Clinical trial NCT03649165: A Study to Evaluate Bioavailability and Food Effect of Selumetinib (AZD6244) in Healthy Male Participants
Official title: A Phase I, Open-label, Single-center Relative Bioavailability and Food Effect Randomized Crossover Study of New Granule and Capsule Formulations of Selumetinib (AZD6244) in Healthy Male Subjects
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Neurofibromatosis Type 1 (NF1)-Related Plexiform Neurofibromas (PNs)
Healthy Participants
Keywords: MEK Inhibitor
Selumetinib capsule
Selumetinib granule
PK
Bioavailibilty
Crossover study
Open-label
Food effect
Lead sponsor: AstraZeneca
Sponsor class: INDUSTRY
First posted: 2018-08-28
Enrollment: 24
Sex: MALE
Minimum age (years): 18
Maximum age (years): 45
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: TREATMENT

Brief summary: This study will evaluate bioavailability and food effect of selumetinib (AZD6244) in healthy male participants. A total of 24 healthy male participants will be included to ensure at least 20 evaluable participants. The study is divided in 2 study parts; the same participants will participate in both parts of the study. Part 1 of the study is to investigate the pharmacokinetics (PK) of the selumetinib granule compared to the PK of selumetinib capsule, when administered with water under the fasted conditions. Part 2 of the study is to investigate the PK of selumetinib granule and capsule under fed conditions. Participants will also receive a single 500 mg dose of acetaminophen at the same time as selumetinib administration.

Detailed description: This study will be a 2-part, open-label, single-center relative bioavailability and food effect randomized crossover study of new granule and capsule formulations of selumetinib. A total of 24 healthy male participants aged between 18 to 45 years (inclusive), will be included to ensure at least 20 evaluable participants. The study is divided in 2 study parts; the same participants will participate in both parts of the study.

Part 1 of the study is designed to investigate the PK of the selumetinib granule compared to the PK of selumetinib capsule, when administered with water under the fasted conditions. Part 2 of the study is designed to investigate the PK of selumetinib granule and capsule under fed conditions. Participants will consume a low-fat, low-calorie meal. Thirty minutes after the start of the meal, selumetinib will be administered to the participants. In all treatment periods, participants will also receive a single 500 mg dose of acetaminophen at the same time as selumetinib administration where it will act as a marker for gastric emptying. The study will also assess the palatability of the selumetinib granule in both parts of the study.

Each participant will receive the following treatments:

* Treatment A: 25 mg granule, fasted state
* Treatment B: 50 mg capsule, fasted state
* Treatment C: 25 mg granule, fed state
* Treatment D: 50 mg capsule, fed state Participant will be randomly assigned to 1 of 4 treatment sequences. In all cases the treatments in Part 1 will be administered before the treatments in Part 2. The study will comprise of a screening period of maximum 28 days. Four treatment periods during which participants will be resident from the day before dosing (Day -1) until at least 48 hours after dosing; discharged on the morning of Day 3. A follow-up visit, will be within 7 to 10 days after the last dose of investigational medicinal product (IMP). There will be a minimum washout period of at least 5 days between each IMP administration. Each participant will be involved in the study for approximately 8 to 9 weeks.

Eligibility criteria: Inclusion Criteria

1. Provision of signed and dated, written informed consent before any study-specific procedures.
2. Healthy male participants aged 18 to 45 years (inclusive) with suitable veins for cannulation or repeated venipuncture.
3. Have a body mass index (BMI) between 18 and 30 kg/m2 inclusive and weigh at least 50 kg.
4. Participants is able to consume a low-fat meal within a 30-minute period.
5. Participants has a creatinine clearance (CRCL) greater than 50 mL/min using Cockcroft-Gault formula.
6. Participants is willing to comply with contraception requirements as described below:

   * Male participants with sexual partners who can become pregnant (i.e., women of childbearing potential) must use 2 highly-effective methods of contraception, one of which must be a barrier method (condom with spermicide) from the time of the first administration of the IMP until 12 weeks after the last administration of the IMP to avoid pregnancy and/or potential adverse effects on the developing embryo.
   * Participants with sexual partners who are pregnant must use an effective method of contraception (barrier method) from the time of the first administration of the IMP until 12 weeks after the last administration of the IMP.
   * Participants must avoid sperm donation during the study and for 12 weeks after the last administration of the IMP.
   * Reliable methods of contraception must be used consistently and correctly.
   * Reliable methods of contraception for participants include: Use of barrier methods (condom and spermicide) for the duration of the study until 12 weeks after the last administration of the IMP.
   * Acceptable methods for participants partners include:

     1. Use of implants, injectables and combined oral contraceptives (must be used in combination with a barrier method of contraception)
     2. Use of intrauterine devices (must be used in combination with a barrier method of contraception)

Exclusion Criteria :

1. Participants of Japanese, non-Japanese Asian or Indian ethnicity.
2. Participants has any one parent or grandparent (maternal or paternal) that was Japanese or non-Japanese Asian (e.g., China, Taiwan, Korea, Philippines, Thailand, Vietnam and Malaysia) or Indian.
3. History or presence of central serous retinopathy or retinal vein thrombosis, IOP greater than 21 mmHg or uncontrolled glaucoma.
4. History of any clinically significant disease or disorder which, in the opinion of the PI, may put the participant at risk because of participation in the study, influence the result of the study or influence the participants ability to participate in the study.
5. Participant has ophthalmologic conditions as follows:

   * Current or past history of central serous retinopathy/retinal pigment epithelial detachment or retinal vein occlusion.
   * Intra-ocular pressure \> 21 mmHg or uncontrolled glaucoma (irrespective of IOP).
6. Participant has any cardiac conditions as follows:

   * Uncontrolled hypertension (BP ≥ 150/95 mmHg despite medical therapy).
   * Acute coronary syndrome within 6 months before starting treatment.
   * Uncontrolled Angina - Canadian Cardiovascular Society grade II-IV despite medical therapy.
   * Symptomatic heart failure New York Heart Association (NYHA) Class II-IV, prior or current cardiomyopathy, or severe valvular heart disease.
   * Prior or current cardiomyopathy including but not limited to the following: 1) Known hypertrophic cardiomyopathy.

     2) Known arrhythmogenic right ventricular cardiomyopathy. 3) Previous moderate or severe impairment of LVEF \< 45% on echocardiography even if full recovery has occurred.
   * Left ventricular ejection fraction below the lower limit of normal (LLN) or \< 55% measured by ECHO at the Screening Visit.
   * Severe valvular heart disease.
   * Atrial fibrillation with a ventricular rate \> 100 beats per minute (bpm) on ECG at rest.
   * QTcF \> 450 ms or other factors that increase the risk of QT prolongation.
7. Any clinically significant illness, medical/surgical procedure, or trauma within 4 weeks of the first administration of IMP.
8. Any clinically relevant abnormal findings in physical examination, hematology, clinical chemistry, urinalysis, vital signs or ECG at the Screening Visit, which in the opinion of the PI, may put the participant at risk because of his participation in the study. Test may be repeated twice at the discretion of the Investigator if abnormal.
9. Any positive result on screening for serum hepatitis B surface antigen, hepatitis C antibody, and human immunodeficiency virus (HIV) antibody.
10. A suspected/manifested infection according to the International Air Transport Association (IATA) Categories A and B infectious substances.
11. History of, or current alcohol or drug abuse, as judged by the principal investigator (PI).
12. Participation in another clinical study (investigational product administered within 30 days before the Screening Visit, or participation in a method development study \[no drug\] 30 days before the Screening Visit). Participation is defined as the completion of a treatment related visit.
13. Planned in-patient surgery, dental procedure or hospitalization during the study.
14. Plasma donation within 30 days of the Screening Visit or any blood donation/loss more than 500 mL during the 90 days before the Screening Visit.
15. A definite or suspected personal history of intolerance or hypersensitivity to drugs and/or their excipients, judged to be clinically relevant by the PI.
16. Known severe hypersensitivity to selumetinib or acetaminophen or any excipient of these medicinal products or history of allergic reactions attributed to compounds of similar chemical or biologic composition to selumetinib.
17. Current smokers or those who have smoked or used nicotine products (including e-cigarettes) within the 90 days before the Screening Visit.
18. Positive screen for drugs of abuse, alcohol or cotinine at the Screening Visit or on each admission to the Clinical Unit or positive screen for alcohol on each admission to the Clinical Unit.
19. Use of drugs with enzyme-inducing properties such as St John's Wort within 4 weeks before the first administration of IMP.
20. Use of any prescribed medicine and over-the-counter (OTC) drugs (including herbal remedies, vitamins and minerals) within 2 weeks or 5 times the half-life, whichever is the longer, of the respective drug before Day -1 or Treatment Period 1. No medications known to prolong the QT/QTc interval are allowed.
21. Excessive intake of caffeine-containing drinks or food e.g., coffee, tea, chocolate, Red Bull or cola (more than 6 units of caffeine per day). One caffeine unit is contained in the following items: 1 (6 oz) cup of coffee, 2 (12 oz) cans of cola, 1 (12 oz) cup of tea, ½ (4 oz) cup of energy drink (e.g., Red Bull) or 3 oz of chocolate.
22. Known or suspected history of alcohol or drug abuse or excessive intake of alcohol as judged by the PI.
23. Involvement of any AstraZeneca, PAREXEL or Clinical Unit employee or their close relatives.
24. Participants who have previously been randomized to treatment in the current study.
25. Judgment by the PI that the participant should not participate in the study if they have any ongoing or recent (i.e., during the screening period) minor medical complaints that may interfere with the interpretation of study data or are considered unlikely to comply with study procedures, restrictions and requirements.
26. Vulnerable participants , e.g., kept in detention, protected adults under guardianship, trusteeship, or committed to an institution by governmental or juridical order.

