Healthy Volunteers, Primary Sclerosing Cholangitis
Conditions
Keywords
Drug Therapy
Brief summary
The main aim of this study is to see if the drug TAK-781 is safe for healthy volunteers and for participants with PSC. The study will also look at how well participants can tolerate TAK-781. In addition, the study will check how the body absorbs, uses, and gets rid of TAK-781 (Pharmacokinetics \[PK\]), how the drug affects the body (Pharmacodynamics \[PD\]), and how the body's immune system reacts to TAK-781 (Immunogenicity). The study consists of two phases (Phase 1a and 1b). Phase 1a includes two parts: Part 1 (Single Ascending Dose \[SAD\]) and Part 2 (Multiple Ascending Dose \[MAD\]). In Part 1, healthy participants will receive either single dose of TAK-781 or a placebo. A placebo looks the same as TAK-781 but has no medicine in it. In Part 2, healthy participants will receive multiple doses of TAK-781 or a placebo. In Phase 1b (Part 3), participants with large duct, non-cirrhotic PSC will receive a single dose of TAK-781. Participants will be in the study for about 36 weeks.
Interventions
DRUGTAK-781
TAK-781 injection.
DRUGPlacebo
TAK-781 matching placebo injection.
Sponsors
Takeda
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Masking description
Phase 1a will be double blind, whereas Phase 1b will be non-blinded.
Eligibility
Sex/Gender
ALL
Age
18 Years to 68 Years
Healthy volunteers
Yes
Inclusion criteria
Phase 1a (SAD and MAD) 1. The participant is willing and able to fully comply with all trial procedures and requirements, in the investigator's opinion. 2. The participant has provided informed consent (that is, in writing, documented via a signed and dated informed consent form (ICF) or electronic consent \[e-consent\] if applicable) and any required privacy authorization prior to the initiation of any trial procedures. 3. Male at birth and female at birth participants aged 18 to 68 years, inclusive, at the time of consent. 4. The participant is judged to be in good health (for example, no evidence of cardiovascular, liver, metabolic, gastroenterological, or kidney disease) by the investigator, based on clinical evaluations including laboratory safety tests, medical history, physical examination, ECG, and vital sign measurements performed at the first screening visit. 5. The participant must have a body mass index (BMI) of less than 30.0 kilograms per square meter (kg/m\^2) at the time of screening. 6. Has not had frequent or heavy use (that is, near-daily) of medical or recreational cannabis for at least 3 months before screening. 7. The participant must not be a person of childbearing potential (POCBP) defined by at least 1 of the following criteria: * Surgically sterile for at least 6 weeks at screening (defined as having undergone one of the following procedures: hysterectomy, bilateral oophorectomy, or bilateral salpingectomy). * Postmenopausal at screening (defined as no menses for 12 months without an alternative medical cause). A high follicle-stimulating hormone (FSH) level (greater than or equal to \[\>=\]40 international units/liter \[IU/L\] in the postmenopausal range may be used to confirm a postmenopausal state in women not using hormonal contraception or hormonal replacement therapy. However, in the absence of 12 months of amenorrhea, a single FSH measurement is insufficient. * Has no uterus as a result of congenital condition. The participant must not donate ova for at least 6 months after the last dose of trial intervention. 8. Male participants (based on sex at birth) must use highly effective contraception, from the date of signing the ICF, throughout the duration of the trial, and for 6 months after the last dose of trial intervention. The participant must not donate sperm for at least 6 months after the last dose of trial intervention. Inclusion Criteria: Phase 1b (Non-Cirrhotic PSC) 1. The participant is willing and able to fully comply with all trial procedures and requirements, in the investigator's opinion. 2. The participant has provided informed consent (that is, in writing, documented via a signed and dated ICF or e-consent if applicable) and any required privacy authorization prior to the initiation of any trial procedures. 3. Male at birth and female at birth participants aged 18 to 68 years, inclusive, at the time of consent. 4. Confirmed diagnosis of large-duct PSC based on any 2 of the following 3 criteria: * Historical evidence of an elevated alkaline phosphatase (ALP) greater than \[\>\] upper limit of normal (ULN) from any laboratory. * Historical liver biopsy with histologic features consistent with large-duct PSC, in the appropriate clinical context (such as cholestatic liver enzyme profile, inflammatory bowel disease \[IBD\] history). * Historical abnormal cholangiography consistent with PSC as measured by magnetic resonance cholangiopancreatography (MRCP), endoscopic retrograde cholangiopancreatography, or percutaneous transhepatic cholangiography. 5. The participants must have a fibrogenesis biomarker over pre-defined level. 6. The participants must have evidence for moderate/advanced fibrosis but not cirrhosis as defined by enhanced liver fibrosis (ELF) \>=7.7 but less than or equal to(\<=)11.3 at Visit 1. 7. No evidence of cholangiocarcinoma or any other malignancy on magnetic resonance imaging (MRI) at screening. 8. Participants with a certain concomitant disease are allowed to enroll if pre-defined criteria are met. 9. Participants must have certain additional laboratory parameters in specified ranges at screening. 10. Has not had frequent or heavy use (that is, near-daily) of medical or recreational cannabis for at least 3 months before screening. 11. A female and male participant (based on sex at birth) must use highly effective contraception, from the date of signing the ICF, throughout the duration of the trial, and for 6 months after the last dose of trial intervention. The participant must not donate ova or sperm for at least 6 months after the last dose of trial intervention. 12. A POCBP must have a negative serum pregnancy test at first screening visit and urine pregnancy test on second screening visit and Day 1 before dosing. 13. Participants must be able to be educated regarding the correct process/procedure, verbally state understanding and comply with the correct process/procedure of the administration SC IP for the duration of the trial.
