Evaluation of Safety, Efficacy and Thermogenesis-induction of RZL-012 in Overweight and Obese Volunteers

Study Overview
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Brief Summary
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Obesity is a direct result of food-intake in excess of body energy expenditure. Thus, induction of increased energy expenditure via the activation of thermogenesis at targeted anatomical sites can counterbalance obesity. This trial aims to study RZL-012, a novel compound, in treating obesity by activating thermogenesis in subcutaneous fat.

Detailed Description
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Obesity is a direct result of food-intake in excess of body energy expenditure. Therefore, a feasible approach to combat obesity is via energy-consuming activities, such as physical exercise. Unfortunately, our modern society is moving in the other direction, spending more time in immobilized positions, at work and at home. An alternative strategy for the induction of increased energy expenditure is via the activation of thermogenic cells that utilize fat to produce heat.RZL-012 is a novel molecule that enables de-novo generation of thermogenic tissue at favorable anatomical sites. As a result, the extra fat accumulated in obese persons will be turned into heat. This is a double blind, randomized, placebo controlled, dose escalation Phase 2a clinical trial for the evaluation of safety, efficacy and thermogenesis-induction of RZL-012 in overweight and obese volunteers. This trial aims to study the ability of RZL-012 in treating obesity via the induction of thermogenic foci in subcutaneous fat.

Official Title
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A Double Blind, Randomized, Placebo Controlled, Dose Escalation Phase 2a Clinical Trial for the Evaluation of Safety, Efficacy and Thermogenesis-induction of RZL-012 in Overweight and Obese Volunteers

Conditions
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Obesity, Weight Loss, Overweight and Obesity

Intervention / Treatment
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* Drug: RZL-012
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adult male subjects, 20-60 years old. Subject is considered overweight and obese, with 27.5 < BMI ≤ 34.9. Significant subcutaneous abdominal fat as defined by Waist to hip ratio (WHR) ≥ 0.9. Subjects with stable weight in the last 3 months by medical history. Not one of the following eating disorders by subject's declaration: anorexia nervosa, bulimia nervosa. Generally considered healthy according to medical history, physical examination, electrocardiogram (ECG) and laboratory evaluation with a special emphasis on metabolic parameters (fasting glucose concentration < 100 mg, normal blood pressure). Subject is willing to refrain from sexual activity or agrees to use a double-barrier contraceptive device (e.g., condom and spermicide) for 4 weeks after treatment with RZL 012. Subjects must be able to adhere to the visit schedule and protocol requirements and be available to complete the study. Subjects must sign an informed consent indicating that they are aware of the investigational nature of the study. Exclusion Criteria: Subjects weighing less than 75 kg. Subjects who have reduced/gained weight more than 5% of their current body weight in the last 3 months. Unable to tolerate subcutaneous injection. Subjects with uncontrolled cardiac, hepatic, renal or neurologic/psychiatric disorders, that in the opinion of the investigator put the subject at significant risk, are not eligible. Subjects who test positive to either Hepatitis B virus (HBV), Hepatitis C virus (HCV), or Human immunodeficiency virus (HIV) are not eligible. Subjects with a clinical history of primary or secondary immunodeficiency, autoimmune disease or subjects taking immunosuppressive drugs such as corticosteroids are ineligible. As a result of medical review, physical examination, the PI (or medically qualified nominee) considers the subject unfit for the study. Medication use on regular basis. Positive drug and alcohol tests. Known sensitivity to components of the injection formulation. Prior wound, tattoo or infection in the treated area. Excessive growth of hair in the abdomen region. Claustrophobia or MRI incompatible device or implant.

Ages Eligible for Study
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Minimum Age: 20 Years
Maximum Age: 60 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: This is a consecutive 4 cohort, dose escalation placebo-controlled clinical trial
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: RZL-012<br>A single-time injection, multiple subcutaneous injections of RZL-012 administered into 8-36 sites (0.1mL per site): 40mg RZL-012 -administered at 8 sites 80mg RZL-012 - administered at 16 sites 120mg RZL-012 - administered at 24 sites 180mg RZL-012 - administered at 36 sited | Drug: RZL-012<br>* Subject receive a single-time injection. Multiple injections of RZL-012 are administered at 8-36 sites (0.1mL per site) into the abdominal subcutaneous fat.<br>|
| Placebo Comparator: Placebo<br>A single-time injection, multiple subcutaneous injections of Placebo administered into 8-36 sites (0.1mL per site) | Drug: Placebo<br>* Subject receive a single-time injection. Multiple injections of the Placebo are administered at 8-36 sites (0.1mL per site) into the abdominal subcutaneous fat.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety: The Incidence of Treatment-related Adverse Events [AEs] | AEs will be assessed by significant clinical changes in safety parameter (e.g. vital signs, ECG, clinical laboratory evaluations)AEs incidence will be by body system, seriousness, severity and relation to study drug by cohort. | 0-168 days | 
| Efficacy: A Significant Thermogenesis at the Injected Site. | Thermogenesis is measured by thermal imaging is non-invasive, non-radiating Infra-Red thermal camera that passively measures the emitting infra-red radiation of body surface. Difference in temperatures between the sites (treated - not treated) by visit treatment along with the change from baseline (net-delta) in these differences by cohort and overall. Significant thermogenesis is defined as net-delta ≥ 1. Outcome measure data table represents the number of subjects who demonstrated an increase that is higher than 1 celsius degree. | 28-168 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Duration of the Thermogenic Effect From Day 28. | The duration of the thermogenic effect for subjects in the active arm with thermogenic effect (net-delta ≥ 1) by visit and cohort. | 28-168 days | 
| Local Reduction in Fat Mass as Measured by MRI. Local Reduction in Fat Will be Measured by Periodically MRI Scans of the Abdomen. | Subcutaneous Fat Mass (SFM) ratio (treated sites / control sites) averaged over the MRI slices by visit, treatment and cohort and the change from baseline in SFM ratio (in % from the ratio at baseline) compared between the treatment arms. | 28-168 days | 
| Changes in Fasting Blood Glucose From Baseline. | Changes from baseline in fasting blood glucose by visit, treatment, and cohort. | 56 days | 
| Changes in Blood Lipid Profile From Baseline. | Changes from baseline in lipid profile by visit, treatment, and cohort. | 56 days | 
| Pharmacokinetics: Establishing Pharmacokinetic Profile of RZL-012. | Averaged Cmax values by cohort. | 1-2 days | 
| Changes in Body Weight | Changes from baseline in body weight by visit, treatment, and cohort. | 56 days | 
| Changes in Waist to Hip Ratio [WHR] | Changes from baseline in WHR by visit, treatment, and cohort. WHR is calculated by measurements of waist circumference and hip circumference. | 56 days | 
| Elucidation of the Histological Changes Account for the Thermogenic Effect. | An abdominal subcutaneous adipose tissue biopsy will be taken from the injected side. Histology results will be assessed for 2 subjects who were injected with 120 mg RZL-012 and for one subject who was injected with placebo. | 56 days | 
| Change From Baseline in Inflammatory Markers and Cytokines. Testing of Inflammatory Markers and Cytokines Will be Conducted by Blood Sampling. | Changes from baseline in inflammatory markers and cytokines by visit, treatment, and cohort. Testing of inflammatory markers and cytokines will be conducted by blood sampling. | 28 days | 
| Pharmacokinetics: Establishing Pharmacokinetic Profile of RZL-012. | Averaged Tmax values by cohort. | 0.5, 1,2,3,4,5,6,8,12,16,24,30 hours | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Obesity, Overweight, Thermogenesis, Fat reduction