COVID-19
Conditions
Keywords
ALG-097558, Dabigatran, Drug-Drug Interaction, Healthy Subjects, Interventional, Itraconazole, SARS-CoV-2, Tablet Formulation
Brief summary
The aim of this multi-part Phase 1 study is to evaluate the drug-drug interaction (DDI) potential of ALG-097558 via co-administration with a P-gp substrate (dabigatran) and a CYP3A4 inhibitor/P-gp inhibitor (itraconazole). In addition, this study will evaluate the relative bioavailability and food effect of a new tablet formulation for ALG-097558. This study consists of 3 parts, all conducted in healthy volunteers (HV). Study Parts A and B are designed to assess the perpetrator or victim DDI risk of ALG-097558 mediated by CYP/P-gp interactions in healthy adult subjects. Part A will evaluate the potential impact of itraconazole, a CYP3A potent inhibitor, while Part B will investigate the potential impact of ALG-097558 (perpetrator) on dabigatran etexilate, a P-gp transporter substrate. Study Part C is designed to study the bioavailability of a new formulation of the ALG-097558 tablet and the food effect on this tablet. This study has one primary objective for each part of the study. For Part A: to evaluate the effect of a CYP3A4 inhibitor/Pg-p inhibitor, itraconazole, on the pharmacokinetics (PK) of ALG-097558 and the metabolite, ALG-097730. For Part B: to evaluate the effect of multiple doses of ALG-097558 on the pharmacokinetics of a P-gp substrate, dabigatran. For Part C: to evaluate the relative bioavailability of 2 different tablet formulations of ALG-097558 and effect of food on the pharmacokinetics of ALG-097558 and the metabolite, ALG-097730.
Detailed description
The aim of this multi-part Phase 1 study is to evaluate the drug-drug interaction (DDI) potential of ALG-097558 via co-administration with a P-gp substrate (dabigatran) and a CYP3A4 inhibitor/P-gp inhibitor (itraconazole). In addition, this study will evaluate the relative bioavailability and food effect of a new tablet formulation for ALG-097558. This study consists of 3 parts, all conducted in healthy volunteers (HV). As ALG-097558 is a substrate of CYP3A4 and P-gp transporters, any concomitant administration of an inhibitor or inducer drug may alter its exposures. Part A will evaluate the potential impact of itraconazole, a CYP3A potent inhibitor, on the ALG-097558 (victim) systemic exposure in a single group, partially-blinded study. Part B will investigate the potential impact of ALG-097558 (perpetrator) on dabigatran etexilate, a P-gp transporter substrate in a single group, open-label study. Study Part C is designed to study the bioavailability of a new formulation of the ALG-097558 tablet and the food effect on this tablet in an open-label, randomized, crossover study. This study has one primary objective for each part of the study. For Part A: to evaluate the effect of a CYP3A4 inhibitor/Pg-p inhibitor, itraconazole, on the pharmacokinetics (PK) of ALG-097558 and the metabolite, ALG-097730. For Part B: to evaluate the effect of multiple doses of ALG-097558 on the pharmacokinetics of a P-gp substrate, dabigatran. For Part C: to evaluate the relative bioavailability of 2 different tablet formulations of ALG-097558 and effect of food on the pharmacokinetics of ALG-097558 and the metabolite, ALG-097730.The study has secondary objectives for each part of the study as well. For Part A: to evaluate the safety and tolerability of single doses of ALG-097558 in HV participants when administered as monotherapy or in combination with itraconazole. For part B: to evaluate the safety and tolerability and PK of multiple doses of ALG-097558 in HV participants when administered alone or in combination with dabigatran. For part C: to evaluate the safety and tolerability of single doses of ALG-097558 in HV participants.
Interventions
DRUGItraconazole
A substrate and strong dual inhibitor of CYP3A4/P-glycoprotein (P-gp)
OTHERPlacebo
Placebo
DRUGALG-097558
A selective, reversible, and potent inhibitor of the SARS-CoV-2 3CLpro with pan-coronavirus activity
DRUGDabigatran
A direct thrombin inhibitor approved for the treatment and prevention of blood clots to reduce the risk of stroke
Sponsors
National Institute of Allergy and Infectious Diseases (NIAID)
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
SINGLE (Subject)
Masking description
Participants are only masked in Part A. Parts B and Part C are open label.