Exclusion criteria
Phase 1a (SAD and MAD) 1. The participant is an employee of the sponsor or trial site, or an immediate family member (for example, spouse, parent, child, sibling) of an employee of the sponsor or trial site who is directly involved in the conduct of the trial. 2. The participant has a known hypersensitivity to any component of the formulation of TAK-781 or related compounds. 3. The participant has a history of significant multiple and/or severe allergies (for example, food, drug, latex allergy) or has had an anaphylactic reaction or significant intolerance to prescription or nonprescription drugs or food. 4. The participant has a history or clinical evidence of bleeding diathesis or any coagulation disorder. 5. The participant has a medical history of prior cholecystectomy. 6. The participant has participated in another investigational trial with other investigational agents or devices for any indication within 4 weeks or within 5 half-lives, for investigational drugs or biologics with a known half-life (whichever is longer), before the screening visit. The interval window from the previous trial will be derived from the date of the last trial medical procedure, and/or AE related to the trial IP or procedure in the previous trial to the screening visit of the current trial. Exceptions may be made for observational, natural history and nonintervention type studies with sponsor or designee approval. 7. The participant has an ALT and/or AST value greater than the ULN during screening. 8. The participant has abnormal cholesterol: total cholesterol \>240 milligrams per deciliter (mg/dL), low-density lipoprotein cholesterol (LDL-C) (\>160 mg/dL), high-density lipoprotein cholesterol (HDL-C) (less than \[\<\]35 mg/dL), and triglycerides (\>250 mg/dL) at screening. Lipid parameters may be repeated once under fasting conditions at the principal investigator's discretion. Eligibility will be determined based on the repeated results. 9. The participant has eGFR rate \<=90milliliter per minutes per 1.73 square meters (mL/min/1.73m\^2) at screening. 10. The participant screening ECG (triplicate) reveals a QT interval with Fridericia correction method (QTcF) \>450 millisecond (ms) (male) or \>460 ms (female). 11. The participant has a history of torsades de pointes, clinically significant ventricular arrhythmias (for example, ventricular tachycardia), heart block (excluding first-degree atrioventricular block), congenital long QT syndrome, or clinically significant ischemic ECG changes, including new ST-segment elevation or depression or new Q waves, as determined by the investigator. Benign ECG variants, such as early repolarization patterns, are not exclusionary if they occur without clinical symptoms or other evidence underlying cardiac disease. 12. The participant has a confirmed supine systolic blood pressure \>=140 millimetres of mercury (mmHg) and/or diastolic blood pressure \>=90 mmHg at screening. If the participant's supine blood pressure exceeds these thresholds, the measurement should be repeated twice after the participant has remained in the supine position for at least 10 minutes. The average of the three supine blood pressure measurements will be used to determine eligibility. Resting BP is defined as a BP measurement obtained after the participant has been resting for a minimum of 5 minutes. 13. The participant has a resting heart rate (HR) outside of the range of 55 to 100 beats per minute (bpm) (inclusive) at screening, confirmed on repeat testing within a maximum of 30 minutes. Athletic participants with HR \<55 bpm may be enrolled based on the investigator's judgement provided that the HR is \>45 bpm. 14. The participant has a positive urine screen for drugs of abuse at screening and Day -3. 15. History of any malignancy diagnosed or treated within 5 years prior to screening. 16. The participant consumes excessive amounts (defined as greater than 600 milligram (mg) of caffeine) of coffee, tea, cola, energy drinks, or other caffeinated beverages per day. 17. Has a positive pregnancy test result during the screening period. 18. Participants who test negative for hepatitis B surface antigen (HBsAg) but positive for hepatitis B core antibody (HBcAb) would be considered eligible if hepatitis B virus (HBV) deoxyribonucleic acid (DNA) results are negative at screening (as confirmed by HBV DNA polymerase chain reaction \[PCR\] reflex testing performed by the central laboratory). Participants with positive HBV DNA test results will not be eligible. 19. Participants who test positive for hepatitis C virus (HCV) ribonucleic acid (RNA) at screening. Participants who are hepatitis C antibody (HCVAb) positive without evidence of HCV RNA may be considered eligible (spontaneous viral clearance or previously treated and cured \[defined as no evidence of HCV RNA at least 12 weeks before screening Visit1\]). 20. The participant tests positive for human immunodeficiency virus (HIV) at screening or currently receiving antiretroviral therapy. 21. Has undergone major surgery or donated or lost 1 unit of blood (approximately 500 milliliters \[mL\]) within 4 weeks before the screening visit. 22. Currently has or previously had a significant illness, as judged by the investigator, within 2 weeks of the first dose of trial intervention. 23. The participant is unable to refrain from or anticipates using prohibited or excluded medications, herbal preparations, grapefruit juice, and other restricted substances or the required washout period prior to administration of the first dose of trial intervention throughout the trial and until the follow-up visit. 24. The participant is unable to refrain from or anticipate using smoking, vaping or nicotine-containing products 2 weeks before screening until the last follow-up visit. 25. Clinically relevant drug or alcohol abuse within 12 months of screening. * A positive drug screen is exclusive unless it can be explained by a prescribed medication. * Participant with alcohol consumption greater than 4 units on any day or 14 units per week for male participants, or greater than 3 units on any day or 7 units per week for female participants \[1 unit of alcohol is present in one 12 ounce (oz)/355 mL beer (approximately 5 percent (%) alcohol), one 5 oz/148 mL glass of wine (approximately 12% alcohol), and one 1.5 oz/44 mL measure of 80-proof liquor (approximately 40% alcohol)\].
