Final Non-interventional Study Report AI444259BMS-790052 Daclatasvir

SYNOPSIS

Final Non-interventional Study Report for Study AI444259

TITLE OF STUDY: Comparative Assessment of Utilization of Antiviral Therapies in Hepatitis C and Effectiveness of Daclatasvir-Containing Regimens in Real-Life Clinical Care in Europe

INVESTIGATORS/STUDY CENTERS: 54 sites in Germany, Belgium, and the Netherlands participated in thestudy, each site enrolling at least 1 subject, with a median of 12 per center.

PUBLICATIONS: None at the time of this report.

STUDY INTIATION DATE: 01-Oct-2014

STUDY COMPLETION DATE: 30-Jun-2017

STUDY PERIOD: 01-Oct-2014 to 30-Jun-2017

OBJECTIVES:

To quantify the effectiveness of daclatasvir-containing regimens in real-life clinical care as measured by thesustained viral response rate at 12 weeks after the end of HCV treatment (SVR12).

To describe and compare demographic and clinical characteristics of patients who start a new HCV treatmentregimen (with or without daclatasvir) by treatment regimen, and to identify those characteristics that areassociated with the initiation of daclatasvir-containing regimens in real-life clinical care.

METHODOLOGY: This was a prospective, observational, multicenter cohort study in Germany, Belgium, and the Netherlands. The study had a cross-sectional component that included subjects starting on any new HCV treatment, and a longitudinal component, in which only subjects starting a DCV-containing HCV treatment were followed for 12 months.

NUMBER OF SUBJECTS (Planned and Analyzed): Overall, 919 subjects were enrolled and 914 were eligible for analysis, including 444 who started non-DCV containing regimen and 470 DCV-containing regimen.

DIAGNOSIS AND MAIN CRITERIA FOR INCLUSION:

The inclusion criteria were as follows:

adult patients (≥ 18 years at inclusion)

diagnosed with chronic hepatitis C

initiation of any new non-daclatasvir-containing HCV treatment (cross-sectional component) or a newdaclatasvir-containing HCV treatment

investigators decided to initiate a new HCV treatment (or a new daclatasvir-containing regimen) before includingthe patient in the study

patient signed an informed consent

Treatments: no treatment was provided by study sponsor. This was an observational study and subjects were enrolled after decision on treatment regimen was made. Choice of treatment regimen, treatment duration, and addition of RBV was at the discretion of investigators and according to the local reimbursement policies. During the time of study conduct, the following IFN-free treatments were available: DCV+SOF, SOF/Ledipasvir (Harvoni©), Paritaprevir/Ombitasvir/ritonavir (Viekirax©), Paritaprevir/Ombitasvir/ritonavir + Dasabuvir (Viekirax©+ Exviera©), SOF+SMV, SOF+RBV. The new DCV-containing regimen was classified as DCV+SOF, DCV+SOF+RBV or other combinations. Treatment duration was categorized as 8 weeks or less (therapies with a duration up to 69 days), 12 weeks (therapies with a duration between 70 and 98 days), other duration (therapies lasting between 99 and 140 days), and 24 weeks (therapies with a duration above 141 days).

Duration of Follow-up: Twelve (12) months.

CRITERIA FOR EVALUATION:

Primary Endpoints:

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Proportion of subjects with SVR12, defined as a documented “undetectable” viral load on or after week 12following the end of treatment

Proportion of subjects with distinct demographic, disease and other characteristics in the group of subjectsinitiated non-DCV and DCV-containing regimen, and what characteristics were associated with the initiation ofDCV-containing treatment.

