None listed
Conditions
Brief summary
DNTH103 is being developed as a potential treatment for autoimmune and inflammatory diseases. This Phase I study will investigate the effects of DNTH103 in healthy participants when given as a single (ascending /SAD) dose subcutaneously (SC) or intravenously (IV) or multiple (ascending/MAD) SC doses. This is a first-in-human, randomised, placebo-controlled, ascending dose study.
Interventions
The study will be conducted in two parts: Part A, the single ascending dose (SAD) portion, and Part B, the multiple ascending dose (MAD) portion. Participants in Part A and Part B will be distinct.
Part A: Up to approximately 72 participants are planned to be enrolled as follows:
• 56 healthy volunteers will be enrolled into seven SAD cohorts, five cohorts receiving study drug as an intravenous (IV) infusion and two receiving study drug as a subcutaneous (SC) injection. Each cohort will enroll
The study will be conducted in two parts: Part A, the single ascending dose (SAD) portion, and Part B, the multiple ascending dose (MAD) portion. Participants in Part A and Part B will be distinct. Part A: Up to approximately 72 participants are planned to be enrolled as follows: • 56 healthy volunteers will be enrolled into seven SAD cohorts, five cohorts receiving study drug as an intravenous (IV) infusion and two receiving study drug as a subcutaneous (SC) injection. Each cohort will enroll 8 participants with 6 participants randomised to receive DNTH103 and 2 participants randomised to receive placebo. The first two subjects dosed in each cohort will be considered sentinel subjects, one each receiving active study drug and placebo. • The study design allows for an intermediate-dose cohort between two previously studied IV and/or SC dose levels . Therefore, one additional IV cohort and one additional SC cohort may be enrolled, each with 8 participants (16 additional participants). Part B: Up to approximately 24 participants are planned to be enrolled as follows: • Up to 16 healthy volunteers will be enrolled into two MAD cohorts; one receiving low dose and one receiving high dose study drug SC. Each cohort will enroll 8 participants with 6 participants randomised to receive DNTH103 and 2 participants randomised to receive placebo. • The study design allows for an additional cohort, with the dose level and route of administration to be reviewed with the Safety Review Committee (SRC). Therefore, a total of 1 additional cohort with 8 participants may be enrolled. Part A cohorts: Single dose DNTH103 or placebo administered on Day 1 (IV or SC) as follows: • SAD IV1, 1 mg/kg • SAD IV2, 3 mg/kg • SAD IV3, 10 mg/kg • SAD IV4, 30 mg/kg • SAD IV5, 60 mg/kg • SAD SC1, 300 mg • SAD SC2, 600 mg An additional two intermediate-dose cohorts may also be added (one IV and one SC cohort), with the dose level to be determined (TBD) based on data from the preceding cohorts. Part B cohorts: DNTH103 or placebo is scheduled to be administered at 2-week intervals on Day 1, Day 15 and Day 29 (total of three doses) as follows: • MAD SC1, 300 mg • MAD SC2, 600 mg The time separation between Part A and Part B is not fixed. Part B will not commence until safety at the higher dose in Part A is determined through an SRC review. An additional cohort may also be added, with the dose level and route of administration TBD based on data from the preceding cohorts. Adherence to intervention will be undertaken via drug accountability.
Sponsors
Dianthus Therapeutics, Inc.
Study design
Allocation
Randomised controlled trial
Intervention model
Parallel
Primary purpose
Treatment
Masking
Blinded (masking used) (Subject, Caregiver)
Eligibility
Sex/Gender
All
Age
18 Years to 65 Years
Healthy volunteers
Yes
Inclusion criteria
1. Adult males and females, 18 to 65 years of age (inclusive) at Screening. 2. Body mass index less than or equal to 32 kg/m2, with a body weight (to 1 decimal place) greater than or equal to 45 kg and less than or equal to 100 kg at Screening. 3. Be non-smokers (including tobacco, e-cigarettes and marijuana) for at least 3 months prior to first study drug administration and have a negative test for cotinine at the Screening visit and at check-in on Day -1. Note: Subjects who smoke no more than 2 cigarettes or equivalent per week may be included in the study but must be willing to abstain from smoking 7 days prior to admission and during the confinement period. Subjects must have a negative test for nicotine prior to check-in on Day -1. 4. Medically healthy without clinically significant abnormalities (in the opinion of the Investigator) at the Screening visit and after check-in on Day -1, prior to dose administration on Day 1, including: a. Physical examination without any clinically significant findings. b. Systolic blood pressure in the range of 90 to 150 mmHg (inclusive) and diastolic blood pressure in the range of 50 to 90 mmHg (inclusive) after 5 minutes rest in a semi-supine position. c. Heart rate (HR) in the range of 40 to 90 bpm (inclusive) after 5 minutes rest in a semi- supine position. d. Body temperature (tympanic) in the range 35.5°C to 37.7°C (inclusive). e. No clinically significant findings in serum chemistry, haematology, coagulation and urinalysis tests as per PI. f. Triplicate 12-lead ECG performed with no clinically significant abnormalities. 5. Female volunteers must: a. Be of nonchildbearing potential i.e., surgically sterilised (hysterectomy, bilateral salpingectomy, bilateral oophorectomy at least 6 weeks before Screening) or postmenopausal (where postmenopausal is defined as no menses for 12 months without an alternative medical cause, and a follicle-stimulating hormone (FSH) level >40 IU/L at the Screening visit), or b. If of childbearing potential, must agree not to donate ova, not to attempt to become pregnant and, if engaging in sexual intercourse with a male partner, must agree to use an acceptable method of contraception from signing the consent form until at least 90 days after the last dose of the study drug. 6. Male volunteers must agree not to donate sperm and, if engaging in sexual intercourse with a female partner who could become pregnant, must agree to use an acceptable method of contraception from signing the consent form until at least 90 days after the last dose of study drug. 7. Previously immunized against encapsulated bacterial pathogens as per country-specific guidelines (Neisseria meningitis, Haemophilus influenza, and Streptococcus pneumonia within past 5 years) or willing and able to be vaccinated during the Screening Period and at least 14 days prior to study drug administration on Day 1. 8. Haematocrit (HCT) and /Haemoglobin (Hb) levels within normal limits for age and sex at Screening and on Day -1, prior to dose administration.
