Clinical trial NCT06019559
Conditions: Obesity
Sponsor: Kallyope Inc.
Start date: 2023-09-15; Completion date: 2024-02-19
Enrollment: 155 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a study to evaluate the safety and efficacy of K-757 alone and in combination with K-833 versus placebo in participants who are obese.

Detailed description:

Arms: arm 1: None arm 2: None arm 3: None
Interventions: intervention 1: K-757 120 mg BID and K-833 100 mg BID intervention 2: K-757 120 mg BID and matching placebo to K-833 intervention 3: Matching placebo to K-757 and matching placebo to K-833
Intervention descriptions: intervention 1: K-757 was titrated to the maintenance dose of 120 mg twice daily (BID) by Day 22. K-833 was initiated at 100 mg once daily in the morning (QAM) and was titrated to the maintenance dose of 100 mg BID on Day 8.

Both administered orally. intervention 2: K-757 was titrated to the maintenance dose of 120 mg twice daily (BID) by Day 22.

Both administered orally. intervention 3: Both administered orally.

Protocol documents:
Prot_000.pdf: 
K-757 
Protocol 
 
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K-757 
P006-03 
A Randomized, Placebo-Controlled, Double-Blind 13-Week 
Study to Evaluate the Safety, Tolerability, and Weight Loss 
Efficacy of K-757 alone and in Combination with K-833 in 
Participants who are Obese 
 
 
 
 
KALLYOPE, Inc. 
430 East 29th Street 
New York, NY 10016 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Protocol Issue Date:  03-OCT-2023 
IND Number: 160779 
Confidentiality Statement 
This protocol and all related information are confidential and proprietary property of 
KALLYOPE, Inc., New York, NY, U.S.A. 


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1.1. 
Summary of Changes 
Reason for Change 
Section 
Added optional genetic blood sample 
collection 
Table 2, Section 14.3.2 
Clarified the BMI upper range as 40.0 at 
screening in Inclusion Criterion #4 
Synopsis, Section 8.1 
Clarified contraception requirements in 
Inclusion Criterion #8 
Synopsis, Section 8.1, Section 11.2 
Clarified obesity exclusion medication use in 
Exclusion Criterion #5 
Synopsis, Section 8.2 
Clarified when a participant may be enrolled 
who has uncontrolled thyroid disease in 
Exclusion Criterion #10 
Synopsis, Section 8.2 
Clarified prohibited medications in Exclusion 
Criterion #17 
Synopsis, Section 8.2 
Clarified Exclusion Criterion #18 regarding 
various diseases and reasons for exclusion 
Synopsis, Section 8.2 
Updated Exclusion Criterion #33 to be 
consistent with Section 14.2: Blood pressure 
should be taken seated not semi-recumbent 
and after resting 5 minutes 
Synopsis, Section 8.2 
Added clarification to Exclusion Criterion 
#36 regarding the use of benzodiazepines 
Synopsis, Section 8.2 
Added hemoglobin and hemoglobinopathy to 
Exclusion Criterion #41 
Synopsis, Section 8.2 
Added clarification to Exclusion Criterion 
#44 pertaining to interpretation of efficacy 
and/or safety results 
Synopsis, Section 8.2 
Added Exclusion Criterion #47 regarding use 
of opiate medications 
Synopsis, Section 8.2 
Added Exclusion Criterion #48 regarding use 
of medications that affect body weight 
Synopsis, Section 8.2 


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Administrative 
Clarified which exclusion criteria need to be 
confirmed prior to randomization 
Fixed Day 57/Week 8 column heading error 
on 2nd page of Table 2 
Table 2 
Added stimulant and opiate medications to 
the Prohibited Medications list 
Section 10.1 
Clarified diet and activity counseling will be 
limited to the protocol guidelines 
Section 11.1 
Clarified dosing interruptions procedures due 
to subject error 
Section 13.4.3 
 




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INVESTIGATOR’S AGREEMENT 
I have received and read the Investigator’s Brochures for K-757 and K-833. I have read K-757 
P006-03 and agree to conduct the study as outlined in the protocol and abide by all provisions of 
this protocol. I agree to conduct the study in accordance with generally accepted standards of Good 
Clinical Practice, the FDA Form 1571 and with all obligations detailed in applicable regulations 
and guidelines. I also agree to report all information or data in accordance with the protocol and, 
in particular, report any serious adverse events as defined in the protocol. I also agree to handle all 
clinical supplies provided by the Sponsor and collect and handle all clinical specimens in 
accordance with the protocol. I understand that information that identifies me will be used and 
disclosed as described in the protocol, and that such information may be transferred to countries 
that do not have laws protecting such information. Since the information in this protocol and 
referenced Investigator Brochure is confidential, I understand that its disclosure to any third 
parties, other than those involved in approval, supervision, or conduct of this trial is prohibited. I 
will ensure that the necessary precautions are taken to protect such information from loss, 
inadvertent disclosure, or access by third parties. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Printed Name of Investigator 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature of Investigator 
 
 
 
 
 
 
 
 
Date 




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2. 
SYNOPSIS 
Name of Sponsor/Company: 
Kallyope, Inc. 
Name of Investigational Product: 
K-757, K-833 
Name of Active Ingredients: 
K-757 
, K-833 
 
Protocol Number: P006-03 
Phase: 2 
Country: USA 
Title of Study: A Randomized, Placebo-Controlled, Double-Blind 13-Week Study to Evaluate the 
Safety, Tolerability, and Weight Loss Efficacy of K-757 alone and in Combination with K-833 in 
Participants who are Obese 
Study center(s): Multi-center study in US 
Studied period (years): 12 months 
Estimated date first patient enrolled: Oct 2023 
Estimated date last patient completed: Jul 2024 
Phase of development: 2 
Number of participants (planned): 
Approximately 150 (50 per treatment group) 
Objectives:  In participants who are obese: 
Primary: 
To assess relative (%) change from baseline in body weight after 13 weeks of treatment with K-757 
alone and in combination with K-833, in comparison to placebo. 
Hypothesis: At least one of the treatment arms is superior to the placebo arm in reducing body weight 
calculated as percentage change from baseline after 13 weeks of treatment. 
Secondary: 
1. To assess the proportion of participants achieving ≥5% weight loss from baseline after 13 weeks 
of treatment with K-757 alone and in combination with K-833, in comparison to placebo. 
2. To assess the absolute change from baseline in body weight after 13 weeks of treatment with 
K-757 alone and in combination with K-833, in comparison to placebo. 
3. To characterize the safety and tolerability of K-757 alone and in combination with K-833 over 
13 weeks of treatment. 
Exploratory: 
1. To assess the change from baseline in hemodynamic parameters (systolic blood pressure, 
diastolic blood pressure and heart rate) after 13 weeks of treatment with K-757 alone and in 
combination with K-833, in comparison to placebo. 
2. To assess the change from baseline in total cholesterol, low-density lipoprotein (LDL), 
high-density lipoprotein (HDL), and triglycerides after 13 weeks of treatment with K-757 alone 
and in combination with K-833, in comparison to placebo. 
Study Design: 
This is a randomized, double-blind, placebo-controlled 13-week study to evaluate the efficacy of K-757 
alone and in combination with K-833 versus placebo in participants who are obese without type 2 
diabetes mellitus (T2DM). Approximately one hundred fifty (150) participants will be enrolled and 
randomized (1:1:1) to receive K-757 alone, K-757+K-833, or matching placeboes.  




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Plasma will be obtained for pharmacokinetics (PK) and potential pharmacodynamics (PD) at select time 
points during treatment (Table 2). 
To mitigate mechanism-related GI intolerance, K-757 will be titrated according to the Dosing Table (see 
above). In the combination arm and the K-757-only arm K-757 will be titrated to the maintenance dose 
of 120 mg twice daily (BID) by Day 22. K-833 will be initiated at 100 mg QAM and will be titrated to 
the maintenance dose of 100 mg BID on Day 8. 
For participants experiencing gastrointestinal (GI) intolerance, all reasonable, medically appropriate 
efforts should be made to support them in adhering to scheduled dosing (see Section 7.1.1). 
Subject/Criteria for Entry into the Trial 
Inclusion criteria: 
All entry criteria, including laboratory test results, need to be confirmed before administration of the first 
dose of study drug. 
In order to be eligible for participation in this trial, the subject must: 
1. Understand the trial procedures and agree to participate by providing written informed consent 
prior to trial related activities. Trial-related activities are any procedures that are carried out as part 
of the trial, including activities to determine suitability for the trial. 
2. Be willing and able to comply with the study schedule of visits, all trial procedures and restrictions, 
including following study diet requirements. 
3. Be a male or female, age 18 to 70 years, inclusive, at the time of signing informed consent. 
4. Have a body mass index (BMI) of 30.0 to 40.0. kg/m2, inclusive at screening. 
5. History of at least one self-reported unsuccessful dietary effort to lose body weight. 
6. Be weight stable (<5% variation) over the last 3 months (by subject report). 
7.  Be a nonsmoker or has smoked ≤10 cigarettes per week for at least 3 months and agrees not to exceed 
this for the duration of study participation; has not used other nicotine containing products (e.g. other 
forms of tobacco, nicotine patch, e-cigarettes, vapes) for at least 3 months and agrees to abstain from 
such products throughout study participation. 
8. Meet the following requirements: 
a. Is a male who agrees to all of the following: 
• 
If partner is a non-pregnant female of child-bearing potential: To use an appropriate 
method of contraception, which must include a condom with spermicidal cream or jelly, 
from the first dose of study drug until 14 days after the last dose of study drug. A male 
subject who has had a vasectomy procedure must use a condom but is not required to 
use spermicidal cream or jelly. 
• 
If partner is pregnant, to use a condom 
Note: Contraception/condom requirements are waived if partner is NOT of 
child-bearing potential (i.e. is male or is a female who is post-menopausal or surgically 
sterile 
[post-hysterectomy, 
post-bilateral 
oophorectomy, 
and/or 
post-bilateral 
salpingectomy]). 
• 
To not donate sperm from the first dose of study drug until 14 days after the last dose of 
study drug. 
OR 


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b. Is a female who is of non-childbearing potential defined by at least 1 of the following 
criteria: 
• 
Postmenopausal (aged >45 years and with a minimum of 12 months of spontaneous 
amenorrhea with a Screening serum follicle-stimulating hormone (FSH) level in the 
menopausal range established for the central laboratory. 
• 
Post hysterectomy, bilateral oophorectomy or bilateral salpingectomy, based on the 
subject’s recall of their medical history. 
OR 
c. Is a female of reproductive potential and: 
• 
agrees to not donate eggs from the first dose of study drug until 14 days after the last 
dose of study drug. 
• agrees to remain abstinent from heterosexual activitya or 
• agrees to use (or have their partner use) a birth control method that is highly effective 
and has low user dependency from the first dose of study drug until 14 days after the last 
dose of study drug. Acceptable methods of birth control are: 
- Progestogen-only implant (e.g. etonogestrel implant) 
- Intrauterine device (IUD) 
- Intrauterine hormone-releasing system (IUS) 
- Bilateral tubal occlusion 
- Vasectomized partner 
a Abstinence can be used as the sole method of contraception if it is in line with the subject’s 
preferred and usual lifestyle and if considered acceptable by local regulatory agencies and 
ethics committees. Periodic abstinence (e.g., calendar, ovulation, sympto-thermal, 
post-ovulation methods, etc.) and withdrawal are not acceptable methods of contraception. 
This condition is waived if the subject is proven to have no child-bearing potential (eg, 
hysterectomy). 
Exclusion criteria: 
Participants are excluded from the trial if any of the following criteria apply: 
Glycemia related: 
1. Has a hemoglobin A1c (HbA1c) ≥6.5% (48 mmol/mol) as measured by the central laboratory at 
screening. 
2. Has a history of clinically significant endocrine disease including T2DM. 
Note: A history of hypothyroidism does not require exclusion if the subject has been on a stable 
dose of thyroid hormone replacement (thyroxine) for at least 3 months prior to screening and the 
screening thyroid-stimulating hormone (TSH) is within the central laboratory normal range. 
3. Has a history of type 1 or type 2 diabetes mellitus. 
4. Had treatment with any glucose-lowering agent(s) within 90 days before screening. 
Obesity related: 
5. Had treatment with any medication approved for the treatment of obesity or any investigational agent 
being tested for obesity treatment within the past 6 months before screening. This includes agents 
that are approved as a component of a multi-drug combination treatment for obesity, regardless of 
the purpose of current use, with the exception of bupropion. 
Bupropion, which is a component of the naltrexone-bupropion combination approved for weight loss 
(ContraveTM), is also approved as a single agent for the treatment of depression. Bupropion is not 


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exclusionary if it is being used for treatment of depression and eligibility criteria for anti-depressant 
medication stability prior to screening are met (see Exclusion Criterion #12). 
6. Has been treated with/used any other medication, supplement, or device for the purpose of 
promoting weight loss (regardless of whether they are approved or promoted for the purpose of 
weight loss) in the 90 days prior to screening. 
7. Treatment with any glucagon-like peptide-1 (GLP-1) receptor agonist in the prior 6 months. 
8. Participation in an organized weight reduction program (e.g. Weight Watchers) within 90 days of 
screening. 
9. Had a previous or has a planned (during the trial period) obesity treatment with surgery or a weight 
loss device. Note: Prior liposuction and/or abdominoplasty are not exclusionary if performed >2 
years before screening). 
10. Has uncontrolled thyroid disease, defined as thyroid stimulating hormone (TSH) outside (above or 
below) the reference range of the central laboratory at screening or has any history of Grave’s 
disease unless all 3 of the following criteria are all met: 1. Grave’s disease was treated with total 
thyroidectomy >2 years prior to screening, 2. There has been no recurrence of hyperthyroidism since 
thyroidectomy, and 3. TSH is the reference range of the central laboratory at screening. 
11. Obesity is induced by an endocrine disorder (e.g. Cushing’s disease). 
Mental health: 
12. Has a history of major depressive disorder within 2 years before screening unless all of the following 
criteria are met: 
a) the depressive disorder has always been unipolar (no history of mania or hypomania) 
b) in the opinion of the investigator, depressive symptoms have been stable and well controlled 
for ≥ 2 years prior to screening. 
c) any anti-depressant drug-treatment regimens (medications and doses) have been stable for 
≥6 months prior to screening.  
13. Has any history of other severe psychiatric disorder (e.g., schizophrenia, bipolar disorder) that was 
not clearly attributable to an intercurrent event/life circumstance, self-limited and fully resolved ≥1 
year prior to screening. 
14. On the screening Patient Health Questionnaire-9 (PHQ-9), has an overall score ≥15 or has a score 
>0 for Question # 9 (Thoughts that you would be better off dead or of hurting 
yourself)(Appendix C). 
Note: See Section 15.1.6 regarding requirements for referral to a mental health professional based 
on the results of the screening PHQ-9 assessment. 
15. Has any lifetime history of suicide attempt or suicidal behavior. Note: Suicidal behavior includes 
any acts/preparation toward making a suicide attempt whether the attempt is never initiated or is 
initiated but interrupted by self or another person (31). 
16. Use of any anti-psychotic agents for any purpose within 2 years before screening. 
17. Use of the following prohibited agents: 
• Prohibited classes of anti-depressant agents (see Section 10.1), for any purpose, within 6 
months of screening. Note: Use of allowable classes of anti-depressant agents (see 
Section 10.1) is permitted only if the anti-depressant regimen (agents and doses) has been 
stable for ≥6 months prior to screening and is not anticipated to change during the trial period. 
• Stimulant medications including amphetamines (e.g. dextroamphetamine, lisdexamfetamine) 
and methylphenidate/dexmethylphenidate within 6 months of screening. 
General Safety: 
18. Has a recent history (within the past 3 years of the screening visit) or current diagnosis or evidence 
of hematological, immunological, renal, respiratory, neurologic, or genitourinary abnormalities or 


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diseases that, per the investigator’s judgement, may jeopardize the subject’s safety or compliance 
with the protocol, or otherwise interfere with interpretation of efficacy and/or safety results. 
19. Has a recent history (within past 3 years of the screening visit) or current diagnosis of any of the 
following GI (gastro-intestinal) related diseases: intestinal obstruction, GI perforation, adhesions, 
Clostridium difficile colitis or have had recent unexplained GI bleeding within 3 months prior to 
screening. 
20. Has any history of pancreatitis (acute or chronic), gastroparesis, ischemic colitis, inflammatory 
bowel disease (IBD), or celiac disease. 
21. Has any personal or first-degree relative history of multiple endocrine neoplasia type 2 or medullary 
thyroid carcinoma. 
22. Has a screening estimated Glomerular Filtration Rate (eGFR) estimated with the Modification of 
Diet in Renal Disease (MDRD) equation of <60 ml/min/1.73 m2. 
23. Has a history of malignant neoplasms within the past 5 years prior to screening. Basal and squamous 
cell skin cancer and any carcinoma in-situ are allowed if they have received treatment and follow-
up consistent with local standard of care. 
24. Has any history of cardiovascular disease including stable and unstable angina pectoris, myocardial 
infarction, transient ischemic attack, stroke, cardiac decompensation, clinically significant 
arrhythmias, clinically significant conduction disorders, or any history or heart failure. 
25. Has any surgery scheduled for the duration of the trial, except for minor surgical procedures, in the 
opinion of the investigator. 
26. Has a history of human immunodeficiency virus (HIV) infection. 
27. Has any active liver disease other than non-alcoholic fatty liver disease (NAFLD), or any 
gallbladder disease that has been active/symptomatic within 6 months of screening. 
28. Has a positive test result for hepatitis B surface antigen (Ag), hepatitis C virus antibody, or HIV 
antibody, at the Screening Visit. Note: Participants with positive hepatitis B virus or hepatitis C 
virus serology may be enrolled if quantitative polymerase chain reaction for hepatitis B virus or 
hepatitis C virus ribonucleic acid is negative. 
29. Has alanine aminotransferase or aspartate aminotransferase (ALT or AST) of >2.0X upper limit of 
normal (ULN) or total bilirubin >1.5X ULN at the Screening visit. Note: An isolated bilirubin >1.5X 
ULN is acceptable if bilirubin is fractionated, and direct bilirubin is within the laboratory normal 
range. 
30. Has serum amylase or lipase >1.2X the ULN at the Screening visit. 
31. Has a triglycerides value of >600mg/dL at the Screening visit (if value is ≥600 mg/dL and the 
sample was obtained in the non-fasted state, a repeat fasting determination may be obtained to assess 
eligibility). 
32. Has a corrected QT interval to Fridericia’s formula (QTcF) >450 milliseconds (msec) for males and 
>470 msec for females at screening. 
33. Has a mean value for triplicate seated systolic blood pressure >160 mmHg and/or diastolic blood 
pressure (BP) >95 mmHg measured after at least 5 minutes at rest at the Screening Visit. 
Note: If a subject’s BP is exclusionary on the first triplicate assessment at the Screening visit, they 
may have 1 repeat triplicate BP assessment at that visit after another rest of at least 10 minutes. 
If a participant’s BP is exclusionary on 2 assessments at the Screening visit, the investigator can, at 
their discretion, adjust and/or add anti-hypertensive medications and re-assess triplicate BP up to 
twice prior to dosing at the Randomization visit (Visit 2). Anti-hypertensive regimens must align 
with the requirements detailed in Section 10.1 (≤2 agents that do not include verapamil)  
If a participant’s BP is exclusionary at the Screening visit and the Randomization visit (Visit 2), 
they must be excluded. 