Primary outcomes:
measure: Selumetinib and N-desmethyl selumetinib plasma PK parameter: Dose normalized area under plasma concentration-time curve from time zero to infinity (AUC/D)
timeFrame: At pre-dose, and 0.25, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.25, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 24, 36 and 48 hours post-dose(Days -1 to 3)
measure: Selumetinib and N-desmethyl selumetinib plasma PK parameter: Dose normalized area under the plasma concentration-time curve from time zero to time of last quantifiable concentration (AUClast/D)
timeFrame: At pre-dose, and 0.25, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.25, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 24, 36 and 48 hours post-dose(Days -1 to 3)
measure: Selumetinib and N-desmethyl selumetinib plasma PK parameter: Dose normalized maximum observed plasma concentration (Cmax/D)
timeFrame: At pre-dose, and 0.25, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.25, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 24, 36 and 48 hours post-dose(Days -1 to 3)
measure: Selumetinib and N-desmethyl selumetinib plasma PK parameter: Fraction of administered selumetinib granule dose systemically available relative to the capsule reference (Frel)
timeFrame: At pre-dose, and 0.25, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.25, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 24, 36 and 48 hours post-dose(Days -1 to 3)
Secondary outcomes:
measure: Selumetinib and N-desmethyl selumetinib plasma PK parameter: Area under plasma concentration time curve from time zero to infinity (AUC)
timeFrame: At pre-dose, and 0.25, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.25, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 24, 36 and 48 hours post-dose(Days -1 to 3)
measure: Selumetinib and N-desmethyl selumetinib plasma PK parameter: Area under the plasma concentration time curve from time zero to time of last quantifiable concentration (AUClast)
timeFrame: At pre-dose, and 0.25, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.25, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 24, 36 and 48 hours post-dose (Days -1 to 3)
measure: Selumetinib and N-desmethyl selumetinib plasma PK parameter: Area under the plasma concentration-time curve from zero to 12 hours post-dose [AUC(0-12)]
timeFrame: At pre-dose, and 0.25, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.25, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 24, 36 and 48 hours post-dose (Days -1 to 3)
measure: Selumetinib and N-desmethyl selumetinib plasma PK parameter: Maximum observed plasma concentration (Cmax)
timeFrame: At pre-dose, and 0.25, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.25, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 24, 36 and 48 hours post-dose (Days -1 to 3)
measure: Selumetinib and N-desmethyl selumetinib plasma PK parameter: Ratio of AUC in fed state to AUC in the fasted state (FRAUC)
timeFrame: At pre-dose, and 0.25, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.25, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 24, 36 and 48 hours post-dose (Days -1 to 3)
measure: Selumetinib and N-desmethyl selumetinib plasma PK parameter: Ratio of Cmax in fed state to Cmax in the fasted state (FRCmax)
timeFrame: At pre-dose, and 0.25, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.25, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 24, 36 and 48 hours post-dose (Days -1 to 3)
measure: Selumetinib and N-desmethyl selumetinib plasma PK parameter: Half-life associated with terminal slope (λz) of a semi-logarithmic concentration-time curve (t½λz)
timeFrame: At pre-dose, and 0.25, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.25, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 24, 36 and 48 hours post-dose (Days -1 to 3)
measure: Selumetinib and N-desmethyl selumetinib plasma PK parameter: Time to reach maximum observed plasma concentration (tmax)
timeFrame: At pre-dose, and 0.25, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.25, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 24, 36 and 48 hours post-dose (Days -1 to 3)
measure: Selumetinib and N-desmethyl selumetinib plasma PK parameter: Terminal elimination rate constant (λz)
timeFrame: At pre-dose, and 0.25, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.25, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 24, 36 and 48 hours post-dose (Days -1 to 3)
