| Eligibility |
Inclusion Criteria:
1. Understand the trial procedures and agree to participate by providing written informed
consent.
2. Be willing and able to comply with all trial procedures and restrictions, including
following study diet requirements.
3. Be between 18 to 70 years of age, inclusive, at the Screening Visit.
4. Has T2DM in accordance with American Diabetes Association (ADA) guidelines at the
Screening Visit.
5. Is on stable metformin monotherapy (total daily dose of 1,000 to 2,000 mg/day) for at
least 3 months and tolerating metformin well in the opinion of the investigator. Note:
Both the immediate release (IR) and extended release (XR) formulations of metformin
are acceptable.
6. HbA1c of =7.5% at Screening.
7. Have a Body Mass Index (BMI) =25.0 and <40.0 (kg/m2) at the Screening Visit.
8. Be weight stable (<5% variation) over the last 3 months, by subject report.
9. Be a nonsmoker who has not used tobacco or nicotine-containing products (e.g. nicotine
patch, e-cigarettes, vapes) for at least 3 months before administration of the initial
dose of trial drug and agrees to abstain from smoking tobacco or the use of
nicotine-containing products while on study.
10. Be judged to be in generally good health by the Investigator, based on clinical
evaluations including laboratory safety tests, medical history, physical examination,
12-lead ECG, and vital sign measurements performed at the Screening Visit and before
administration of the initial dose of trial drug.
11. Meet the following requirements:
1. 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, including 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
2. 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 as established for the laboratory
performing the test.
- Post hysterectomy, bilateral oophorectomy or bilateral salpingectomy, based
on the subject's recall of their medical history.
OR
3. 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. 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.
Exclusion Criteria:
1. Has participated in another interventional investigational study within 30 days of the
Screening Visit. The window will be derived from the date of the last study procedure
and/or AE related to the study procedure in the previous study to the Screening Visit
of the current study. If the subject received an investigational medication in the
prior study, at least 5 half-lives (or longer if required by local regulations) must
have passed between the last dose of the investigational product and the Screening
Visit.
2. Is an employee or immediate family member (e.g., spouse, parent, child, sibling) of
the Sponsor or study site.
3. Has a history of multiple significant and/or any severe allergies (eg, food, drug,
latex allergy) or has had an anaphylactic reaction or significant intolerance to
prescription or nonprescription drugs or food.
4. Has a known hypersensitivity or contraindication to any component of K-757, K-833,
including excipients.
5. Has a positive alcohol or drug screen at Screening or admission.
6. Has a positive pregnancy test.
7. Is a lactating/nursing female.
8. Has a positive test result for hepatitis B surface antigen (Ag), hepatitis C virus
antibody, or human immunodeficiency (HIV) antibody, at the Screening Visit. Note:
Subjects 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.
9. Does not meet study site COVID-19 admission/study participation restrictions.
10. Has a fever (>38°C)*
11. Had major surgery or donated or lost 1 unit of blood (approximately 500 mL) within 4
weeks prior to the Screening Visit*
12. Is unable to refrain from the use of prohibited prescription or non-prescription drugs
including vitamins, herbal and dietary supplements (including St John's Wort) within 7
days (or 14 days if the drug is a potential enzyme inducer) or 5 half-lives (whichever
is longer) prior to the first dose of study medication through completion of study
participation.
13. Allowable concomitant medications may include 3-hydroxy-3-methylglutaryl coenzyme A
(HMG-CoA) reductase inhibitors (statins), =2 permissible anti-hypertensive agents,
postmenopausal hormone replacement therapy (HRT), and/or proton pump inhibitors
(PPIs).
14. Has been on any GLP-1 receptor agonist, any dipeptidyl peptidase IV (DPP-4) inhibitor,
or any approved or investigational medications known to cause weight loss in the prior
3 months.
15. Has a history of type 1 diabetes mellitus (T1DM) or a history of diabetic ketoacidosis
or subject assessed by the investigator as possibly having T1DM.
16. Has a history of other specific types of diabetes (e.g. genetic syndromes, secondary
pancreatic diabetes, diabetes due to endocrinopathies, drug- or chemical-induced, and
post organ transplant diabetes).