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
Yes
Inclusion criteria
1. Participant is able to read the written informed consent, states willingness to comply with all study procedures, and is anticipated to be available for all study visits. 2. Male or female adults between 18 and 65 years of age, inclusive. 3. Female participants must either be postmenopausal\*, permanently sterile\*\*, or of childbearing potential with acceptable birth control methods\*\*\*. \*Postmenopausal: a postmenopausal state is defined as no menses for at least 12 months without an alternative medical explanation, confirmed by a high follicle-stimulating hormone (FSH) level in the postmenopausal range at screening. NOTE: If there is a question about menopausal status in women on hormone replacement therapy (HRT), the woman will be required to use one of the protocol-defined non-estrogen-containing hormonal highly effective contraceptive methods if she wishes to continue HRT during the study. \*\*Permanently sterile: methods include hysterectomy, bilateral salpingectomy, bilateral oophorectomy, bilateral tubal ligation, or bilateral tubal occlusion. * Women of childbearing potential (WOCBP): are only eligible if they and any non-sterile, male sexual partners agree to use protocol-defined highly effective (dependent or independent) contraceptive therapy, from the start of dosing until at least 90 days after the last dose. Acceptable method of contraception, hormonal contraceptives (e.g., oral, injectable, implantable, insertable, and transdermal patch), intrauterine device (with or without hormones), or double-barrier method (e.g., condom and spermicide) for 30 days prior to Screening, during the study, and for 90 days following the last administration of investigational product (IP). WOCBP must also agree to refrain from egg donations during the study and for at least 90 days following the last administration of IP. 4. Male participants who must agree to wear a condom with spermicide during sexual intercourse.\* \*These contraceptive measures must be implemented, at a minimum, from the start of dosing until at least 90 days after the last dose. Male volunteers must agree not to donate sperm during the study and for 90 days following the last administration of IP. 5. Participants must have a body mass index (BMI) of 18.0 to 32.0 kg/m\^2, extremes included. 6. Participants must be nonsmokers for at least 3 months prior to randomization/enrollment. 7. Participants must have a 12-lead electrocardiogram (ECG) that considered in an acceptable range for inclusion.\* \*Criteria includes: heart rate between 40 and 100 beats per minute \[bpm\], extremes included; QT interval corrected for heart rate (QTc) according to Fridericia's formula (QTcF) \</= 450 ms (males) or \</= 470 ms (females); QRS interval \</=120 ms; PR interval \>/=110 to \</=220 ms; and in addition to fulfilling the above ECG criteria, ECG morphology must have no clinically significant abnormalities observed. NOTE: Retesting of an apparently exclusionary ECG will be allowed once without prior approval from the Sponsor (following ECG collections described in Section 8.3.4). Participants with a retest ECG without clinically significant abnormalities as per this inclusion criterion may be included. 8. Participants must be deemed to be in good overall health by the Investigator on the basis of a medical evaluation\* performed at Screening. \*Medical evaluation that includes the absence of any clinically significant abnormality and includes a physical examination, medical history, vital signs, and the results of blood chemistry, blood coagulation and hematology tests, and urinalysis. 9. Subject must be willing and able to adhere to the Prohibited Medication requirements and Special Precautions as specified in the protocol.