measure: Selumetinib plasma PK parameters: Apparent total body clearance of drug from plasma after extravascular administration (parent drug only) (CL/F)
timeFrame: At pre-dose, and 0.25, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.25, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 24, 36 and 48 hours post-dose (Days -1 to 3)
measure: Selumetinib plasma PK parameters: Apparent volume of distribution during the terminal phase after extravascular administration (Vz/F)
timeFrame: At pre-dose, and 0.25, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.25, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 24, 36 and 48 hours post-dose (Days -1 to 3)
measure: Selumetinib and N-desmethyl selumetinib plasma PK parameter: AUC
timeFrame: At pre-dose, and 0.25, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.25, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 24, 36 and 48 hours post-dose (Days -1 to 3)
measure: Selumetinib and N-desmethyl selumetinib plasma PK parameter: AUClast
timeFrame: At pre-dose, and 0.25, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.25, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 24, 36 and 48 hours post-dose (Days -1 to 3)
measure: Selumetinib and N-desmethyl selumetinib plasma PK parameter: AUC(0-12)
timeFrame: At pre-dose, and 0.25, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.25, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 24, 36 and 48 hours post-dose (Days -1 to 3)
measure: Selumetinib and N-desmethyl selumetinib plasma PK parameter: Cmax
timeFrame: At pre-dose, and 0.25, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.25, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 24, 36 and 48 hours post-dose (Days -1 to 3)
measure: Selumetinib and N-desmethyl selumetinib plasma PK parameter: FRAUC
timeFrame: At pre-dose, and 0.25, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.25, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 24, 36 and 48 hours post-dose (Days -1 to 3)
measure: Selumetinib and N-desmethyl selumetinib plasma PK parameter: FRCmax
timeFrame: At pre-dose, and 0.25, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.25, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 24, 36 and 48 hours post-dose (Days -1 to 3)
measure: Selumetinib and N-desmethyl selumetinib plasma PK parameter: t½λz
timeFrame: At pre-dose, and 0.25, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.25, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 24, 36 and 48 hours post-dose (Days -1 to 3)
measure: Selumetinib and N-desmethyl selumetinib plasma PK parameter: tmax
timeFrame: At pre-dose, and 0.25, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.25, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 24, 36 and 48 hours post-dose (Days -1 to 3)
measure: Selumetinib and N-desmethyl selumetinib plasma PK parameter: λz
timeFrame: At pre-dose, and 0.25, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.25, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 24, 36 and 48 hours post-dose (Days -1 to 3)
measure: Selumetinib plasma PK parameters: CL/F
timeFrame: At pre-dose, and 0.25, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.25, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 24, 36 and 48 hours post-dose (Days -1 to 3)
measure: Selumetinib plasma PK parameters: Vz/F
timeFrame: At pre-dose, and 0.25, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.25, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 24, 36 and 48 hours post-dose (Days -1 to 3)
measure: Taste questionnaire
timeFrame: At Days -1 to 3 (within 10 minutes following intake of selumetinib granule)
measure: Number of participants with adverse events (AEs)
timeFrame: From the time of informed consent, throughout the treatment periods up to and including the Follow-up Visit (7 to 10 days after last dose)
measure: Vital signs (systolic blood pressure [BP])
timeFrame: Change from baseline up to follow-up/early termination visit (7 to 10 days after last dose)
measure: Vital signs (diastolic BP)
timeFrame: Change from baseline up to follow-up/early termination visit (7 to 10 days after last dose)
measure: Pulse rate
timeFrame: Change from baseline up to follow-up/early termination visit (7 to 10 days after last dose)
measure: 12-lead electrocardiogram (ECG)