Secondary Endpoints

Proportion of subjects with SVR12 in sub populations of interest, including HCV GT, cirrhosis status, HCVtreatment experience, HIV co-infection, and use of illicit drugs

Proportion of subjects initiated DCV-containing regimen by HCV regimen criteria (described in Section 3.4.3.1)and concomitant treatments (coded by ATC)

Proportion of subjects with SVR24. The SVR24 was defined in the same way as for SVR12

Change in quality of life measured using EQ-5D, EQ-VAS, SF-36 Physical health and SF36 Mental health surveys

STATISTICAL CONSIDERATIONS: To ensure that both primary objectives would be addressed, 400 enrolled subjects were targeted in each sample, with a minimum of 300. Enrollment in each stratified sample was independent. The inclusion period was determined in each sample separately. See the Statistical Analysis Plan, Appendix 1.5, formore information.

Primary analysis was conducted on observed values for study primary and secondary endpoints. The sensitivity analyses on the primary endpoint were also conducted. The Sensitivity analysis 1 was conducted to impute missing SVR12 results caused by death or treatment discontinuation due to adverse events as failure. The Sensitivity analysis 2 was conducted to impute missing SVR12 results caused by death, treatment discontinuation due to adverse event, or with any documented premature withdrawal, as failure.

SUMMARY OF RESULTS:

Disposition:

A total of 919 subjects were enrolled. Of this total, 914 subjects (99.5%) were eligible for analysis. The reason for non-eligibility of the 5 subjects was that no new HCV regimen was documented as initiated. The DCV-containing regimen was comprised of 470 subjects, while the non-DCV regimen group included 444 subjects. Of subjects initiated DCV-containing regimen, 467 (99%) had at least one follow-up visit after baseline, and 446 (95%) had at least one visit after the DCV regimen stop. 376 (80%) subjects had a viral load assessment 12 weeks after the DCV regimen stop, and 254 (54%) had a viral load assessment 24 weeks after the DCV regimen stop. In DCV treatment group, 224 (48%) subjects discontinued study prematurely.

Baseline Demographic and Disease Characteristics:

The baseline demographic and disease characteristics of subjects initiating non-DCV and DCV-containing treatmentare summarized in Table 1 and Table 2. Subjects who initiated DCV vs non DCV containing treatments were younger (median age 50.0 vs 53.0 years), less likely to be ≥65 years old (12.6% vs 19.4%), have been infected with HCV GT-1a (13.2% vs 34.8%) or 1b (11.9% vs 41.5%), have HIV-HCV coinfection (8.5% vs 15.2%), or severe hypertension (7.9% vs 22.3%). However, they were more likely to have cirrhosis (35.5% vs 26.8%), to have been infected with HCV GT-3 (69.1% vs 2.5%), to be illicit drug users (24% vs 12.2%), and to be exposed to SOF (12.6% vs 4.0%) or PI-containing (6.9% vs 1.7%) all oral regimens.

Table 1: Demographic characteristics of the overall study subjects

All subjects Non-DCV containing regimen

(N=444)

DCV-containing regimen (N=470)

Age: years, median (range) 52.0 (19.0; 82.0) 53.0 (19.0; 82.0) 50.0 (19.0; 88.0)

Age >= 65 years, n (%) 145 (15.9%) 86 (19.4%) 59 (12.6%)

Male gender, n (%) 591 (64.7%) 270 (60.8%) 321 (69.3%)

BMI: kg/m2 24.9 (15.0-50.5) 25.2 (15.0; 50.5) 24.5 (15.8; 47.0)

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Table 2: Baseline disease characteristics of the overall study subjects

ParametersAll subjects

N=914

Non-Daclatasvir Containing

regimen

N=444

Daclatasvir Containing

regimen

N=470

HCV RNA at baseline (IU/mL)

Median (Range)1055410.50

(167 - 45900000)

1,160,000

(503-33000000)

912,011

(167 - 45900000)p=0.113

< 800,000 n (%) 386 (44.0%) 175 (40.8%) 211 (47.0%)

800,000 - < 2,000,000

n (%) 173 (19.7%) 94 (21.9%) 79 (17.6%)

2,000,000 - < 6,000,000

n (%) 214 (24.4%) 116 (27.0%) 98 (21.8%)

6,000,000 n (%) 105 (12.0%) 44 (10.3%) 61 (13.6%)

