent change from baseline to week 52 in triglycerides • Percent change from baseline to week 52 in free fatty acids (FFA) |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | No |
E.6.5 | Efficacy | No |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | Yes |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 18 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 21 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Hong Kong |
Taiwan |
Australia |
Canada |
Japan |
Korea, Republic of |
United Kingdom |
United States |
Czechia |
Germany |
Hungary |
Poland |
Spain |
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E.8.7 | Trial has a data monitoring committee | No |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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The end of study date is defined as the date when the last subject across all sites is assessed or receives an intervention for evaluation in the study (ie, last subject last visit), including any additional parts in the study (eg, long-term follow-up, antibody testing), as applicable. |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 3 |
E.8.9.1 | In the Member State concerned months | 1 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 3 |
E.8.9.2 | In all countries concerned by the trial months | 1 |