Clinical trial NCT02569710: A Study to Evaluate the Safety, Pharmacokinetics and Efficacy of the Combination of AL-335, Odalasvir, and Simeprevir
Official title: A Phase 2a, Open-Label Study to Evaluate the Safety, Pharmacokinetics and Efficacy of the Combination of AL-335 and Odalasvir, With or Without Simeprevir, in Treatment-Naïve Subjects With Genotype 1, 2 or 3 Chronic Hepatitis C Infection With or Without Compensated Child Pugh A Cirrhosis
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Chronic Hepatitis C
Lead sponsor: Alios Biopharma Inc.
Sponsor class: INDUSTRY
First posted: 2015-10-07
Enrollment: 161
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The purpose of this study is to evaluate the safety and tolerability of AL-335 in combination with odalasvir (ODV) with or without simeprevir (SMV) in participants with genotype (GT)1 or GT2 or GT3 chronic hepatitis C (CHC) infection.


Eligibility criteria: Inclusion Criteria:

1. Participant has provided written consent
2. In the Investigator's opinion, the participant is able to understand and comply with protocol requirements, instructions, and protocol stated restrictions and is likely to complete the study as planned
3. Male or female, 18-70 years of age
4. Body mass index (BMI) 18-35 kilogram per meter square (kg/m\^2), inclusive
5. A woman of childbearing potential must have a negative serum (beta-human chorionic gonadotropin) pregnancy test at screening
6. Female participants must either:

   * not be of childbearing potential defined as: i. Postmenopausal for at least 12 months (that is \[i.e.\], 2 years of amenorrhea without an alternative medical cause) and a serum follicle stimulating hormone (FSH) level in the postmenopausal range (per reference laboratory), OR ii. Surgically sterile (example \[e.g.\], underwent total hysterectomy, bilateral oophorectomy, or bilateral tubal ligation/bilateral tubal clips without reversal operation), or otherwise incapable of becoming pregnant, OR
   * be of childbearing potential AND
   * not heterosexually active (e.g., abstinent or homosexual) from screening until 6 months after study drug administration (or longer, if dictated by local regulations), OR
   * if heterosexually active

     * have a vasectomized partner (confirmed sterile per verbal account of the participant), OR
     * using an acceptable method of birth control from screening and agree to continue to use the same method of contraception throughout the study and for 6 months after study drug administration (or longer, if dictated by local regulations). Oral hormone based contraceptives are not allowed from 14 days before the planned study drug administration until 6 months after the last dose of treatment due to the potential for drug-drug interactions which might undermine their efficacy. An intrauterine device (IUD), being either hormonal (i.e., Intra-Uterine System \[IUS\*\]) or non-hormonal, is considered highly effective and reliable; therefore participants using an IUD/IUS are not required to use additional contraceptive methods (no double-barrier method is required). Other non-oral hormone-based contraception methods (e.g., injectable, implants, transdermal system, vaginal ring) may be continued, but as the interaction of the study drug with hormone-based contraception is unknown, these methods are not considered to be reliable and therefore participants should use a double-barrier method (e.g., male condom+either diaphragm or cervical cap with or without spermicide).

       * An IUS does not rely on systemic plasma concentrations and is therefore not expected to be impacted by a potential drug-drug interaction (DDI)

   Note 1: Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual intercourse during the entire period of risk associated with the study drug. The reliability of sexual abstinence needs to be evaluated in relation to the duration of the study and the preferred and usual lifestyle of the participant.

   Note 2: A male and female condom should not be used together due to risk of breakage or damage caused by latex friction
7. A post-menopausal female who is receiving hormone replacement therapy and is willing to discontinue hormone therapy 30 days before study drug dosing and agrees to remain off hormone replacement therapy for the duration of the study may be eligible for study participation.