17. Has been treated with insulin or any other anti-hyperglycemic agents (AHAs) other than
metformin within 4 weeks of screening or within 12 weeks of screening if the AHA was a
thiazolidinedione (e.g., rosiglitazone, pioglitazone).
18. At Screening or Day 1 has a site fasting fingerstick glucose of >270 mg/dL. If the Day
-1 fasting fingerstick glucose is >270 mg/dL, a re-test may be conducted the morning
of Day1 in fasted state prior to randomization. If the result is =270 mg/dL, the
subject may be randomized if all other entry criteria are met.
19. Has evidence or history of diabetic complications or significant end organ damage, eg,
proliferative retinopathy and/or macular edema, eGFR Modification of Diet in Renal
Disease (MDRD) =60 mL/min, diabetic neuropathy.
20. One or more self-reported episodes of hypoglycemia (fingerstick glucose <60 mg/dL with
symptoms consistent with hypoglycemia or <50 mg/dL irrespective of symptoms) within
the last 3 months.
21. Is using or anticipates the need for using concomitant medications which are
inhibitors of P-glycoprotein (P-gp) or breast cancer resistance protein (BCRP) or any
prohibited medications listed in Section 10.1 from screening until the post study
visit.
22. 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 any 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.
23. Is unwilling or unable to refrain from consuming alcohol from 7 days prior to the
first dose of study medication through the completion of study participation.
24. Has a substance abuse disorder.
25. Had a previous major psychotic disorder.
26. Has a corrected QT interval to Fridericia's formula (QTcF) >450 milliseconds (msec)
for males and >470 msec for females at screening or admission.
27. Has a mean value for triplicate semi-recumbent systolic blood pressure >160
millimeters of mercury (mmHg) and/or diastolic blood pressure (BP) >95 mmHg measured
after at least 10 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, to qualify for the study.
If a subject's BP is exclusionary at screening but the investigator feels that BP is
likely to be below the exclusionary thresholds at admission (Day -1), this criterion
can be re-assessed at admission. Adjustment of doses of anti-hypertensives already
being taken at screening is permissible, but initiation of new agents is not
permissible. For subjects whose BP is exclusionary at Screening and at the first
triplicate assessment on Day -1, triplicate assessments can be repeated up to twice on
Day -1, as needed.
Triplicate assessments should occur after a rest of at least 10 min. Also, the first
measurement of any triplicate assessment should be separated from the last measurement
in a prior triplicate assessment by at least 10 minutes.
28. Has alanine aminotransferase or aspartate aminotransferase (ALT or AST) of >1.5X upper
limit of normal (ULN) or total bilirubin >1.5X ULN (isolated bilirubin >1.5 ULN is
acceptable if bilirubin is fractionated and direct bilirubin is within the laboratory
normal range) at Screening or admission. (Note: Subjects who do not meet this
criterion at Screening or at admission may not be rescreened/retested).
29. Has serum amylase or lipase >1.2X the ULN at the Screening Visit.
30. Has a recent history (within past 3 years) or current diagnosis of any of the
following GI (gastro-intestinal) related diseases: intestinal obstruction, GI
perforation, GI motility disorders, adhesions, Clostridium difficile colitis or have
had recent unexplained GI bleeding within 3 months prior to screening.
31. Has any history of pancreatitis (acute or chronic), gastroparesis, ischemic colitis,
inflammatory bowel disease (IBD), celiac disease, irritable bowel syndrome (IBS), or
colitis.
32. Has any past surgical history of gastric banding or bariatric surgery or bowel
resection.
33. Has a history of clinically significant endocrine, gastrointestinal, cardiovascular,
hematological, hepatic, immunological, renal, respiratory, neurologic disorder,
neoplastic, or genitourinary abnormalities or diseases.
34. Has a history of any illness that, in the opinion of the study investigator, might
confound the results of the study or poses an additional risk to the subject by their
participation in the study.
note* Subject may be included if they are able to return to the site within 7 days of
initial screening and the exclusion criterion is no longer met.
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