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34. Has known history or suspected abuse of alcohol or recreational drugs at Screening. 
35. Has excessive consumption of alcohol within 6 months prior to screening (>14 drinks/week for men 
and >7 drinks/week for women, where l drink= 5 ounces [150 mL] of wine or 12 ounces [360 mL] 
of beer or 1.5 ounces [45 mL] of hard liquor) or use of soft drugs (such as marijuana or any 
substances containing tetrahydrocannabinol (THC) or cannabidiol (CBD)) within 3 months prior to 
Screening, or hard drugs (such as cocaine) within 6 months prior to Screening. 
36. Has a positive drug screen at Screening. Note: If benzodiazepines are detected on the drug screen, 
this is not exclusionary if they are prescribed a benzodiazepine for a therapeutic purpose (e.g. for 
insomnia) and confirmatory documentation is obtained from the prescribing physician. 
37. Has known or suspected hypersensitivity to trial product(s) or related products. 
38. Has a history of multiple significant and/or any severe allergies (e.g., food, drug, latex allergy) or 
has had an anaphylactic reaction or significant intolerance to prescription or nonprescription drugs 
or food. 
39. Has previous participation in this trial. Participation is defined as signed informed consent. 
40. Has participated in any clinical trial of an approved or non-approved investigational medicinal 
product within 90 days before screening. 
41. Had major surgery or donated or lost 1 unit of blood (approximately 500 mL) within 4 weeks prior 
to the Screening Visit; has a screening hemoglobin <11.0 g/dL (males) or <10.0 g/dL (females), or 
has a known hemoglobinopathy (e.g. sickle cell anemia, hemolytic anemia). 
42. Is a female who is pregnant, breast-feeding or intends to become pregnant during the planned course 
of the study. Note: Participants must have a negative serum pregnancy test (β-human chorionic 
gonadotropin (β-hCG)) performed by the central laboratory prior to enrollment in the study and 
prior to the randomization visit. 
43. Is currently in violation of study requirements for prohibited and permissible concomitant 
medications or is anticipated to violate these requirements during study participation. These 
requirements are detailed in Section 10.1. 
44. Has any disorder, unwillingness or inability, not covered by any of the other exclusion criteria, which 
in the investigator’s opinion, might jeopardize the subject’s safety or compliance with the protocol, 
or otherwise interfere with interpretation of efficacy and/or safety results. 
45. Is unable or unwilling to follow the study nutritional and physical activity counseling and to refrain 
from alternative lifestyle modification strategies throughout study participation. Refer to Section 10. 
46. Is an employee or immediate family member (e.g., spouse, parent, child, sibling) of the Sponsor or 
study site. 
47. Has any use of opiate medications within 14 days of screening or any anticipated/potential use of 
opiates during study participation. 
48. Use of any other medications within 6 months of screening that, in the investigator’s judgement, 
can significantly impact (increase or decrease) body weight, regardless of the purpose for their 
use. 
Note: Rescreening/retesting is not permitted unless specified above. 
Investigational product, dosage and mode of administration: 
All study medication will be orally administered. 
K-757: 30 mg, and 60 mg capsules and matching placebo 
K-833 100 mg and matching placebo 
Duration of Treatment Period: Approximately 13 weeks 
Endpoints 
Efficacy 


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Primary:  
• 
Percentage change from baseline in body weight (%) after 13 weeks of treatment 
Secondary 
• 
Proportion of participants achieving ≥5% of weight reduction after 13 weeks of treatment 
• 
Change from baseline in body weight (kg) after 13 weeks of treatment. 
• 
Proportion of participants who experienced 1 or more treatment-emergent AEs 
• 
Proportion of participants who discontinued study medication due to an AE 
Exploratory  
• 
Change from baseline in hemodynamic parameters (systolic blood pressure, diastolic blood 
pressure and heart rate) after 13 weeks of treatment. 
• 
Change from baseline in total cholesterol, LDL, HDL, and triglycerides after 13 weeks of 
treatment. 
Additional Safety 
• 
Adverse events 
• 
Vital signs 
• 
Laboratory assessments 
• 
12-lead ECGs 
Statistical methods: 
Sample size justification: 
For the primary endpoint of percentage change from baseline in body weight, a sample size of 
150 participants (stratified by gender and randomized 1:1:1 into three treatment arms) provides >95% 
power to detect a treatment difference of 4% weight reduction after 13 weeks of treatment with a 2-sided 
alpha of 0.05, assuming a standard deviation of 4% and 20% drop out. 
Populations: 
The modified Intent-to-Treat (mITT) analysis set will consist of all randomized participants who receive 
at least one dose of the study drug during the double-blind treatment period. The participants will be 
analyzed as randomized. The mITT analysis set will be used for demographic, baseline characteristics, 
and efficacy analyses. 
The Safety analysis set will consist of all randomized participants who receive at least one dose 
of the study drug during the double-blind treatment period. The safety analysis set will be used 
for safety analyses and analyzed as treated. 
The PK analysis set will consist of all participants who receive study drug and have at least 1 measurable 
plasma concentration. 
Pharmacokinetics: 
Plasma concentrations will be summarized for K-757 for K-757 alone and the combination of 
K-757+K-833. Plasma concentrations will be summarized for K-833 for the combination of 
K-757+K-833. 
Mean plasma concentrations measured over time will be displayed graphically by treatment. 
Efficacy: 
For the primary endpoints, the primary estimand or the percentage change from baseline in body weight 
is defined as the average treatment effect of K-757 alone and the combination of K-757+K-833 relative 
to placebo in the mITT analysis population, had they remained on their randomized treatment for the 
entire planned duration of the trial. A mixed model for repeated measurements (MMRM) analysis will 


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be applied with gender, treatment, visit and treatment-by-visit interaction as fixed effect and baseline 
body weight as a covariate. The MMRM model will use assessments only from participants who are 
taking the randomized treatment until end of treatment or until first discontinuation of randomized 
treatment. An unstructured covariance will be used. If the unstructured covariance structure leads to 
nonconvergence, Akaike’s information criteria will be used to select the best covariance structure. For 
the secondary continuous endpoints, the same approach will be used. 
For the secondary categorical endpoint of proportion of subject achieving 5% weight reduction after 
13 weeks, the same MMRM described for the primary endpoints will be used to address the primary 
estimand. The missing data will be imputed using MMRM assuming missing at random (MAR) and the 
imputed value will be used to classify each subject as a responder or not. A logistical regression using 
gender and treatment as factors and baseline body weight as covariate will be applied to analyze the 
imputed data. 
Safety: 
Safety analyses will be based on the Safety Analysis Set. No formal statistical tests or inference will be 
performed for safety analyses. 
Adverse events will be coded using the version of the Medical Dictionary for Regulatory Activities 
(MedDRA) in effect at the time of study start. AEs will be summarized as treatment-emergent AEs 
(TEAEs) (defined as events that are newly reported after randomization or reported to worsen in severity 
from baseline). The incidence of participants with at least 1 TEAE and the incidence of TEAEs by 
preferred term and system organ class will be presented by treatment group. The frequency and 
percentage of TEAEs will be presented. The incidence of participants with at least 1 TEAE assessed as 
related to the study drug will be summarized by treatment group. All serious AEs (SAEs) will be 
summarized and listed by patient. Discontinuations to study and study drug due to TEAEs will be 
summarized by treatment group. All adverse events will be listed by patient. 
Other safety endpoints (safety laboratory endpoint, vital signs, and ECGs) will be summarized by 
treatment group and nominal timepoint. 
Multiplicity 
The study tests the primary hypothesis that at least one of the treatment arms is superior to the placebo 
arm in reducing the body weight calculated as percentage change from baseline after 13 weeks of 
treatment. Each of two comparisons between K-757 alone and the combination of K-757+K-833 vs 
placebo is tested at two-sided alpha of 0.05 with a familywise error rate of 0.10. No other multiplicity 
adjustment will be performed for secondary and exploratory objectives, which will be tested at two-sided 
alpha of 0.05. 










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e Week indicates the duration of treatment completed prior to the visit, not the week in which the visit occurs. For example, the “Week 1” visit is targeted to occur on Day 8 (the 
first day of the 2nd week of treatment). 
f Titration will occur according to Table 9. On trial site visit days when laboratory safety tests are collected, participants will fast overnight and prior to study drug administration. 
Dosing will end with the PM dose on Day 91. 
g Telephone calls at Visits 7 and 11 (Day 85) to confirm drug compliance, assess AEs, and concomitant medications. 
h The optional genetic sample may be collected at any time during the study. 
Abbreviations:  EoT = end of treatment; ET = end of trial; FU = follow up; hCG = human chorionic gonadotropin 


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3. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF 
FIGURES 
TABLE OF CONTENTS 
1. 
TITLE PAGE ................................................................................................................1 
1.1. 
Summary of Changes ....................................................................................................2 
SIGNATURE PAGE .......................................................................................................................4 
INVESTIGATOR’S AGREEMENT ...............................................................................................5 
PROCEDURES IN CASE OF EMERGENCY ...............................................................................6 
2. 
SYNOPSIS ...................................................................................................................7 
3. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF FIGURES ...............21 
4. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS.............................28 
5. 
INTRODUCTION ......................................................................................................33 
5.1. 
Program and Study Rationale .....................................................................................33 
5.2. 
Prior Human Experience With K-757 and K-833 ......................................................36 
5.2.1. 
New Data from Study K-757 P004 Supporting Amendment P006-01 .......................42 
5.3. 
Rationale for Study Design .........................................................................................50 
5.4. 
Rationale for Doses .....................................................................................................51 
5.4.1. 
Rationale for Dosing Regimen ...................................................................................52 
5.5. 
Rationale for Study Population ...................................................................................53 
6. 
TRIAL OBJECTIVES, HYPOTHESES AND PURPOSE ........................................55 
6.1. 
Primary Objective/Hypothesis ....................................................................................55 
6.2. 
Secondary Objectives .................................................................................................55 
6.3. 
Exploratory Objectives ...............................................................................................55 
7. 
INVESTIGATIONAL PLAN .....................................................................................56 
7.1. 
Overall Study Design ..................................................................................................56 
7.1.1. 
GI Intolerance Management .......................................................................................57 
7.2. 
Number of Participants ...............................................................................................57 
7.3. 
Treatment Assignment ................................................................................................57 
7.3.1. 
Assignment of Screening and Randomization Numbers ............................................57 
7.3.2. 
Study Drug Assignment ..............................................................................................58 
7.3.3. 
Subject Replacement ..................................................................................................58 


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7.4. 
Dose Adjustment Criteria ...........................................................................................58 
7.5. 
Criteria for Study Termination ...................................................................................58 
7.5.1. 
Criteria for Premature Termination or Suspension of Trial or Site ............................58 
7.5.2. 
Procedures for Premature Termination or Suspension of the Trial or Site .................59 
8. 
SELECTION AND WITHDRAWAL OF PARTICIPANTS.....................................60 
8.1. 
Subject Inclusion Criteria ...........................................................................................60 
8.2. 
Subject Exclusion Criteria ..........................................................................................61 
8.3. 
Subject Withdrawal Criteria .......................................................................................66 
8.3.1. 
Procedures for Discontinuation or Withdrawal of a Subject ......................................66 
8.3.1.1. 
Discontinuation of Trial Treatment ............................................................................66 
8.3.1.2. 
Early Withdrawal from the Trial ................................................................................67 
8.3.1.3. 
Lost to Follow-up .......................................................................................................67 
9. 
STUDY SCHEDULE AND STUDY PROCEDURES ..............................................69 
9.1. 
Prestudy (Screening) Procedures ................................................................................69 
9.2. 
Procedures Weeks 1 through 13 (Treatment Period) ..................................................70 
9.3. 
Poststudy Procedures ..................................................................................................70 
10. 
STUDY RESTRICTIONS ..........................................................................................71 
10.1. 
Prior and Concomitant Medications ...........................................................................71 
11. 
STUDY RESTRICTIONS AND REQUIREMENTS ................................................75 
11.1. 
Dietary and Physical Activity Requirements and Restrictions ...................................75 
11.1.1. 
Alcohol Restrictions ...................................................................................................76 
11.1.2. 
Caffeine Restrictions ..................................................................................................76 
11.1.3. 
Smoking Restrictions ..................................................................................................76 
11.1.4. 
Activity Restrictions ...................................................................................................76 
11.2. 
Contraceptive Requirements .......................................................................................76 
12. 
RANDOMIZATION AND BLINDING ....................................................................78 
12.1. 
Randomization and Blinding ......................................................................................78 
12.1.1. 
Randomization Code Creation and Storage ................................................................78 
12.1.2. 
Clinical Study Drug Blinding .....................................................................................78 
12.1.3. 
Clinical Trial Blind Maintenance/Unblinding Procedure (Blinded Studies 
Only) ...........................................................................................................................78 
13. 
STUDY DRUG MATERIALS AND MANAGEMENT ...........................................79 
13.1. 
Study Drug ..................................................................................................................79 


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13.2. 
Study Drug Packaging and Labeling ..........................................................................80 
13.3. 
Study Drug Storage .....................................................................................................80 
13.4. 
Administration ............................................................................................................80 
13.4.1. 
Dose Timing ...............................................................................................................80 
13.4.2. 
Missed Doses ..............................................................................................................80 
13.4.3. 
Dosing Interruptions ...................................................................................................81 
13.5. 
Study Drug Accountability .........................................................................................81 
13.6. 
Study Drug Handling and Disposal ............................................................................81 
13.7. 
Treatment Compliance ................................................................................................81 
14. 
EFFICACY ASSESSMENTS ....................................................................................82 
14.1. 
Body Measurements ...................................................................................................82 
14.2. 
Blood Pressure and Heart Rate ...................................................................................82 
14.3. 
Blood Sample Collection ............................................................................................83 
14.3.1. 
Blood for Plasma PK Measurements ..........................................................................83 
14.3.2. 
Blood for Plasma PD and DNA Measurements .........................................................83 
15. 
ASSESSMENT OF SAFETY .....................................................................................85 
15.1. 
Safety Parameters .......................................................................................................85 
15.1.1. 
Demographic/Medical History ...................................................................................85 
15.1.2. 
Vital Signs ..................................................................................................................85 
15.1.3. 
Physical Examination (PE) .........................................................................................85 
15.1.4. 
Electrocardiogram (ECG) ...........................................................................................85 
15.1.5. 
Laboratory Assessments .............................................................................................86 
15.1.5.1. 
Hematology .................................................................................................................86 
15.1.5.2. 
Blood Chemistry .........................................................................................................86 
15.1.5.3. 
Urinalysis ....................................................................................................................87 
15.1.5.4. 
Virus Serology ............................................................................................................87 
15.1.5.5. 
Drug Screen ................................................................................................................87 
15.1.5.6. 
Pregnancy Screen ........................................................................................................87 
15.1.6. 
Patient Health Questionnaire-9 (PHQ-9) ....................................................................87 
15.2. 
Adverse Events and Serious Adverse Events .............................................................88 
15.2.1. 
Definition of Adverse Events (AEs) and Serious Adverse Events (SAEs) ................88 
15.2.1.1. 
Adverse Event (AE) ....................................................................................................88 
15.2.1.2. 
Serious Adverse Event (SAE) ....................................................................................88 


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15.2.2. 
Time Period and Frequency for Collecting AE and SAE Information .......................89 
15.2.3. 
Identifying AEs and SAEs ..........................................................................................89 
15.2.4. 
Recording of AEs and SAEs .......................................................................................89 
15.2.5. 
Follow-Up of AEs and SAEs ......................................................................................92 
15.2.6. 
Reporting Serious Adverse Events (AEs) to the Sponsor ..........................................93 
15.2.7. 
Reporting AEs to Regulatory Authorities and IRBs/IECs .........................................93 
15.2.8. 
Adverse Events of Special Interest (AESI) ................................................................94 
15.2.9. 
Pregnancy and Lactation .............................................................................................94 
16. 
STATISTICS ..............................................................................................................96 
16.1. 
General Statistical Considerations ..............................................................................96 
16.2. 
Sample Size Justification ............................................................................................96 
16.3. 
Analysis Populations ..................................................................................................96 
16.4. 
Disposition ..................................................................................................................96 
16.5. 
Demographics and Baseline Characteristics ...............................................................97 
16.6. 
Efficacy Analyses .......................................................................................................97 
16.6.1. 
Primary Endpoints ......................................................................................................97 
16.6.2. 
Secondary Endpoints ..................................................................................................97 
16.6.3. 
Exploratory Endpoints ................................................................................................98 
16.7. 
Safety Analyses ..........................................................................................................98 
16.7.1. 
Treatment-emergent Adverse Events (TEAE) ............................................................98 
16.7.2. 
Clinical Laboratory Evaluation ...................................................................................98 
16.7.3. 
Vital Signs ..................................................................................................................98 
16.7.4. 
Electrocardiogram .......................................................................................................98 
16.7.5. 
Prior and Concomitant Medications ...........................................................................99 
16.8. 
Pharmacokinetics ........................................................................................................99 
16.8.1. 
Sample Analysis .........................................................................................................99 
16.8.2. 
Plasma PK ...................................................................................................................99 
16.9. 
Multiplicity .................................................................................................................99 
16.10. 
Interim Analysis ..........................................................................................................99 
17. 
ADMINISTRATIVE AND REGULATORY DETAILS .........................................100 
17.1. 
Direct Access to Source Data/Documents ................................................................100 
17.1.1. 
Study Monitoring ......................................................................................................100 
17.1.2. 
Audits and Inspections ..............................................................................................100 