   * Male participants must either:
   * be surgically sterile (had a vasectomy), or otherwise incapable of fathering a child, OR
   * not be heterosexually active (e.g., abstinent or homosexual) from enrollment (Day 1) in the study until at least 6 months after study drug administration, OR
   * if heterosexually active:

     * have a partner who is postmenopausal (2 years amenorrhea), surgically sterile (e.g., has had a total hysterectomy, bilateral oophorectomy, or bilateral tubal ligation/bilateral tubal clips without reversal operation), or otherwise incapable of becoming pregnant OR
     * be practicing an acceptable method of birth control from enrollment in the study (Day 1) and agree to continue to use the same method of contraception throughout the study and for at least 6 months after study drug administration (or longer, if dictated by local regulations). An acceptable method of birth control for male participants is a double-barrier method (e.g., male condom+either diaphragm or cervical cap with or without spermicide).

   Note: Male participants with a female partner who uses hormonal contraceptives (oral, injectable, implants) or a hormonal (IUS) or non-hormonal IUD and male participants who are vasectomized or otherwise incapable of fathering a child are not required to use additional contraceptive methods.

   Note 1: Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual intercourse during the entire period of risk associated with the study drug. The reliability of sexual abstinence needs to be evaluated in relation to the duration of the study and the preferred and usual lifestyle of the participant.

   Note 2: A male and female condom should not be used together due to risk of breakage or damage caused by latex friction.

   NOTE: Contraceptive use by men and women should be consistent with local regulations regarding the use of contraceptive methods for participants participating in clinical studies if these are stricter than what is proposed in these inclusion criteria
8. Participants must agree to refrain from sperm/egg donation from start of dosing through 6 months after the completion of study drug administration
9. Genotype (GT) 1a or 1b or GT2 or 3 chronic hepatitis C (CHC), depending on cohort, with positive Hepatitis C virus (HCV) antibody and a positive HCV ribonucleic acid (RNA) at screening including documentation of CHC infection for at least 6 months. Genotype testing must occur at a screening visit. NOTE: GT1 patients are eligible for inclusion even if they cannot be successfully subtyped unless a specific subtype is required for a cohort
10. Screening HCV RNA viral load greater than or equal to (\>=) 50,000 International Units per milliliter (IU/mL), except for participants with compensated cirrhosis (Child Pugh Class A) who may have HCV RNA viral load \>=10\^4 IU/mL
11. No prior treatment for CHC (defined as no prior exposure to any approved or investigational drug including direct-acting antivirals, and interferon-based treatments)
12. Fibroscan, collected within 6 months of baseline visit, with liver stiffness score less than or equal to (\<=) 12.5 kilo Pascal (kPa) to be eligible (except for participants with cirrhosis, see below).

    * participants with compensated cirrhosis must meet the Child-Pugh Class A definition (see Appendix G) and at least one of the following criteria: i. Liver biopsy result indicating the presence of cirrhosis (e.g., Metavir F4; Ishak \>5) or ii. Fibroscan evaluation with a liver stiffness score \>12.5 kPa
13. Participant is otherwise in good health as deemed by the investigator, based on the findings of a medical evaluation including medical history, physical examination, laboratory tests and electrocardiogram (ECG)
14. Willing to avoid prolonged sun exposure and use of tanning devices while taking Simeprevir (SMV) and through 4 weeks of follow up. Participant should also be advised to use a broad-spectrum sunscreen and lip balm of at least sun protection factor \>30 to help protect against potential sunburn

Exclusion Criteria:

1. Pregnant, planning on becoming pregnant (during treatment and up to 6 months after the end of treatment \[EOT\]), or breast-feeding female participant, or male participant whose female partner is pregnant or planning on becoming pregnant (during treatment and up to 6 months after the EOT)
2. Other than CHC with or without compensated cirrhosis, clinically significant cardiovascular, respiratory, renal, gastrointestinal, hematologic, neurologic, thyroid or any other medical illness or psychiatric disorder, as determined by the Investigator and/or Sponsor's Medical Monitor
3. History or other clinical evidence of significant or unstable cardiac disease (e.g., angina, congestive heart failure, myocardial infarction, diastolic dysfunction, significant arrhythmia, coronary heart disease, and/or clinically significant ECG abnormalities), moderate to severe valvular disease or uncontrolled hypertension at screening
4. Screening echocardiogram ejection fraction \<55 percentage (%) or any other echocardiographic finding suggestive of clinically relevant cardiomyopathy
5. Creatinine clearance of \<60 mL/min (Cockcroft-Gault)
6. Positive test for Hepatitis A virus immunoglobulin (HAV) Immunoglobulin M (IgM), Hepatitis B surface antigen (HBsAg), or Human Immunodeficiency Virus (HIV) Ab
7. Abnormal screening laboratory results that are considered clinically significant by the investigator
8. History of clinical hepatic decompensation, e.g., variceal bleeding, spontaneous bacterial peritonitis, ascites, hepatic encephalopathy or active jaundice (within last year)
9. Any condition that, in the opinion of the investigator, would compromise the study's objectives or the well-being of the participant or prevent the participant from meeting the study requirements
10. Participation in an investigational drug trial or having received an investigational vaccine within 30 days or 5 half lives (whichever is longer) prior to study medication
11. Clinically significant abnormal screening ECG findings (e.g., PR \>200 msec, QRS interval \>120 millisecond (msec) or corrected QT interval (QTc) \>450 msec for male participants and \>470 msec for female participants), based on an average of triplicate ECGs. Any evidence of heart block or bundle branch block is also exclusionary
12. History or family history of abnormal ECG intervals, for example prolonged QT syndrome (torsade de pointes) or sudden cardiac death
13. The participant has a positive prestudy drug screen, including methadone unless the drug is prescribed by the participant's physician. The list of drugs that should be screened for includes amphetamines, barbiturates, cocaine, opiates, phencyclidine (PCP), and benzodiazepines
14. Laboratory abnormalities including:

    * Hematocrit \<0.34
    * White blood cell counts \<3,500/millimeter (mm)\^3 (\<1,000/mm\^3 for participants with compensated cirrhosis)
    * Absolute neutrophil count \<1,000/mm\^3 (\<750/mm\^3 for participants with compensated cirrhosis)
    * Platelets \<=120,000/mm\^3 (platelets ≤90,000/mm\^3 for participants with compensated cirrhosis)
    * Glycosylated hemoglobin (HbA1C) \>55 mmol/mol
    * Prothrombin time \>=1.5 \* upper limit of normal (ULN)
    * Albumin \<=32 gram per liter (g/L), bilirubin \>=1.5 milligram per deciliter (mg/dL) at screening (participants with documented Gilbert's disease allowed)
    * Serum ALT concentration \>=5\* ULN
    * CK \>1.5\* ULN A single repeat laboratory evaluation under appropriate conditions (e.g., fasted, no antecedent exercise) is allowed for eligibility determination
15. Any condition possibly affecting drug absorption (e.g., gastrectomy or other significant gastrointestinal tract surgery, such as gastroenterostomy, small bowel resection, or active enterostomy)
16. Clinically significant blood loss or elective blood donation of significant volume (i.e., \>500 mL) within 60 days of first dose of study drug; \>1 unit of plasma within 7 days of first dose of study drug
17. Evidence of clinically relevant active infection that would interfere with study conduct or its interpretation
18. History of regular alcohol intake \>10 standard drinks per week of alcohol for females and \>15 standard drinks per week for males (one unit is defined as 10 g alcohol) within 3 months of the screening visit
19. The use of prohibited medications, including prescription, over the counter (OTC) medications, herbal medications, inducers or inhibitors of Cytochrome P450 (CYP450) enzymes or drug transporters (including P-gp) within 14 days prior to the first dose of study medication is excluded, unless previously approved by the Sponsor's Medical Monitor. NOTE: Chronic medication use is permitted so long as they are medically necessary, deemed acceptable by the Principal Investigator and Medical Monitor, and not Prohibited Medications (see Section 5.12)
20. Hypersensitivity to the active substances (including sulfa allergy) or to any of the excipients of AL-335, Odalasvir (ODV) or SMV
21. Evidence on recent (within 6 months) liver ultrasound of hepatic mass or lesion concerning for malignancy (participants with cirrhosis only)