Exclusion criteria
1. Participants with any current or previous illness that, in the opinion of the Investigator, might confound the results of the study or pose risk in administering study drug to the subject.\* \*Additionally illnesses that could prevent, limit, or confound the protocol specified assessments or study results' interpretation. This may include, but is not limited to, renal, cardiac, vascular, pulmonary, gastrointestinal, hepatologic, endocrine, neurologic, dermatologic, hematologic, rheumatologic, psychiatric, neoplastic, or metabolic disturbances. 2. Participants with a past history of cardiac arrhythmias, risk factors for Torsade de Pointes syndrome or clinical evidence at screening of significant or unstable cardiac disease.\* \*Risk factors for Torsade de Pointes syndrome include hypokalemia and family history of long QT syndrome. Clinical evidence of cardiac disease include angina, congestive heart failure, myocardial infarction, diastolic dysfunction, significant arrhythmia, coronary heart disease, clinically significant ECG abnormalities, moderate to severe valvular disease or uncontrolled hypertension. Evidence of heart block or bundle branch block, inclusive of first-degree AV block and incomplete bundle branch block, on ECG is also exclusionary. 3. Participants with a history of clinically significant drug allergy such as, but not limited to, sulfonamides or drug allergy witnessed in previous studies with experimental drugs. 4. Participants with a recent (within 1 year of randomization/enrollment) history of use of amphetamines, barbiturates, narcotic or other drugs of abuse/recreational drug use.\* \*Use of these drugs under physician supervision (e.g., prescription narcotics for known pain disorder) are not exclusionary. Cannabis use is also not exclusionary unless detected at screening or Day -1 (
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Concentration-time Curve From Time Zero to Infinity [Extrapolated] (AUC0-inf): ALG-097558 in Part A and Part C, Dabigatran (Total) in Plasma in Part B | Part A-0 to 72 hours post dose on Days 1 to 10 Part B-0 to 72 hours post dose on Days 1 to 8 Part C-0 to 72 hours post dose on Days 1 to 9 | Drug-drug interaction in Parts A and B was evaluated using the geometric mean ratio (log-transformed) of ALG-097558 (Part A) and dabigatran (Part B) in the test treatment condition (combined-treatment condition) relative to the reference treatment condition (single-treatment condition) was estimated by ANOVA with the 90% CI calculated for AUC0-inf. The evaluation of the potential food effect on the PK of ALG-097558 and the relative bioavailability assessment of Formulation 2 versus Formulation 1 in Part C was performed in 2 separate 2-treatment ANOVAs. |
| Area Under the Concentration-time Curve From Time Zero to the Last Measurable Concentration (AUClast) for ALG-097558 in Part A and Part C, Dabigatran (Total) in Plasma in Part B | Part A-0 to 72 hours post dose on Days 1 to 10 Part B-0 to 72 hours post dose on Days 1 to 8 Part C-0 to 72 hours post dose on Days 1 to 9 | Drug-drug interaction in Parts A and B was evaluated using the geometric mean ratio (log-transformed) of ALG-097558 (Part A) and dabigatran (Part B) in the test treatment condition (combined-treatment condition) relative to the reference treatment condition (single-treatment condition) was estimated by ANOVA with the 90% CI calculated for AUClast. The evaluation of the potential food effect on the PK of ALG-097558 and the relative bioavailability assessment of Formulation 2 versus Formulation 1 in Part C was performed in 2 separate 2-treatment ANOVAs. |
| Elimination Half-life (t1/2):ALG-097558 in Part A and Part C, Dabigatran (Total) in Plasma in Part B | Part A-0 to 72 hours post dose on Days 1 to 10 Part B-0 to 72 hours post dose on Days 1 to 8 Part C-0 to 72 hours post dose on Days 1 to 9 | Drug-drug interactions for t1/2 were evaluated using the geometric mean ratio (log-transformed) of ALG-097558 (Part A and Part C) and dabigatran (Part B) |
