A Study to Evaluate the Safety, Pharmacokinetics and Efficacy of the Combination of AL-335, Odalasvir, and Simeprevir

NCT02569710 | Completed Phase 2 Results FDA Drug

• 1 other identifier: AL-335-604
• Study Type: interventional
• Target: 161
• Locations: 4 countries
• Sites: 11

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.

Conditions

Chronic Hepatitis C

Outcome Measures

Primary Outcomes (10)

• Number of Participants With Treatment Emergent Adverse Event (TEAE)

  An adverse event (AE) was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. Treatment-emergent were events between administration of study drug and up to 43 weeks that were absent before treatment or that worsened relative to pre-treatment state.

  Up to 43 weeks

• Body Weight at End of Treatment

  Body weight (measured using a calibrated scale) at end of treatment was reported.

  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)

• Body Mass Index (BMI) at End of Treatment

  BMI was calculated by dividing the body weight (in kilogram) by the square of height (in meters). BMI at end of treatment was reported.

  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)

• Percentage of Participants With Worst Post-Baseline Values of Vital Signs

  Percentage of participants with worst post-baseline values of vital signs (Systolic blood pressure \[sBP\], Diastolic blood pressure \[dBP\], and Heart rate) were reported. For sBP, abnormally low: less than or equal to \[\<=\] 90 millimeters mercury \[mmHg\]; Grade 1 or mild: greater than \[\>\] 140 to less than \[\<\] 160 mmHg; Grade 2 or moderate: \>=160 to \<180 and Grade 3 or severe: \>=180 mmHg. For dBP, abnormally low: \<=50 mmHg; Grade 1 or mild: \>90 to \<100 mmHg; Grade 2 or moderate: \>=100 to \<110 mmHg and Grade 3 or severe: \>=110 mmHg. For Heart Rate, abnormally low: \<=50 beats per minute \[bpm\] and abnormally high: \>=120 bpm.

  Up to 43 weeks

• Percentage of Participants With Maximum Decrease From Baseline in Mean Ejection Fraction

  Percentage of participants with maximum decrease from baseline in mean ejection fraction was reported. Percentages are based on the number of participants with available data.

  Baseline up to End of treatment (up to 43 weeks)

• Percentage of Participants by Treatment Emergent Toxicity Grade - Hematology Parameters

  Percentage of participants by treatment emergent toxicity grade (1, 2, 3, 4 and 3+4) for Hematology parameters (hemoglobin, lymphocytes, neutrophils, leukocytes, platelets) were reported. Toxicity grades were defined as Grade 1: Mild; Grade 2: Moderate; Grade 3: Severe and Grade 4: potentially life-threatening. A toxicity is treatment-emergent if it is worse than the baseline or if baseline is missing.

  Up to 43 weeks

• Percentage of Participants by Treatment Emergent Toxicity Grade - Blood Chemistry Parameters

  Percentage of participants by treatment emergent toxicity grade (Grade 1,2,3,4,3+4) for Blood Chemistry (Calcium, Phosphate, Potassium, Sodium, Bicarbonate, Alanine aminotransferase, Alkaline phosphatase, Aspartate aminotransferase, Bilirubin, Direct bilirubin, Glucose, Cholesterol, Triglycerides, Urate, Triacylglycerol lipase, Creatinine, Creatinine clearance, Albumin and Creatine kinase) were reported. Toxicity grades were defined as Grade 1: Mild; Grade 2: Moderate; Grade 3: Severe and Grade 4: potentially life-threatening. A toxicity is treatment-emergent if it is worse than the baseline or if baseline is missing.

  Up to 43 weeks

• Percentage of Participants by Treatment Emergent Toxicity Grade - Prothrombin International Normalized Ratio (INR)

  Percentage of participants by treatment emergent toxicity grade for coagulation parameter (Prothrombin International Normalized Ratio) were reported. Toxicity grades were defined as Grade 1: Mild; Grade 2: Moderate; Grade 3: Severe and Grade 4: potentially life-threatening. A toxicity is treatment-emergent if it is worse than the baseline or if baseline is missing.

  Up to 43 weeks

• Percentage of Participants by Treatment Emergent Toxicity Grade - Urinalysis Parameter (Protein)

  Percentage of participants by treatment emergent toxicity grade (Grade 1, 2, 3, 4, 3+4) for urinalysis parameter (protein) was reported. Toxicity grades were defined as Grade 1: Mild; Grade 2: Moderate; Grade 3: Severe and Grade 4: potentially life-threatening. A toxicity is treatment-emergent if it is worse than the baseline or if baseline is missing.

  Up to 43 weeks

• Percentage of Participants With Worst Treatment Emergent Abnormalities of Electrocardiogram (ECG) Parameters

  Percentage of participants with worst treatment emergent abnormalities of ECG parameters (Fridericia Corrected QT interval \[QTcF\], Bazett Corrected QT interval \[QTcB\], Heart rate, QRS and PR, was reported. For QTcF abnormality was defined as 30 milliseconds (ms) less than or equal to (\<=) QTcF increase from baseline \<= 60 ms; for QTcB abnormality was defined as 30 ms \<= QTcB increase from baseline \<= 60 ms; for heart rate - abnormal low: \<= 50 beats per minute (bpm) and abnormal high: \>= 120 bpm; for QRS - abnormal high: \>120 ms; for PR - abnormally low: PR \< 120 ms; abnormally high - 200 ms \< PR \<= 240 ms and 240 ms \< PR \<= 300 ms.

  Up to 43 weeks

Secondary Outcomes (34)

• Percentage of Participants With Sustained Virologic Response (SVR) at Week 4, 12 and 24 After End of Treatment

  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)

• Minimum Observed Plasma Concentration (Cmin) of AL-335 and Its Metabolites (ALS-022399 and ALS-022227)

  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)

• Maximum Observed Plasma Concentration (Cmax) of AL-335 and Its Metabolites (ALS-022399 and ALS-022227)

  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)

• Trough Plasma Concentration (Ctrough) for AL-335 and Its Metabolites (ALS-022399 and ALS-022227)

  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)

• Time to Reach the Maximum Plasma Concentration (Tmax) of AL-335 and Its Metabolites (ALS-022399 and ALS-022227)

  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)

Study Arms (8)

Cohorts 1 and 2 (Without Cirrhosis) : AL-335+ODV+SMV

EXPERIMENTAL

Treatment-naïve non-cirrhotic Hepatitis C virus (HCV)-infected participants will receive AL-335 and Odalasvir (ODV) with Simeprevir (SMV) for 8 weeks.

Drug: AL-335; Drug: Odalasvir (ODV); Drug: Simeprevir (SMV)

Cohort 1b (Without Cirrhosis) : AL-335+ODV

EXPERIMENTAL

Treatment-naïve non-cirrhotic HCV-infected participants will receive AL-335 and ODV for 8 weeks.

Drug: AL-335; Drug: Odalasvir (ODV)

Cohort 3 (Without Cirrhosis) : AL-335+ODV+SMV

EXPERIMENTAL

Treatment-naïve non-cirrhotic HCV-infected participants will receive AL-335 and ODV with SMV for 6 weeks.

Drug: AL-335; Drug: Odalasvir (ODV); Drug: Simeprevir (SMV)

Cohort 4 (Without Cirrhosis) : AL-335+ODV

EXPERIMENTAL

Treatment-naïve non-cirrhotic HCV-infected participants will receive AL-335 and ODV up to 8 or 12 weeks.

Drug: AL-335; Drug: Odalasvir (ODV)

Cohort 5 (Without Cirrhosis) : AL-335+ODV + SMV

EXPERIMENTAL

Treatment-naïve non-cirrhotic HCV-infected participants will receive AL-335 and ODV with SMV up to 8 or 12 weeks.

Drug: AL-335; Drug: Odalasvir (ODV); Drug: Simeprevir (SMV)

Cohorts 6, 7, 8 and 12 (With Cirrhosis) : AL-335+ODV+SMV

EXPERIMENTAL

Treatment naïve or treatment experienced HCV-infected participants with compensated cirrhosis will receive AL-335 and ODV with SMV for 8 weeks.

Drug: AL-335; Drug: Odalasvir (ODV); Drug: Simeprevir (SMV)

Cohorts 9, 10 and 11 (With Cirrhosis) : AL-335+ODV+SMV

EXPERIMENTAL

Treatment naïve or treatment experienced HCV-infected participants with compensated cirrhosis will receive AL-335 and ODV with SMV for 12 weeks.

Drug: AL-335; Drug: Odalasvir (ODV); Drug: Simeprevir (SMV)

Cohorts 12 to 15: AL-335+ODV With/without SMV

EXPERIMENTAL

Based on safety, pharmacokinetic (PK), and viral load data, the treatment duration (4 to 12 weeks) and dose levels (AL-335: 400-1,200 milligram \[mg\], ODV: 25-50 mg with/without SMV: 75-150 mg) may be changed for ongoing and future cohorts (up to 15) after obtaining agreement from the Sponsor and the Principal Investigator.

Drug: AL-335; Drug: Odalasvir (ODV); Drug: Simeprevir (SMV)

Interventions

AL-335 DRUG

AL-335 tablets will be administered in a dose range of 400 to 1200 mg once daily (QD).

Cohort 1b (Without Cirrhosis) : AL-335+ODV; Cohort 3 (Without Cirrhosis) : AL-335+ODV+SMV; Cohort 4 (Without Cirrhosis) : AL-335+ODV; Cohort 5 (Without Cirrhosis) : AL-335+ODV + SMV; Cohorts 1 and 2 (Without Cirrhosis) : AL-335+ODV+SMV; Cohorts 12 to 15: AL-335+ODV With/without SMV; Cohorts 6, 7, 8 and 12 (With Cirrhosis) : AL-335+ODV+SMV; Cohorts 9, 10 and 11 (With Cirrhosis) : AL-335+ODV+SMV

Odalasvir (ODV) DRUG

ODV capsules will be administered in a dose range of 25 to 50 mg.

Also known as: ACH-3102

Cohort 1b (Without Cirrhosis) : AL-335+ODV; Cohort 3 (Without Cirrhosis) : AL-335+ODV+SMV; Cohort 4 (Without Cirrhosis) : AL-335+ODV; Cohort 5 (Without Cirrhosis) : AL-335+ODV + SMV; Cohorts 1 and 2 (Without Cirrhosis) : AL-335+ODV+SMV; Cohorts 12 to 15: AL-335+ODV With/without SMV; Cohorts 6, 7, 8 and 12 (With Cirrhosis) : AL-335+ODV+SMV; Cohorts 9, 10 and 11 (With Cirrhosis) : AL-335+ODV+SMV

Simeprevir (SMV) DRUG

SMV tablets will be administered in a dose range of 75 to 150 mg QD or every other day (QOD).

Cohort 3 (Without Cirrhosis) : AL-335+ODV+SMV; Cohort 5 (Without Cirrhosis) : AL-335+ODV + SMV; Cohorts 1 and 2 (Without Cirrhosis) : AL-335+ODV+SMV; Cohorts 12 to 15: AL-335+ODV With/without SMV; Cohorts 6, 7, 8 and 12 (With Cirrhosis) : AL-335+ODV+SMV; Cohorts 9, 10 and 11 (With Cirrhosis) : AL-335+ODV+SMV

Eligibility Criteria

• Age: 18 Years - 70 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Participant has provided written consent
• 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
• Male or female, 18-70 years of age
• Body mass index (BMI) 18-35 kilogram per meter square (kg/m\^2), inclusive
• A woman of childbearing potential must have a negative serum (beta-human chorionic gonadotropin) pregnancy test at screening
• 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

You may not qualify if:

• 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)
• 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
• 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
• Screening echocardiogram ejection fraction \<55 percentage (%) or any other echocardiographic finding suggestive of clinically relevant cardiomyopathy
• Creatinine clearance of \<60 mL/min (Cockcroft-Gault)
• Positive test for Hepatitis A virus immunoglobulin (HAV) Immunoglobulin M (IgM), Hepatitis B surface antigen (HBsAg), or Human Immunodeficiency Virus (HIV) Ab
• Abnormal screening laboratory results that are considered clinically significant by the investigator
• History of clinical hepatic decompensation, e.g., variceal bleeding, spontaneous bacterial peritonitis, ascites, hepatic encephalopathy or active jaundice (within last year)
• 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
• 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
• History or family history of abnormal ECG intervals, for example prolonged QT syndrome (torsade de pointes) or sudden cardiac death
• 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
• Laboratory abnormalities including:
• Hematocrit \<0.34
• White blood cell counts \<3,500/millimeter (mm)\^3 (\<1,000/mm\^3 for participants with compensated cirrhosis)

Sponsors & Collaborators

• Alios Biopharma Inc.: lead

Study Sites (11)

CAP Research Ltd

Phoenix, Mauritius

Location

Republican Clinical Hospital

Chisinau, Moldova

Location

Auckland Clinical Studies

Auckland, 1150, New Zealand

Location

Christchurch Clinical Studies Trust

Christchurch, 8011, New Zealand

Location

Waikato Hospital

Hamilton, New Zealand

Location

P3 Research Ltd - Hawkes Bay

Havelock North, New Zealand

Location

P3 Research Ltd - Wellington

Wellington, New Zealand

Location

Wellington Hospital

Wellington, New Zealand

Location

King's College Hospital

Brixton, United Kingdom

Location

NHS Greater Glasgow and Clyde Glasgow Royal Infirmary

Glasgow, United Kingdom

Location

Pennine Acute Hospitals Trust

Oldham, United Kingdom

Location

MeSH Terms

Conditions

Hepatitis C, Chronic

Interventions

adafosbuvir; odalasvir; Simeprevir

Condition Hierarchy (Ancestors)

Hepatitis C; Blood-Borne Infections; Communicable Diseases; Infections; Hepatitis, Viral, Human; Virus Diseases; Flaviviridae Infections; RNA Virus Infections; Hepatitis, Chronic; Hepatitis; Liver Diseases; Digestive System Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Sulfonamides; Sulfones; Sulfur Compounds; Organic Chemicals; Heterocyclic Compounds, 3-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Limitations and Caveats

Limitations of the study included the open-label design, limited sample size, and the lack of a comparator group.

Results Point of Contact

• Title: Director
• Organization: Alios BioPharma, Inc

ClinicalTrialDisclosure@its.jnj.com

844-434-4210

Study Officials

• Alios Biopharma Inc. Clinical Trial

  Alios Biopharma Inc.

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 1, 2015
• First Posted: October 7, 2015
• Study Start: October 31, 2015
• Primary Completion: May 11, 2018
• Study Completion: May 11, 2018
• Last Updated: July 16, 2019
• Results First Posted: July 16, 2019

Record last verified: 2019-06

Locations

MA (1); MO (1); NZ (6); GB (3)