Efficacy and Safety Study of Pegylated Interferon Lambda-1a With Ribavirin and Daclatasvir, to Treat naïve Subjects With Chronic HCV Genotypes 1, 2, 3, and 4 Who Are Co-infected With HIV

Phase 3 Open Label Study Evaluating the Efficacy and Safety of Pegylated Interferon Lambda-1a, in Combination With Ribavirin and Daclatasvir, for Treatment of Chronic HCV Infection With Treatment naïve Genotypes 1, 2, 3 or 4 in Subjects Co-infected With HIV

Status

Terminated

Phases

Phase 3

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT01866930

Acronym

DIMENSION

Enrollment

453

Registered

2013-06-03

Start date

2013-07-11

Completion date

2015-08-27

Last updated

2023-06-13

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Chronic Hepatitis C Infection

Brief summary

To evaluate Sustained Virologic Response at post treatment Week 12 (SVR12)following treatment with Lambda/RBV/DCV in chronic HCV GT-1, -2, -3 or -4 subjects co-infected with HIV-1

Detailed description

Study Classification: Safety/Efficacy and Pharmacokinetics/dynamics GT=genotype

Interventions

BIOLOGICALPegylated Interferon Lambda-1a

DRUGDaclatasvir (DCV)

DRUGRibasphere (RBV)

Study design

Allocation

NON_RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

NONE

Eligibility

Sex/Gender

ALL

Age

18 Years to No maximum

Healthy volunteers

Inclusion criteria

* HCV Genotype-1, -2, -3 or -4 treatment naïve; * HCV RNA ≥10,000 IU/mL at screening; * HIV-1 infection \[(approximately 200 subjects receiving HAART, approximately 100 subjects not receiving highly active antiretroviral therapy (HAART)\]; * For subjects receiving HAART, HIV RNA must be below \<40 copies/mL at screening and \<200 copies/mL for at least 8 weeks prior to screening; * CD4 cell count at screening must be ≥100 cells/μL if receiving HAART or ≥350 cells/μL if not receiving HAART) * Seronegative for Hepatitis B Surface Antigen (HBsAg) * Body Mass Index (BMI) of 18 to 35 kg/m2, inclusive. BMI=weight (kg)/\[height (m)\]2 at screening; * Subjects with compensated cirrhosis are permitted, but the number of subjects will be capped at approximately 30%. If a subject does not have cirrhosis, a liver biopsy within 3 years prior to enrollment is required to demonstrate the absence of cirrhosis. If cirrhosis is present, any prior liver biopsy is sufficient. Fibroscan® or FibroTest are acceptable if performed within 1 year prior to treatment in countries where liver biopsy is not required prior to treatment and where non-invasive imaging tests are approved for staging of liver disease * Subjects with mild to moderate hemophilia as defined as: 1. Mild-factor level activity of 6-4% OR 2. Moderate defined as factor level activity of 1-5%

Exclusion criteria

* Any evidence of liver disease other than chronic HCV; * Subjects infected with human immunodeficiency virus (HIV-2); * Diagnosed or suspected hepatocellular carcinoma; * Decompensated liver disease; * Presence of acquired immunodeficiency syndrome (AIDS)-defining opportunistic infections within 12 weeks prior to study entry (AIDS-defining opportunistic infections as defined by the CDC, (CDC, JAMA 1993 Feb 10;269(6):729-30) * Laboratory values: ANC \<1.5 x 109 cells/L (\<1.2 x 109 cells/L for Blacks), platelet count \<90 x 109 cells/L, hemoglobin \<11 g/dL for females, hemoglobin \<12 g/dL for males; * Subjects (receiving HAART) who had first initiated anti-retroviral therapy within last 8 weeks prior to Day 1; however, if changes are required to a subject's HAART regimen to meet the requirements of the protocol, these changes are allowed at the screening visit. Subjects should wait a minimum of 1 month prior to Day 1 after a repeat of HIV viral load has been confirmed, \<40 copies/mL * Subjects on Zidovudine (AZT), Didanosine (ddI), or Stavudine (d4T); * Active drug or alcohol use or dependence that, in the opinion of the site investigator, would interfere with adherence to study requirements * Subjects with severe hemophilia (defined as \<1% factor activity level)

Design outcomes

Primary

Measure	Time frame	Description
Number of Participants With Sustained Virologic Response at Post-treatment Week 12 (SVR12)	Follow-up week 12	SVR12 was defined as HCV RNA less than lower limit of quantification (\< LLOQ) (25 IU/mL; target detected or not detected) at follow-up week 12.

Secondary

Measure	Time frame	Description
Number of Subjects With Sustained Virologic Response at Post-treatment Week 24 (SVR24)	Follow-up week 24	SVR24 was defined as HCV RNA \< LLOQ (25 IU/mL; target detected or not detected) at 24 weeks post treatment.
Number of Participants With Treatment Emergent Cytopenic Abnormalities	After Day 1 to end of treatment; up to Weeks 24 or 48	All treated participants were monitored for treatment emergent cytopenic abnormalities (anemia as defined by hemoglobin (Hb) \< 10 g/dL, and/or neutropenia as defined by absolute neutrophil count (ANC) \< 750 mm3 and/or thrombocytopenia as defined by platelets \< 50,000/mm3) during the treatment period (Weeks 1, 2, 4, 6, 8, 12, 20, and 24, and at Weeks 28, 32, 36, 40, 44, and 48 for subjects requiring those visits).
Number of Participants With On-treatment IFN-associated Flu-like or Musculoskeletal Symptoms	After Day 1 to end of treatment; up to Weeks 24 or 48	All treated participants were monitored for IFN-associated Flu-like and Musculoskeletal symptoms. Flu-like symptoms were defined as pyrexia, chills, or pain. Musculoskeletal symptoms were defined as arthralgia, myalgia, or back pain. Subjects were monitored throughout the treatment period during the treatment period (After day 1 up to week 24, or After day 1 up to week 48 for subjects requiring those visits).
Number of Participants Who Died or Experienced Severe Adverse Events (SAEs), Dose Reductions of Lambda or Discontinuation Due to Adverse Events (AEs)	After Day 1 to end of treatment; up to Weeks 24 or 48	AE=any new unfavorable symptom, sign, or disease or worsening of a preexisting condition that may not have a causal relationship with treatment. SAE=a medical event that. at any dose, results in death, persistent or significant disability/incapacity, or drug dependency/abuse; is life-threatening, an important medical event, or a congenital anomaly/birth defect; or requires or prolongs hospitalization. Treatment-related=having certain, probable, possible, or missing relationship to study drug.
Number of Participants With Treatment-emergent Grade 3/4 Lab Abnormalities	After Day 1 to end of treatment; up to Weeks 24 or 48	Grade 3/4 treatment-emergent lab abnormalities that occurred in \>=5% of subjects in either cohort are reported. The analysis included all treated subjects up to the end of the treatment period (Day 1 to week 24, or Day 1 to week 48 for subjects requiring those visits). Grade (Gr) 1=Mild, Gr 2=Moderate, Gr 3=Severe, Gr 4= Potentially Life-threatening or disabling. AST = Aspartate aminotransferase, ALT = Alanine aminotransferase.
Number of Participants With Rapid Virologic Response (RVR) and Extended Rapid Virologic Response (eRVR)	Treatment weeks 4 and 12	RVR is defined as HCV RNA \< LLOQ target not detected at Week 4 and eRVR defined as HCV RNA \< LLOQ target not detected at Weeks 4 and 12
Mean Percent Change in Absolute CD4 T Lymphocyte Count From Baseline to End of Treatment	Day 1 to end of treatment; up to week 24 or week 48	All treated participants were monitored for percent change in CD4 T Lymphocyte count from Baseline to the end of the treatment period. The mean percent change in each arm is presented for all evaluable participants.
Mean Change in Total Lymphocyte Count From Baseline to End of Treatment	Day 1 to end of treatment; up to week 24 or week 48	All treated participants were monitored for change in Total Lymphocyte Count from Baseline to the end of the treatment period. The mean change in each arm for all evaluable participants is reported in Cells/µL.
Mean Percent Change in Total Lymphocyte Count From Baseline to End of Treatment	Day 1 to end of treatment; up to week 24 or week 48	All treated participants were monitored for percent change in Total Lymphocyte Count from Baseline to the end of the treatment period. The mean percent change in each arm is presented for all evaluable participants.
Mean Change in Platelet Count From Baseline to End of Treatment	Day 1 to end of treatment; up to week 24 or week 48	All treated participants were monitored for change in Platelet Count from Baseline to the end of the treatment period. The mean change in each arm for all evaluable participants (units of measurement = x10\^9 cells/L).
Mean Percent Change in Platelet Count From Baseline to End of Treatment	Day 1 to end of treatment; up to week 24 or week 48	All treated participants were monitored for percent change in Platelet Count from Baseline to the end of the treatment period. The mean percent change in each arm is presented for all evaluable participants.
Mean Change in Absolute CD4 T Lymphocyte Count From Baseline to End of Treatment	Day 1 to end of treatment; up to week 24 or week 48	All treated participants were monitored for change in Absolute CD4 T Lymphocyte count from Baseline to the end of the treatment period. The mean change in each arm for all evaluable participants is reported in Cells/µL.

Countries

Argentina, Belgium, Canada, France, Germany, Italy, Mexico, Poland, Russia, Spain, United Kingdom, United States

Participant flow

Pre-assignment details

A total of 453 participants were enrolled in the study. 300 participants were randomized and received treatment. 153 participants were not randomized to a treatment group due to Adverse Event (3), withdrawal of consent (13), loss to follow-up (4), administrative reasons per sponsor (5), no longer met study criteria (105), or other reasons (23).

Participants by arm

Arm	Count
Cohort A: HCV GT-2 or GT-3 Participants with HCV (Genotype 2 or 3) and HIV co-infection were treated with Lambda/RBV/DCV for 12 weeks followed by Lambda/RBV for 12 weeks, for a total treatment duration of 24 weeks. Participants received 180μg of Lambda via subcutaneous injection, once weekly, 800 mg/day Ribavirin tablets, orally, twice daily, for a planned duration of 24 weeks. Participants were administered 30 mg Daclatasvir tablets, orally, once daily, for a maximum of 12 weeks. The total daily dose was 30, 60 or 90 mg depending on the HIV concomitant regimen. Participants were followed up for a duration of 24 weeks after 24 weeks of treatment.	104
Cohort B: HCV GT-1 or GT-4 Participants with HCV (Genotype 1 or 4) and HIV co-infection were treated with Lambda/RBV/DCV for 12 weeks followed by Lambda/RBV for either 12 or 36 weeks. Participants were administered 180μg of Lambda via subcutaneous injection, once weekly, for a maximum of 48 weeks; body weight stratified dose of Ribavirin tablets, orally, twice daily, for maximum duration of 48 weeks (\<75 kg, total dose was 1000 mg/day, weighing \>=75 kg, total dose was 1200 mg/day); and 30 mg Daclatasvir tablets, orally, once daily, for a maximum of 12 weeks. The total daily dose was 30, 60 or 90 mg depending on the HIV concomitant regimen. Participants who achieved an extended rapid virologic response (eRVR) during initial 12 weeks were treated with Lambda/RBV for 12 weeks for total of 24 weeks. Participants who did not achieve eRVR during initial 12 weeks were treated with Lambda/RBV for 36 weeks for total of 48 weeks. Participants were followed up for a duration of 24 weeks after 24 or 48 weeks of treatment.	196
Total	300

Withdrawals & dropouts

Period	Reason	FG000	FG001
Follow-up Period	Lost to Follow-up	1	1
Follow-up Period	No longer required per protocol	1	0
Follow-up Period	Other	1	5
Follow-up Period	Withdrawal by Subject	3	3
Treatment Period	Adverse Event	4	12
Treatment Period	Death	0	2
Treatment Period	Lack of Efficacy	1	9
Treatment Period	Lost to Follow-up	1	1
Treatment Period	No longer meets study criteria	0	1
Treatment Period	Other	1	0
Treatment Period	Poor/non compliance	0	2
Treatment Period	Withdrawal by Subject	2	8

Baseline characteristics

Characteristic	Total	Cohort A: HCV GT-2 or GT-3	Cohort B: HCV GT-1 or GT-4
Age, Continuous	45.6 years STANDARD_DEVIATION 8.27	43.7 years STANDARD_DEVIATION 8.88	46.6 years STANDARD_DEVIATION 7.76
Ethnicity (NIH/OMB) Hispanic or Latino	21 Participants	10 Participants	11 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	120 Participants	41 Participants	79 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	159 Participants	53 Participants	106 Participants
HCV Genotype HCV GT-1	149 Participants	0 Participants	149 Participants
HCV Genotype HCV GT-2	20 Participants	20 Participants	0 Participants
HCV Genotype HCV GT-3	83 Participants	83 Participants	0 Participants
HCV Genotype HCV GT-4	41 Participants	0 Participants	41 Participants
HCV Genotype Unknown	7 Participants	1 Participants	6 Participants
Race (NIH/OMB) American Indian or Alaska Native	2 Participants	1 Participants	1 Participants
Race (NIH/OMB) Asian	2 Participants	0 Participants	2 Participants
Race (NIH/OMB) Black or African American	24 Participants	6 Participants	18 Participants
Race (NIH/OMB) More than one race	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Unknown or Not Reported	8 Participants	4 Participants	4 Participants
Race (NIH/OMB) White	264 Participants	93 Participants	171 Participants
Sex: Female, Male Female	68 Participants	28 Participants	40 Participants
Sex: Female, Male Male	232 Participants	76 Participants	156 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk
deaths Total, all-cause mortality	0 / 104	3 / 196
other Total, other adverse events	70 / 104	159 / 196
serious Total, serious adverse events	6 / 104	12 / 196

Outcome results

Primary

Number of Participants With Sustained Virologic Response at Post-treatment Week 12 (SVR12)

SVR12 was defined as HCV RNA less than lower limit of quantification (\< LLOQ) (25 IU/mL; target detected or not detected) at follow-up week 12.

Time frame: Follow-up week 12

Population: The analysis was performed in all treated subjects using modified intent-to-treat algorithm, where the numerator is based on subjects meeting the response criteria and the denominator is based on all treated subjects (Non-completer = Failure).

Arm	Measure	Value (COUNT_OF_PARTICIPANTS)
Cohort A: HCV GT-2 or GT-3	Number of Participants With Sustained Virologic Response at Post-treatment Week 12 (SVR12)	88 Participants
Cohort B: HCV GT-1 or GT-4	Number of Participants With Sustained Virologic Response at Post-treatment Week 12 (SVR12)	149 Participants

Secondary

Mean Change in Absolute CD4 T Lymphocyte Count From Baseline to End of Treatment

All treated participants were monitored for change in Absolute CD4 T Lymphocyte count from Baseline to the end of the treatment period. The mean change in each arm for all evaluable participants is reported in Cells/µL.

Time frame: Day 1 to end of treatment; up to week 24 or week 48