Primary outcomes:
measure: Number of Participants With Treatment Emergent Adverse Event (TEAE)
timeFrame: Up to 43 weeks
measure: Body Weight at End of Treatment
timeFrame: End of treatment (Cohort 3: 6 weeks; Cohort 1, Cohort 1b+ Cohort 4, Cohort 2, Cohort 5a, and Cohort 6, 7, 8: 8 weeks; Cohort 4, Cohort 5b, Cohort 9 and Cohort 11: 12 weeks)
measure: Body Mass Index (BMI) at End of Treatment
timeFrame: End of treatment (Cohort 3: 6 weeks; Cohort 1, Cohort 1b+ Cohort 4, Cohort 2, Cohort 5a, and Cohort 6, 7, 8: 8 weeks; Cohort 4, Cohort 5b, Cohort 9 and Cohort 11: 12 weeks)
measure: Percentage of Participants With Worst Post-Baseline Values of Vital Signs
timeFrame: Up to 43 weeks
measure: Percentage of Participants With Maximum Decrease From Baseline in Mean Ejection Fraction
timeFrame: Baseline up to End of treatment (up to 43 weeks)
measure: Percentage of Participants by Treatment Emergent Toxicity Grade - Hematology Parameters
timeFrame: Up to 43 weeks
measure: Percentage of Participants by Treatment Emergent Toxicity Grade - Blood Chemistry Parameters
timeFrame: Up to 43 weeks
measure: Percentage of Participants by Treatment Emergent Toxicity Grade - Prothrombin International Normalized Ratio (INR)
timeFrame: Up to 43 weeks
measure: Percentage of Participants by Treatment Emergent Toxicity Grade - Urinalysis Parameter (Protein)
timeFrame: Up to 43 weeks
measure: Percentage of Participants With Worst Treatment Emergent Abnormalities of Electrocardiogram (ECG) Parameters
timeFrame: Up to 43 weeks
Secondary outcomes:
measure: Percentage of Participants With Sustained Virologic Response (SVR) at Week 4, 12 and 24 After End of Treatment
timeFrame: At Week 4, 12 and Week 24 after end of treatment (Cohort 3: 6 weeks; Cohort 1, Cohort 1b+ Cohort 4, Cohort 2, Cohort 5a, and Cohort 6, 7, 8: 8 weeks; Cohort 4, Cohort 5b, Cohort 9 and Cohort 11: 12 weeks)
measure: Minimum Observed Plasma Concentration (Cmin) of AL-335 and Its Metabolites (ALS-022399 and ALS-022227)
timeFrame: Predose, 0.5, 1, 2, 3, 4, 6, 9, and 24 hours postdose (Week 2), 2-4 hours postdose (Weeks 3 and 6), 6-8 hours postdose (Weeks 4 and 8)
measure: Maximum Observed Plasma Concentration (Cmax) of AL-335 and Its Metabolites (ALS-022399 and ALS-022227)
timeFrame: Predose, 0.5, 1, 2, 3, 4, 6, 9, and 24 hours postdose (Week 2), 2-4 hours postdose (Weeks 3 and 6), 6-8 hours postdose (Weeks 4 and 8)
measure: Trough Plasma Concentration (Ctrough) for AL-335 and Its Metabolites (ALS-022399 and ALS-022227)
timeFrame: Predose, 0.5, 1, 2, 3, 4, 6, 9, and 24 hours postdose (Week 2), 2-4 hours postdose (Weeks 3 and 6), 6-8 hours postdose (Weeks 4 and 8)
measure: Time to Reach the Maximum Plasma Concentration (Tmax) of AL-335 and Its Metabolites (ALS-022399 and ALS-022227)
timeFrame: Predose, 0.5, 1, 2, 3, 4, 6, 9, and 24 hours postdose (Week 2), 2-4 hours postdose (Weeks 3 and 6), 6-8 hours postdose (Weeks 4 and 8)
measure: Area Under the Plasma Concentration-Time Curve From Time 0 to Last Measurable Plasma Concentration (AUC [0-last]) of AL-335 and Its Metabolites (ALS-022399 and ALS-022227)