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17.2. 
Institutional Review Board (IRB)/ Independent Ethics Committee (IEC) ...............100 
17.3. 
Written Informed Consent ........................................................................................100 
17.4. 
Data Handling and Recordkeeping ...........................................................................100 
17.4.1. 
Data Collection and Reporting .................................................................................100 
17.5. 
Retention of Records ................................................................................................101 
17.6. 
PK and PD Sample Retention ...................................................................................101 
17.7. 
Publication Policy .....................................................................................................101 
17.8. 
Financial Disclosure .................................................................................................102 
17.9. 
Compliance with Law, Audit, and Debarment .........................................................102 
17.10. 
Compliance with Trial Registration and Results Posting Requirements ..................103 
17.11. 
Confidentiality ..........................................................................................................103 
17.11.1. 
Confidentiality of Data .............................................................................................103 
17.11.2. 
Confidentiality of Subject Records ...........................................................................104 
17.11.3. 
Confidentiality of Investigator Information ..............................................................104 
18. 
REFERENCES .........................................................................................................105 
19. 
APPENDICES ..........................................................................................................109 
APPENDIX A. MANAGEMENT OF PARTICIPANTS WITH ELEVATED LIVER 
ENZYMES (ALT OR AST >/=3X ULN) ................................................................110 
APPENDIX B. ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS........................113 
APPENDIX C. PHQ-9 DEPRESSION SCALE .......................................................................114 
 


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LIST OF TABLES 
Table 1: 
Emergency Contact Information ...................................................................................6 
Table 2: 
Study Schedule of Assessments..................................................................................16 
Table 3: 
Abbreviations and Specialist Terms ...........................................................................28 
Table 9: 
Dosing Table ...............................................................................................................56 
Table 10: Equation for Estimated BMR .....................................................................................76 
Table 11: K-757 Investigational Product ....................................................................................79 
Table 12: K-833 Investigational Product ....................................................................................80 
Table 13: Severity Grading of GI AEs .......................................................................................91 
 


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Figure 4: 
Study Schematic .........................................................................................................56 
 


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4. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
The following abbreviations and specialist terms are used in this study protocol. 
Table 3: 
Abbreviations and Specialist Terms 
Abbreviation or Specialist Term 
Explanation 
AE 
Adverse event 
AESI 
Adverse events of special interest 
Ag 
Antigen 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
AUC 
Area under the concentration-time curve 
AUC0-24h 
Area under the concentration time curve from time 0 to 24 
hours 
BCRP 
Breast cancer resistance protein 
BID 
Twice daily dosing 
BMI 
Body mass index 
BP 
Blood pressure 
BSEP 
Bile salt exporting protein 
CCK 
Cholecystokinin 
CFR 
Code of Federal Regulations Code of Federal Regulations 
CI 
Coordinating Investigator, Confidence Interval 
Cl 
Clearance 
Cmax 
Maximum concentration 
COVID-19 
Corona Virus Disease 19  
CRF 
Case report form 
CSR 
Clinical Study Report 
CTCAE 
Common Terminology Criteria for Adverse Events 
CV 
Curriculum vitae, Cardiovascular 
CVD 
Cardiovascular disease 
CVOT 
Cardiovascular outcomes trials 
DDI 
Drug-drug interaction 
DILI 
Drug induced liver injury 
DPP-4i 
Dipeptidyl peptidase-IV inhibitors 


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Abbreviation or Specialist Term 
Explanation 
EC 
Ethics committee 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
EEC 
Enteroendocrine cell 
EFD 
Embryofetal development 
eGFR 
Estimated glomerular filtration rate 
EOT 
End of treatment 
ERCP 
Endoscopic retrograde cholangiopancreatography 
ET 
Early Termination 
FDAAA 
Food and Drug Administration Amendments Act 
FDAMA 
Food and Drug Administration Modernization Act 
FIH 
First in human 
FOCBP 
Females of childbearing potential 
FSH 
Follicle stimulating hormone 
F/U 
Follow-up 
g 
Gram 
GCP 
Good Clinical Practice 
GD 
Gestational day 
GDIS 
Glucose-dependent insulin secretion 
GGT 
Gamma-glutamyl transferase 
GI 
Gastrointestinal 
GIP 
Glucose-dependent insulinotropic polypeptide 
GLP 
Good Laboratory Practices 
GLP-1 
Glucagon-like peptide-1 
GLP-1R 
Glucagon-like peptide-1 receptor 
GPR40 
G-protein coupled receptor 40 
GPR119 
G-protein coupled receptor 119 
HbA1c 
Hemoglobin A1C 
HBE 
Harris Benedict Equation 
hCG 
Human chorionic gonadotropin 
HDL 
High-density lipoprotein 
HDPE 
High density polyethylene 


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Abbreviation or Specialist Term 
Explanation 
HIV 
Human immunodeficiency virus 
HMG-CoA 
3-hydroxy-3-methylglutaryl coenzyme A 
HPMC 
Hydroxypropyl cellulose 
HR 
Heart rate 
hr or h 
Hour 
HRT 
Hormone replacement therapy 
IB 
Investigational Brochure 
IBD 
Inflammatory bowel disease 
IBS 
Irritable bowel syndrome 
ICH 
International Conference on Harmonization 
ID 
Identification 
IEC 
Independent Ethics Committee 
IgG 
Immunoglobulin G 
IgM 
Immunoglobulin M 
IMP 
Investigational medicinal product 
IRB 
Institutional Review Board 
IUD 
Intrauterine device 
IUS 
Intrauterine hormone-releasing system 
IWRS 
Interactive web response system 
kcal 
Kilocalorie 
kg 
Kilogram 
L 
Liter 
LCFA 
Long chain fatty acids 
LDL 
Low-density lipoprotein 
LFT 
Liver function test 
m 
Meter 
M 
Male 
MAR 
Missing at random 
MATE 
Multidrug and toxin extrusion protein 
MBA 
Multiple biochemical analysis 
MCH 
Mean corpuscular hemoglobin 
MCHC 
Mean corpuscular hemoglobin concentration 


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Abbreviation or Specialist Term 
Explanation 
MCV 
Mean corpuscular volume 
MDRD 
Modification of Diet in Renal Disease 
MedDRA 
Medical Dictionary for Regulatory Activities 
μM 
Micromolar 
μM•h 
Micromolar-hour 
mg 
Milligram 
MHP 
Mental health professional 
min 
Minute 
mITT 
Modified Intent-to-Treat 
mIU 
Mili-international unit 
mL 
Milliliter 
mmHg 
Millimeters of mercury 
MMRM 
Mixed model for repeated measurements 
mpk 
Milligram per kilogram 
msec 
Millisecond 
N 
Number 
NAFLD 
Non-alcoholic fatty liver disease 
NCI 
National Cancer Institute 
NOAEL 
No adverse effect level 
NSAID 
Nonsteroidal anti-inflammatory drug 
OAT 
Organic anion transporter 
OXM 
Oxyntomodulin 
PBO 
Placebo 
PD 
Pharmacodynamic 
PE 
Physical examination 
P-gp 
P-glycoprotein 
PHQ-9 
Patient Health Questionnaire-9 
PI 
Principal Investigator 
PK 
Pharmacokinetic 
PR 
Period, in milliseconds, that extends from the beginning of 
the P wave until the beginning of the QRS in an ECG 
tracing 
PVC 
Polyvinyl chloride 


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Abbreviation or Specialist Term 
Explanation 
PvDC 
Polyvinylidene chloride 
PYY 
Peptide YY 
QD 
Once daily 
QTc 
QT corrected 
QTcF 
QT corrected with Fridericia’s formula  
RBC 
Red blood cells 
RDW 
Red cell distribution width 
RR 
Respiratory rate 
RUQ 
Right upper quadrant 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SD 
Standard deviation 
SOA 
Schedule of assessments 
SOC 
System Organ Class 
SOP 
Standard operating procedure 
SSRI 
Selective serotonin reuptake inhibitors 
SUSAR 
Suspected unexpected serious adverse reaction 
t1/2 
Terminal half-life 
T2DM 
Type 2 diabetes mellitus 
TEE 
Total energy expenditure 
THC 
Tetrahydrocannabinol 
TEAE 
Treatment emergent adverse event 
TK 
Toxicokinetics 
Tmax 
Time of maximum concentration 
TSH 
Thyroid stimulating hormone 
ULN 
Upper limit of normal 
Vdss 
Volume of distribution at steady-state 
WBC 
White blood cells 






























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5.3. 
Rationale for Study Design 
This study is designed to assess the weight loss efficacy and safety/tolerability of K-757 alone 
and in combination with K-833 in comparison to placebo. The overall study goal is to inform 
whether K-757+K-833 combination and/or K-757 alone merit further clinical evaluation as 
pharmacologic therapy for weight loss. Up-titration of K-757 or the combination is being used to 
mitigate mechanism-related GI intolerance as was observed in Phase 1 and has been consistently 
reported for GLP-1 analogs. No K-833-only arm is included in this first proof of concept study 
as neither the reported human experience with other GPR119 agonists, nor the Phase 1 
experience with K-833 support the potential for K-833 monotherapy to achieve meaningful 
weight loss. Should weight loss with the combination of K-757+K-833 be superior to K-757 
alone in the present study, future characterization of the efficacy and safety/tolerability of K-833 
monotherapy may be needed to provide the necessary regulatory justification for co-development 
of K-757 and K-833. 
The randomized, double-blind, double-dummy approach is being used to minimize the potential 
impact of bias on study assessments. The 13-week duration of dosing is the longest treatment 
duration supported by completed toxicology studies. Though 13 weeks may not be long enough 








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Sex is an important response covariate with females typically achieving greater weight loss that 
males in obesity trials. Randomization will be stratified by sex to minimize potential bias. 
Weight loss trials have historically enrolled substantially more female than male participants. To 
ensure meaningful representation of both sexes, neither strata will be permitted to exceed 70% of 
total enrollment. Females of childbearing potential (FOCBP) are eligible for participation. 
Given the early stage of development and current lack of definitive embryo-fetal toxicology 
data for either K-757 or K-833, FOCBP must be using highly effective contraception with low 
user-dependence and undergo pregnancy testing at screening and specified timepoints during 
study participation. 
Given the priority of avoiding spurious liver toxicity signals, excessive alcohol consumption, 
known history of liver disease (other than non-alcoholic fatty liver disease [NAFLD]), and 
excessive elevations in ALT, AST, and/or bilirubin at screening are exclusionary as specified in 
Section 8.2. 
Observational data have suggested the possibility that agents enhancing Glucagon-like peptide-1 
receptor (GLP-1R) mediated pharmacology, including GLP-1R agonists and DPP-4is, may 
increase the risk of acute pancreatitis, though statistically significant effects have not been 
identified in large cardiovascular outcomes trials (CVOTs) conducted with these agents. A recent 
metanalysis of CVOT data did identify a 75% risk increase of acute pancreatitis with DPP-4is, 
though found no effect of GLP-1R agonists (9). No preclinical or clinical data generated to date 
have suggested that K-757 may increase the risk of pancreatitis. However, given the early stage 
of K-757 development, individuals with any history of acute or chronic pancreatitis are excluded 
from this study, as are those with excessively elevated amylase and/or lipase at screening. 
Markedly elevated fasting triglycerides are also exclusionary given the potential for 
hypertriglyceridemia to precipitate pancreatitis. Though GLP-1R agonists and DPP-4 is are 
commonly associated with increases in serum amylase and lipase activity, such isolated 
biochemical changes in the absence of suggestive signs/symptoms have not been predictive of 
pancreatitis (10, 11). Serum lipase will be assessed at specified junctures during treatment (see 
Table 2). Note that protocol criteria for interrupting and discontinuing study medication for 
suspicion of acute pancreatitis require symptoms and/or imaging consistent with pancreatitis (see 
Section 8.3). 
Review to Section 10.1 for discussion of prohibited and allowed concomitant medications. 
Full inclusion and exclusion criteria are provided in Section 8.1 and Section 8.2, respectively. 


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6. 
TRIAL OBJECTIVES, HYPOTHESES AND PURPOSE 
6.1. 
Primary Objective/Hypothesis 
To assess relative (%) change from baseline in body weight after 13 weeks of treatment with 
K-757 alone and in combination with K-833, in comparison to placebo. 
Hypothesis: At least one of the treatment arms is superior to the placebo arm in reducing body 
weight calculated as percentage change from baseline after 13 weeks of treatment. 
6.2. 
Secondary Objectives 
1. To assess the proportion of participants achieving ≥5% weight loss from baseline after 
13 weeks of treatment with K-757 alone and in combination with K-833, in comparison 
to placebo. 
2. To assess the absolute change from baseline in body weight after 13 weeks of treatment 
with K-757 alone and in combination with K-833, in comparison to placebo. 
3. To characterize the safety and tolerability of K-757 alone and in combination with K-833 
over 13 weeks of treatment. 
6.3. 
Exploratory Objectives 
1. To assess the change from baseline in hemodynamic parameters (systolic blood pressure, 
diastolic blood pressure and heart rate) after 13 weeks of treatment with K-757 alone and 
in combination with K-833, in comparison to placebo. 
2. To assess the change from baseline in total cholesterol, low-density lipoprotein (LDL), 
high-density lipoprotein (HDL), and triglycerides after 13 weeks of treatment with K-757 
alone and in combination with K-833, in comparison to placebo. 






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Participants will be assigned to either placebo, K-757 alone, K-757+K-833. Participants who 
meet all criteria for enrollment will be randomized at Visit 2 and assigned to their respective 
treatment groups via IWRS using the following stratification variables: gender (male/female). 
There will be equal randomization to the treatment arms (1:1:1). The randomization scheme will 
be performed using IWRS that will ensure balance between treatment arms. 
7.3.2. 
Study Drug Assignment 
The randomization number encodes the subject assignment to either K-757 alone, K-757 + 
K-833, or placebo, according to the randomization schedule generated before the study. Each 
subject will be dispensed study drug in a double-blinded manner, labeled with his/her unique 
randomization number, throughout the study. 
7.3.3. 
Subject Replacement 
No participants will be replaced. 
7.4. 
Dose Adjustment Criteria 
No dose adjustment will be allowed, as this is a forced titration study. 
7.5. 
Criteria for Study Termination 
The overall study begins when the first subject signs the study informed consent form. 
The overall study ends when the last subject completes the last planned or follow-up 
visit/interaction associated with a planned visit (this can be a phone contact), discontinues from 
the study, or is lost to follow-up (e.g., the Investigator is unable to contact the subject). 
Study discontinuation because of non-safety reasons, such as the following: 
• A finding (e.g., PK, PD, efficacy) from another nonclinical or clinical study using the 
study treatment(s) results in the study being stopped for a non-safety related reason. 
• The study is stopped because of nonscientific and non-safety reasons, such as slow 
enrollment. 
Study discontinuation because of safety reasons: 
Early study termination because of unanticipated concerns of safety to the study participants 
arising from clinical or nonclinical studies with the study treatment(s), comparator(s), drug(s) of 
the same class, or methodology(ies) used in this study. 
7.5.1. 
Criteria for Premature Termination or Suspension of Trial or Site 
A study site may be terminated prematurely or suspended if the site (including the Investigator) 
is found in significant violation of Good Clinical Practice (GCP), protocol, or contractual 
agreement, or is unable to ensure adequate performance of the study, or as otherwise permitted 
by the contractual agreement. 


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7.5.2. 
Procedures for Premature Termination or Suspension of the Trial or Site 
In the event that the Sponsor, an Investigational Review Board (IRB)/Independent Ethics 
Committee (IEC), or regulatory authority elects to terminate or suspend the study or the 
participation of an investigational site, a study-specific procedure for early termination or 
suspension will be provided by the Sponsor; the procedure will be followed by applicable 
investigational sites during the course of termination or study suspension.


