| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Chronic Hepatitis C infection |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Virus Diseases [C02] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10076789 |
| E.1.2 | Term | Chronic hepatitis C genotype 2 |
| E.1.2 | System Organ Class | 100000004862 |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10076831 |
| E.1.2 | Term | Chronic hepatitis C genotype 3 |
| E.1.2 | System Organ Class | 100000004862 |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10076786 |
| E.1.2 | Term | Chronic hepatitis C genotype 1 |
| E.1.2 | System Organ Class | 100000004862 |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To evaluate the safety and tolerability of AL-335 in combination with odalasvir (ODV) with or without simeprevir (SMV) in subjects with GT1 or GT2 or GT3 CHC infection |
|
| E.2.2 | Secondary objectives of the trial |
- To evaluate the efficacy of treatment with AL-335 in combination with ODV±SMV in subjects with GT1 or GT2 or GT3 CHC infection
- To evaluate the pharmacokinetics of AL-335 (and metabolites), ODV±SMV in plasma
- To evaluate the dynamics of HCV RNA in subjects with GT1 or GT2 or GT3 CHC infection treated with AL-335 in combination with ODV±SMV
- To evaluate the effect of baseline host and disease-related characteristics on treatment outcome
- To evaluate the impact of the presence of an (NS) 3 polymorphism (e.g., Q80K; SMV-containing arms only) and/or NS5A and NS5B polymorphisms at baseline on treatment outcome
- To evaluate the viral resistance profile after ≤12 weeks administration of AL-335 in combination with ODV±SMV |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Subject has provided written consent.
2. In the Investigator’s opinion, the subject 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 kg/m2, inclusive.
5. A woman of childbearing potential must have a negative serum (β-human chorionic gonadotropin) pregnancy test at screening.
6. Female subjects must either:
- not be of childbearing potential
or
- be of childbearing potential and not heterosexually active or if heterosexually active, have a vasectomized partner or be using an acceptable method of birth control
7. Male subjects must either:
- be surgically sterile
- not be heterosexually active
- if heterosexually active, have a partner who is postmenopausal or be practicing an acceptable method of birth control
8. Subjects must agree to refrain from sperm/egg donation from start of dosing through 6 months after the completion of study drug administration.
9. GT1a or 1b or GT2 or 3 CHC, depending on cohort, with positive HCV antibody and a positive HCV RNA at screening including documentation of CHC infection for at least 6 months. Genotype testing must occur at a screening visit.
10. Screening HCV RNA viral load ≥50,000 IU/mL, except for subjects with compensated cirrhosis (Child-Pugh Class A) who may have HCV RNA viral load ≥104 IU/mL.
11. Treatment naïve (i.e. no prior exposure to any approved or investigational drug(s) including direct-acting antivirals, and interferon-based treatment regimens) or, in subjects with cirrhosis, treatment experienced (defined as subjects who experienced virologic relapse after receiving a full course of pegylated interferon+ribavirin (peg/riba) treatment). Prior use of any direct acting antiviral in combination with peg/riba is not permitted.
12. Fibroscan, collected within 6 months of baseline visit, with liver stiffness score ≤12.5 kPa to be eligible
13. Subject 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 ECG.
14. Willing to avoid prolonged sun exposure and use of tanning devices while taking SMV and through 4 weeks of follow up. Subjects 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. |
|
| E.4 | Principal exclusion criteria |
1. Pregnant, planning on becoming pregnant (during treatment and up to 6 months after the EOT), or breast-feeding female subject, or male subject 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% or any other echocardiographic finding suggestive of clinically relevant cardiomyopathy.
5. Creatinine clearance of <60 mL/min (Cockcroft-Gault).
6. Positive test for HAV IgM, HBsAg, or 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 subject or prevent the subject 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 msec or corrected QT interval (QTc) >450 msec for male subjects and >470 msec for female subjects), 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 subject has a positive prestudy drug screen, including methadone unless the drug is prescribed by the subject’s physician. The list of drugs that should be screened for includes amphetamines, barbiturates, cocaine, opiates, phencyclidine (PCP), and benzodiazepines. Drug use without a physician prescription may be permitted on a case by case basis after review by the Sponsor in consultation with the investigator.
14. Laboratory abnormalities including: Hematocrit, White blood cell counts, Absolute neutrophil count, Platelets, Glycosylated hemoglobin, Prothrombin time, Albumin, Serum ALT concentration, CK
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 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
20. Hypersensitivity to the active substances (including sulfa allergy) or to any of the excipients of AL-335, ODV or SMV.
21. Evidence on recent (within 6 months) liver ultrasound of hepatic mass or lesion concerning for malignancy (subjects with cirrhosis only). |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Safety data including but not limited to tabulation of AEs, physical exam, vital signs, 12-lead ECGs, echocardiograms, and clinical laboratory results (including chemistry, hematology, and urine) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
1. The proportion of subjects who have a sustained virologic response (SVR; i.e., HCV RNA concentration <LLOQ (<15 IU/mL) at 4, 8, 12, 18 and 24 weeks after the last actual dose of treatment
2. PK parameters for AL-335 (and metabolites), ODV and SMV in plasma
3. The proportion of subjects who experience virologic relapse during the follow-up period.
4. The proportion of subjects who have treatment failure while receiving study medication
5. Viral kinetics, as determined at different timepoints during treatment by the proportion of subjects who achieve
- HCV RNA <LLOQ Undetectable
- HCV RNA <LLOQ
6. Time to achieve undetectable HCV RNA and <LLOQ HCV RNA
7. The amino acid sequence of the NS5A, NS5B and NS3/4A proteins at baseline and post-baseline in subjects who fail treatment
8. Effect of various baseline and host disease-related characteristics on treatment outcome |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. As per section E.5.2.1
2. Day 1, Weeks 2-4, 6, 8 (plus 10 and 12 for 12 week treatment cohorts)
3. Follow-up weeks 4, 8, 12, 18, 24
4. Day 1-3, weeks 1-8 (9-12 for 12 week treatment cohorts)
5. All timepoints
6. All timepoints
7. All timepoints
8. All timepoints |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 9 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 10 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Georgia |
| Mauritius |
| Moldova, Republic of |
| New Zealand |
| Romania |
|
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
| Week 24 Virology Follow-up Visit either after last planned dose date, if virologic failure occurred prior to this date, or after time of failure for the last subject treated |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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