timeFrame: From baseline up to follow-up/early termination visit (7 to 10 days after last dose)
measure: Number of participants with abnormal findings in physical examination
timeFrame: From baseline up to follow-up/early termination visit (7 to 10 days after last dose)
measure: Ophthalmic examinations
timeFrame: At screening Visit or on Day -1 of Treatment Period 1
measure: Laboratory assessments: hematology - Hemoglobin (Hb)
timeFrame: Change from baseline up to follow-up/early termination visit (7 to 10 days after last dose)
measure: Laboratory assessments: hematology - erythrocyte count
timeFrame: Change from baseline up to follow-up/early termination visit (7 to 10 days after last dose)
measure: Laboratory assessments: hematology: Platelet count
timeFrame: Change from baseline up to follow-up/early termination visit (7 to 10 days after last dose)
measure: Laboratory assessments: hematology: leucocyte differential count (absolute count)
timeFrame: Change from baseline up to follow-up/early termination visit (7 to 10 days after last dose)
measure: Laboratory assessments: hematology: leucocyte cell count
timeFrame: Change from baseline up to follow-up/early termination visit (7 to 10 days after last dose)
measure: Laboratory assessments:hematology - differential count
timeFrame: Change from baseline up to follow-up/early termination visit (7 to 10 days after last dose)
measure: Laboratory assessments: Serum clinical chemistry - electrolytes
timeFrame: Change from baseline up to follow-up/early termination visit (7 to 10 days after last dose)
measure: Laboratory assessments: Serum clinical chemistry - urea nitrogen
timeFrame: Change from baseline up to follow-up/early termination visit (7 to 10 days after last dose)
measure: Laboratory assessments: Serum clinical chemistry - creatinine
timeFrame: Change from baseline up to follow-up/early termination visit (7 to 10 days after last dose)
measure: Laboratory assessments: Serum clinical chemistry: albumin
timeFrame: Change from baseline up to follow-up/early termination visit (7 to 10 days after last dose)
measure: Laboratory assessments: Serum clinical chemistry: Total Calcium
timeFrame: Change from baseline up to follow-up/early termination visit (7 to 10 days after last dose)
measure: Laboratory assessments: Serum clinical chemistry: Total protein
timeFrame: Change from baseline up to follow-up/early termination visit (7 to 10 days after last dose)
measure: Laboratory assessments: Serum clinical chemistry: Total bilirubin
timeFrame: Change from baseline up to follow-up/early termination visit (7 to 10 days after last dose)
measure: Laboratory assessments: Serum clinical chemistry: Creatine phosphokinase (CPK)
timeFrame: Change from baseline up to follow-up/early termination visit (7 to 10 days after last dose)
measure: Laboratory assessments: Serum clinical chemistry: Troponin (isoform as per institutional norm)
timeFrame: Change from baseline up to follow-up/early termination visit (7 to 10 days after last dose)
measure: Laboratory assessments: Serum clinical chemistry - Liver enzymes
timeFrame: Change from baseline up to follow-up/early termination visit (7 to 10 days after last dose)
measure: Laboratory assessments: Clinical urinalysis - glucose
timeFrame: Change from baseline up to follow-up/early termination visit (7 to 10 days after last dose)
measure: Laboratory assessments: Clinical Urinalysis - protein
timeFrame: Change from baseline up to follow-up/early termination visit (7 to 10 days after last dose)
measure: Laboratory assessments: Clinical Urinalysis - blood
timeFrame: Change from baseline up to follow-up/early termination visit (7 to 10 days after last dose)
Other outcomes:
Locations:
city: Baltimore
country: United States
facility: Research Site
state: Maryland
Study officials:
affiliation: PAREXEL Early Phase Clinical Unit Baltimore
name: Ronald Goldwater, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Cohen-Rabbie S, Mattinson A, So K, Wang N, Goldwater R. A Phase I, Open-label, Randomized, Crossover Study of the Relative Bioavailability of Capsule and Granule Formulations of Selumetinib. Clin Ther. 2022 Apr;44(4):565-576. doi: 10.1016/j.clinthera.2022.02.009. Epub 2022 Apr 9.
citation: Cohen-Rabbie S, Mattinson A, So K, Wang N, Goldwater R. Effect of food on capsule and granule formulations of selumetinib. Clin Transl Sci. 2022 Apr;15(4):878-888. doi: 10.1111/cts.13209. Epub 2022 Feb 15.