A Phase 1 Study Investigating the Safety, Tolerability and Pharmacokinetics of KNX100 in Healthy Volunteers

Study Overview
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Brief Summary
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The primary objectives of this study are to evaluate the safety and tolerability of KNX100 administered orally as a single and multiple ascending doses in healthy volunteers.

Detailed Description
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This is an adaptive, Phase 1, first-in-human (FIH), single treatment, double blind, placebo controlled, randomized, single and multiple ascending dose study of KNX100 administered to healthy volunteers. Approximately 64 male and female healthy subjects will be enrolled into this study. Healthy subjects who meet all the eligibility criteria will be randomly assigned to Cohorts 1-5 for the Single Ascending Dose and Cohorts 1-3 for the Multiple Ascending Dose. Each cohort will evaluate 8 subjects; 6 subjects will receive KNX100 (study drug) and 2 subjects will receive placebo. Each cohort will be enrolled sequentially, and dose escalation decisions will be made according to protocol by the Cohort Review Committee (CRC) consisting of the investigators and medical monitor. Subjects and clinical staff will be blinded to therapy assignment. KNX100 will be provided in capsule form as 5, 25 and 100 mg capsules for oral administration and the dose range will be 5 to 50mg.

Official Title
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A Phase 1 Study Investigating the Safety, Tolerability and Pharmacokinetics of KNX100 in Healthy Volunteers

Conditions
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Healthy Volunteer Study, Opioid-use Disorder

Intervention / Treatment
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* Drug: KNX100