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8. 
SELECTION AND WITHDRAWAL OF PARTICIPANTS 
8.1. 
Subject Inclusion Criteria 
All entry criteria, including laboratory test results, need to be confirmed before administration of 
the first dose of study drug. 
In order to be eligible for participation in this trial, the subject must: 
1. Understand the trial procedures and agree to participate by providing written informed 
consent prior to trial related activities. Trial-related activities are any procedures that are 
carried out as part of the trial, including activities to determine suitability for the trial. 
2. Be willing and able to comply with all trial procedures and restrictions, including 
following study diet requirements. 
3. Be a male or female, age 18 to 70 years of age, inclusive, at the time of signing informed 
consent. 
4. Have a body mass index (BMI) of 30.0 to 40.0. kg/m2, inclusive at screening. 
5. History of at least one self-reported unsuccessful dietary effort to lose body weight. 
6. Be weight stable (<5% variation) over the last 3 months (by subject report). 
7. Be a nonsmoker or has smoked ≤10 cigarettes per week for at least 3 months and agrees 
not to exceed this for the duration of study participation; has not used other nicotine 
containing products (e.g. other forms of tobacco, nicotine patch, e-cigarettes, vapes) for 
at least 3 months and agrees to abstain from such products throughout study participation. 
8. Meet the following birth control requirements: 
a. Is a male subject who agrees to all of the following: 
− If partner is a non-pregnant female of child-bearing potential: To use an 
appropriate method of contraception, which must include a condom with 
spermicidal cream or jelly, from the first dose of study drug until 14 days after the 
last dose of study drug. A male subject who has had a vasectomy procedure must 
use a condom, but is not required to use spermicidal cream or jelly. 
− If partner is pregnant, to use a condom 
− Note: Contraception/condom requirements are waived if partner is NOT of 
child-bearing potential (i.e.  is male or is a female who is post-menopausal or 
surgically sterile [post-hysterectomy, post-bilateral oophorectomy, and/or post-
bilateral salpingectomy]). 
− To not donate sperm from the first dose of study drug until 14 days after the last 
dose of study drug. 
OR 
b. Is a female who is of non-childbearing potential defined by at least 1 of the following 
criteria: 


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− Postmenopausal (aged >45 years and with a minimum of 12 months of 
spontaneous amenorrhea with a Screening serum follicle-stimulating hormone 
(FSH) level in the menopausal range established for the central laboratory. 
− Post hysterectomy, bilateral oophorectomy or bilateral salpingectomy, based on 
the subject’s recall of their medical history. 
OR 
c. Is a female of reproductive potential and: 
− agrees to not donate eggs from the first dose of study drug until 14 days after the 
last dose of study drug. 
− agrees to remain abstinent from heterosexual activitya or 
− agrees to use (or have their partner use) a birth control method that is highly 
effective and has low user dependency from the first dose of study drug until 14 
days after the last dose of study drug. Acceptable methods of birth control are: 
− Progestogen-only implant (e.g. etonogestrel implant) 
− Intrauterine device (IUD) 
− Intrauterine hormone-releasing system (IUS) 
− Bilateral tubal occlusion 
− Vasectomized partner 
a Abstinence can be used as the sole method of contraception if it is in line with the subject’s 
preferred and usual lifestyle and if considered acceptable by local regulatory agencies and 
ethics committees. Periodic abstinence (e.g., calendar, ovulation, sympto-thermal, 
post-ovulation methods, etc.) and withdrawal are not acceptable methods of contraception. 
This condition is waived if the subject is proven to have no child-bearing potential (eg, 
hysterectomy). 
8.2. 
Subject Exclusion Criteria 
Participants are excluded from the trial if any of the following criteria apply: 
Glycemia related: 
1. Has a HbA1c ≥6.5% (48 mmol/mol) as measured by the central laboratory at screening. 
2. Has a history of clinically significant endocrine disease including T2DM. 
Note: A history of hypothyroidism does not require exclusion if the subject has been on a 
stable dose of thyroid hormone replacement (thyroxine) for at least 3 months prior to 
screening and the screening TSH is within the central laboratory normal range. 
3. Has a history of type 1 or type 2 diabetes mellitus. 
4. Had treatment with any glucose-lowering agent(s) within 90 days before screening. 
Obesity related: 


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5. Had treatment with any medication approved for the treatment of obesity or any 
investigational agent being tested for obesity treatment within the past 6 months before 
screening. This includes agents that are approved as a component of a multi-drug 
combination treatment for obesity, regardless of the purpose of current use, with the 
exception of bupropion. 
Bupropion, which is a component of the naltrexone-bupropion combination approved for 
weight loss (ContraveTM), is also approved as a single agent for the treatment of depression. 
Bupropion is not exclusionary if it is being used for treatment of depression and eligibility 
criteria for anti-depressant medication stability prior to screening are met (see Exclusion 
Criterion #12). 
6. Has been treated with/used any other medication, supplement, or device for the purpose 
of promoting weight loss (regardless of whether they are approved or promoted for the 
purpose of weight loss) in the 90 days prior to screening. 
7. Treatment with any GLP-1 receptor agonist in the prior 6 months. 
8. Participation in an organized weight reduction program (e.g. Weight Watchers) within 
90 days of screening. 
9. Had a previous or has a planned (during the trial period) obesity treatment with surgery 
or a weight loss device. Note: Prior liposuction and/or abdominoplasty are not 
exclusionary if performed >2 years before screening). 
10. Has uncontrolled thyroid disease, defined as thyroid stimulating hormone (TSH) outside 
(above or below) the reference range of the central laboratory at screening or has any 
history of Grave’s disease unless all 3 of the following criteria are all met: 1. Grave’s 
disease was treated with total thyroidectomy >2 years prior to screening, 2. There has 
been no recurrence of hyperthyroidism since thyroidectomy, and 3. TSH is the reference 
range of the central laboratory at screening. 
11. Obesity is induced by an endocrine disorder (e.g. Cushing’s disease). 
Mental health: 
12. Has a history of major depressive disorder within 2 years before screening, unless all of 
the following criteria are met: 
a. the depressive disorder has always been unipolar (no history of mania or hypomania) 
b. in the opinion of the investigator, depressive symptoms have been stable and well 
controlled for ≥2 years prior to screening 
c. any anti-depressant drug-treatment regimens (medications and doses) have been 
stable for ≥6 months prior to screening 
13. Has any history of other severe psychiatric disorder (e.g., schizophrenia, bipolar disorder) 
that was not clearly attributable to an intercurrent event/life circumstance, self-limited 
and fully resolved ≥1 year prior to screening. 
14. On the screening Patient Health Questionnaire-9 (PHQ-9), has an overall score ≥15 or 
has a score >0 for Question # 9 (Thoughts that you would be better off dead or of hurting 
yourself). Note: See Section 15.1.6 regarding requirements for referral to a mental health 
professional based on the results of the screening PHQ-9 assessment (Appendix C). 


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15. Has any lifetime history of suicide attempt or suicidal behavior. Note: Suicidal behavior 
includes any acts/preparation toward making a suicide attempt whether the attempt is 
never initiated or is initiated but interrupted by self or another person(31). 
16. Use of any anti-psychotic agents for any purpose within 2 years before screening. 
17. Use of the following prohibited agents: 
• Prohibited classes of anti-depressant agents (see Section 10.1) for any purpose, within 
6 months of screening. Note: Use of allowable classes of anti-depressant agents (see 
Section 10.1) is permitted only if the anti-depressant regimen (agents and doses) has 
been stable for ≥6 months prior to screening and is not anticipated to change during 
the trial period. 
• Stimulant medications including amphetamines (e.g. dextroamphetamine, 
lisdexamfetamine) and methylphenidate/dexmethylphenidate within 6 months of 
screening. 
General Safety: 
18. Has a recent history (within the past 3 years of screening visit) or current diagnosis or 
evidence of hematological, immunological, renal, respiratory, neurologic, or 
genitourinary abnormalities or diseases that, per the investigator’s judgement, may 
jeopardize the subject’s safety or compliance with the protocol, or otherwise interfere 
with interpretation of efficacy and/or safety results. 
19. Has a recent history (within past 3 years of screening visit) or current diagnosis of any of 
the following GI (gastrointestinal) related diseases: intestinal obstruction, GI perforation, 
adhesions, Clostridium difficile colitis or have had recent unexplained GI bleeding within 
3 months prior to screening. 
20. Has any history of pancreatitis (acute or chronic), gastroparesis, ischemic colitis, 
inflammatory bowel disease (IBD), or celiac disease. 
21. Has a personal or first-degree relative history of multiple endocrine neoplasia type 2 or 
medullary thyroid carcinoma. 
22. Has a screening estimated Glomerular Filtration Rate (eGFR) estimated with the 
Modification of Diet in Renal Disease (MDRD) equation of <60 ml/min/1.73 m2. 
23. Has a history of malignant neoplasms within the past 5 years prior to screening. Basal 
and squamous cell skin cancer and any carcinoma in-situ are allowed if they have 
received treatment and follow-up consistent with local standard of care. 
24. Has any history of cardiovascular disease including stable and unstable angina pectoris, 
myocardial infarction, transient ischemic attack, stroke, cardiac decompensation, 
clinically significant arrhythmias, clinically significant conduction disorders, or any 
history or heart failure. 
25. Has surgery scheduled for the duration of the trial, except for minor surgical procedures, 
in the opinion of the investigator. 
26. Has a history of human immunodeficiency virus (HIV) infection. 


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27. Has any active liver disease other than non-alcoholic fatty liver disease (NAFLD), or any 
gallbladder disease that has been active/symptomatic within 6 months of screening. 
28. Has a positive test result for hepatitis B surface antigen (Ag), hepatitis C virus antibody, 
HIV antibody, at the Screening Visit. Note: Participants with positive hepatitis B virus or 
hepatitis C virus serology may be enrolled if quantitative polymerase chain reaction for 
hepatitis B virus or hepatitis C virus ribonucleic acid is negative. 
29. Has alanine aminotransferase or aspartate aminotransferase (ALT or AST) of >2.0X 
upper limit of normal (ULN) or total bilirubin >1.5X ULN at the Screening visit. Note: 
An isolated bilirubin >1.5X ULN is acceptable if bilirubin is fractionated, and direct 
bilirubin is within the laboratory normal range). 
30. Has serum amylase or lipase >1.2X the ULN at the Screening Visit. 
31. Has a triglyceride value >600mg/dL at the Screening visit (if value is ≥600 mg/dL and 
the sample was obtained in the non-fasted state, a repeat fasting determination may be 
obtained to assess eligibility). 
32. Has a corrected QT interval to Fridericia’s formula (QTcF) >450 milliseconds (msec) for 
males and >470 msec for females at screening. 
33. Has a mean value for triplicate seated systolic blood pressure >160 mmHg and/or 
diastolic blood pressure (BP) >95 mmHg measured after at least 5 minutes at rest at the 
Screening Visit. Note: If a subject’s BP is exclusionary on the first triplicate assessment 
at the Screening visit, they may have 1 repeat triplicate BP assessment at that visit after 
another rest of at least 10 minutes. If a participant’s BP is exclusionary on 2 assessments 
at the Screening visit, the investigator can, at their discretion, adjust and/or add anti-
hypertensive medications and re-assess triplicate BP up to twice at the Randomization 
visit (Visit 2). Anti-hypertensive regimens must align with the requirements detailed in 
Section 10.1 (≤2 agents that do not include verapamil). If a participants BP is 
exclusionary at the Screening visit and the randomization visit (Visit 2), they must be 
excluded. 
34. Has known history or suspected abuse of alcohol or recreational drugs. 
35. Has excessive consumption of alcohol within 6 months prior to screening (>14 
drinks/week for men and >7 drinks/week for women, where l drink = 5 ounces [150 mL] 
of wine or 12 ounces [360 mL] of beer or 1.5 ounces [45 mL] of hard liquor) or use of 
soft drugs (such as marijuana or any substances containing tetrahydrocannabinol (THC) 
or cannabidiol (CBD)) within 3 months prior to Screening, or hard drugs (such as 
cocaine) within 6 months prior to Screening. 
36. Has a positive drug screen at Screening. Note: If benzodiazepines are detected on the 
drug screen, this is not exclusionary if they are prescribed a benzodiazepine for a 
therapeutic purpose (e.g. for insomnia) and confirmatory documentation is obtained from 
the prescribing physician. 
37. Has known or suspected hypersensitivity to trial product(s) or related products. 


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38. Has a history of multiple significant and/or any severe allergies (e.g., food, drug, latex 
allergy) or has had an anaphylactic reaction or significant intolerance to prescription or 
nonprescription drugs or food. 
39. Has previous participation in this trial. Participation is defined as signed informed 
consent. 
40. Has participated in any clinical trial of an approved or non-approved investigational 
medicinal product within 90 days before screening. 
41. Had major surgery or donated or lost 1 unit of blood (approximately 500 mL) within 
4 weeks prior to the Screening Visit; has a screening hemoglobin <11.0 g/dL (males) or 
<10.0 g/dL (females), or has a known hemoglobinopathy (e.g. sickle cell anemia, 
hemolytic anemia). 
42. Is a female who is pregnant, breast-feeding or intends to become pregnant during the 
planned course of the study. Note: Participants must have a negative serum pregnancy 
test (β-human chorionic gonadotropin (β-hCG)) performed by the central laboratory prior 
to enrollment in the study and prior to the randomization visit. 
43. Is currently in violation of study requirements for prohibited and permissible concomitant 
medications or is anticipated to violate these requirements during study participation. 
These requirements are detailed in Section 10.1. 
44. Has any disorder, unwillingness or inability, not covered by any of the other exclusion 
criteria, which in the investigator’s opinion, might jeopardize the subject’s safety or 
compliance with the protocol, or otherwise interfere with interpretation of efficacy and/or 
safety results. 
45. Is unable or unwilling to follow to follow the study nutritional and physical activity 
counseling and to refrain from alternative lifestyle modification strategies throughout 
study participation. Refer to Section 11.1. 
46. Is an employee or immediate family member (e.g., spouse, parent, child, sibling) of the 
Sponsor or study site. 
47. Has any use of opiate medications within 14 days of screening or any anticipated/potential 
use of opiates during study participation. 
48. Use of any other medications within 6 months of screening that, in the investigator’s 
judgement, can significantly impact (increase or decrease) body weight, regardless of the 
purpose for their use. 
Note: Rescreening/retesting is not permitted unless specified above. 


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8.3. 
Subject Withdrawal Criteria 
8.3.1. 
Procedures for Discontinuation or Withdrawal of a Subject 
8.3.1.1. 
Discontinuation of Trial Treatment 
Discontinuation of trial product can be decided by either the investigator or the subject. A 
participant may discontinue his or her participation without giving a reason at any time during 
the trial. 
Participants who discontinue trial product should continue with the scheduled visits and 
assessments to ensure continued counselling and data collection. 
If the subject does not wish to attend the scheduled clinic visits, efforts should be made to have 
the visits converted to phone contacts. However, all efforts should be made to have the subject 
attend at least the ‘end of treatment’ clinic visit containing the final data collection of primary 
and confirmatory secondary efficacy endpoints, and the ‘end of trial’ visit. 
The ‘end of trial’ visit is scheduled approximately 2 weeks after the final data collection, to 
ensure the safety of the subject. If the subject has discontinued trial product >2 weeks prior to the 
‘end of treatment’ visit, and the requirements for the follow-up period prior to the ‘end of trial’ 
visit is fulfilled, then the ‘end of trial’ visit can be performed in combination with ‘end of 
treatment’ visit. 
If the subject refuses to attend the ‘end of treatment’ and/or ‘end of trial’ visit, information about 
the attempts to follow up with the subject must be documented in the subject’s medical record. 
The subject must be discontinued from trial product if any of the following applies: 
1. Safety concern as judged by the investigator 
2. Pregnancy 
3. Intention of becoming pregnant 
4. Liver function test (LFT) abnormalities meeting specified discontinuation criteria (refer 
to Appendix A for discontinuation criteria and instruction on management of LFT 
abnormalities 
5. Confirmed pancreatitis (see below) 
If acute pancreatitis is suspected based on clinical signs and symptoms, blinded study medication 
should be interrupted immediately, and appropriate diagnostic assessments should be performed. 
• A diagnosis of acute pancreatitis requires at least 2 of the following 3 findings (14): 
− abdominal pain consistent with acute pancreatitis (persistent, severe epigastric 
pain, frequently radiating to the back); abdominal pain is often associated with 
nausea and vomiting. 
− serum lipase and/or amylase activity ≥3X the laboratory ULN 
− characteristic findings of acute pancreatitis on imaging 


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• If a diagnosis of pancreatitis is confirmed, the subject will be discontinued from 
blinded K-757/placebo and appropriate treatment and monitoring must be initiated. 
• If the investigator and Sponsor agree that acute pancreatitis has been ruled out, all 
investigational medicinal products (IMP) should be resumed. 
The primary reason for discontinuation of trial product must be specified in the source data at the 
time of discontinuation, and the subject should continue to follow the visit and assessment 
schedule. The reasons for treatment discontinuations are: 
• Adverse event 
• Withdrawal of consent 
• Lost to follow up 
• Pregnancy/Intention to become pregnant 
• Death 
• Investigator decision 
• Significant protocol deviation 
8.3.1.2. 
Early Withdrawal from the Trial 
Early withdrawal from the trial may occur due to voluntary withdrawal of consent, lost to follow 
up (see below), or death. 
In all other cases of trial product discontinuation, participants should be followed as described 
above in Section 8.3.1.1. 
If a subject ends his/her participation, the investigator must ask the subject if he/she is willing, as 
soon as possible, to have assessment performed according to the ‘end of treatment’ visit. 
Final drug accountability must be performed even if the subject is not able to come to the trial 
site. 
Although a subject is not obliged to give his/her reason(s) for withdrawing early, the investigator 
must make a reasonable effort to ascertain the reason(s), while fully respecting the subject's 
rights. Where the reasons are obtained, the primary reason for withdrawal must be specified in 
the end of trial form in the case report forms (CRF). 
8.3.1.3. 
Lost to Follow-up 
A subject will be considered lost to follow-up if he or she repeatedly fails to return for scheduled 
visits and is unable to be contacted by the trial site. 
The following actions must be taken if a subject fails to return to the trial site for a required visit: 
• The site must attempt to contact the subject and reschedule the missed visit as soon as 
possible and counsel the subject on the importance of maintaining the assigned visit 
schedule and ascertain whether the subject wishes to and/or should continue in the 
trial. 


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• Before a subject is deemed lost to follow-up, the investigator must make every effort 
to regain contact with the subject (where possible, at least three telephone calls and, if 
necessary, a certified letter to the subject's last known mailing address or local 
equivalent methods). These contact attempts should be documented in the subject's 
source document. Should the subject continue to be unreachable at the ‘end of 
treatment’ visit, he/she will be considered to have withdrawn from the trial with a 
primary reason of lost to 'follow-up'. 


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9. 
STUDY SCHEDULE AND STUDY PROCEDURES 
The order of priority can be changed during the study with joint agreement of the Investigator 
and KALLYOPE, Inc. 
Any nonscheduled procedures required for urgent evaluation of safety concerns take precedence 
over all routine scheduled procedures. 
• Adherence to the trial design requirements, including those specified in the flowchart, 
is essential and required for trial conduct. 
• Assessments should be carried out according to the clinic’s standard of practice 
unless otherwise specified in the current section. Efforts should be made to limit the 
bias between assessments. The suggested order of the assessments: 
− Electrocardiogram (ECGs) and vital signs (including body weight when assessed) 
− Blood samples 
− Mental health assessment instrument 
− Other assessments 
• Source data of clinical assessments performed and recorded in the CRF must be 
available and will usually be the subject’s medical records. Additional recording to be 
considered source data includes, but is not limited to laboratory reports, ECG and 
Mental Health assessments. 
• Subject’s weight history must be recorded in the subject’s medical record. 
• Review of mental health assessment instruments, ECG and laboratory reports must be 
documented either on the documents or in the subject's source documents. 
− Repeat laboratory samples may be taken for technical issues. 
− Efficacy assessments and procedures are described in Section 14 
− Safety assessments and procedures are described in Section 15 
− Procedures related to AE evaluation and reporting are in Section 15.2 
− Procedures around study drug admin are in Section 13 
9.1. 
Prestudy (Screening) Procedures 
Informed consent must be obtained before any trial related activity. 
At screening the investigator should ascertain whether there may be important barriers to 
participant motivation for lifestyle change and compliance with the protocol (e.g. density and 
timing of study visits). The interview must be conducted at screening to assist in identifying 
subjects who are unable or unwilling to comply with protocol procedures as per the exclusion 
criteria. In addition, the interview will ensure that any minor barriers are addressed during 
lifestyle counselling. 