| Maximum Observed Concentration (Cmax):ALG-097558 in Plasma in Part A and Part C, Dabigatran (Total) in Plasma in Part B | Part A-0 to 72 hours post dose on Days 1 to 10 Part B-0 to 72 hours post dose on Days 1 to 8 Part C-0 to 72 hours post dose on Days 1 to 9 | Drug-drug interaction in Parts A and B was evaluated using the geometric mean ratio (log-transformed) of ALG-097558 (Part A) and dabigatran (Part B) in the test treatment condition (combined-treatment condition) relative to the reference treatment condition (single-treatment condition) was estimated by ANOVA with the 90% CI calculated for Cmax. The evaluation of the potential food effect on the PK of ALG-097558 and the relative bioavailability assessment of Formulation 2 versus Formulation 1 in Part C was performed in 2 separate 2-treatment ANOVAs. |
| Time of Observed Maximum Concentration (Tmax):ALG-097558 in Part A and Part C, Dabigatran (Total) in Plasma in Part B | Part A-0 to 72 hours post dose on Days 1 to 10 Part B-0 to 72 hours post dose on Days 1 to 8 Part C-0 to 72 hours post dose on Days 1 to 9 | Drug-drug interactions for Tmax were evaluated using the geometric mean ratio (log-transformed) of ALG-097558 (Part A and Part C) and dabigatran (Part B) |
| Area Under the Concentration-time Curve From Time Zero to Infinity [Extrapolated] (AUC0-inf) for ALG-097730 Plasma in Part A and Part C | Part A-0 to 72 hours post dose on Days 1 to 10 Part C-0 to 72 hours post dose on Days 1 to 9 | Drug-drug interactions for AUC0-inf were evaluated using the geometric mean ratio (log-transformed) in Part A and Part C |
| Area Under the Concentration-time Curve From Time Zero to the Last Measurable Concentration (AUClast) for ALG-097730 in Plasma in Part A and Part C | Part A-0 to 72 hours post dose on Days 1 to 10 Part C-0 to 72 hours post dose on Days 1 to 9 | Drug-drug interactions for AUClast were evaluated using the geometric mean ratio (log-transformed) in Part A and Part C |
| Elimination Half-life (t1/2) for ALG-097730 in Plasma in Part A and Part C | Part A-0 to 72 hours post dose on Days 1 to 10 Part C-0 to 72 hours post dose on Days 1 to 9 | Drug-drug interactions for t1/2 were evaluated using the geometric mean ratio (log-transformed) in Part A and Part C |
| Maximum Observed Concentration (Cmax) for ALG-097730 in Plasma in Part A and Part C | Part A-0 to 72 hours post dose on Days 1 to 10 Part C-0 to 72 hours post dose on Days 1 to 9 | Drug-drug interactions for Cmax were evaluated using the geometric mean ratio (log-transformed)in Part A and Part C |
| Time of Observed Maximum Concentration (Tmax) for ALG-097730 in Part A and Part C | Part A-0 to 72 hours post dose on Days 1 to 10 Part C-0 to 72 hours post dose on Days 1 to 9 | Drug-drug interactions for Tmax were evaluated using the geometric mean ratio (log-transformed) in Part A and Part C |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Observed Concentration (Cmax) of ALG-097558 in Plasma After Co-administration With a Single Dose of Dabigatran in Part B | 0 to 72 hours post dose on Days 1 to 8 | PK parameter of Cmax was assessed following 600 mg ALG 097558 Q12H co-administered with a single 75 mg dabigatran dose |
| Time of Observed Maximum Concentration (Tmax):ALG-097558 in Plasma After Coadministration With a Single Dose of Dabigatran in Part B | Part B-0 to 72 hours post dose on Days 1 to 8 | PK parameter of Tmax was assessed following 600 mg ALG 097558 Q12H co-administered with a single 75 mg dabigatran dose |
| Area Under the Concentration-time Curve From Time Zero to the Last Measurable Concentration (AUClast) for ALG-097558 in Plasma After Coadministration With a Single Dose of Dabigatran in Part B | Part B-0 to 72 hours post dose on Days 1 to 8 | PK parameter of AUClast was assessed following 600 mg ALG 097558 Q12H co-administered with a single 75 mg dabigatran dose |