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Ability to understand and provide written informed consent. Body mass index (BMI) within the range of 18-32 (inclusive). Healthy male and female volunteers ≥18 and ≤55 years old at Screening. Able and willing to comply with the requirements of the study and complete the full sequence of protocol related doses, procedures, and evaluations. Willing to agree not to use alcohol or recreational drugs and willing to have drug screening, prior to the first dose of KNX100 and if drug use is suspected while active in the study. Willing to agree not to smoke cigarettes or use tobacco based products prior to the first dose of KNX100 and for the entire duration of the study. Males who are sexually active must use a condom OR be abstinent OR have the same sex partner OR be surgically sterile OR have partner who is of non-childbearing potential, for at least 90 days after the last dose of investigational drug. If female partner is a Woman of Child-Bearing Potential (WOCBP), the female partner must use highly effective methods of contraception, defined as below: Hormonal methods of contraception including oral contraceptives containing combined estrogen and progesterone, a vaginal ring, injectable and implantable hormonal contraceptives, intrauterine hormone-releasing system (e.g., Mirena) and progestogen-only hormonal contraception associated with inhibition of ovulation. Nonhormonal intrauterine device, Bilateral tubal occlusion. Exclusion Criteria: Clinically significant history or presence of significant cardiovascular, respiratory, hepatic, renal, gastrointestinal, endocrinological, hematological, neurological, or psychiatric disorder. Any surgical or medical history which may significantly alter the absorption, metabolism, or elimination of drugs or constitute a risk when taking the study intervention; or interfering with the interpretation of data (e.g., gastric bypass, cyclical vomiting, etc.). This includes a history of lymphoma, leukemia, or any malignancy within 5 years except for basal cell or squamous epithelial carcinomas of the skin that have been resected with no evidence of metastatic disease for 3 years. Subjects who have a sitting or semi-supine blood pressure at screening or Day-1, after resting for at least 3 minutes of systolic blood pressure >140 or <100 mmHg, or diastolic blood pressure >90 or <60 mmHg. Subjects who have a sitting or semi-supine pulse rate at screening or Day-1, after resting for at least 3 minutes, outside the range of <50 or >90 beats/minute Subjects who donated blood or who had a comparable blood loss (approximately 500 mL) during the last 30 days prior to start of this study and while on study. Clinically significant findings on the screening, Day -1, or predose Day 1 electrocardiogram (ECG) or physical examination, including QTcF duration >450 ms for males and >470 ms for females on ECG. Thyroid function tests outside the normal reference ranges and deemed clinically significant by the study PI (and upon repeat). Safety laboratory tests that are outside the normal reference ranges and deemed clinically significant by the study PI (and upon repeat). Any history of meningitis, septicemia, or pneumonia. Any history or family history (first or second degree relative) of seizure disorder, febrile convulsions. Any clinically significant medical history of closed head trauma. Any history of anaphylaxis or other significant allergy. Any current diagnosis or clinically significant medical history of psychiatric illness as diagnosed and documented by a medical practitioner and as defined by the American Psychiatric Association Diagnostic and statistical manual of mental disorders 5th edition (DSM-5). Subjects with a history of chronic alcohol (regular daily intake of more than three standard drinks) or drug abuse within the last 6 months prior to first administration, or evidence of such abuse as indicated by the laboratory profile conducted during the screening examination. Subjects who have received prescription drugs or over-the-counter (OTC) medication including dietary supplements, COVID-19 vaccine, standard dose vitamins, or herbal products within 14 days prior to the first administration (with the exception of the oral contraceptive pill). Subjects who received any treatment agents known to alter the major organs or systems within 30 days prior to the first administration (e.g., diuretics, nephro- or liver toxic medication, barbiturates, phenothiazines, cimetidine, more than 1.0 L of caffeine-containing beverages per day, etc.). Diagnosed infection of any kind, e.g., viral, bacterial, fungal, or mycobacterial within 1 month prior to the first dose of KNX100 or current fever or clinical signs or symptoms of infection at screening or Day -1. Treatment with an unapproved investigational therapeutic agent within 30 days (or 5 half-lives for small molecule agents) prior to the first dose of KNX100. Females who are pregnant (positive pregnancy test at screening or prior to first dose), lactating or unable/unwilling to use defined methods of contraception throughout the study.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: Dosing will be based on the assigned treatment group. The single ascending dose cohorts will evaluate doses of KNX100 starting with 25 mg and increasing up to a maximum of 50 mg per day. The multiple ascending dose cohorts will evaluate a low-, mid-, and high-dose KNX100 administered for 7 consecutive days. Individual doses will be dispensed by unblinded site pharmacy staff. Dose escalation will progress upon Cohort Review Committee (CRC) approval.
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Active<br>KNX100 which will be provided in capsule form as 5, 25 and 100 mg capsules for oral administration. Study drug will be encapsulated in hydroxypropyl methylcellulose (HPMC) dark green opaque size 0 capsules and packaged in 100 mL high density polyethylene (HDPE) bottles with polypropylene (PP) twist-off closures. | Drug: KNX100<br>* KNX100 will be provided in capsule form as 5, 25 and 100 mg capsules for oral administration. Study drug will be encapsulated in hydroxypropyl methylcellulose (HPMC) dark green opaque size 0 capsules and packaged in 100 mL high density polyethylene (HDPE) bottles with polypropylene (PP) twist-off closures.<br>* Other names: KNX100 placebo;|
| Placebo Comparator: Placebo<br>KNX100 matching placebo will be provided in capsule form for oral administration. The placebo will be encapsulated in HPMC dark green opaque size 0 capsules and packaged in 100 mL HDPE bottles with PP twist-off closures. | Drug: KNX100<br>* KNX100 will be provided in capsule form as 5, 25 and 100 mg capsules for oral administration. Study drug will be encapsulated in hydroxypropyl methylcellulose (HPMC) dark green opaque size 0 capsules and packaged in 100 mL high density polyethylene (HDPE) bottles with polypropylene (PP) twist-off closures.<br>* Other names: KNX100 placebo;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from Baseline to safety parameters | • Spontaneously reported or observed AEs | From Time of Consent to Follow Up Visit (38 days) | 
| Change from Baseline to safety parameters | Spontaneously reported or observed AEs | From Time of Consent to Follow Up Visit (44 days) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of Treatment Emergent Adverse Events (TEAE's) in subjects treated with KNX100 as compared to placebo | Proportion of subjects discontinuing due to Adverse Events (AE's). | From Time of Consent to Follow Up Visit (38 and 44 days) | 
| Pharmacokinetics properties of KNX100 | • Maximum observed concentrations (Cmax). | From Time of Consent to Follow Up Visit (38 and 44 days) | 
| Pharmacokinetics properties of KNX100 | Area under the concentration-time curve from time zero to last quantifiable concentration (AUC0-t). | From Time of Consent to Follow Up Visit (38 and 44 days) | 
| Pharmacokinetics properties of KNX100 | Area under the concentration-time curve from time zero to infinity (AUC0). | From Time of Consent to Follow Up Visit (38 and 44 days) | 
| Proportion of Treatment Emergent Adverse Events (TEAE's) in subjects treated with KNX100 as compared to placebo | • Maximum Tolerated Dose (MTD) of KNX100. | From Time of Consent to Follow Up Visit (38 and 44 days) |