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Within 4 weeks of Randomization, potential participants will be evaluated to determine that they 
fulfill the entry requirements as set forth in the Inclusion and Exclusion Criteria. The Investigator 
will discuss with each subject the nature of the study, its requirements, and its restrictions. 
The pre-study screening assessments (V1) are detailed in the SOA. Subjects need not be fasted 
for this visit. 
• All screening evaluations must be completed and reviewed to confirm that potential 
subjects meet all eligibility criteria. 
• The investigator will maintain a screening log to record details of all subjects 
screened and to confirm eligibility or record reason for screen failure, as applicable.  
• At screening, subjects will be provided with a card stating that they are participating 
in a trial and giving contact details of relevant trial site staff. 
• For details on the procedures, please refer to Table 2 and Section 15. 
9.2. 
Procedures Weeks 1 through 13 (Treatment Period) 
Participants will return to the clinical research unit at various Weeks/Visits until completion of 
the Visit 12 post-dose procedures (Day 92). The specific procedures that will be performed 
during this timeframe and at each visit are detailed in Table 2. Details related to timing of 
specific procedures relative to meals and dosing are in Section 15. 
Visits 2 through 12 will be performed during the Treatment Period. Two of these visits (V7 (Day 
36) and V11 (Day 85)) are phone call only visits with the others requiring a clinic visit. At these 
visits, the clinical research unit will conduct a telephone call to all participants to determine if 
any new AEs have arisen or concomitant medications have been taken. Study drug compliance 
will also be checked. 
Mandatory fasted visits: 
Amongst the in-person clinic visits during the Treatment Period, V2 (randomization), V6 (Day 
29), V9 (Day 57) and V12 (Day 92), subjects should come to the clinic in the fasted state 
because body weight and fasting lipids need to be assessed in the fasted state. These fasted visits 
should be scheduled in the morning and the AM dose of study medication should be taken after 
collection of blood. Dosing should be witnessed at these visits. Other in-person visits during the 
Treatment Period can be in the fasted or fed state and may be scheduled without regard to timing 
of study medication. 
9.3. 
Poststudy Procedures 
Participants will return to the clinical research unit for the Poststudy procedures at V13. 
Participants should fast prior to this visit and arrive at the clinic in the fasted state. The specific 
assessments to be performed are list in the SOA (Table 2). 


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10. 
STUDY RESTRICTIONS 
10.1. 
Prior and Concomitant Medications 
Participants should be instructed not to start any new medications (prescription or 
non-prescription) or supplements without first consulting with the investigator. If this is not 
possible due to medical urgency, the participant should inform the investigator as soon as 
possible. 
Any medication (including over-the-counter and prescription medicines) other than the trial 
product, that the participant is taking at the time of screening or receives during the trial must be 
recorded on the appropriate electronic case report form (eCRF). Information collected will 
include: 
1. Medication name 
2. Indication 
3. Dates of administration including start and stop dates 
4. Dose 
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed 
during the ongoing trial. If there is a clinical indication for any medication or vaccination 
specifically prohibited during the trial, discontinuation of study medication may be required. The 
investigator should discuss any questions regarding this with the Sponsor Clinical Director. The 
final decision on any supportive therapy or vaccination rests with the investigator and/or the 
subject's primary physician. However, the decision to continue the subject on trial therapy 
requires the agreement of the Sponsor. 
Prohibited Medications 
Medications listed below are prohibited from screening through the post-study follow-up visit. 
2. Corticosteroids: Treatment for ≥14 consecutive days or repeated courses of 
pharmacologic doses of corticosteroids. Note: Inhaled, nasal, and topical corticosteroids 
and physiological replacement doses of adrenal steroids are permitted. 
3. Any anti-hyperglycemic medications 
4. Any weight-loss medications: Treatment with or initiation of any weight-loss medication 
(e.g., semaglutide, liraglutide, orlistat, phentermine, phentermine-topiramate, 
bupropion-naltrexone) is prohibited. This includes agents that are approved as a 


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component of a multi-drug combination treatment for obesity, regardless of the purpose 
of current use, with the exception of bupropion. 
Bupropion, which is a component of the naltrexone-bupropion combination approved for 
weight loss (ContraveTM), is also approved as a single agent for the treatment of 
depression. Bupropion is allowed if it is being used for treatment of depression and 
eligibility criteria for anti-depressant medication stability prior to screening are met (see 
Exclusion Criterion #12). 
5. Marijuana: Legal (including medicinal marijuana and any marijuana-derived product 
including THC or CBD) or illegal use is prohibited. 
6. Supplements and/or Traditional Medicines: The introduction of new agents during the 
course of the study is not allowed. The use of prior agents is described below. 
7. Lipid-lowering agents other than HMG-CoA reductase inhibitors (statins) and ezetimibe 
are prohibited. Prohibited agents include: 
• Bile acid binding resins (e.g. cholestyramine, colesevelam) 
• Fibric acid derivatives (e.g. fenofibrate, clofibrate) 
8. Anti-psychotic agents are prohibited, regardless of the purpose for their use. 
9. Use of the following anti-depressants is prohibited, regardless of the purpose for their 
use: 
• Tricyclic (e.g. amitriptyline, clomipramine) and tetracyclic (maprotiline) 
anti-depressants 
• Mirtazapine 
10. Stimulant medications including amphetamines (e.g. dextroamphetamine, 
lisdexamfetamine) and methylphenidate/dexmethylphenidate. 
11. Opiates: Brief (≤2 total days) use of opiates for unanticipated pain management needs 
during study participation is permitted. All other use of opiates is prohibited. 
12. Use of any other medications that, in the investigator’s judgement, can significantly impact 
(increase or decrease) body weight, regardless of the purpose for their use. 
Guidance for Other Medications 
The investigator or participant’s physician/health care provider are permitted to make 
adjustments in other therapies throughout the trial if clinically warranted. Guidance for specific 
medications which are permitted during the study is provided below. 
1. Non-steroidal anti-inflammatory drugs (NSAIDs): NSAIDs may be used for minor 
ailments (e.g. minor injuries, osteoarthritis, upper respiratory tract infections) without 
prior consultation with the Sponsor Clinical Director. Note: Acetaminophen is a known 
hepatotoxin and is therefore prohibited. 
2. HMG-CoA reductase inhibitors (statins) and ezetimibe: Concomitant use of a statin (e.g. 
atorvastatin, simvastatin) and/or ezetimibe is permitted if the regimen (agents and doses) 
has been stable for ≥3months prior to screening. It is preferable that the lipid-lowering 


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regimen (agents and doses) remain stable throughout study participation (from screening 
through the post-study follow-up visit). 
3. Antihypertensive medications: ≤2 anti-hypertensive agents are permitted. These may not 
include verapamil given potential for verapamil to perpetrate a DDI with K-757. It is 
preferable that doses of anti-hypertensive medications remain stable from randomization 
through the post-study follow-up visit. 
4. Post-menopausal hormonal replacement therapy (HRT): Post-menopausal HRT is 
permissible, but participants should be on a stable HRT regimen at screening and are 
expected to remain on this stable regimen throughout study participation. 
5. Thyroid Hormone Replacement Therapy: Thyroid hormone replacement medication (e.g., 
thyroxine) is permitted, but subjects should be on a stable dose for at least 3 months prior 
to screening. It is preferable that doses of thyroid hormone replacement remain stable 
throughout study participation (from screening through the post-study follow-up visit). 
6. Nicotine/Nicotine products: Smoking is permitted during the study; however, 
participants should refrain from smoking >10 cigarettes per week. No other forms of 
nicotine (other forms of tobacco, nicotine patch, e-cigarettes, vapes) are permitted during 
study participation. Note: Participants should avoid cigarette use at least 30 minutes prior 
to measuring blood pressure. 
7. Ondansetron may be used as necessary to manage GI intolerance (see Section 7.1.1). 
8. Anti-depressants: Anti-depressant agents that are not prohibited (see above) are 
permissible if the treatment regimen (agents and doses) has been stable for ≥6 months 
prior to screening. Permissible classes/agents include selective serotonin reuptake 
inhibitors (SSRIs; e.g. fluoxetine, sertraline), serotonin-norepinephrine reuptake 
inhibitors (e.g. desvenlafaxine, duloxetine), serotonin modulators (e.g. nefazadone, 
trazadone), and bupropion. It is preferable that anti-depressant regimens (agents and 
doses) remain stable throughout study participation (from screening through the post-
study follow-up visit). 
9. Supplements and/or Traditional Medicines: The use of herbal supplements and other 
natural products is allowed provided doses have been stable for at least 90 days prior to 
the screening visit. Increases in dose/frequency during the study are prohibited. Use of all 
such agents should be captured on the prior/concomitant medication CRFs. 
Drug-drug interaction considerations 
No formal drug-drug interaction studies in humans have been conducted with K-757 or K-833. 


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Contact the Sponsor if there any questions about potential drug interactions with concomitant 
medications. 


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11. 
STUDY RESTRICTIONS AND REQUIREMENTS 
11.1. 
Dietary and Physical Activity Requirements and Restrictions 
Fasting Prior to Study Visits 
1. Participants must attend visits V2, V6, V9, V12, and V13 in the fasted state. These visits 
should be scheduled in the morning. 
2. Fasting is defined as at least 8 hours before the visit without food or liquids, except for 
water. 
3. At fasted visits, the morning doses of study medication should be withheld until blood 
samples have been obtained (except V12 and V13 where there is no dosing). 
Diet and Physical Activity Counseling 
All participants will receive nutritional and physical activity counseling according to the SOA 
(Table 2). This counseling will be provided by a dietician or similar qualified healthcare 
professional. 
Nutritional counseling will focus on calorie-reduction with an energy deficit of approximately 
500 kcal/day based on the total energy expenditure (TEE) estimated once based on the weight at 
V2. Physical activity will also be encouraged (minimum 150 min of physical activity per week, 
e.g. walking or use of the stairs). Note: To minimize potential for variability in counseling 
between study sites, diet and activity counseling must be limited to that specified for the study 
and occur only at the site visits specified in Table 2. No diet or activity counseling may occur at 
other site visits or outside of site visits (e.g. by phone, text, email). 
If a BMI ≤22.5 kg/m2 is reached, the recommended energy intake should be recalculated with no 
kcal deficit (maintenance diet) for the remainder of the trial. As necessary, the investigator may 
consult with the Kallyope Clinical Director to discuss when a maintenance diet should be 
initiated. 
Calculation of Estimated TEE 
The TEE is calculated by multiplying the estimated Basal Metabolic Rate (BMR) (Table 10) 
with a Physical Activity Level value of 1.3. 


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Table 10: 
Equation for Estimated BMR 
Sex 
Age (years) 
BMR (kcal/day) 
Men 
18 to 30 
31 to 60 
>60 
15.057 x weight at randomization in kg + 692.2 
11.472 x weight at randomization in kg + 873.1 
11.711 x weight at randomization in kg + 587.7 
Women 
18 to 30 
31 to 60 
>60 
14.818 x weight at randomization in kg + 486.6 
8.126 x weight at randomization in kg + 845.6 
9.082 x weight at randomization in kg + 658.5 
11.1.1. 
Alcohol Restrictions 
Participants are permitted to consume alcohol, as long as the amount is lower than 
14 drinks/week for men and >7 drinks/week for women, where l drink= 5 ounces (150 mL) of 
wine or 12 ounces (360 mL) of beer or 1.5 ounces (45 mL) of hard liquor. 
11.1.2. 
Caffeine Restrictions 
Participants should avoid caffeine at least 30 minutes prior to measuring blood pressure. 
11.1.3. 
Smoking Restrictions 
Smoking is permitted during the study; however, participants will refrain from smoking 
>10 cigarettes per week. In addition, no other forms of nicotine (e.g. other forms of tobacco, 
nicotine patch, e-cigarettes, vapes) are permitted during the study. 
Participants should avoid cigarette use at least 30 minutes prior to measuring blood pressure. 
11.1.4. 
Activity Restrictions 
See activity counseling above (Section 11.1). 
11.2. 
Contraceptive Requirements 
Male study participants: 
Must not donate sperm from the first dose of study drug until 14 days after the last dose of study 
drug. 
If the partner is a non-pregnant female of child-bearing potential, they must use an appropriate 
method of contraception, which must include a condom with spermicidal cream or jelly, from the 
first dose of study drug until 14 days after the last dose of study drug which is more than 5 times 
the estimated half-life of K-757 and K-833. A male subject who has had a vasectomy must use a 
condom but is not required to use spermicidal jelly. 
If a partner is pregnant, they must use a condom. 
Note: Contraception/condom requirements are waived if partner is NOT of child-bearing 
potential (i.e.  is male or is a female who is post-menopausal or surgically sterile 
[post-hysterectomy, post-bilateral oophorectomy, and/or post-bilateral salpingectomy]). 
Female study participants of reproductive potential 


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Must agree to not donate eggs from the first dose of study drug until 14 days after the last dose 
of study drug. 
Must agree to not donate eggs from the first dose of study drug until 14 days after the last dose 
of study drug. 
Must either agree to remain abstinent from heterosexual activitya or use (or have their partner 
use) a birth control method that is highly effective and has low user dependency. Acceptable 
methods of birth control are: 
− Progestogen-only implant (e.g. etonogestrel implant) 
− Intrauterine device (IUD) 
− Intrauterine hormone-releasing system (IUS) 
− Bilateral tubal occlusion 
− Vasectomized partner 
a 
Abstinence can be used as the sole method of contraception if it is in line with the subject’s 
preferred and usual lifestyle and if considered acceptable by local regulatory agencies and ethics 
committees. Periodic abstinence (e.g., calendar, ovulation, sympto-thermal, post-ovulation 
methods, etc.) and withdrawal are not acceptable methods of contraception. 
The criteria specified in Section 8.1, Inclusion Criterion #8 must be met for a female subject to 
be considered not of reproductive potential for the purpose of this study. 


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12. 
RANDOMIZATION AND BLINDING 
12.1. 
Randomization and Blinding 
12.1.1. 
Randomization Code Creation and Storage 
Randomization personnel of the Sponsor or designee will generate the randomization schedule. 
All randomization information will be stored in a secured area, accessible only by authorized 
personnel. 
12.1.2. 
Clinical Study Drug Blinding 
This is a double-blind study where the Sponsor, site staff and participants will be blinded to the 
treatment assignment. 
12.1.3. 
Clinical Trial Blind Maintenance/Unblinding Procedure (Blinded Studies Only) 
The study drug blind shall not be broken by the investigator unless information concerning the 
study drug is necessary for the medical treatment of the subject. If possible, the Sponsor medical 
monitor should be contacted before the blind is broken, unless doing so poses a risk to subject 
safety. The need for investigator unblinding should be discussed with the Sponsor first unless the 
unblinding needs to occur urgently to ensure subject safety. 
Unblinding will be performed per the standard operating procedures of the study site. Any 
intentional or unintentional unblinding will be documented in the unblinding log and Clinical 
Study Report (CSR). 




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Table 12: 
K-833 Investigational Product 
 
Investigational Product 
Product Name: 
K-833 
Dosage Form: 
 
Unit Dose 
Capsules: placebo, 100-mg potencies 
Route of Administration 
Oral 
Physical Description 
100 mg of K-833 and placebo 
 
primary packaged in PVC/PvDC blisters with aluminum 
base and secondary packaged into wallet cards based on dosing 
regimen. 
Manufacturer 
 
Packaging / Distribution 
 
13.2. 
Study Drug Packaging and Labeling 
A clinical label will be affixed to study drug containers in accordance with local regulatory 
requirements. 
13.3. 
Study Drug Storage 
Study drug must be stored in a secure, limited-access location under the storage conditions 
specified on the label and must remain in the original container until dispensed. A daily 
temperature log of the drug storage area must be maintained. 
K-757 and K-833 capsules should be stored in well-closed containers at room temperature 
(15 to 25 °C / 59 to 77 °F). The temperature excursion information can be found in the pharmacy 
manual or in the referenced compounding manual when applicable. Receipt and dispensing of 
study drug must be recorded by authorized personnel at the study site. 
13.4. 
Administration 
Participants will be blinded to treatment assignment and dose level at all times. 
Study medication may be taken without regard to food. 
13.4.1. 
Dose Timing 
The morning dose should be taken between 6 and 10AM. 
The evening dose should be taken approximately 10 hours after the morning dose. 
There should always be at least 6 hours in between doses. 
13.4.2. 
Missed Doses 
If a subject did not take their scheduled dose: 
1. If a morning dose is not taken by 12 noon, it should not be taken. 


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2. If an evening dose is not taken by 12 midnight, it should not be taken. 
3. If a dose is missed, that dose should not be taken at a later time. It should be left in the 
blister pack and returned to the study site at the next site visit. 
13.4.3. 
Dosing Interruptions 
If multiple days of dosing are missed due to subject error, the participant may resume QD dosing 
for 3 days under PI discretion before returning to the BID regimen. If less than 2 days (4 
consecutive doses) are missed, the subjects should resume the BID regimen. 
If study medication is missed for ≥7 consecutive days, for any reason, the decision to resume 
should be based on discussion between the PI and Sponsor Clinical Director. 
All dosing interruptions should be documented in the case report forms. 
13.5. 
Study Drug Accountability 
The Investigator is responsible for keeping accurate records of the study drug received from the 
Sponsor or designee, the amount dispensed to and returned by the participants, and the amount 
remaining at the end of the study. For all study sites, the local country sponsor personnel or 
designee will provide appropriate documentation that must be completed for study drug 
accountability, return, and destruction. 
All ancillary supplies will be provided by either the study site or the Sponsor or designee, 
depending upon availability. The list of ancillary supplies and source information can be found 
in the Pharmacy Manual or in the referenced compounding manual when applicable. If provided 
by the Sponsor, unused ancillary supplies will be accounted for and disposed of as directed by 
the Sponsor or designee. 
13.6. 
Study Drug Handling and Disposal 
For all study sites, the local country sponsor personnel or designee will provide appropriate 
documentation that must be completed for study drug accountability, return, and destruction. 
13.7. 
Treatment Compliance 
Treatment compliance will be monitored throughout the duration of the study. Study medication 
will be reconciled at each visit, when new treatment wallets are administered to participants. A 
system to support subject adherence to BID dosing will be used at participating sites during the 
study. Dosing reminder texts and capture of anonymized subject AM/PM dosing will be done via 
a smart phone application and monitored centrally. No data from the application-based tool will 
be collected during the study. Actual dosing compliance is to be confirmed between the site staff 
and subjects at each study visit and upon return of the subject IMP blister cards. Missed doses 
will be quantified within the eCRF and tracked within the site drug accountability logs. 


