Safety, Tolerability, and Pharmacokinetics of ASCT-83 in Healthy Adults

Официальное название

A Phase 1, First-in-human, Randomized, Double-blind, Placebo-controlled, Single and Multiple Ascending Dose Study to Assess the Safety, Tolerability, and Pharmacokinetics of ASCT-83 Subcutaneous Injection in Healthy Adults

Обзор

The goal of this clinical trial is to learn if ASCT-83 is safe and well-tolerated and measure how ASCT-83 is absorbed, distributed, and eliminated from the body over time. The study will be conducted in healthy adults. The main questions this study will answer are: * Is ASCT-83 safe at clinical doses? * Does ASCT-83 have side effects at clinical doses? * How is ASCT-83 absorbed, distributed, and eliminated from the body? Researchers will compare ASCT-83 to a placebo (a look-alike substance that contains no drug). The study has two parts: participants in Part 1 will receive only one dose of ASCT-83 or placebo participants in Part 2 will receive one dose of ASCT-83 or placebo a day for 7 days. Participants will visit the clinic to take ASCT-83 or placebo, to receive health checkups and undergo health tests. Participants in Part 1 will spend 5 days/4 nights in the clinic, participants in Part 2 will spend 11 days/10 nights in the clinic. In addition, there will be up to 3 outpatient visits. The results of this study will help determine safe dose levels and support the design of future clinical trials.

Подробное описание

Seventy-two healthy participants will be randomized to the following groups:

* Part 1, Single Ascending Dose (SAD): Healthy adult participants (age 18-64, inclusive) will be enrolled in 6 dose cohorts: 0.5 mg, 1 mg, 2 mg, 4 mg, 7.5 mg, or 10 mg. Each cohort consists of 8 participants (6 ASCT-83, 2 placebo), totaling 48 participants. * Part 2, Multiple Ascending Dose (MAD): 3 dose cohorts of 8 participants each (6 ASCT-83, 2 placebo), totaling 24 participants. Dosing and regimens for Part 2 will be determined following review of SAD data by the Data Safety Monitoring Committee (DSMC).

All doses (ASCT-83 or placebo) will be administered as two subcutaneous (SC) injections (arm or thigh), with the second injection occurring within 10 minutes of the first.

The first two participants in every cohort - one administered ASCT-83 and one administered placebo - will be the sentinel participants. In every cohort, the two sentinel participants must be observed for 72 hours before the rest of the cohort is dosed.

The maximum dose escalation increment between any two cohorts will be two-fold. The maximum daily dose will not exceed the maximum tolerated dose established in the SAD study.

Additional cohorts may be recruited based on the emerging safety, tolerability, and PK data.

Вмешательства

• Препарат ASCT-83
  ASCT-83 is a 23-amino acid, macrocyclic peptide with a molecular weight of approximately 3 kilodaltons under development for the treatment of neuropathic pain (NeP). ASCT-83 25 mg/mL sterile solution for injection consists of 25 mg of ASCT-83 drug substance dissolved in 1 mL of histidine buffer. The product also contains mannitol to adjust the osmolarity of the final product. The product is stored at -20°C prior to dilution to achieve the target dose.
• Препарат Placebo
  Placebo solution contaninig the same histidine buffer and mannitol concentrations as ASCT-83, with polyoxyl 35 castor oil (0.1% w/v) added to match the appearance of the active solution.

Первичные конечные точки

• Incidence, severity and dose relationships of Treatment-Emergent Adverse Events (TEAEs) and non-TEAEs, Adverse Events of Special Interest (AESIs), Serious Adverse Events (SAEs), premature treatment and study discontinuation due to Adverse Events (AEs) [Срок оценки: Single dose part of the study: from enrollment to 30-32 days after the end of treatment. Multiple dose part of the study: from enrollment to 36-38 days after the end of treatment.]
• Incidence and severity of changes in clinical safety parameters, including vital signs (including body weight), laboratory (including markers of inflammation), ECG results, and skin assessments (including injection site reactions). [Срок оценки: Single dose part of the study: from enrollment to 30-32 days after the end of treatment. Multiple dose part of the study: from enrollment to 36-38 days after the end of treatment.]
• Incidence of suicidality [Срок оценки: Single dose part of the study: from enrollment to 30-32 days after the end of treatment. Multiple dose part of the study: from enrollment to 36-38 days after the end of treatment.]
• Incidence and type of abnormal skin assessments, including injection-site reactions. [Срок оценки: Single dose part of the study: from enrollment to 30-32 days after the end of treatment. Multiple dose part of the study: from enrollment to 36-38 days after the end of treatment.]

Вторичные конечные точки (11)