| Elimination Half-life (t1/2) of ALG-097558 in Plasma After Coadministration With a Single Dose of Dabigatran in Part B | Part B-0 to 72 hours post dose on Days 1 to 8 | PK parameter of t1/2 was assessed following 600 mg ALG 097558 Q12H co-administered with a single 75 mg dabigatran dose |
| Time of Last Measurable Concentration (Tlast):ALG-097558 in Plasma After Coadministration With a Single Dose of Dabigatran in Part B | Part B-0 to 72 hours post dose on Days 1 to 8 | PK parameter of Tlast was assessed following 600 mg ALG 097558 Q12H co-administered with a single 75 mg dabigatran dose |
| Maximum Observed Concentration (Cmax) of ALG-097730 in Plasma After Co-administration of ALG-097558 With a Single Dose of Dabigatran in Part B | 0 to 72 hours post dose on Days 1 to 8 | PK parameter of Cmax for metabolite ALG-097730 was assessed following 600 mg ALG 097558 Q12H co-administered with a single 75 mg dabigatran dose |
| Time of Observed Maximum Concentration (Tmax):ALG-097730 in Plasma After Coadministration of ALG-097558 With a Single Dose of Dabigatran in Part B | Part B-0 to 72 hours post dose on Days 1 to 8 | PK parameter of Tmax for metabolite ALG-097730 was assessed following 600 mg ALG 097558 Q12H co-administered with a single 75 mg dabigatran dose |
| Area Under the Concentration-time Curve From Time Zero to the Last Measurable Concentration (AUClast) for Metabolite ALG-097730 in Plasma After Coadministration of ALG-097558 With a Single Dose of Dabigatran in Part B | Part B-0 to 72 hours post dose on Days 1 to 8 | PK parameter of AUClast for metabolite ALG-097730 was assessed following 600 mg ALG 097558 Q12H co-administered with a single 75 mg dabigatran dose |
| Elimination Half-life (t1/2) for Metabolite ALG-097730 in Plasma After Coadministration of ALG-097558 With a Single Dose of Dabigatran in Part B | Part B-0 to 72 hours post dose on Days 1 to 8 | PK parameter of t1/2 for metabolite ALG-097730 was assessed following 600 mg ALG 097558 Q12H co-administered with a single 75 mg dabigatran dose |
| Time of Last Measurable Concentration (Tlast):ALG-097730 in Plasma After Coadministration of ALG-097558 With a Single Dose of Dabigatran in Part B | Part B-0 to 72 hours post dose on Days 1 to 8 | PK parameter of Tlast for metabolite ALG-097730 was assessed following 600 mg ALG 097558 Q12H co-administered with a single 75 mg dabigatran dose |
| Metabolite to Parent Area Under the Concentration-time Curve Ratio From Time Zero to the Last Measurable Concentration (MPAUClast) for ALG-097730 in Plasma After Coadministration of ALG-097558 With a Single Dose of Dabigatran in Part B | Part B-0 to 72 hours post dose on Days 1 to 8 | PK parameter of MPAUClast for metabolite ALG-097730 was assessed following 600 mg ALG-097558 Q12H co-administered with a single 75 mg dabigatran dose |
Countries
United States
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Categorical <=18 years | 1 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 50 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 5 Participants |
| Race (NIH/OMB) More than one race | 3 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 21 Participants |
| Sex: Female, Male Female | 32 Participants |
| Sex: Female, Male Male | 10 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk | EG008 affected / at risk | EG009 affected / at risk | EG010 affected / at risk | EG011 affected / at risk | EG012 affected / at risk | EG013 affected / at risk | EG014 affected / at risk | EG015 affected / at risk | EG016 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 12 | 0 / 12 | 0 / 12 | 0 / 12 | 0 / 12 | 0 / 24 | 0 / 24 | 0 / 24 | 0 / 5 | 0 / 5 | 0 / 5 | 0 / 5 | 0 / 5 | 0 / 5 | 0 / 5 | 0 / 5 | 0 / 5 |
| other Total, other adverse events | 1 / 12 | 4 / 12 | 1 / 12 | 3 / 12 | 4 / 12 | 5 / 24 | 0 / 24 | 5 / 24 | 0 / 5 | 0 / 5 | 0 / 5 | 2 / 5 | 1 / 5 | 1 / 5 | 1 / 5 | 0 / 5 | 2 / 5 |
| serious Total, serious adverse events | 0 / 12 | 0 / 12 | 0 / 12 | 0 / 12 | 0 / 12 | 0 / 24 | 0 / 24 | 0 / 24 | 0 / 5 | 0 / 5 | 0 / 5 | 0 / 5 | 0 / 5 | 0 / 5 | 0 / 5 | 0 / 5 | 0 / 5 |
Outcome results
None listed