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14. 
EFFICACY ASSESSMENTS 
14.1. 
Body Measurements 
Body weight should be measured at all site visits where indicated in the SOA, in the fasted state. 
The scale should be calibrated prior to study start. A recalibration is not needed if calibration 
occurred within 3 months prior to the study start. 
Body weight will be measured, in kilograms (kg) or pounds (lbs), using a standardized, digital 
scale. The scale must provide body weight in kg or lbs (unit conversion from pounds to 
kilograms by site staff is not permitted). The weighing process is as follows: 
• The same scale should be used for each patient at all study visits where weight is 
measured. 
• Weight will be taken in duplicate throughout the trial at approximately the same time 
of day, after voiding (i.e., forced void) and while wearing only a gown and underwear 
(no street clothes or shoes; socks do not need to be removed). 
• Participants should be instructed to step gently onto the scale, place both feet together 
in the center of the scale and stand straight with eyes directed ahead. Participants 
should be instructed to stand still and not sway. Measurement will be recorded after 
the weight has stabilized. 
• Body weight should be reported with precision to one decimal place (i.e., 0.1 kg or 
lbs). The 2 measurements should be recorded in the source documents. If the 
2 measurements differ by more than 0.2 kg or lbs, a second set of duplicate 
measurements must be obtained as follows: (1) check the subject to ensure proper 
positioning as indicated above and (2) re-measure weight in duplicate. This process 
should be repeated, as needed until duplicate measurements that agree within 0.2 kg 
or lbs are obtained. This set of measurements should be recorded in the source 
documents and in the clinical database. 
Height is measured without shoes in centimeters (one decimal). BMI will be calculated from 
screening data and must agree with inclusion criterion no. 4. Height will be measured at 
Screening only and will not need to be reassessed at subsequent visits where weight is required 
per the SOA. Body mass index equals a subject' s weight in kilograms divided by the square of 
the height in meters (body mass index=kg/m2). Body mass index will be rounded to the nearest 
whole number according to the standard convention of 0.1 to 0.4, round down, and 0.5 to 0.9, 
round up. 
14.2. 
Blood Pressure and Heart Rate 
Vital sign measurements include a triplicate measurement of sitting blood pressure and heart 
rate. Blood pressure and heart rate will be measured using an automated, oscillometric blood 
pressure measuring device at time points noted in the SOA (Table 2). Site personnel should use 
the same blood pressure measuring device throughout the study for each subject. The following 
method should be used to record sitting blood pressure and heart rate for participants in 
triplicate: 


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• Participants will refrain from nicotine-containing products and/or ingesting caffeine 
for at least 30 minutes preceding the measurements. 
− Participants should be seated in a chair with their back supported, feet flat on the 
floor and arm bared (free of restrictions such as rolled up sleeves) and supported 
at heart level. 
− The appropriate cuff size must be used to ensure accurate measurement. Each 
subject’s cuff size should be noted in his/her source file to assure the same cuff 
size is used throughout the trial. 
− Measurements should be taken on the same arm at each visit (preferably the 
non-dominant arm). 
− Measurements should begin after at least 5 minutes of rest. 
− The three measurements of both the blood pressure and heart rate must be taken 
approximately 2 minutes apart with the triplicate set recorded in the source 
document and eCRFs. 
− Assessment of heart rate can be manual (rather than using an automated device); 
however, when done manually, heart rate must be measured in the brachial/radial 
artery for at least 30 seconds. 
− Other procedures should not be performed during the time of the blood pressure 
and heart rate measurements. 
14.3. 
Blood Sample Collection 
Blood samples for determination of K-757 and K-833 will be collected according to times noted 
in the SOA. Also refer to Section 17.6. 
14.3.1. 
Blood for Plasma PK Measurements 
Refer to the Operations Manual for plasma PK collection, handling, storage, and shipping 
information. 
Actual sampling times will be involved in the final computations of plasma PK parameters for 
final and preliminary analyses, if available. Preliminary analyses may use nominal sampling 
times to characterize the PK parameters for dose escalation meetings. 
All efforts will be made to obtain the PK samples at the scheduled nominal time relative to 
dosing (trough). The actual time of sample collection and the most recent dosing time both prior 
to and after each sample collection will be recorded on the source document and electronic case 
report form. 
14.3.2. 
Blood for Plasma PD and DNA Measurements 
Refer to the Operations Manual for plasma PD collection, handling, storage, and shipping 
information. Trough samples will be collected and analyzed for disease related markers such as 
gut hormone levels (eg, GLP-1, PYY). Additionally, archived samples may be used for analysis 
of additional gut hormones, such as GIP, active GIP, active GLP-1, or other markers relevant to 
the investigation (such as bile acids). 


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Refer to the Operations Manual for the collection, handling, storage, and shipping information 
pertaining to the optional blood sample for DNA. A one-time blood sample will be collected in 
consenting participants. DNA may be isolated from these samples and analyzed for genetic 
markers related to obesity and diabetes. These may include factors predicting response to 
treatment with the investigational agents or other types of obesity treatments. 


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15. 
ASSESSMENT OF SAFETY 
15.1. 
Safety Parameters 
15.1.1. 
Demographic/Medical History 
Qualified site personnel will collect subject significant medical history (past and concurrent 
medical conditions), per the clinical site' s standard of care and appropriate clinical judgment, 
and subject demographics. 
Qualified site personnel will review subject prior and concomitant medication use. Medications 
are defined as prescription and over-the-counter drugs, vaccines, supplements, nutraceuticals, 
and oral herbal preparations. 
15.1.2. 
Vital Signs 
Refer to Section 14.2 for details pertaining to heart rate and blood pressure measurements. 
Body temperature will be measured with either an oral (temperature taken at floor of the mouth) 
or tympanic thermometer. The same method (ie, oral or tympanic) must be used for all 
measurements for each individual subject and should be the same for all participants. 
15.1.3. 
Physical Examination (PE)  
Qualified site personnel will conduct full PE during visits noted in the SOA. 
The PE will include assessment of skin, head, ears, eyes, nose, throat, neck, thyroid, lungs, heart, 
cardiovascular, abdomen, lymph nodes, and musculoskeletal system/extremities. Interim PEs 
will be performed at the discretion of the Investigator, if necessary, to evaluate AEs or clinical 
laboratory abnormalities. 
15.1.4. 
Electrocardiogram (ECG) 
A triplicate 12-lead ECG will be collected at all the timepoints specified in the Schedule of 
Assessments following a rest period of at least 5 minutes. 
The Investigator will interpret the Safety ECG using 1 of the following categories: within normal 
limits, abnormal but not clinically significant, or abnormal and clinically significant. The time 
that the ECG was performed will be recorded. 
The following parameters will be recorded on the eCRF from the subject's ECG trace: heart rate, 
QRS interval, PR interval, QT interval, and QT (corrected) (Fredericia's). 
Trial sites will calculate the triplicate average QTcF at the screening visit to assess the QTcF 
exclusion criterion. No other calculation of ECG parameter averages is required for trial sites. 
The Investigator will be responsible for providing the interpretation of all safety ECGs 
(normal/abnormal). These results will be reviewed by the Investigator for subject safety and will 
be provided in an appropriate format with the clinical study report. 
An electronic copy of the 12-lead ECG, which includes the Investigator’s approval or a copy of 
the 12-lead ECG with the Investigator's signature and date of assessment, will be filed with the 
source and captured in the appropriate eCRF where required. If the original ECG is printed on 


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thermal paper, the ECG report must be photocopied and signed by the Investigator or archival 
quality paper can be utilized for ECG printouts, with a 25-year (or more) guarantee from the 
manufacturer (assuming appropriate storage conditions are satisfied). If a photocopy is made, it 
will be filed with the original ECG in the source. 
15.1.5. 
Laboratory Assessments 
Laboratory samples will be collected in accordance with acceptable laboratory procedures. 
Except for screening safety laboratory samples, safety laboratory samples will be collected at the 
time points and observing fasting requirements where stipulated in the Schedule of Assessments. 
15.1.5.1. Hematology 
Hematology includes the following assessments: 
White blood cell (WBC) counta 
Hemoglobin 
Red blood cell (RBC) countb 
Hematocrit 
Platelet count 
HbA1c 
a Differential white blood cell count will include percentages for neutrophils, lymphocytes, monocytes, eosinophils, 
and basophils and absolute counts for neutrophils, lymphocytes, monocytes, eosinophils, and basophils. 
b Differential red blood cell count will include mean corpuscular volume (MCV), mean corpuscular hemoglobin 
(MCH), mean corpuscular hemoglobin concentration (MCHC), red cell distribution width (RDW). 
15.1.5.2. Blood Chemistry 
Blood chemistry testing includes the following assessments: 
Alanine aminotransferase (ALT) 
Phosphorus 
Albumin 
Potassium 
Alkaline phosphatase (ALP) 
Sodium 
Aspartate aminotransferase (AST) 
Total bilirubin 
Bicarbonate 
Direct bilirubin  
Chloride 
Total Protein 
Cholesterol (full lipid panel on Day 1 and 
EoT only) 
Triglycerides 
Creatinine 
Urea 
Calcium 
Gamma-glutamyl transferase (GGT) 
Glucose 
Magnesium 
TSH (Screening) 
Multiple biochemical analysis (MBA)a 
 
Amylase 
 
Lipase 
a MBA testing will include, in addition to above tests: estimated glomerular filtration rate (eGFR) measured by 
MDRD at screening. 


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Please refer to Section 8.3 for subject discontinuation criteria related to abnormal liver test results, 
and Appendix A for details on management and follow-up of LFT elevations. 
15.1.5.3. Urinalysis 
Urinalysis includes the following assessments (Screening Visit only): 
Dipstick: 
Microscopic: 
Nitrite 
WBC 
Protein 
RBC 
Glucose 
Epithelial cells 
pH 
Casts (specify) 
Specific gravity 
 
Ketones 
 
Bilirubin 
 
Urobilinogen 
 
Leucocyte Esterase 
 
Blood 
 
15.1.5.4. Virus Serology 
Human immunodeficiency virus antibody, hepatitis B surface antigen, and hepatitis C virus 
antibody will be assessed at screening. 
15.1.5.5. Drug Screen 
The urine drug screening assessment will include the following tests: 
Amphetamines, barbiturates, benzodiazepines, tetrahydrocannabinol (THC), cocaine/metabolites, 
3,4-methylenedioxy-methamphetamine, methadone/metabolite, opiates. 
15.1.5.6. Pregnancy Screen 
Serum and urine hCG tests as per SOA. 
15.1.6. 
Patient Health Questionnaire-9 (PHQ-9) 
The PHQ-9 is the 9-item depression module of the patient health questionnaire, which is a 
self-administered diagnostic tool used for assessment of mental disorders. The questionnaire 
takes approximately 10 minutes to complete. The PHQ-9 will be assessed at screening. The 
questionnaire is located in Appendix C. 
Referral to a mental health professional (MHP) 
If a participant’s screening PHQ-9 score is 10-14 (inclusive) the participant should be referred to 
a MHP if this is considered appropriate by the investigator. If a referral is not considered 
appropriate, the reason for this decision must be documented in the subject’s medical records. 


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If a participant has a screening PHQ-9 score of ≥15 or has a score >0 for Question # 9 (Thoughts 
that you would be better off dead or of hurting yourself), they will be excluded from the study. 
However, they must be referred to a MHP. 
At any point during the study, MHP referral is required if a participant has any suicidal behavior 
or if the investigator considers referral necessary for the safety of the participant for any reason. 
If any of the referral criteria are met, the reason for referral should be explained to the 
participant. If the participant refuses the referral, this should be documented. 
15.2. 
Adverse Events and Serious Adverse Events 
15.2.1. 
Definition of Adverse Events (AEs) and Serious Adverse Events (SAEs) 
15.2.1.1. Adverse Event (AE) 
An Adverse Event/Experience is any untoward medical occurrence in a patient or clinical 
investigation subject administered a pharmaceutical product and which does not necessarily have 
to have a causal relationship with this treatment [ICH E2A]. 
The following can be considered AEs: 
• An exacerbation of a pre-existing illness 
• An increase in frequency or intensity of a pre-existing episodic event or condition 
• A condition detected or diagnosed after the initiation of treatment with study 
medication, even though it may have been present prior to the start of the study. 
• Continuous persistent disease or symptoms present at baseline that worsen after 
informed consent or following the initiation of treatment with study medication. 
• Laboratory values and ECG findings: Changes in laboratory values or ECG 
parameters may be considered AEs if they are judged to be clinically significant (i.e., 
if some action or intervention is required or if the Investigator judges the change to be 
beyond the range of normal physiologic fluctuation). If the value results in a 
discontinuation of investigational study drug, then the occurrence should be reported 
as an AE. 
• If abnormal laboratory values or ECG findings are the result of pathology for which 
there is an overall diagnosis (e.g., increased creatinine in renal failure), the diagnosis 
only should be reported appropriately as an AE. Any laboratory AE should be 
recorded in the eCRF, whether or not it is related to study drug. 
• Any change in vital signs that are considered clinically significant by the Investigator 
may be recorded as an AE. If the value results in a discontinuation of investigational 
study drug, then the occurrence should be reported as an AE. 
15.2.1.2. Serious Adverse Event (SAE) 
A serious adverse event is any untoward medical occurrence that at any dose: 
• Results in death 


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• Is immediately life-threatening 
• Requires in-patient hospitalization or prolongation of existing hospitalization 
• Results in persistent or significant disability or incapacity 
• Results in a congenital abnormality or birth defect 
• Is an important medical event that may jeopardize the patient or may require medical 
intervention to prevent one of the outcomes listed above. 
Additional details and clarifications for AEs and SAEs are in Appendix B. 
15.2.2. 
Time Period and Frequency for Collecting AE and SAE Information 
All AEs and SAEs will be collected from time of consent through the Poststudy/End of Trial 
visit. 
15.2.3. 
Identifying AEs and SAEs 
Adverse events spontaneously reported by the patient/subject and/or in response to an open 
question from the study personnel or revealed by observation will be recorded during the study at 
the investigational site. 
15.2.4. 
Recording of AEs and SAEs 
All AEs that occur after any patient/subject has been consented, before treatment, during 
treatment, during all visits, and within 14 days following the cessation of treatment, whether or 
not they are related to the study drug, must be recorded on the eCRFs provided by Kallyope, Inc. 
Each event should be recorded to represent a single diagnosis. Accompanying signs (including 
abnormal laboratory values or ECG findings) or symptoms should NOT be recorded as 
additional AEs. If a diagnosis is unknown, sign(s) or symptom(s) should be recorded 
appropriately as an AE(s) and updated once the information becomes available. 
The following information will be documented for each event: 
• Event term 
• Start and end date and time 
• Pattern of AE (frequency) 
• Severity/intensity 
• Causality Assessment (Investigator's opinion of the causal relationship between the 
event and administration of study drug[s]) 
• Action taken with trial drug 
• Outcome of event 
• Seriousness 
Event Term 


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The AE term should be reported in standard and current medical terminology (e.g., MedDRA) 
when possible. 
Start Date 
The start date of the AE is the date that the first signs/symptoms were noted by the 
patient/subject and/or Investigator. 
End Date 
The end date of the AE is the date at which the patient/subject recovered, the event resolved but 
with sequelae, or the patient/subject died. 
Pattern of AE (Frequency) 
Episodic AEs (eg, headache) or those which occur repeatedly over a period of non-consecutive 
days are intermittent. All other events are continuous. 
Severity/Intensity  
It is important to distinguish between serious and severe AEs. Severity is a measure of intensity 
whereas seriousness is defined by the criteria under Section 15.2.1.2. An AE of severe intensity 
may or may not be considered “serious.” 
Intensity will be assessed according to the following scale: 
• Mild (awareness of sign or symptom, but easily tolerated) 
• Moderate (discomfort sufficient to cause interference with normal activities) 
• Severe (incapacitating, with inability to perform normal activities) 
For assessment of the severity of GI AEs, the grading scales below may be taken as a reference 
per investigator discretion (Table 13): 


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Table 13: 
Severity Grading of GI AEs 
AE 
Mild 
Moderate 
Severe 
Nausea/ 
Vomiting* 
-No interference with 
activity 
-1-2 episodes/24 hours** 
-Some interference with 
activity 
-3-5 episodes/24 hours** 
-Prevents daily activity 
-6 or more episodes/24 
hours** 
-Requires IV hydration 
-More severe (e.g. 
hypotensive shock) 
Diarrhea* 
-2-3 loose stools 
-<400gms/24 hours 
-4-5 stools 
-400-800 gms/24 hours 
-6 or more watery stools 
-> 800 gms/24 hours 
-Requires IV hydration 
-More severe (e.g. 
hospitalization indicated) 
Constipation*** 
-Occasional or 
intermittent symptoms 
-Occasional use of stool 
softeners, laxatives, 
dietary modification or 
enema 
-Persistent symptoms with 
regular use of laxatives or 
enemas 
-Limiting instrumental 
activities of daily living 
-Obstipation with manual 
evaluation indicated 
-Limiting self-care 
activities of daily living 
-more severe (e.g. urgent 
intervention indicated) 
*Based on the Guidance for Industry-Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled 
in Preventive Vaccine Clinical Trials (2007); https://www.fda.gov/media/73679/download 
**Individual episodes separated by at least 5 min.*** Table is based on the Constipation Grading Scale National   
   Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) (version 5.0) 
Causality Assessment 
An Investigator who is qualified in medicine must make the determination of relationship to the 
study drug for each AE. 
The relationship of each AE to study drug will be assessed using the following categories: 
Related: An AE that follows a reasonable temporal sequence from administration of study drug 
(including the course after withdrawal of the study drug), or for which a causal relationship is at 
least a reasonable possibility that the study drug caused the AE, ie, it is medically plausible. 
“Reasonable possibility means” there is evidence to suggest a causal relationship between the 
study drug and the AE. 
Not Related: An AE that does not follow a reasonable temporal sequence from administration of 
study drug and/or that can reasonably be explained by other factors, such as underlying diseases, 
complications, concomitant medications, and/or concurrent treatments. 
Action Taken with Study Treatment 
• Drug withdrawn (ie, discontinuation due to an AE) - a study medication is stopped 
due to the particular AE. 
• Dose not changed - the particular AE did not require stopping a study medication. 