Exclusion criteria
1. History or presence of significant cardiovascular, pulmonary, hepatic, renal, haematological, gastrointestinal, endocrine, immunologic, dermatologic or neurological disease, including any acute illness or major surgery within 3 months prior to screening determined by the PI to be clinically significant. 2. History of autoimmune disease or positive autoantibody test result at Screening. 3. History of active malignancy within 5 years prior to Screening, except basal cell carcinoma of the skin, curatively resected squamous cell carcinoma of the skin, cervical carcinoma in situ curatively treated or low-grade prostate adenocarcinoma for which appropriate management is observation alone. 4. Liver test results during Screening or at check-in day (Day 1) that are elevated more than 1.5-fold above the ULN for gamma glutamyl transferase, bilirubin (total), aspartate aminotransferase (AST) or alanine aminotransferase (ALT), unless a diagnosis of Gilbert syndrome. For history of Gilbert syndrome, the limit is extended to 2-fold above the ULN. The above assessment may be repeated once, if abnormal values were recorded in the first instance, at the discretion of the PI. 5. Positive test results for human immunodeficiency virus (HIV-1 or HIV-2) antibody/antigen, hepatitis B surface antigen (HBsAg) or hepatitis C virus (HCV) antibodies at the Screening visit. Healthy volunteers who have no evidence of cirrhosis, have completed a curative intent regimen for HCV, and deemed by a gastroenterologist to have no active HCV will not be excluded. 6. Estimated creatinine clearance (CrCl) < 60 mL/min during Screening or at check-in day (Day -1) using the Cockcroft-Gault formula or serum creatinine more than 1.5-fold above the ULN. 7. History of substance abuse or alcohol abuse (defined as more than 10 standard drinks per week or regularly consuming more than 4 standard drinks on any one day; within 12 weeks prior to the Screening visit. 8. Positive drugs of abuse or alcohol breath test results at the Screening visit or at check-in (Day -1). 9. Use of any prescription or over-the-counter medication (including herbal products, vitamins, health supplements, diet aids, and hormone supplements) within 2 weeks or 5 half-lives of the medication (whichever is longer) prior to the first study drug administration, except use of contraceptives, occasional use of paracetamol (doses of 500 mg up to every 6 hours or 2 g per day maximum for no more than 3 consecutive days) or where in the opinion of the Investigator, particular use would not interfere with the volunteer’s ability to participate in the trial. 10. Demonstrated clinically significant (required intervention, e.g., emergency room visit, epinephrine administration) allergic reactions (e.g., food, drug, or atopic reactions, asthmatic episodes) which, in the opinion of the Investigator, would interfere with the volunteer’s ability to participate in the trial. 11. Administration of any live, attenuated vaccines within 30 days and all other vaccinations within 14 days prior to study drug administration. 12. For women of childbearing potential (WOCBP), a positive serum pregnancy test at the Screening visit or a positive urine pregnancy test (with confirmatory serum pregnancy test) at check-in (Day -1). 13. Females who are breastfeeding or planning to breast feed at any time during the study. 14. Donation of blood or plasma within 30 days prior to first study drug administration, or loss of whole blood of more than 500 mL within 30 days prior to first study drug administration, or receipt of a blood transfusion within 1 year of first study drug administration. 15. Participation in another clinical trial of an investigational drug within 60 days or 5 half-lives of the investigational agent (whichever is longer) prior to the first study drug administration. 16. Any other condition, including mental illness or prior therapy that in the opinion of the Investigator would make the volunteer unsuitable for this study, including inability to cooperate fully with the requirements of the study protocol or likelihood of noncompliance with any study requirements.
Outcome results
None listed