timeFrame: Predose, 0.5, 1, 2, 3, 4, 6, 9, and 24 hours postdose (Week 2), 2-4 hours postdose (Weeks 3 and 6), 6-8 hours postdose (Weeks 4 and 8)
measure: Area Under the Plasma Concentration Time-Curve at 24 Hours (AUC0-24) for AL-335 and Its Metabolites (ALS-022399 and ALS-022227)
timeFrame: Predose, 0.5, 1, 2, 3, 4, 6, 9, and 24 hours postdose
measure: Last Measurable Plasma Concentration (Clast) of AL-335 and Its Metabolite (ALS-022399 and ALS-022227)
timeFrame: Predose, 0.5, 1, 2, 3, 4, 6, 9, and 24 hours postdose (Week 2), 2-4 hours postdose (Weeks 3 and 6), 6-8 hours postdose (Weeks 4 and 8)
measure: Time Corresponding to Last Measurable Plasma Concentration (Tlast) for AL-335 and Its Metabolites (ALS-022399 and ALS-022227)
timeFrame: Predose, 0.5, 1, 2, 3, 4, 6, 9, and 24 hours postdose (Week 2), 2-4 hours postdose (Weeks 3 and 6), 6-8 hours postdose (Weeks 4 and 8)
measure: Average Plasma Concentration at Steady State (Css,Avg) of ALS-022227
timeFrame: Predose, 0.5, 1, 2, 3, 4, 6, 9, and 24 hours postdose (Week 2), 2-4 hours postdose (Weeks 3 and 6), 6-8 hours postdose (Weeks 4 and 8)
measure: Cmin of Simeprevir
timeFrame: Predose, 0.5, 1, 2, 3, 4, 6, 9, and 24 hours postdose (Week 2), 2-4 hours postdose (Weeks 3 and 6), 6-8 hours postdose (Weeks 4 and 8)
measure: Cmax of Simeprevir
timeFrame: Predose, 0.5, 1, 2, 3, 4, 6, 9, and 24 hours postdose (Week 2), 2-4 hours postdose (Weeks 3 and 6), 6-8 hours postdose (Weeks 4 and 8)
measure: Ctrough of Simeprevir
timeFrame: Predose, 0.5, 1, 2, 3, 4, 6, 9, and 24 hours postdose (Week 2), 2-4 hours postdose (Weeks 3 and 6), 6-8 hours postdose (Weeks 4 and 8)
measure: Tmax of Simeprevir
timeFrame: Predose, 0.5, 1, 2, 3, 4, 6, 9, and 24 hours postdose (Week 2), 2-4 hours postdose (Weeks 3 and 6), 6-8 hours postdose (Weeks 4 and 8)
measure: AUC (0-last) of Simeprevir
timeFrame: Predose, 0.5, 1, 2, 3, 4, 6, 9, and 24 hours postdose (Week 2), 2-4 hours postdose (Weeks 3 and 6), 6-8 hours postdose (Weeks 4 and 8)
measure: AUC (0-24) of Simeprevir
timeFrame: Predose, 0.5, 1, 2, 3, 4, 6, 9, and 24 hours postdose
measure: Clast of Simeprevir
timeFrame: Predose, 0.5, 1, 2, 3, 4, 6, 9, and 24 hours postdose (Week 2), 2-4 hours postdose (Weeks 3 and 6), 6-8 hours postdose (Weeks 4 and 8)
measure: Tlast of Simeprevir
timeFrame: Predose, 0.5, 1, 2, 3, 4, 6, 9, and 24 hours postdose (Week 2), 2-4 hours postdose (Weeks 3 and 6), 6-8 hours postdose (Weeks 4 and 8)
measure: Average Plasma Concentration at Steady State (Css,Avg) of Simeprevir
timeFrame: Predose, 0.5, 1, 2, 3, 4, 6, 9, and 24 hours postdose (Week 2), 2-4 hours postdose (Weeks 3 and 6), 6-8 hours postdose (Weeks 4 and 8)
measure: Cmin of Odalasvir
timeFrame: Predose, 0.5, 1, 2, 3, 4, 6, 9, and 24 hours postdose (Week 2), 2-4 hours postdose (Weeks 3 and 6), 6-8 hours postdose (Weeks 4 and 8)
measure: Cmax of Odalasvir
timeFrame: Predose, 0.5, 1, 2, 3, 4, 6, 9, and 24 hours postdose (Week 2), 2-4 hours postdose (Weeks 3 and 6), 6-8 hours postdose (Weeks 4 and 8)
measure: Ctrough of Odalasvir
timeFrame: Predose, 0.5, 1, 2, 3, 4, 6, 9, and 24 hours postdose (Week 2), 2-4 hours postdose (Weeks 3 and 6), 6-8 hours postdose (Weeks 4 and 8)
measure: Tmax of Odalasvir
