To Assess the Safety, Tolerability and Pharmacokinetics of ACH-000029 in Healthy Subjects

Study Overview
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Brief Summary
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Randomized single ascending dose placebo controlled treatment of ACH-000029 administered orally via capsule in healthy volunteers.

Detailed Description
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This study will be conducted in up to 3 dosing groups of 8 total subjects each. The purpose of this trial is to determine the safety and tolerability of a single dose of ACH-000029 or placebo.

Official Title
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A Phase 1, Single-center, Placebo-controlled, Double-blind, Randomized Trial to Assess the Safety, Tolerability, and Pharmacokinetics of Single Ascending Oral Doses of ACH-000029 in Healthy Subjects

Conditions
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Healthy Volunteers

Intervention / Treatment
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* Drug: ACH-000029
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Healthy male or non-childbearing potential female. Surgically sterile male and female. Exclusion Criteria: Breastfeeding female subjects. Clinical abnormal past medical history. History of drug and/or alcohol abuse within 2 years prior to screening. History of or current hepatitis or acquired immunodeficiency syndrome or carriers of hepatitis B surface antigen and/or anti-hepatitis C virus antibodies, or human immunodeficiency virus (HIV) antibodies. History of any significant drug allergy or known or suspected hypersensitivity. A positive urine or breath alcohol test and/or urine drug screen for substances of abuse at screening or upon admission to the trial site (Day -1). Subjects having taken an investigational drug within 30 days prior to screening or a biological investigational product within 30 days or 5 half-lives (whichever is longer) preceding screening, except the last dose of severe acute respiratory syndrome coronavirus (SARS-CoV-2 [COVID-19]) vaccine, which must be administered at least 7 days prior to screening. Any history of significant bleeding or hemorrhagic tendencies. Any history of difficulty in donating blood. The donation of blood or plasma within 30 days prior to the first dose of IMP. Use of prescription, over-the-counter, or herbal medications or vitamin supplements within 14 days prior to the first dose of IMP and oral antibiotics within 30 days prior to the first dose of IMP. Use of tobacco products or daily exposure to second-hand smoke within 2 months prior to the screening visit. Presenting with, or having a history of, uncontrolled hypertension (SBP > 140 mmHg or DBP > 90 mmHg) or symptomatic hypotension, or orthostatic hypotension, which is defined as a decrease of ≥ 30 mmHg in SBP or a decrease of ≥ 20 mmHg in DBP after at least 3 minutes of standing compared with the previous supine BP, OR development of symptoms. Supine HR, after resting for at least 3 minutes, outside the range of 50 to 90 bpm. Abnormal ECG findings at screening or check-in. History of unexplained syncope, where orthostatic likely event. Personal or family history of sudden death or long QT syndrome. History of serious mental disorders that, in the opinion of the investigator, would exclude the subject from participating in this trial. No permanent place of residence. Subjects with active suicidal ideation prior to dosing.