• Area under the concentration-time curve from time zero to infinity (AUC0-inf) of ASCT-83 [Срок оценки: SAD: pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48, 72 hours post-dose. MAD: pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24 hours post-dose on Day 1; pre-dose on Days 3 to 7; 24, 36, 48, and 72 hours after the final dose on Day 7]
• Area under the concentration-time curve from time zero to 24 h (AUC0-24h) of ASCT-83 [Срок оценки: SAD: pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48, 72 hours post-dose. MAD: pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24 hours post-dose on Day 1; pre-dose on Days 3 to 7; 24, 36, 48, and 72 hours after the final dose on Day 7]
• Peak plasma concentration (Cmax) of ASCT-83 [Срок оценки: SAD: pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48, 72 hours post-dose. MAD: pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24 hours post-dose on Day 1; pre-dose on Days 3 to 7; 24, 36, 48, and 72 hours after the final dose on Day 7]
• Time to reach maximum plasma concentration (Tmax) of ASCT-83 [Срок оценки: SAD: pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48, 72 hours post-dose. MAD: pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24 hours post-dose on Day 1; pre-dose on Days 3 to 7; 24, 36, 48, and 72 hours after the final dose on Day 7]
• Terminal elimination half-life (t½) of ASCT-83 [Срок оценки: SAD: pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48, 72 hours post-dose. MAD: pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24 hours post-dose on Day 1; pre-dose on Days 3 to 7; 24, 36, 48, and 72 hours after the final dose on Day 7]
• Apparent clearance (CL/F) of ASCT-83 [Срок оценки: SAD: pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48, 72 hours post-dose. MAD: pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24 hours post-dose on Day 1; pre-dose on Days 3 to 7; 24, 36, 48, and 72 hours after the final dose on Day 7]
• Apparent volume of distribution (Vz/F) of ASCT-83 [Срок оценки: SAD: pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48, 72 hours post-dose. MAD: pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24 hours post-dose on Day 1; pre-dose on Days 3 to 7; 24, 36, 48, and 72 hours after the final dose on Day 7]
• Amount of ASCT-83 excreted in urine [Срок оценки: Pre-dose, then at 0-4 hours, 4-8 hours, 8-12 hours, 12-24 hours, 24-36 hours, 36-48 hours, 48-60 hours, 60-72 hours post-dose.]
• Fraction of ASCT-83 excreted in urine unchanged [Срок оценки: Pre-dose, then at 0-4 hours, 4-8 hours, 8-12 hours, 12-24 hours, 24-36 hours, 36-48 hours, 48-60 hours, 60-72 hours post-dose.]
• Renal clearance (CLR) of ASCT-83 [Срок оценки: Pre-dose, then at 0-4 hours, 4-8 hours, 8-12 hours, 12-24 hours, 24-36 hours, 36-48 hours, 48-60 hours, 60-72 hours post-dose.]
• Incidence of anti-drug antibodies (ADA) and titers (in ADA positive participants). [Срок оценки: Prior to initiation of dosing on Day 1, and on Days 7, 14, 25, 37.]

Критерии участия

Критерии включения

To participate in the study, you must:

• be medically healthy based on medical history, physical exam, labs, and ECG
• be 18-64 years (inclusive)
• at screening, have a body mass index (BMI) > 19 to < 35 kg/m²
• be willing and able to understand and voluntarily sign an informed consent
• Female participants of childbearing potential (women who can become pregnant) must:

• agree to follow the study contraceptive requirements from screening through 28 days after the final dose of study drug.
• agree to undergo pregnancy testing, including a negative pregnancy test at screening and at admission.
• agree not to donate ova (eggs) from screening through 28 days after the final dose of study drug.
• Male participants must:

• have a vasectomy greater than 6 months prior to screening or be willing to follow the contraceptive requirements from screening through 90 days after final study drug administration
• agree to be willing to abstain from sperm donation from screening through 90 days after final study drug administration

Критерии исключения

You cannot participate in the study if you:

• are a study site staff, Alcamena employee or immediate family member, or have participated in another clinical trial within 30 days or 5 half-lives of a prior investigational product.
• have evidence of liver disease or abnormal liver tests (ALT/AST, Alk Phos, GGT, or bilirubin > ULN); positive hepatitis B or C serology (people with Gilbert syndrome may be included).
• have a history of kidney disease, protein in the urine or reduced kidney function based on screening blood tests.
• have a history of cancer with active disease, suspected relapse, treatment within 6 months, or ongoing therapy affecting immune, liver, or kidney function.
• have a history of heart disease, including abnormal heart rhythm, heart attack, long QT syndrome, or abnormal heart rhythm findings on screening ECG, or a family history of sudden unexplained death.
• are currently receiving medications that affect or suppress the immune system, including steroids given by any route.
• have a known autoimmune condition (such as lupus, rheumatoid arthritis, sarcoidosis, or vitiligo), even if it is not being treated.
• have a positive HIV test at screening or a history of immune deficiency.
• have abnormal blood tests suggesting ongoing inflammation
• have an active infection or is currently being treated for an infection.
• have a skin condition that could interfere with study skin assessments (such as psoriasis).
• are allergic or sensitive to the study drug or its ingredients.
• have a history of alcohol or drug abuse or addiction within the past five years, have a positive drug or alcohol test at screening, or have smoked within one month before screening.
• have a serious mental health condition, such as major depression, schizophrenia, severe anxiety, eating disorders, severe attention deficit disorder, personality disorders, or suicidal thoughts or behavior within the past five years that could affect safety or study participation.
• have low blood pressure upon standing, defined as a significant drop in blood pressure when moving from lying down to standing during screening or baseline testing.
• have abnormally low white blood cell counts or neutrophil counts, unless this finding is due to a known benign condition such as benign ethnic neutropenia.

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Да

Дизайн исследования

Распределение

Рандомизированное

Модель

Последовательный дизайн

Маскирование

Тройное слепое

Основная цель

Лечение

Центры проведения

США · 1 центр

• Nucleus Network Minneapolis Clinic — Saint Paul

Идентификаторы

NCT: NCT07363395 · ASCT-83-101 · 1R44NS145934-01 · CDMRP-HT94252510912

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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