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• Unknown - only to be used if it has not been possible to determine what action has 
been taken. 
• Not applicable - a study medication was stopped for a reason other than the particular 
AE, e.g., the study has been terminated, the subject died, dosing with study 
medication had not yet started or dosing with study medication was already stopped 
before the onset of the AE. 
• Dose reduced - the dose was reduced due to the particular AE. 
• Dose increased - the dose was increased due to the particular AE. 
• Drug interrupted - the dose was interrupted due to the particular AE. 
Outcome 
• Recovered/resolved - subject returned to first assessment status with respect to the 
AE. 
• Recovering/resolving - the intensity is lowered by one or more stages: the diagnosis 
has or signs/symptoms have almost disappeared; the abnormal laboratory value 
improved, but has not returned to the normal range or to the baseline value; the 
subject died from a cause other than the particular AE with the condition remaining 
"recovering/resolving." 
• Not recovered/not resolved - there is no change in the diagnosis, signs or symptoms; 
the intensity of the diagnosis, signs /symptoms or laboratory value on the last day of 
the observed study period has become worse than when it started; is an irreversible 
congenital anomaly; the subject died from another cause with the particular AE state 
remaining "Not recovered/not resolved." 
• Recovered/ Resolved with sequelae - the subject recovered from an acute AE but was 
left with permanent/significant impairment (e.g., recovered from a cardiovascular 
accident but with some persisting paresis). 
• Fatal - an AE that is considered as the cause of death. 
• Unknown - the course of the AE cannot be followed up due to hospital change or 
residence change at the end of the subject's participation in the study. 
Seriousness 
• See Section 15.2.1.2 for the criteria for an SAE. Seriousness is a factor in determining 
regulatory obligations. 
15.2.5. 
Follow-Up of AEs and SAEs 
All participants/participants experiencing AEs, whether considered associated with the use of the 
study medication or not, must be monitored until the symptoms subside (the patient’s/subject’s 
health has returned to baseline status) and any clinically relevant changes in laboratory values 
have returned to baseline, or until there is a satisfactory explanation for the changes observed, 
regardless of whether the patient/subject is still participating in the study. The exception are 


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nonserious AEs that begin prior to the first exposure to investigational product, related or 
unrelated to the study procedure, which need not be followed-up for the purposes of the protocol. 
All appropriate therapeutic measures will be undertaken and recorded. Where appropriate, 
medical tests and examinations will be performed to document resolution of the event(s). 
15.2.6. 
Reporting Serious Adverse Events (AEs) to the Sponsor  
The study designated SAE form (or equivalent) must be completed, in English, and signed by the 
Investigator immediately or within 24 hours of first onset or notification of the event. 
The SAE must also be entered into the EDC within 24 hours of the Investigator’s (or other study 
personnel’s) initial knowledge of the event. A paper form may be used as back-up. 
The SAE form should be transmitted within 24 hours of awareness by email to the safety 
mailbox address listed below and in Table 1. 
 
The information should be completed as fully as possible but contain, at a minimum: 
• A short description of the event and the reason why the event is categorized as 
serious 
• Subject identification number 
• Investigator's name/site 
• Name of the study medication(s) 
• Causality assessment 
The Investigator must verify the accuracy of the information recorded on the SAE pages with the 
corresponding source documents. Supporting documents (e.g. discharge summaries, imaging 
reports, ECGs, laboratory tests, autopsy reports, etc.) should also be provided with the SAE or as 
soon as obtained. 
Additional follow-up information, if requested or becomes available at a later date, should be 
transmitted to Kallyope, Inc. and its designated contact address within 24 hours of receipt. The 
investigator should complete a follow-up SAE form. All SAE information, including initial and 
all follow-ups, should be kept with the appropriate section of the CRF and/or study file. 
All SAEs should be followed up as described in Section 15.2.5. The timelines and procedure for 
follow-up reports are the same as those for the initial report. 
15.2.7. 
Reporting AEs to Regulatory Authorities and IRBs/IECs 
The Sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study intervention under clinical investigation. The 
Sponsor will comply with country-specific regulatory requirements for safety reporting to 
regulatory authorities, IRBs/IECs, and investigators.  
A SAE may qualify for expedited reporting to regulatory authorities if it is determined to be a 
sudden unexpected serious adverse reaction (SUSAR). A SUSAR is an AE associated with the 
use of the study drug which is serious, unexpected, and assessed as related to the study drug. An 


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AE is considered “unexpected” if the nature of the AE is not consistent with what is not listed in 
the Reference Safety Information section of the Investigator Brochure. Reports that add 
significant information on specificity or severity of a known, already documented serious 
adverse event constitute unexpected events. The Sponsor is responsible for determining whether 
a SAE is expected or unexpected for the purpose of regulatory reporting. 
The Sponsor or its designated representative will be responsible for reporting all suspected 
unexpected serious adverse reactions (SUSARs) and any other applicable SAEs to regulatory 
authorities, Investigators, and IRBs or IECs, as applicable, in accordance with national 
regulations in the countries where the study is conducted. Relative to the first awareness of the 
event by/or further provision to the sponsor or sponsor' s designee, SUSARs will be submitted 
within 7 days for fatal and life-threatening SUSARs and 15 days for non-fatal and 
non-life-threatening SUSARs, unless otherwise required by national regulations. The Sponsor 
will also prepare an expedited report for other safety issues where these might materially alter 
the current benefit-risk assessment of an investigational medicinal product or that would be 
sufficient to consider changes in the investigational medicinal products administration or in the 
overall conduct of the trial. 
It is the Principal Investigator’s responsibility to promptly notify the IRB or IEC of all SAEs that 
occur at his or her site. Investigators will also be notified of all SUSARs (7/15 Day Safety 
Reports) that occur during the clinical trial. Each site is responsible for notifying its IRB or IEC 
of these additional SAEs, in accordance with its regulations and guidelines. 
15.2.8. 
Adverse Events of Special Interest (AESI) 
An AESI is an AE (serious or non-serious) of scientific and medical interest to the Sponsor’s 
product or program. Ongoing monitoring and rapid communication to the Sponsor is requested 
as such an event might warrant further investigation in order to further characterize it. 
AESIs and any follow-up information must be reported to the Sponsor within 24 hours of first 
awareness (Section 15.2.6). 
• For this study, there are no AESIs. 
15.2.9. 
Pregnancy and Lactation 
Although pregnancy and lactation are not considered an AE, it is the responsibility of the 
Investigator to report the pregnancy/lactation in either a female subject or the partner of a male 
subject to the Sponsor and its designee during the trial (within 24 hours) up until the post-study 
Visit. All participants and partners of participants who become pregnant must be followed to the 
completion or termination of pregnancy.  
Should a pregnancy occur, it must be recorded on the eCRFs and designated pregnancy form and 
reported within 24 hours to the designated safety mailbox at:  
 
Pregnancy, in itself, is not regarded as an AE unless a negative or consequential outcome occurs 
in the participant or child/fetus, or there is a suspicion that the study drug may have interfered 
with the effectiveness of a contraceptive medication. 


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Pregnancy outcomes (e.g. spontaneous abortion, missed abortion, benign hydatidiform mole, 
blighted ovum, ectopic pregnancy, pre-eclampsia, fetal death, intrauterine death, miscarriage, 
and stillbirth must be reported as SAEs (important medical events). If the pregnancy continues to 
term, the outcome (health of infant) must also be followed up and documented even if the patient 
was discontinued from the study. All reports of congenital abnormalities/birth defects are SAEs. 
SAEs should be reported as per Section 15.2.6. 


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16. 
STATISTICS 
16.1. 
General Statistical Considerations 
A Statistical Analysis Plan (SAP) will be developed and finalized before database lock and will 
describe details of the summaries and analyses to be performed. Any changes in the planned 
analyses will be reported in the CSR. 
All summaries and analyses will be presented in tabular or graphical form. Continuous data will 
be summarized by reporting number of observations, mean, standard deviation (SD), median, 
minimum, and maximum by treatment and visit. Categorical data will be summarized using 
frequency tables reporting the number and percentage of participants falling within each category 
by treatment and by visit. 
All tests of treatment effects will be conducted at a two-sided alpha level of 0.05 and/or 
two-sided 95% confidence interval, unless otherwise stated. 
Baseline will be taken as the last available observation prior to dosing during the double-blind 
treatment period. 
16.2. 
Sample Size Justification 
For the primary endpoint of percentage change from baseline in body weight, a sample size of 
150 participants (stratified by gender and randomized 1:1:1 into three treatment arms) provides 
>95% power to detect a treatment difference of 4% weight reduction after 13 weeks of treatment 
with a 2-sided alpha of 0.05, assuming a standard deviation of 4% and 20% drop out. 
16.3. 
Analysis Populations 
The modified Intent-to-Treat (mITT) analysis set will consist of all randomized participants who 
receive at least one dose of the study drug during the double-blind treatment period. The 
participants will be analyzed as randomized. The mITT analysis set will be used for 
demographic, baseline characteristics, efficacy analyses. 
The Safety analysis set will consist of all randomized participants who receive at least one dose 
of the study drug during the double-blind treatment period. The safety analysis set will be used 
for safety analysis and analyzed as treated. 
The PK analysis set will consist of all participants who receive study drug and have at least 
1 measurable plasma concentration. 
16.4. 
Disposition 
The number and percentage of participants who were randomized, and randomized but did not 
receive the study product as randomized will be summarized by treatment group. The number 
and percentage of participants who completed the double-blind treatment and/or the study, 
prematurely discontinued to treatment and/or study, and primary reason for discontinuation will 
be summarized by treatment group. 


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16.5. 
Demographics and Baseline Characteristics 
Demographic and baseline characteristics will be summarized by treatment group. Descriptive 
statistics (N, mean, SD, median, minimum, and maximum) will be generated for continuous 
demographic variables and baseline characteristics variables (e.g., age, height, weight, and BMI). 
The number and percentage of participants in each class of the categorical demographic variables 
and baseline characteristics variables (e.g., gender, ethnicity, race) will be summarized. 
Individual subject demographic and baseline characteristics data will be listed. 
16.6. 
Efficacy Analyses 
16.6.1. 
Primary Endpoints 
The primary efficacy outcome is the % weight change from baseline (Week 0) to Week 13. 
Primary Estimand 
For the primary endpoints, the primary estimand for the percentage change from baseline in body 
weight is defined as the average treatment effect of K-757 alone and the combination of K-757 + 
K-833 relative to placebo in the mITT analysis population, had they remained on their 
randomized treatment for the entire planned duration of the trial (“hypothetical” estimand). 
A mixed model for repeated measurements (MMRM) analysis will be applied with gender, 
treatment, visit and treatment-by-visit interaction as fixed effect and baseline body weight as a 
covariate. The MMRM model will use assessments only from participants who are taking the 
randomized treatment until end of treatment or until first discontinuation of randomized 
treatment. An unstructured covariance will be used. If the unstructured covariance structure leads 
to nonconvergence, Akaike’s information criteria will be used to select the best covariance 
structure. 
Secondary Estimand 
The secondary Estimand for the percentage change from baseline in body weight is defined as 
the average treatment effect of K-757 alone and the combination of K-757 + K-833 relative to 
placebo in the mITT analysis population regardless of adherence to treatment (“treatment policy” 
estimand). 
All available data at Week 13 including the participants who have discontinued treatment but 
completed week 13 visit ("retrieved dropouts”) are used for the analysis of the secondary 
estimand. A mixed model for repeated measurements (MMRM) analysis will be applied with 
gender, treatment, visit and treatment-by-visit interaction as fixed effect and baseline body 
weight as a covariate. Additional imputation for missing data at Week 13 may be performed 
using multiple imputation approach. 
16.6.2. 
Secondary Endpoints 
The confirmatory secondary continuous endpoints will be analyzed to address the primary 
estimand using the same MMRM described for the primary endpoint. 
For the secondary categorical endpoint of proportion of subject achieving ≥5% weight reduction 
after 13 weeks, the same MMRM described for the primary endpoints will be used to address the 
primary estimand. The missing data will be imputed using MMRM assuming missing at random 


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(MAR) and the imputed value will be used to classify each subject as a responder or not. A 
logistical regression using gender and treatment as factors and baseline body weight as covariate 
will be applied to analyze the imputed data. 
16.6.3. 
Exploratory Endpoints 
The exploratory endpoints will be analyzed using the same approach described for the secondary 
endpoint. 
16.7. 
Safety Analyses 
Safety analyses will be based on the Safety Analysis Set. No formal statistical tests or inference 
will be performed for safety analyses. All summaries will be summarized by treatment. 
16.7.1. 
Treatment-emergent Adverse Events (TEAE) 
Safety analyses will be based on the Safety Analysis Set. No formal statistical tests or inference 
will be performed for safety analyses. 
Adverse events will be coded using the version of the Medical Dictionary for Regulatory 
Activities (MedDRA) in effect at the start of the study. AEs will be summarized as TEAEs 
(defined as events that are newly reported after randomization or reported to worsen in severity 
from baseline). The incidence of participants with at least 1 TEAE and the incidence of TEAEs 
by preferred term and system organ class will be presented by treatment group. The frequency 
and percentage of TEAEs will be presented. The incidence of participants with at least 1 TEAE 
assessed as related to the study drug will be summarized by treatment group. All SAEs will be 
listed by patient. If a sufficient number of SAEs are reported, summaries will be included. 
Discontinuations to study and study drug due to TEAEs will be summarized by treatment group. 
All adverse events will be listed by patient. 
16.7.2. 
Clinical Laboratory Evaluation 
Baseline, post baseline measurements and changes from baseline for clinical laboratory 
evaluations will be summarized by treatment and timepoint. Individual measurements of 
laboratory tests from hematology, chemistry, and urinalysis that meet KALLYOPE, Inc.’s 
abnormal criteria will be summarized. 
16.7.3. 
Vital Signs 
Baseline, post baseline measurements and changes from baseline for vital sign data will be 
summarized by treatment and timepoint. 
16.7.4. 
Electrocardiogram 
Baseline, post baseline measurements and changes from baseline for electrocardiogram data will 
be summarized by treatment and timepoint. QTc values and changes form baseline that reach the 
threshold of clinical concern will be summarized. All electrocardiogram data will be provided in 
the data listings. 


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16.7.5. 
Prior and Concomitant Medications 
Prior and concomitant medications will be summarized by treatment group. 
16.8. 
Pharmacokinetics 
16.8.1. 
Sample Analysis 
The PK analysis set will consist of all participants who receive study drug and have at least 
1 measurable plasma concentration. 
16.8.2. 
Plasma PK 
Plasma concentrations will be summarized for K-757 for K-757 alone and the combination of 
K-757 + K-833. Plasma concentrations will be summarized for K-833 for the combination of 
K-757 + K-833. 
Mean plasma concentrations measured over time will be displayed graphically by treatment. 
16.9. 
Multiplicity  
The study tests the primary hypothesis that at least one of the treatment arms is superior to the 
placebo arm in reducing the body weight calculated as percentage change from baseline after 
13 weeks of treatment. Each of two comparisons between K-757 alone and the combination of 
K-757+K-833 vs placebo is tested at two-sided alpha of 0.05 with a familywise error rate of 0.10 
No other multiplicity adjustment will be performed for secondary and exploratory objectives, 
which will be tested at two-sided alpha of 0.05. 
16.10. 
Interim Analysis 
No interim analysis is planned for this study. 


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17. 
ADMINISTRATIVE AND REGULATORY DETAILS 
17.1. 
Direct Access to Source Data/Documents 
17.1.1. 
Study Monitoring 
Study progress will be monitored by the Sponsor or its representative as frequently as necessary 
to perform source document verification, ensure a accurate data collection, protocol compliance, 
and study conduct in accordance with accepted regulatory requirements. The Principal 
Investigator must make all the subject data available to the monitor for review during the 
planned site monitoring visits. Arrangements for monitoring visits will be made in advance, 
except in emergency cases. 
17.1.2. 
Audits and Inspections 
Authorized representatives of Kallyope, Inc., a regulatory authority, an Independent Ethics 
Committee or an Institutional Review Board may conduct inspections or audits of the clinical 
study. If the investigator is notified of an inspection by a regulatory authority the investigator 
agrees to notify the Sponsor -- medical monitor immediately. The investigator agrees to provide 
to representatives of a regulatory agency or Sponsor -- access to records, facilities, and personnel 
for the effective conduct of any inspection or audit. 
17.2. 
Institutional Review Board (IRB)/ Independent Ethics Committee 
(IEC) 
The Principal Investigator must obtain IRB/IEC approval for the investigation. Initial IRB/IEC 
approval, and all materials approved by the IRB/IEC for this study including the patient consent 
form and recruitment materials must be maintained by the Investigator and made available for 
inspection. 
17.3. 
Written Informed Consent 
The Principal Investigator(s) at each center will administer an IRB/EC approved informed 
consents to all subjects who are screened on this trial. The subject’s/patient’s signed and dated 
informed consent must be obtained before conducting any study procedures. 
17.4. 
Data Handling and Recordkeeping 
17.4.1. 
Data Collection and Reporting 
Data for this study will be collected using eCRFs. The Investigator and study site staff will 
receive system documentation, training, and support for the use of the eCRF. 
All protocol-required information collected during the study must be entered by the Investigator 
or designated representative in the source documents and eCRF. All data entry, modification, or 
deletion will be recorded automatically in an electronic audit trail indicating the individual 
subject, original value, the new value, the reason for change, who made the change, and when 
the change was made. All data changes will be clearly indicated with a means to locate prior 
values. The system will be secured to prevent unauthorized access to the data or the system. This 


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will include the requirement for a user identification (ID) and password to enter or change data. 
The Investigator will maintain a list of individuals who are authorized to enter or correct data and 
their system ID. 
The Investigator or designated sub-Investigator, following review of the data in the eCRF, will 
confirm the validity of each subject’s data by electronic signature. 
17.5. 
Retention of Records 
The investigator must maintain adequate and accurate records to enable the conduct of the study 
to be fully documented and the study data to be subsequently verified. These documents should 
be classified into at least the following two categories: (1) investigator’s study file, and 
(2) subject clinical source documents. Refer to (Refer to ICH E6 (R2) Good clinical practice 
Section 8 Essential documents for the conduct of a clinical trial). 
The Principal Investigator must maintain all documentation relating to the study for a period of 
2 years after the last marketing application approval, or if not approved 2 years following the 
discontinuance of the test article for investigation. If it becomes necessary for Kallyope, Inc. or 
the Regulatory Authority to review any documentation relating to the study, the Investigator 
must permit access to such records. 
17.6. 
PK and PD Sample Retention 
Blood samples collected in this study will be used for analysis of K-757 and K-833 PK and PD 
levels, as outlined in Section 9. Any leftover samples, if not used, will be preserved and retained 
at the Sponsor-selected long-term storage facility for up to 5 years from the end of the study to 
conduct additional analyses, as mentioned above. 
17.7. 
Publication Policy 
The Investigator is obliged to provide the Sponsor with complete test results and all data derived 
information available to other study Investigators or to regulatory agencies, except as required by 
law or regulation. Except as otherwise allowable in the clinical study site agreement, any public 
disclosure (including publicly accessible websites) related to the protocol or study results, other 
than study recruitment materials and/or advertisements, is the sole responsibility of the Sponsor. 
Investigators will be asked to review primary publications. The Sponsor may publish any data 
and information from the study (including data and information generated by the Investigator). 
Manuscript authorship for any peer-reviewed publication will appropriately reflect contributions 
to the production and review of the document. All publications and presentations must be 
prepared in accordance with this section and the Clinical Study Site Agreement. In the event of 
any discrepancy between the protocol and the Clinical Study Site Agreement, the Clinical Study 
Site Agreement will prevail. 
Investigators must seek approval from the Sponsor prior to publishing information from this trial. 
The Sponsor must have the opportunity to review all proposed abstracts, manuscripts, or 
presentations regarding this trial 45 days prior to submission for publication/presentation. Any 
information identified by the Sponsor as confidential must be deleted prior to submission; this 
confidentiality does not include efficacy and safety results. Sponsor review can be expedited to 
meet publication timelines. 