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: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: SAD Cohorts 1 to 3 - Participants Receiving ACH-000029<br>Each SAD cohort participant will be randomized to receive 10mg for cohort 1; up to 30mg and up to 60mg for cohorts 2 and 3 respectively dependent on dose review committee. | Drug: ACH-000029<br>* ACH-000029 will be administered orally via a capsule.<br>|
| Placebo Comparator: SAD Cohorts 1 to 3 - Participants Receiving Placebo<br>Each SAD cohort participant will be randomized to receive placebo on a ratio of 3:1 (active: placebo). | Drug: Placebo<br>* Placebo will be administered orally via a capsule.<br>* Other names: Matching Placebo;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number (%) of subjects experiencing orthostatic hypotension at any timepoint | Orthostatic assessment will be with the criteria ≥ 20 mmHg decrease in SBP and a > 25 bpm increase in HR from supine to standing. | Screening (Days -28 to Day -2) to end of treatment Day 7 | 
| Maximum change in timepoint-matched systolic blood pressure and diastolic blood pressure. |  | Screening (Days -28 to Day -2) to end of treatment Day 7 | 
| Maximum change in timepoint-matched resting heart rate. |  | Screening (Days -28 to Day -2) to end of treatment Day 7 | 
| Assessment of abnormal clinical laboratory tests (Hemoglobin & mean corpuscular hemoglobin concentration) |  | Screening (Days -28 to Day -2) to end of treatment Day 7 | 
| Assessment of abnormal clinical laboratory tests (Hematocrit) |  | Screening (Days -28 to Day -2) to end of treatment Day 7 | 
| Assessment of abnormal clinical laboratory tests (Mean corpuscular volume) |  | Screening (Days -28 to Day -2) to end of treatment Day 7 | 
| Assessment of abnormal clinical laboratory tests (RBC count) |  | Screening (Days -28 to Day -2) to end of treatment Day 7 | 
| Assessment of abnormal clinical laboratory tests (WBC count (absolute and differential)) |  | Screening (Days -28 to Day -2) to end of treatment Day 7 | 
| Assessment of abnormal clinical laboratory tests (Platelets) |  | Screening (Days -28 to Day -2) to end of treatment Day 7 | 
| Assessment of abnormal clinical laboratory tests (Mean platelet volume) |  | Screening (Days -28 to Day -2) to end of treatment Day 7 | 
| Assessment of abnormal clinical laboratory tests (Anion gap, bicarbonate, calcium, chloride, cholesterol, glucose, magnesium, potassium, sodium, creatinine, uric acid, triglycerides, urea) |  | Screening (Days -28 to Day -2) to end of treatment Day 7 | 
| Assessment of abnormal clinical laboratory tests (Lactate Dehydrogenase (LDH), Alanine Transaminase (ALT), gamma-glutamyl transferase (GGT), Alkaline phosphatase (ALP) , aspartate aminotransferase (AST), phosphatase, creatinine phosphokinase) |  | Screening (Days -28 to Day -2) to end of treatment Day 7 | 
| Assessment of abnormal clinical laboratory tests (Albumin) |  | Screening (Days -28 to Day -2) to end of treatment Day 7 | 
| Assessment of abnormal clinical laboratory tests (Glomerular filtration rate) |  | Screening (Days -28 to Day -2) to end of treatment Day 7 | 
| Assessment of abnormal clinical laboratory tests (Globulin) |  | Screening (Days -28 to Day -2) to end of treatment Day 7 | 
| Assessment of abnormal clinical laboratory tests (Total bilirubin) |  | Screening (Days -28 to Day -2) to end of treatment Day 7 | 
| Assessment of abnormal clinical laboratory tests (Total protein) |  | Screening (Days -28 to Day -2) to end of treatment Day 7 | 
| Coagulation | Blood sample assessments will include activated partial thromboplastin time, prothrombin time-international normalized ratio. | Screening (Days -28 to Day -2) to end of treatment Day 7 | 
| Assessment of abnormal Urinalysis (Bilirubin, blood, glucose, ketones, nitrites, protein) |  | Screening (Days -28 to Day -2) to end of treatment Day 7 | 
| Assessment of abnormal Urinalysis (Leukocyte esterase) |  | Screening (Days -28 to Day -2) to end of treatment Day 7 | 
| Assessment of abnormal Urinalysis (Microscopic analysis) |  | Screening (Days -28 to Day -2) to end of treatment Day 7 | 
| Assessment of abnormal Urinalysis (pH) |  | Screening (Days -28 to Day -2) to end of treatment Day 7 | 