HCV GT

1a 232 (25.4%) 170 (38.4%) 62 (13.2%) p=<.001

1b 240 (26.3%) 184 (41.5%) 56 (11.9%) p=<.001

3 335 (36.7%) 11 (2.5%) 324 (69.1%) p=<.001

4 54 (5.9%) 43 (9.7%) 11 (2.3%) p=<.001

5 or 6 2 (0.2%) 2 (0.5%) 0 (0.0%) p=0.237

others 4 (0.4%) 4 (0.9%) 0 (0.0%) p=0.056

Cirrhosis n (%) 286 (31.3%) 119 (26.8%) 167 (35.5%) p=0.005

compensated 268 (94%) 114 (95.8%) 154 (92.8%)

decompensated 17 (6%) 5 (4.2%) 12 (7.2%)

HCC n (%) 16 (1.8%) 11 (2.5%) 5 (1.1%) p=0.135

HIV-coinfected n (%) 96 (11.7%) 60/336 (15.2) 36/386 (8.5) p=0.002

Treatment-naive n (%) 560 (61.7%) 266 (60.5%) 294 (62.8%) p=0.496

Treatment-experienced

n (%) 348/908 (38.3%) 174/440 (39.5%) 174/468 (37.2%)

Last HCV regimen - IFN

containing292 (83.9%) 160 (92.0%) 132 (75.9%) p=<.001

Last HCV regimen -IFN/RBV

256 (73.6%) 141 (81.0%) 115 (66.1%) p=0.002

INF-free with SOF

29 (8.3%) 7 (4.0%) 22 (12.6%) p=0.005

IFN-free with PI 15 (4.3%) 3 (1.7%) 12 (6.9%) p=0.031

IFN-free with NS5A

5 (1.4%) 5 (2.9%) 0 (0.0%) p=0.062

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Results:

Primary Endpoint Results: SVR12

Of the 420 subjects with SVR12 assessment available, 413 (98.3%) achieved SVR12. Results of the sensitivity analyses for SVR12 were consistent with those for the primary analysis (Table 3). The SVR12 rates were 96.9% [94.8%; 98.4%] as per sensitivity analysis 1 (death and discontinuations due to AEs were considered as failure) and 91.4% [88.4%; 93.8%] as per sensitivity analysis 2 (all discontinuations and missing data were considered as failure).

Table 3: Primary and sensitivity analyses for study primary end point (SVR12)

Type of analysis

Approach N SVR12 SuccessN (%) [CI 95%]

SVR12 FailureN (%) [CI 95%]

Primary analysis

Standard approach 420 413 (98.3%) [96.6% ; 99.3%]

7 (1.7%) [0.7% ; 3.4%]

Sensitivity 1 analysis

Missing SVR12 caused by death or treatment discontinuation due

to AE considered as failure

426 413 (96.9%) [94.8% ; 98.4%]

13 (3.1%) [1.6% ; 5.2%]

Sensitivity 2 analysis

Any monotone SVR12 considered as failure

452 413 (91.4%) [88.4% ; 93.8%]

39 (8.6%) [6.2% ; 11.6%]

Secondary Endpoint Results:

Proportion of subjects with SVR12 in sub-populations of interest

There was no meaningful difference between subjects irrespective of treatment duration, presence of RBV, HCVGT, HIV-coinfection status, presence of liver cirrhosis, or baseline HCV RNA levels. The SVR12 rates were 98.8% and 97.5% in subjects treated with DCV+SOF or DCV+SOF+RBV, respectively. Consistently high SVR12 rates were shown for subjects infected with HCV GT-1a (96.4%), -1b (100%) or -3 (98.6%). Importantly, HCV GT-3 subjects with cirrhosis also demonstrated high SVR12 rates of 98.8%.