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17.8. 
Financial Disclosure 
Investigators who participate on this study will be required to provide the sponsor and/or its 
designees financial disclosure documentation as required per regulatory requirements. Financial 
Disclosure requirements are outlined in the US Food and Drug Administration Regulations, 
Financial Disclosure by Clinical Investigators (21 CFR Part 54). 
17.9. 
Compliance with Law, Audit, and Debarment 
By signing this protocol, the Investigator agrees to conduct the trial in an efficient and diligent 
manner and in conformance with this protocol; generally accepted standards of Good Clinical 
Practice (eg, International Conference on Harmonization of Technical Requirements for 
Registration of Pharmaceuticals for Human Use Good Clinical Practice: Consolidated Guideline 
and other generally accepted standards of good clinical practice); and all applicable federal, state 
and local laws, rules and regulations relating to the conduct of the clinical trial. 
The Investigator also agrees to allow monitoring, audits, IRB/ERC review and regulatory 
authority inspection of trial-related documents and procedures and provide for direct access to all 
trial-related source data and documents. 
The Investigator agrees not to seek reimbursement from participants, their insurance providers or 
from government programs for procedures included as part of the trial reimbursed to the 
Investigator by the Sponsor. 
The Investigator shall prepare and maintain complete and accurate trial documentation in 
compliance with GCP standards and applicable federal, state, and local laws, rules, and 
regulations; and, for each subject participating in the trial, provide all data, and, upon completion 
or termination of the clinical trial, submit any other reports to the Sponsor as required by this 
protocol or as otherwise required pursuant to any agreement with the Sponsor. 
Trial documentation will be promptly and fully disclosed to the Sponsor by the Investigator upon 
request and also shall be made available at the trial site upon request for inspection, copying, 
review and audit at reasonable times by representatives of the Sponsor or any regulatory 
authorities. The Investigator agrees to promptly take any reasonable steps that are requested by 
the Sponsor as a result of an audit to cure deficiencies in the trial documentation and 
worksheets/case report forms. 
The Investigator must maintain copies of all documentation and records relating to the conduct 
of the trial in compliance with all applicable legal and regulatory requirements. This 
documentation includes, but is not limited to, the protocol, worksheets/case report forms, 
advertising for subject participation, adverse event reports, subject source data, correspondence 
with regulatory authorities and IRBs/ERCs, consent forms, Investigator’s curricula vitae, 
monitor visit logs, laboratory reference ranges, laboratory certification or quality control 
procedures and laboratory director curriculum vitae. By signing this protocol, the Investigator 
agrees that documentation shall be retained until at least 2 years after the last approval of a 
marketing application in an ICH region or until there are no pending or contemplated marketing 
applications in an ICH region or until at least 2 years have elapsed since the formal 
discontinuation of clinical development of the investigational product. Because the clinical 
development and marketing application process is variable, it is anticipated that the retention 
period can be up to 15 years or longer after protocol database lock. The Sponsor will determine 


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the minimum retention period and notify the Investigator when documents may be destroyed. 
The sponsor also recognizes that documents may need to be retained for a longer period if 
required by local regulatory requirements. All trial documents shall be made available if required 
by relevant regulatory authorities. The Investigator must consult with and obtain written 
approval by the Sponsor prior to discarding trial and/or subject files. 
ICH GCP guidelines recommend that the Investigator inform the subject’s primary physician 
about the subject’s participation in the trial if the subject has a primary physician and if the 
subject agrees to the primary physician being informed. 
The Investigator will promptly inform the Sponsor of any regulatory authority inspection 
conducted for this trial. 
Persons debarred from conducting or working on clinical trials by any court or regulatory 
authority will not be allowed to conduct or work on this Sponsor’s trials. The Investigator will 
immediately disclose in writing to the Sponsor if any person who is involved in conducting the 
trial is debarred or if any proceeding for debarment is pending or, to the best of the Investigator’s 
knowledge, threatened. 
In the event the Sponsor prematurely terminates a particular trial site, the Sponsor will promptly 
notify that trial site’s IRB/IEC. 
17.10. 
Compliance with Trial Registration and Results Posting 
Requirements 
Under the terms of the Food and Drug Administration Modernization Act (FDAMA) and the 
Food and Drug Administration Amendments Act (FDAAA), the Sponsor of the trial is solely 
responsible for determining whether the trial and its results are subject to the requirements for 
submission to the Clinical Trials Data Bank, http://www.clinicaltrials.gov. KALLYOPE, as 
Sponsor of this trial, will review this protocol and submit the information necessary to fulfill 
these requirements. KALLYOPE entries are not limited to FDAMA/FDAAA mandated trials. 
Information posted will allow participants to identify potentially appropriate trials for their 
disease conditions and pursue participation by calling a central contact number for further 
information on appropriate trial locations and trial site contact information. 
By signing this protocol, the Investigator acknowledges that the statutory obligations under 
FDAMA/FDAAA are that of the Sponsor and agrees not to submit any information about this 
trial or its results to the Clinical Trials Data Bank. 
17.11. 
Confidentiality 
17.11.1. 
Confidentiality of Data 
By signing this protocol, the Investigator affirms to the Sponsor that information furnished to the 
Investigator by the Sponsor will be maintained in confidence, and such information will be 
divulged to the institutional review board, ethics review committee (IRB/ERC) or similar expert 
committee; affiliated institution and employees, only under an appropriate understanding of 
confidentiality with such board or committee, affiliated institution and employees. Data 
generated by this trial will be considered confidential by the Investigator, except to the extent 


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that it is included in a publication as provided in the Publications section (Section 17.7) of this 
protocol. 
17.11.2. 
Confidentiality of Subject Records 
By signing this protocol, the Investigator agrees that the Sponsor (or Sponsor representative), 
IRB/ERC, or regulatory authority representatives may consult and/or copy trial documents in 
order to verify worksheet/case report form data. The subject is informed about this process 
within the Informed Consent Form. Participants will be identified in CRFs and other documents 
submitted to the Sponsor only in a pseudonymized form (eg, by a subject number and/or birth 
year, but not by name). 
By signing this protocol, the Investigator agrees to treat all subject data used and disclosed in 
connection with this trial in accordance with all applicable privacy laws, rules, and regulations. 
17.11.3. 
Confidentiality of Investigator Information 
By signing this protocol, the Investigator recognizes that certain personal identifying information 
with respect to the Investigator, and all sub-Investigators and trial site personnel, may be used 
and disclosed for trial management purposes, as part of a regulatory submissions, and as required 
by law. This information may include: 
1. name, address, telephone number and e-mail address; 
2. hospital or clinic address and telephone number; 
3. curriculum vitae or other summary of qualifications and credentials; and 
4. other professional documentation. 
5. financial information such as the declaration of financial interests, if applicable, and other 
financial information collected for the purpose of payment and reporting of payments in 
connection with the conduct of trials. 
Consistent with the purposes described above, this information may be transmitted to the 
Sponsor, and subsidiaries, affiliates, and agents of the Sponsor, in your country and other 
countries, including countries that do not have laws protecting such information. Additionally, 
the Investigator’s name and business contact information may be included when reporting certain 
serious adverse events to regulatory authorities or to other Investigators. By signing this 
protocol, the Investigator expressly consents to these uses and disclosures. 
If this is a multicenter trial, in order to facilitate contact between Investigators, the Sponsor may 
share an Investigator’s name and contact information with other participating Investigators upon 
request. 


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18. 
REFERENCES 
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20. Tan T, Behary P, Tharakan G, Minnion J, Al-Najim W, Albrechtsen NJW, Holst JJ, 
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PMC5505203. 
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Kumari P, Hayakawa M, Masuda C, Okada T, Hara H, Drucker DJ, Yamada Y, Tokuda 
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GLP-1 Receptors in Vagal Afferents Affects Normal Food Intake and Glycemia. 
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28. Katz LB, Gambale JJ, Rothenberg PL, et al. Effects of JNJ-38431055, a novel GPR119 
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19. 
APPENDICES 


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APPENDIX A. MANAGEMENT OF PARTICIPANTS WITH ELEVATED 
LIVER ENZYMES (ALT OR AST >/=3X ULN) 
If baseline ALT/AST is normal (below the laboratory ULN), increases to ≥3X ULN are defined 
as clinically significant in this study. If baseline ALT/AST is elevated (> the laboratory ULN), 
increases that are both ≥3X ULN and ≥2X baseline are defined as clinically significant in this 
study. The Investigator will review safety labs and determine if an ALT/AST meets either of 
these thresholds. In studies where a central laboratory is used, the central lab will also alert the 
Investigator if these thresholds are met. 
When a randomized subject who is receiving IMP has an ALT or AST elevation beyond these 
thresholds, the Investigator should select the appropriate set of instructions (A or B below), 
depending on 1. whether the baseline (pre-dose Day 1) ALT/AST value is normal or elevated, 2. 
the magnitude of ALT/ALT elevation, 3. the presence or absence of symptoms of potential liver 
injury, and 4. whether there is a corresponding increase in bilirubin. Note: ALT and AST should 
be evaluated against these criteria independently. 
A. Criteria for starting close observation: If the criteria noted here are met and there is no 
immediately obvious alternate cause of the ALT/AST elevation, close observation (see 
below) must initiate. IMP dosing may continue if no criteria for dosing interruption are 
met (see B below). 
If the participant’s baseline (predose Day 1) ALT/AST value is normal (≤ lab ULN) 
• ALT/AST is ≥3X the ULN 
 
If the participant’s baseline (predose Day 1) ALT/AST value is elevated (> lab ULN) 
• ALT/AST is ≥3X the ULN and ≥2x baseline.  
 
B. Criteria for interrupting IMP administration: If any of the criteria noted here are met 
and there is no immediately obvious alternate cause of the ALT/AST elevation, IMP 
dosing must be interrupted, and close observation (see below) must initiate, unless 
already ongoing. IMP dosing may not resume unless/until criteria for resumption (see 
below) are met and both the investigator and the Sponsor medical monitor agree this is 
appropriate.  
If participant’s baseline (predose Day 1) ALT/AST value is normal (≤ lab ULN) 
1. ALT or AST is ≥ 3X ULN plus any of the following: 
• Total bilirubin is ≥ 2X ULN* or 
• INR is >1.5** or 
• There are symptoms of potential liver injury (ie. severe fatigue, nausea, vomiting, 
and/or RUQ pain 
2. ALT or AST is ≥ 8X ULN 
3. ALT or AST is ≥ 5X ULN for ≥ 2 weeks 
If participant’s baseline (predose Day 1) ALT/AST value is elevated (> lab ULN) 
1. ALT or AST is ≥ 3X ULN and ≥2X baseline plus any of the following: 


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• Total bilirubin is ≥ 2X ULN* or 
• INR is >1.5** or 
• There are symptoms of potential liver injury (ie. severe fatigue, nausea, vomiting, 
and/or RUQ pain 
2. ALT or AST is ≥ 8X ULN 
3. ALT or AST is ≥ 5X ULN and ≥3X baseline for ≥ 2 weeks  
*If a participant has Gilbert’s syndrome, a direct bilirubin ≥2X baseline will be used 
instead of total bilirubin. 
**INR criteria is not applied if a participant is on therapeutic anticoagulation. 
Criteria for considering resumption of IMP after interruption:  
If any of these criteria for interruption of IMP are met, dosing may not resume unless/until 
all the following criteria are met: 
1. Another etiology for the abnormal liver biochemistries leading to IMP interruption 
(e.g., active hepatitis with specific etiology demonstrated, cholecystitis, biliary 
obstruction) is established and 
2. Liver biochemistries have normalized or returned to ~ baseline for ≥2 weeks and 
3. The participant is able and willing to undergo close observation after resumption of 
IMP and 
4. Both the investigator and the Sponsor medical monitor agree that resumption of IMP 
is appropriate. 
Close observation must be initiated at the resumption of IMP. Close observation may stop 
if liver biochemistries have remained normal or at ~baseline for ≥2 weeks and both the 
investigator and the Sponsor medical monitor agree this is appropriate. 
Close observation 
Close observation includes liver biochemistry monitoring and assessment of etiology as detailed 
below. If monitoring requirements cannot be met for any reason, IMP dosing must be 
interrupted. 
Monitoring 
• Repeat testing must occur within 48-72 hours. This should include liver biochemistries (ALT, 
AST, alkaline phosphatase, GGT, total bilirubin, INR) and creatinine phosphokinase (CPK). 
• Liver biochemistries (ALT, AST, alkaline phosphatase, GGT, total bilirubin, INR) should be 
repeated at least twice weekly. 
o Frequency can decrease to once weekly with approval of the Sponsor medical monitor 
if abnormalities are stable for ≥2 weeks. 
o Close monitoring may stop if abnormalities have normalized or returned to ~ baseline 
for ≥4 weeks, if both the investigator and the Sponsor medical monitor agree this is 
appropriate. 
o Dosing must be interrupted if any criteria for interruption (see B above) are met. 
 


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Etiology assessment 
• Questions to assess etiology: Investigate potential causes for the subject’s elevated liver 
enzymes using the questions below. Answers to questions should be recorded in the subject’s 
source documents and appropriate eCRFs. 
1. Has the subject recently: 
a. Had a change in his/her pattern of alcohol use?  
b. Administered an illegal drug(s)? 
c. Been exposed to a chemical agent or other environmental toxin? 
d. Consumed any unusual food (e.g., mushrooms), seasonal foods, or initiated 
treatment with new herbal/nutritional supplements? 
e. Initiated a new diet regimen, started a rigorous exercise program, or experienced 
any form of severe physical exertion? 
f. Traveled to another country or region? 
2. Does the subject have a relevant concomitant illness (e.g., cholelithiasis, hepatitis, etc.) or 
has the subject had potential exposure to viral hepatitis (transfusion, tattoo, new sexual 
partner)? 
3. Does the subject have a relevant medical history (e.g., autoimmune disorder, cancer, 
Gilbert’s syndrome, obesity, Wilson’s disease, NASH, alcohol or infectious hepatitis, 
biliary tract disease, hemochromatosis)? 
4. Has the subject: 
a. recently been treated with a concomitant medication(s) with demonstrated or 
suspected effects on the liver (e.g., acetaminophen, amiodarone, aspirin, 
chlorpromazine, dantrolene, erythromycin, halothane, isoniazid, methyldopa, 
nitrofurantoin, oxyphenisatin, perhexiline maleate, phenytoin, propylthiouracil, 
rifampin, sulfonamides, tetracyclines)? 
b. initiated treatment with another new medication? 
• Additional Laboratory/Imaging Evaluations to assess etiology: In participants for whom 
an etiology for the abnormal liver enzymes is unknown or whose elevated liver enzymes 
persist for >1 week: 
1. Consider performing serologic tests including: (a) Hepatitis A (Immunoglobulin M, IgM); 
(b) Hepatitis B (surface Antigen (Ag) and core IgM); (c) Hepatitis C (antibody); (d) 
Hepatitis E (Immunoglobulin G (IgG) and IgM). Obtain consent prior to testing, if 
required locally. Additional evaluations may be performed at the discretion of the 
Investigator. 
2. Consider an ultrasound of the subject’s RUQ and additional scans [endoscopic retrograde 
cholangiopancreatography (ERCP) or magnetic resonance cholangiopancreatography 
(MRCP) if needed]. 
• Refer to the FDA Guidance for Industry on pre-marketing clinical evaluation for 
drug-induced liver injury (https://www.fda.gov/media/116737/download) for additional 
guidance on assessment of etiology. 


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APPENDIX B. ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS 
Further Details and Clarifications on the AE Definition 
The following events are NOT considered Adverse Events 
• Stable chronic conditions that are present prior to clinical trial entry and do not worsen. 
These will be accounted for in the subject’s medical history. 
• Laboratory values that are abnormal but not of clinical significance. This includes a 
laboratory re-test and/or continued monitoring of an abnormal value. In addition, 
repeated or additional noninvasive testing for verification, evaluation or monitoring of a 
laboratory or ECG abnormality is not considered an AE. 
• Medical or surgical procedures (e.g., surgery, endoscopy, tooth extraction, or 
transfusion); the condition that leads to the procedure is an AE 
• Situations where an untoward medical occurrence has not occurred (e.g., hospitalizations 
for cosmetic surgery or elective surgery or social/convenience admissions) 


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APPENDIX C. PHQ-9 DEPRESSION SCALE 



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