| Assessment of abnormal Urinalysis (Specific gravity) |  | Screening (Days -28 to Day -2) to end of treatment Day 7 | 
| Assessment of abnormal Vital signs (temperature) | Temperature will be assessed after subject has been in supine position for at least 3 minutes. | Screening (Days -28 to Day -2) to end of treatment Day 7 | 
| Assessment of abnormal Vital signs (respiratory rate) | Respiratory rate will be assessed after subject has been in supine position for at least 3 minutes. | Screening (Days -28 to Day -2) to end of treatment Day 7 | 
| Assessment of abnormal Vital signs (blood pressure) | Blood pressure will be assessed in supine and standing positions in each position for at least 3 minutes. | Screening (Days -28 to Day -2) to end of treatment Day 7 | 
| Assessment of abnormal Vital signs (heart rate) | Heart rate will be assessed in supine and standing positions in each position for at least 3 minutes. | Screening (Days -28 to Day -2) to end of treatment Day 7 | 
| Assessment of Physical examinations (height) |  | Screening (Days -28 to Day -2) to end of treatment Day 7 | 
| Assessment of Physical examinations (weight) |  | Screening (Days -28 to Day -2) to end of treatment Day 7 | 
| Assessment of Physical examinations (BMI) |  | Screening (Days -28 to Day -2) to end of treatment Day 7 | 
| Assessment of Physical examinations | Subjects will be visually assessed for any abnormalities with head, eyes, ears, nose and throat; thorax; abdomen; urogenital; skin and mucosae. | Screening (Days -28 to Day -2) to end of treatment Day 7 | 
| Assessment of Neurological examinations | Subjects will be assessed for any abnormalities and evaluated for mental status, cranial nerves, motor system, reflexes, sensory system, coordination and station and gait. | Screening (Days -28 to Day -2) to end of treatment Day 7 | 
| 12-lead ECG assessment of PR interval | Change in electrocardiograms | Screening (Days -28 to Day -2), Day -1, Day 1, Day 2, Day 4 and end of treatment Day 7 | 
| 12-lead ECG assessment of QRS duration | Change in electrocardiograms | Screening (Days -28 to Day -2), Day -1, Day 1, Day 2, Day 4 and end of treatment Day 7 | 
| 12-lead ECG assessment of QT interval | Change in electrocardiograms | Screening (Days -28 to Day -2), Day -1, Day 1, Day 2, Day 4 and end of treatment Day 7 | 
| 12-lead ECG assessment of QTc | Change in electrocardiograms | Screening (Days -28 to Day -2), Day -1, Day 1, Day 2, Day 4 and end of treatment Day 7 | 
| C-SSRS | Subjects will be interviewed to capture the occurrence, severity and frequency of suicide-related thoughts and behaviors. | Screening (Days -28 to Day -2) to end of treatment Day 7 | 
| Monitoring of adverse events | Any untoward medical occurrence in a subject, whether considered related to the treatment or not. | Screening (Days -28 to Day -2) to end of treatment Day 7 | 
| Pharmacokinetic assessment 1 | Peak Plasma Concentration (Cmax) | Day 1 to end of treatment Day 7 | 
| Pharmacokinetic assessment 2 | Time of peak plasma concentration (Tmax) | Day 1 to end of treatment Day 7 | 
| Pharmacokinetic assessment 3 | Area under the concentration-time curve calculated to the last observable concentration at time (AUCt) | Day 1 to end of treatment Day 7 | 
| Pharmacokinetic assessment 4 | Area under the concentration-time curve from zero to infinity (AUC∞) | Day 1 to end of treatment Day 7 | 
| Pharmacokinetic assessment 5 | Apparent clearance of the drug normalized to body weight (CL/F) | Day 1 to end of treatment Day 7 | 
| Pharmacokinetic assessment 6 | Apparent clearance of the drug normalized to body weight (CL/F) | Day 1 to end of treatment Day 7 | 
| Pharmacokinetic assessment 7 | Terminal-phase elimination half-life (t1/2,z) | Day 1 to end of treatment Day 7 | 
| Pharmacokinetic assessment 8 | Cmax normalized to dose (Cmax/Dose) | Day 1 to end of treatment Day 7 | 
| Pharmacokinetic assessment 9 | Cmax normalized to dose (Cmax/Dose) | Day 1 to end of treatment Day 7 | 
| Pharmacokinetic assessment 10 | AUCt normalized to dose (AUCt/Dose) | Day 1 to end of treatment Day 7 | 
| Pharmacokinetic assessment 11 | AUC∞ normalized to dose (AUC∞/Dose) | Day 1 to end of treatment Day 7 |