7 (1.7%) subjects experienced virologic failure in this study as per primary analysis. Subjects who failedDCV-containing treatment compared with those who achieved SVR12 had lower median platelet levels (126.5 vs 181.0), higher proportion of subjects with viral load ≥ 6 Mln IU/mL (28.6% vs 12.7%), and higher proportion of subjects with prior treatment-experience (57.1% vs 38.0%). Subjects with more advanced liver disease that is reflected by the lower platelet counts, and those with other negative predictors of response (prior treatment failure, high baseline HCV RNA levels) had a higher rates of failure.

Proportion of subjects with SVR24

Of the 256 subjects in the DCV regimen group with SVR24 assessment available, 97.3% achieved SVR24. Therewas 100% concordance between SVR12 and SVR24 rates in subjects who had both assessments.

Factors associated with DCV treatment initiation

In multivariate models, the strongest factors associated with initiation of DCV-containing treatment were HCVGT-3 infection (OR=85.9), presence of cirrhosis (OR=3.3) or clinically significant thrombocytopenia (OR=3.4). Age ≥65 years (OR=2.0), and presence of any fibrosis in the liver (OR=1.7) were also associated with initiation of DCV-containing treatment. Presence of severe hypertension (OR=0.34) was inversely associated with initiation of DCV-containing treatment, an artificial phenomenon that reflects the limitations of drug prescription by treatment availability and reimbursement policies.

Pattern of use of DCV-containing regimen

The study results provide insights into how pattern of use of DCV-containing regimens in real life practice isimpacted by HCV genotype and liver disease status. Subjects without cirrhosis were mainly treated for 12 weeks without RBV irrespective of HCV GT - 61.5%, 60% and 85.9% of subjects with HCV GT-1a, -1b or 3 respectively. In subjects with cirrhosis DCV+SOF was predominantly administered with RBV either for 12 (30.5%) or 24 weeks (41.3%). Subjects with decompensated cirrhosis more frequently received DCV+SOF for 24 weeks (33.3%) compared with subjects who had compensated cirrhosis (9.7%). The majority (61.1%) of HCV

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GT-3 subjects with cirrhosis received DCV+SOF+RBV for 24 weeks, while those without cirrhosis mainly (85.9%) received DCV+SOF for 12 weeks.

Change in quality of life measured using SF-36 and EQ-5D scores

Treatment with DCV+SOF, with or without RBV, led to improvements in patient-reported outcomes both on andafter treatment. Overall, by month 12 the EQ-5D total score declined by 0.35 units [95%CI: -0.54; -0.16], the EQ-VAS improved by 7.53 units (95%CI: 5.29; 9.77), the SF-36 Global Physical score improved by 2.97 units (95%CI: 1.87; 4.99), and the SF-36 Global Mental score also improved by 4.09 units (95%CI: 2.62; 5.56).Subjects with compensated cirrhosis demonstrated greater improvement for all four measures (EQ-5D (-0.57; 95%CI: -0.86; -0.28), EQ-VAS (+9.29; 95%CI: 6.37; 12.21), SF36 Global physical health score (+3.43; 95% CI: 1.87; 4.99), SF36 Global mental health score (5.06; 95%CI: 2.86; 7.26 )

Other Results: Not applicable.

Adverse Events:

An overview of treatment emergent adverse events is presented in Table 4. Treatment with DCV-containing regimen was safe and well tolerated with no unexpected safety findings, and consistent with prior real world and clinical trials observations. Any AEs were reported in 199 subjects (42.3%), including 94 (20.0) subjects with DCV-related AEs. There were 5 deaths (1.1%) in this study, all of which were not related to DCV. SAEs and AEs leading to treatment discontinuation were reported in 19 (4%) and 3 (0.6%) subjects, respectively. Hepatic AEs associated with liver disease progression or liver enzyme elevation reported in 14 subjects (3%), all these AEs were not considered to be related to DCV.