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Phase 1a (SAD and MAD) and Phase 1b: Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Phase 1a (SAD) and 1b: From start of study drug administration up to End of Treatment (EOT)/Early termination (ET) (up to Week 20); Phase 1a (MAD): From start of study drug administration up to EOT/ET (up to Week 32) | An AE is any untoward medical occurrence in a clinical trial participant, temporally associated with the use of the trial intervention, whether or not the occurrence is considered related to the trial intervention. TEAE is defined as any event emerging or manifesting at or after the initiation of treatment with a trial intervention or medicinal product or any existing event that worsens in either intensity or frequency following exposure to the trial intervention. |
| Phase 1a (SAD and MAD) and Phase 1b: Number of Participants With Clinically Significant Changes in Clinical Laboratory Values | Phase 1a (SAD) and 1b: From start of study drug administration up to EOT/ET (up to Week 20); Phase 1a (MAD): From start of study drug administration up to EOT/ET (up to Week 32) | Laboratory parameters will include hematology, chemistry and urinalysis. Any clinically significant change in laboratory values will be determined at the investigator's discretion. |
| Phase 1a (SAD and MAD) and Phase 1b: Number of Participants With Clinically Significant Changes in 12-Lead Electrocardiogram (ECG) Parameters | Phase 1a (SAD) and 1b: From start of study drug administration up to EOT/ET (up to Week 20); Phase 1a (MAD): From start of study drug administration up to EOT/ET (up to Week 32) | The 12-lead ECG will be evaluated. Any clinically significant change in ECG assessment will be determined at the investigator's discretion. |
| Phase 1a (SAD and MAD) and Phase 1b: Number of Participants With Clinically Significant Changes in Vital Sign Values | Phase 1a (SAD) and 1b: From start of study drug administration up to EOT/ET (up to Week 20); Phase 1a (MAD): From start of study drug administration up to EOT/ET (up to Week 32) | Vital signs will include measurement of oral body temperature, supine blood pressure and heart rate. Any clinically significant change in vital signs will be determined at the investigator's discretion. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Phase 1a and 1b: Maximum Observed Plasma Concentration (Cmax) of TAK-781 | Predose up to 2 days post-dose | Cmax of TAK-781 will be reported. |
| Phase 1a and 1b: Time of First Occurrence of Plasma Cmax (Tmax) of TAK-781 | Predose up to 2 days post-dose | Tmax of TAK-781 will be reported. |
| Phase 1a and 1b: Area Under the Plasma Concentration-time Curve From Time 0 to Infinity (AUCinf) of TAK-781 | Predose up to 2 days post-dose | AUCinf of TAK-781 will be reported. |
| Phase 1a and 1b: Area Under the Plasma Concentration-time Curve From Time 0 to Time of the Last Quantifiable Concentration (AUClast) of TAK-781 | Predose up to 2 days post-dose | AUClast of TAK-781 will be reported. |
| Phase 1a: Percentage Change From Baseline in TE Biomarker Area Under the Effect Curve 0 to 9 Hours (AUEC0-9h) | Phase 1a: 0 to 9 hours post-dose | Percentage change from baseline in TE biomarker AUEC0-9h will be reported. |
| Phase 1b: Percentage Change From Baseline in Fibrogenesis Biomarker Levels | Baseline up to Week 12 | Percentage change from baseline in fibrogenesis biomarker levels will be reported. |
| Phase 1b: Percentage Change From Baseline in TE Biomarker Through Week 12 | Baseline up to Week 12 | Percentage change from baseline in TE biomarker through Week 12 will be reported. |
| Phase 1a (SAD and MAD) and 1b: Number of Participants With Anti-drug Antibodies (ADAs) to TAK-781 | Phase 1a (SAD) and 1b: Baseline up to Week 20; Phase 1a (MAD): Baseline up to Week 32 | Number of participants with ADAs to TAK-781 will be reported. |
Countries
United States
Contacts
CONTACTTakeda Contact
STUDY_DIRECTORStudy Director
Takeda
Outcome results
None listed