timeFrame: Predose, 0.5, 1, 2, 3, 4, 6, 9, and 24 hours postdose (Week 2), 2-4 hours postdose (Weeks 3 and 6), 6-8 hours postdose (Weeks 4 and 8)
measure: AUC (0-last) of Odalasvir
timeFrame: Predose, 0.5, 1, 2, 3, 4, 6, 9, and 24 hours postdose (Week 2), 2-4 hours postdose (Weeks 3 and 6), 6-8 hours postdose (Weeks 4 and 8)
measure: AUC (0-24) for Odalasvir
timeFrame: Predose, 0.5, 1, 2, 3, 4, 6, 9, and 24 hours postdose
measure: Clast of Odalasvir
timeFrame: Predose, 0.5, 1, 2, 3, 4, 6, 9, and 24 hours postdose (Week 2), 2-4 hours postdose (Weeks 3 and 6), 6-8 hours postdose (Weeks 4 and 8)
measure: Tlast of Odalasvir
timeFrame: Predose, 0.5, 1, 2, 3, 4, 6, 9, and 24 hours postdose (Week 2), 2-4 hours postdose (Weeks 3 and 6), 6-8 hours postdose (Weeks 4 and 8)
measure: Average Plasma Concentration at Steady State (Css,Avg) of Odalasvir
timeFrame: Predose, 0.5, 1, 2, 3, 4, 6, 9, and 24 hours postdose (Week 2), 2-4 hours postdose (Weeks 3 and 6), 6-8 hours postdose (Weeks 4 and 8)
measure: Percentage of Participants With Virologic Relapse During the Follow-up Period
timeFrame: Follow up period (Up to Week 12 after end of treatment)
measure: Percentage of Participants With On-treatment Failure
timeFrame: Up to 12 weeks
measure: Percentage of Participants Who Achieved HCV RNA Less Then (<) LLOQ Undetectable
timeFrame: Day 2, 3, Week 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 and End of treatment (Cohort 3: 6 weeks; Cohort 1, Cohort 1b+ Cohort 4, Cohort 2, Cohort 5a, and Cohort 6, 7, 8: 8 weeks; Cohort 4, Cohort 5b, Cohort 9 and Cohort 11: 12 weeks)
measure: Percentage of Participants Who Achieved HCV RNA <LLOQ
timeFrame: Day 2, 3, Week 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 and End of treatment (Cohort 3: 6 weeks; Cohort 1, Cohort 1b+ Cohort 4, Cohort 2, Cohort 5a, and Cohort 6, 7, 8: 8 weeks; Cohort 4, Cohort 5b, Cohort 9 and Cohort 11: 12 weeks)
measure: Time to Achieve Undetectable HCV RNA or < LLOQ HCV RNA
timeFrame: Up to Week 24 (follow up visit)
measure: Number of Participants With HCV Nonstructural Protein NS5A, NS5B, and NS3/4A Sequence in Participants With Virologic Failure
timeFrame: Up to Week 24 (Follow up visit)
Other outcomes:
Locations:
city: Phoenix
country: Mauritius
facility: CAP Research Ltd
city: Chisinau
country: Moldova, Republic of
facility: Republican Clinical Hospital
city: Auckland
country: New Zealand
facility: Auckland Clinical Studies
city: Christchurch
country: New Zealand
facility: Christchurch Clinical Studies Trust
city: Hamilton
country: New Zealand
facility: Waikato Hospital
city: Havelock North
country: New Zealand
facility: P3 Research Ltd - Hawkes Bay
city: Wellington
country: New Zealand
facility: P3 Research Ltd - Wellington
city: Wellington
country: New Zealand
facility: Wellington Hospital
city: Brixton
country: United Kingdom
facility: King's College Hospital
city: Glasgow
country: United Kingdom
facility: NHS Greater Glasgow and Clyde Glasgow Royal Infirmary
city: Oldham
country: United Kingdom
facility: Pennine Acute Hospitals Trust
Study officials:
affiliation: Alios Biopharma Inc.
name: Alios Biopharma Inc. Clinical Trial
role: STUDY_DIRECTOR
References: