Study Assessing Dolutegravir in HIV-1 Infected Subjects With Virus Resistant to Raltegravir and/or Elivitegravir

HIV Infections Clinical Trial

— VIKING-4  

Official title:

A Phase III Randomized, Double-blind Study to Demonstrate the Antiviral Activity of Dolutegravir (DTG) 50 mg Twice Daily Versus Placebo Both Co-Administered With a Failing Antiretroviral Regimen Over Seven Days, Followed by an Open Label Phase With All Subjects Receiving DTG 50 mg Twice Daily Co-administered With an Optimised Background Regimen (OBR) in HIV-1 Infected, Integrase Inhibitor Therapy-Experienced and Resistant, Adults

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01568892
• Other study ID #: 116529
• Status: Completed
• Phase: Phase 3
• Start date: April 18, 2012
• Est. completion date: December 16, 2013

Study information

• Verified date: June 2018
• Source: ViiV Healthcare
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Study ING116529 is a multicenter, randomized, study with an initial 7 day placebo- controlled, functional monotherapy phase to quantify the antiviral activity attributable to dolutegravir (DTG) in HIV-1 infected, ART-experienced adults who are experiencing virological failure on an Integrase inhibitor containing regimen (current RAL or ELV failures), with evidence of genotypic resistance to RAL or ELV at study entry. Thirty subjects will be randomized (1:1) to receive either DTG 50mg BID (Arm A) or Placebo (Arm B) with the current failing regimen for 7 days (RAL or ELV should be discontinued prior to dosing with DTG). At Day 8, subjects from both arms will enter an open label phase and receive open label DTG 50mg BID with an optimized background regimen containing at least one fully active drug.

Description:

Study ING116529 is a multicenter, randomized, study with an initial 7 day placebo-controlled, functional monotherapy phase to assess the antiviral activity and safety of a dolutegravir (DTG, GSK1349572) containing regimen in HIV-1 infected, ART-experienced adults with virological failure on an integrase inhibitor (INI) containing regimen.

Subjects must have evidence of genotypic resistance to raltegravir [RAL] or elvitegravir [ELV] at Screening and documented current or historical genotypic or phenotypic resistance to at least two other antiretroviral therapy drug classes.

The study is designed to provide an accurate measure of the intrinsic antiviral activity of DTG 50mg twice daily versus placebo both administered with the current failing regimen in a randomised double-blind phase to Day 8. This will be followed by an open label phase with all subjects receiving DTG 50mg twice daily with an optimized background regimen (containing at least one fully active drug) until subjects no longer derive clinical benefit or until DTG is locally available. Thirty subjects will be randomized (1:1) to receive either DTG 50mg BID (Arm A) or Placebo (Arm B) with the current failing regimen for 7 days (RAL or ELV should be discontinued prior to dosing at Day 1). At Day 8, subjects from both arms will enter an open label phase and receive open label DTG 50mg BID with an optimized background regimen containing at least one fully active drug The primary analysis will be conducted after the last subject enrolled has completed the randomised, double-blind phase at Day 8. Additional analyses may be performed prior to study closure when all ongoing subjects transition to locally available commercial DTG.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 30
• Est. completion date: December 16, 2013
• Est. primary completion date: October 31, 2012
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Screening plasma HIV-1 RNA =1000 copies/mL

• ART-experienced, INI-experienced, DTG naïve

• Current virological failure on raltegravir (RAL) or elvitegravir (ELV) regimen

• The subject's HIV-1 shows genotypic resistance to RAL or ELV at Screening

• Subject has been on stable ART for at least one month prior to Screening and through Day 1(with exceptions for ETV, EFV and NVP that can be interrupted within 14 days of Day 1, see Exclusion Criterion)

• Documented resistance to at least one drug from each of two or more of any approved classes of ART other than integrase inhibitors

• Be able to receive at least one fully active drug as part of the OBR from Day 8

• Women capable of becoming pregnant must use appropriate contraception during the study (as defined by the protocol)

• Willing and able to understand and provide signed and dated written informed consent prior to Screening.

Exclusion Criteria:

• Women who are pregnant or breast feeding

• An active AIDS-defining condition at Screening (except cutaneous Kaposi's sarcoma not requiring systemic therapy or CD4+ <200c/mm3)

• Moderate to severe hepatic impairment as defined by Child-Pugh classification

• Anticipated need for HCV therapy during the first 24 weeks of the study

• Recent history (less than or equal to 3 months) of any upper or lower gastrointestinal bleed, with the exception of anal or rectal bleeding

• Allergy or intolerance to the study drugs or their components or drugs of their class

• Malignancy within the past 6 months

• Treatment with an HIV-1 therapeutic vaccine within 90 days of Screening

• Treatment with radiation therapy, cytotoxic chemotherapeutic agents or any immunomodulator within 28 days of Screening

• Treatment with any agent, other than licensed ART, with documented in vitro/vivo activity against HIV-1 within 28 days of first dose of investigational product (with the exception of entecavir if required for Hep B treatment)

• Treatment with etravirine, efavirenz, or nevirapine within 14 days of Day 1(etravirine may be used if coadministered with lopinavir/ritonavir or darunavir/ritonavir)

• Treatment with tipranivir/ritonavir, fosamprenavir, or fosamprenavir/ritonavir within 28 days prior to Screening

• Exposure to an experimental drug or vaccine within either 28 days, 5 half-lives of the test agent, or twice the duration of the biological effect of the test agent, which ever is longer, prior to the first dose of IP.

• Any acute or verified Grade 4 laboratory abnormality (with the exception of Grade 4 lipids) at Screening

• ALT> 5 times the upper limit of normal (ULN) at Screening

• ALT = 3X ULN and bilirubin > 1.5 X ULN (with 35% direct bilirubin) at Screening

Related Conditions & MeSH terms

• HIV Infections

Intervention

Drug:
• Dolutegravir 50 mg twice daily
Active dolutegravir plus failing background regimen (Day 1 to Day 7). Open label dolutegravir plus optimized background regimen (from Day 8)
• Dolutegravir placebo twice daily
Dolutegravir placebo plus failing background regimen (Day 1 to Day 7)

Locations

Country	Name	City	State
United States	GSK Investigational Site	Annandale	Virginia
United States	GSK Investigational Site	Augusta	Georgia
United States	GSK Investigational Site	Austin	Texas
United States	GSK Investigational Site	Bakersfield	California
United States	GSK Investigational Site	Beverly Hills	California
United States	GSK Investigational Site	Boston	Massachusetts
United States	GSK Investigational Site	Bronx	New York
United States	GSK Investigational Site	Buffalo	New York
United States	GSK Investigational Site	Dallas	Texas
United States	GSK Investigational Site	Durham	North Carolina
United States	GSK Investigational Site	Fort Lauderdale	Florida
United States	GSK Investigational Site	Fort Pierce	Florida
United States	GSK Investigational Site	Hillsborough	New Jersey
United States	GSK Investigational Site	Little Rock	Arkansas
United States	GSK Investigational Site	Los Angeles	California
United States	GSK Investigational Site	Maywood	Illinois
United States	GSK Investigational Site	New York	New York
United States	GSK Investigational Site	Norwalk	Connecticut
United States	GSK Investigational Site	Orlando	Florida
United States	GSK Investigational Site	Philadelphia	Pennsylvania
United States	GSK Investigational Site	San Diego	California
United States	GSK Investigational Site	Savannah	Georgia
United States	GSK Investigational Site	Valhalla	New York
United States	GSK Investigational Site	Washington	District of Columbia
United States	GSK Investigational Site	Washington	District of Columbia

Sponsors (3)

Lead Sponsor	Collaborator
ViiV Healthcare	GlaxoSmithKline, Shionogi

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Mean Change From Baseline in Plasma Human Immunodeficiency Virus Type 1 (HIV-1) Ribonucleic Acid (RNA) at Day 8	Plasma samples were collected for quantitative HIV-1 RNA analysis at Baseline (Day 1) and Day 8. Change from Baseline was calculated as the value at Day 8 minus the value at Baseline (Day 1). The analysis was performed using statistical modeling correcting for Baseline plasma HIV-1 RNA, Baseline Dolutegravir (DTG) fold change (FC), the overall susceptibility score (OSS) of the failing regimen, and the interaction between DTG FC and treatment. Means and differences were calculated using the average Baseline DTG FC of the entire Intent-to-Treat Exposed (ITT-E) Population. The last observation carried forward with discontinuation equals Baseline (LOCFDB) dataset was used for the analysis. For the LOCFDB dataset, missing values were carried forward from the previous, non-missing, available on-treatment assessment, except formissing values due to premature withdrawal or Day 8 missing values, which had the Baseline value imputed.	Baseline and Day 8
Secondary	Absolute Values in Plasma HIV-1 RNA Over Time	Plasma samples were collected for quantitative HIV-1 RNA analysis at Baseline (Day 1), Day 8, Day 28, Week 8, Week 12, Week 16, Week 24, Week 32, Week 40, Week 48, Week 60, Week 72, and Week 84. NA indicates data was not available.	Baseline; Day 8; Day 28; Weeks 8, 12, 16, 24, 32, 40, 48, 60, 72, and 84
Secondary	Mean Change From Baseline in Plasma HIV-1 RNA Over Time	Plasma samples were collected for quantitative HIV-1 RNA analysis at Baseline (Day 1), Day 8, Day 28, Week 8, Week 12, Week 16, Week 24, Week 32, Week 40, Week 48, Week 60, Week 72, and Week 84. Change from Baseline was calculated as the post-Baseline value minus the value at Baseline. NA indicates data was not available.	Baseline; Day 8; Day 28; Weeks 8, 12, 16, 24, 32, 40, 48, 60, 72, and 84
Secondary	Number of Participants With Plasma HIV-1 RNA <50 c/mL Over Time	Plasma samples were collected for quantitative HIV-1 RNA analysis at Baseline (Day 1); Day 8; Day 28; Weeks 8, 12, 16, 24, 32, 40, and 48. Number of participants with plasma HIV-1 RNA level <50 c/mL was obtained using Food and Drug Administration's (FDA's) snapshot algorithm, where all participants without HIV-1 RNA data at the visit of interest (due to missing data or discontinuation of investigational product prior to the visit window) were treated as non-responders. Also, participants who switched their concomitant antiretroviral therapy (ART) prior to the visit of interest as follows were also treated as non-responders: background ART substitutions not permitted per protocol; background ART substitutions permitted per protocol; however, the decision to switch is not documented as being before or at the first On-treatment visit after switching to optimized background regimen (OBR) (i.e. Day 28) where HIV-1 RNA is assessed.	Baseline; Day 8; Day 28; Weeks 8, 12, 16, 24, 32, 40 and 48
Secondary	Number of Participants With Plasma HIV-1 RNA <400 c/mL Over Time	Plasma samples were collected for quantitative HIV-1 RNA analysis at Baseline (Day 1); Day 8; Day 28; Weeks 8, 12, 16, 24, 32, 40 and 48. Number of participants with plasma HIV-1 RNA level <400 c/mL was obtained using FDA's snapshot algorithm, where all participants without HIV-1 RNA data at the visit of interest (due to missing data or discontinuation of investigational product prior to the visit window) were treated as non-responders. Also, participants who switch their concomitant ART prior to the visit of interest as follows were also treated as non-responders: background ART substitutions not permitted per protocol; background ART substitutions permitted per protocol; however the decision to switch is not documented as being before or at the first On-treatment visit after switching to OBR (i.e. Day 28) where HIV-1 RNA is assessed.	Baseline; Day 8; Day 28; Weeks 8, 12, 16, 24, 32, 40 and 48
Secondary	Absolute Values in Cluster of Differentiation 4+ (CD4+) Cell Counts Over Time	Blood samples were collected for lymphocyte subset assessment by flow cytometry at Baseline; Day 8; Day 28; Weeks 8, 12, 16, 24, 32, 40, 48, 60, 72, and 84.	Baseline; Day 8; Day 28; Weeks 8, 12, 16, 24, 32, 40, 48, 60, 72, and 84
Secondary	Median Change From Baseline in CD4+ Cell Counts Over Time	Blood samples were collected for lymphocyte subset assessment by flow cytometry at Baseline; Day 8; Day 28; Weeks 8, 12, 16, 24, 32, 40, 48, 60, 72, and 84. Change from Baseline was calculated as the post-Baseline value minus the value at Baseline.	Baseline; Day 8; Day 28; Weeks 8, 12, 16, 24, 32, 40, 48, 60, 72, and 84
Secondary	Absolute Values in Cluster of Differentiation 8+ (CD8+) Cell Counts Over Time	Blood samples were collected for lymphocyte subset assessment by flow cytometry at Baseline; Day 28; and Weeks 12, 24, and 48.	Baseline; Day 28; Weeks 12, 24, and 48
Secondary	Median Change From Baseline in CD8+ Cell Counts Over Time	Blood samples were collected for lymphocyte subset assessment by flow cytometry at Baseline; Day 28; and Weeks 12, 24, and 48. Change from Baseline was calculated as the post-Baseline value minus the value at Baseline.	Baseline; Day 28; Weeks 12, 24, and 48
Secondary	Number of Participants With the Indicated Type of HIV-1 Disease Progression (Acquired Immunodeficiency Syndrome [AIDS] or Death [DT])	The number of participants with HIV-1 disease progression (AIDS or death) was assessed per the Centers for Disease Control and Prevention (CDC) 1993 revised classification system for HIV infection and expanded surveillance case definition for AIDS among adolescents and adults. The CDC classifies HIV infection as Category A (participants with asymptomatic HIV infection, acute HIV infection with accompanying illness, or persistent generalized lymphadenopathy), Category B (participants with symptomatic non-AIDS condition, i.e., conditions that are attributed to HIV infection or are indicative of a defect in cell-mediated immunity; or conditions are considered by physicians to have a clinical course or to require management that is complicated by HIV infection), and Category C (includes AIDS indicator conditions as defined by diagnostic or presumptive measures).	From the day of the first dose of study drug until early withdrawal or the Week 48 analysis cut-off date (median of 55 study weeks)
Secondary	Number of Participants With Any Adverse Event (Serious and Non-serious) of the Indicated Grade	An adverse event (AE) is defined as any untoward medical occurrence in a participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. A serious adverse event (SAE) is defined as any untoward medical occurrence that, at any dose: results in death; is life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity; or is a congenital anomaly/birth defect. Medical or scientific judgment should be exercised in other situations. Adverse events were graded for severity according to the Division of AIDS (DAIDS) toxicity scales as: Grade 1 (mild), Grade 2 (moderate), Grade 3 (severe), or Grade 4 (potentially life threatening).	From the first dose of study medication until early withdrawal or through the Week 48 analysis data cut-off date (median of 55 study weeks)
Secondary	Number of Participants With the Maximum Post-Baseline-emergent Clinical Chemistry Toxicities of the Indicated Grade	Participants with post-Baseline-emergent clinical chemistry toxicities were analyzed. Clinical chemistry toxicities were graded for severity according to the DAIDS toxicity scales as: Grade 1 (mild), Grade 2 (moderate), Grade 3 (severe), or Grade 4 (potentially life threatening).	From the first dose of study medication until early withdrawal or through the Week 48 analysis data cut-off date (median of 55 study weeks)
Secondary	Number of Participants With the Maximum Post-Baseline-emergent Hematology Toxicities of the Indicated Grade	Participants with post-Baseline-emergent hematology toxicities were analyzed. Hematology toxicities were graded for severity according to the DAIDS toxicity scales as: Grade 1 (mild), Grade 2 (moderate), Grade 3 (severe), or Grade 4 (potentially life threatening).	From the first dose of study medication until early withdrawal or through the Week 48 analysis data cut-off date (median of 55 study weeks)
Secondary	AUC(0-tau) of DTG	The area under the time concentration curve over the dosing interval (AUC[0-tau]) of DTG was assessed by a population pharmacokinetic (PK) modeling approach using pooled DTG PK data from multiple studies. Blood samples for the determination of plasma DTG concentration were collected at the following time points: pre-dose and 1-3 hours post-dose on Day 8; pre-dose and within a post-dose window (1-3 hours or 4-12 hours) on Day 28 and Week 24. For Day 8 PK, only samples collected from participants randomized to the active DTG arm were analyzed.	Day 8, Day 28, and Week 24
Secondary	Cmax of DTG	The maximal concentration (Cmax) of DTG was assessed by a population PK modeling approach using pooled DTG PK data from multiple studies. Blood samples for the determination of plasma DTG concentration were collected at the following time points: pre-dose and 1-3 hours post-dose on Day 8; pre-dose and within a post-dose window (1-3 hours or 4-12 hours) on Day 28 and Week 24. For Day 8 PK, only samples collected from participants randomized to the active DTG arm were analyzed.	Day 8, Day 28, and Week 24
Secondary	Plasma DTG Pre-dose Concentration (C0) at Day 8, Day 28, and Week 24; and Average DTG C0 (C0 Avg) at Week 24	Blood samples for the determination of plasma DTG pre-dose concentration were collected pre-dose on Day 8, Day 28, and Week 24. For Day 8 PK, only samples collected from participants randomized to the active DTG arm were analyzed. C0 Avg was calculated at Week 24 as the mean of the concentration at Day 8, Day 28, and Week 24.	Day 8, Day 28, and Week 24
Secondary	Number of Participants With the Indicated Treatment-emergent Integrase (IN) Mutations Detected at the Time of Defined Virologic Failure (PDVF), as a Measure of Genotypic Resistance	For participants meeting one of the criteria for PDVF, plasma samples collected at the time point of virologic failure were tested to evaluate any potential genotypic and/or phenotypic evolution of resistance. PDVF was defined as (A) Virologic Non-response: a decrease in plasma HIV-1 RNA of <1 log10 copies/mL by Day 28, with subsequent confirmation, unless plasma HIV-1 RNA is <400 copies/mL; confirmed plasma HIV-1 RNA levels >=400 copies/mL on or after Week 24 or (B) Virologic Rebound: confirmed rebound in plasma HIV-1 RNA levels to >=400 copies/mL after prior confirmed suppression to <400 copies/mL; confirmed plasma HIV-1 RNA levels >1 log10 copies/mL above the nadir value, where nadir is >=400 copies/mL.Treatment-emergent IN mutations are those detected at the time of PDVF but not at Baseline.	From the first dose of study medication until early withdrawal or through the Week 48 analysis data cut-off date (median of 55 study weeks)
Secondary	Number of Participants With the Indicated Fold Increase in Fold Change (FC) in the 50% Inhibitory Concentration Relative to Wild-type Virus for DTG (i.e. PDVF FC/Baseline FC Ratio) at the Time of PDVF, as a Measure of Phenotypic Resistance	For participants meeting one of the criteria for PDVF, plasma samples collected at the time point of virologic failure were tested to evaluate any potential genotypic and/or phenotypic evolution of resistance. The FC in IC50 (50% inhibitory concentration) for DTG relative to wild-type virus was determined for virus isolated at Baseline and at the time of PDVF. The number of participants with the indicated change (ratio) in the two values at the time of PDVF is presented. PDVF was defined as (A) Virologic Non-response: a decrease in plasma HIV-1 RNA of <1 log10 copies/mL by Day 28, with subsequent confirmation, unless plasma HIV-1 RNA is <400 copies/mL; confirmed plasma HIV-1 RNA levels >=400 copies/mL on or after Week 24 or (B) Virologic Rebound: confirmed rebound in plasma HIV-1 RNA levels to >=400 copies/mL after prior confirmed suppression to <400 copies/mL; confirmed plasma HIV-1 RNA levels >1 log10 copies/mL above the nadir value, where nadir is >=400 copies/mL.	From the first dose of study medication until early withdrawal or through the Week 48 analysis data cut-off date (median of 55 study weeks)
Secondary	Number of Participants Who Discontinued Study Treatment Due to AEs	The number of participants who permanently discontinued study treatment due to AEs is presented.	From the first dose of study medication until early withdrawal or through the Week 48 analysis data cut-off date (median of 55 study weeks)
Secondary	Number of Participants With Clinically Significant Electrocardiogram (ECG) Findings	Twelve lead ECG was performed using an automated ECG machine. The number of participants with abnormal-clinically significant ECG findings at any time on-treatment is reported.	Up to Week 24
Secondary	Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP)	Vital signs including SBP and DBP were measured at Baseline, Week 24 and Week 48. Baseline was defined as the last pre-treatment value. Change from Baseline was calculated as the post-Baseline value minus the value at Baseline.	Baseline and Weeks 24 and 48
Secondary	Change From Baseline in Heart Rate	Vital signs including heart rate was measured at Baseline, Week 24 and Week 48. Baseline was defined as the last pre-treatment value. Change from Baseline was calculated as the post-Baseline value minus the value at Baseline.	Baseline and Weeks 24 and 48
Secondary	Change From Baseline in Albumin Level	Blood samples were collected for the analysis of clinical chemistry parameters such as albumin. Baseline was defined as the last pre-treatment value. Change from Baseline was calculated as the post-Baseline value minus the value at Baseline.	Baseline, Week 24 and 48
Secondary	Change From Baseline in Alkaline Phosphatase (ALP), Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST) and Creatine Kinase	Blood samples were collected for the analysis of clinical chemistry parameters such as ALP, ALT, AST and creatine kinase. Baseline was defined as the last pre-treatment value. Change from Baseline was calculated as the post-Baseline value minus the value at Baseline. NA indicates data was not available.	Baseline, Day 8, Day 28, Weeks 8, 12, 16, 24, 32, 40, 48, 60, 72 and 84
Secondary	Change From Baseline in Total Bilirubin (T. Bil) and Creatinine Levels	Blood samples were collected for the analysis of clinical chemistry parameters such as T. Bil and creatinine. Baseline was defined as the last pre-treatment value. Change from Baseline was calculated as the post-Baseline value minus the value at Baseline. NA indicates data was not available.	Baseline, Day 8, Day 28, Weeks 8, 12, 16, 24, 32, 40, 48, 60, 72 and 84
Secondary	Change From Baseline in Cholesterol, Chloride, Carbon Dioxide (CO2)/Bicarbonate (HCO3), Glucose, High Density Lipoprotein Cholesterol, Potassium, Low Density Lipoprotein (LDL) Cholesterol, Sodium, Phosphorus, Triglycerides and Urea/Blood Urea Nitrogen	Blood samples were collected for the analysis of clinical chemistry parameters such as cholesterol, chloride, CO2/HCO3, glucose, high density lipoprotein (HDL) cholesterol, potassium, LDL cholesterol, sodium, phosphorus inorganic, triglycerides and urea/blood urea nitrogen (BUN). Baseline was defined as the last pre-treatment value. Change from Baseline was calculated as the post-Baseline value minus the value at Baseline. NA indicates data was not available.	Baseline, Day 8, Day 28, Weeks 8, 12, 16, 24, 32, 40, 48, 60, 72 and 84
Secondary	Change From Baseline in Creatinine Clearance	Creatinine clearance was calculated using Cockcroft-Gault formula. Baseline was defined as the last pre-treatment value. Change from Baseline was calculated as the post-Baseline value minus the value at Baseline.	Baseline, Day 8, Day 28, Week 8, Week 16, Week 24, Week 32 and Week 48
Secondary	Change From Baseline in Lipase Levels	Blood samples were collected for the analysis of clinical chemistry parameters such as lipase level. Baseline was defined as the last pre-treatment value. Change from Baseline was calculated as the post-Baseline value minus the value at Baseline. NA indicates data was not available.	Baseline, Day 8, Day 28, Weeks 8, 12, 16, 24, 32, 40, 48, 60, 72 and 84
Secondary	Change From Baseline in Basophils, Eosinophils, Lymphocytes, Monocytes, Total Neutrophils, Platelet and White Blood Cell (WBC) Count	Blood samples were collected for the analysis of hematology parameters such as basophils, eosinophils. Baseline was defined as the last pre-treatment value. Change from Baseline was calculated as the post-Baseline value minus the value at Baseline. NA indicates data was not available.	Baseline, Day 8, Day 28, Weeks 8, 12, 16, 24, 32, 40, 48, 60, 72 and 84
Secondary	Change From Baseline in Hemoglobin Level	Blood samples were collected for the analysis of hematology parameters such as hemoglobin. Baseline was defined as the last pre-treatment value. Change from Baseline was calculated as the post-Baseline value minus the value at Baseline. NA indicates data was not available.	Baseline, Day 8, Day 28, Weeks 8, 12, 16, 24, 32, 40, 48, 60, 72 and 84
Secondary	Change From Baseline in Hematocrit Level	Blood samples were collected for the analysis of hematology parameters such as hematocrit level. Baseline was defined as the last pre-treatment value. Change from Baseline was calculated as the post-Baseline value minus the value at Baseline. NA indicates data was not available.	Baseline, Day 8, Day 28, Weeks 8, 12, 16, 24, 32, 40, 48, 60, 72 and 84
Secondary	Change From Baseline in Mean Corpuscle Volume	Blood samples were collected for the analysis of hematology parameters such as mean corpuscle volume. Baseline was defined as the last pre-treatment value. Change from Baseline was calculated as the post-Baseline value minus the value at Baseline. NA indicates data was not available.	Baseline, Day 8, Day 28, Weeks 8, 12, 16, 24, 32, 40, 48, 60, 72 and 84
Secondary	Change From Baseline in Red Blood Cell Count	Blood samples were collected for the analysis of hematology parameters such as RBC. Baseline was defined as the last pre-treatment value. Change from Baseline was calculated as the post-Baseline value minus the value at Baseline. NA indicates data was not available.	Baseline, Day 8, Day 28, Weeks 8, 12, 16, 24, 32, 40, 48, 60, 72 and 84