Table 4: Overview of treatment emergent adverse events

Overview

DCVContaining

regimenN=470

A. Treatment-emergent adverse event 199 (42.3%)

B. Treatment-emergent adverse event related to DCV 94 (20.0%)

C. Serious treatment-emergent adverse event 19 (4.0%)

D. Serious treatment-emergent adverse event related to DCV 1 (0.2%)

E. Hepatic Treatment-emergent adverse event 14 (3.0%)

F. Hepatic Treatment-emergent adverse event related to DCV 0 (0.0%)

G. Hematologic Treatment-emergent adverse event 35 (7.4%)

H. Hematologic Treatment-emergent adverse event related to DCV 8 (1.7%)

I. Treatment-emergent adverse event leading to death 5 (1.1%)

J. Treatment-emergent adverse event leading to death and related to DCV 0 (0.0%)

K. Treatment-emergent adverse event leading to liver-related death 0 (0.0%)

L. Treatment-emergent adverse event leading to liver-related death and related to DCV 0 (0.0%)

M. Treatment-emergent adverse event leading to permanent treatment discontinuation 3 (0.6%)

N. Treatment-emergent adverse event related to other HCV treatment 116 (24.7%)

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CONCLUSIONS:

DCV-based regimens (DCV+SOF +/- RBV) administered for 12 or 24 weeks achieved SVR12 rates of 98.3%

(95% CI: 96.6; 99.3) per primary analysis (as observed) in real-world setting. SVR12 rates were similar for either12 or 24 weeks of treatment with or without RBV and consistent across demographic and disease characteristics

of study subjects.

o SVR12 rates were 96.4%, 100% and 98.6% in subjects with HCV GT-1a, GT-1b and GT-3, respectively

o SVR12 rates in subjects with compensated cirrhosis were 98.6%; all patients (n=6) with decompensated

cirrhosis with available data achieved SVR12

o SVR12 rates were also high in illicit drug users (98.8%) and HIV/HCV-co-infected subjects (97.1%)

SVR24 was achieved by 97.3% [95%CI 94.5%; 98.9%] of subjects initiated DCV-based regimen with available

data for analysis (n=256). There was 100% concordance between SVR12 and SVR24 rates in subjects who had

both assessments.

Pattern of use of DCV-containing regimens in real-life practice was impacted by HCV GT and liver disease status.

o majority of GT-1a (80.6%) and GT-1b (69.6%) subjects received 12 weeks of DCV+SOF (+/- RBV)

treatment, while the majority (61.1%) of HCV GT-3 subjects received DCV+SOF+RBV for 24 weeks

o subjects with cirrhosis tended to receive RBV-containing regimens (either for 12 or 24 weeks)

Major factors associated with initiation of DCV-based regimens in this study were:

o HCV GT-3 infection (OR 85.9; 95%CI 43.5-169.7),

o presence of cirrhosis (OR 3.3; 95%CI 2.0-5.3), and

o presence of clinically significant abnormalities in platelet counts (OR 3.4; 95%CI 1.5-7.6)

There was an improvement of PROs between baseline and Month 12 evaluation across all assessed scores (EQ-

5D (-0.35; 95% CI: -0.54; -0.16), EQ-VAS (+7.5; 95%CI: 5.29; 9.77), SF36 Global physical health score (2.97;

95%CI: 1.9; 4.04), SF36 Global mental health score (+4.09; 95%CI: 2.62; 5.56)) in the overall DCV-regimengroup. Improvement of PROs were also observed in the sub-groups of interest:

o subjects with compensated cirrhosis demonstrated greater improvement of PROs (EQ-5D (-0.57;

95%CI: -0.86; -0.28), EQ-VAS (+9.29; 95%CI: 6.37; 12.21), SF36 Global physical health score (+3.43;95% CI: 1.87; 4.99), SF36 Global mental health score (5.06; 95%CI: 2.86; 7.26 )

o illicit drug users reported mixed dynamic with improvement in some (EQ-5D (-0.6; 95%CI: -1.2; 0),

EQ-VAS (+9.03; 95%CI: 3.07; 15) and no statistically significant changes in others (SF36 Globalphysical health score (2.16; 95%CI: -0.61; 4.93) and SF36 Global mental health score (+1.81; 95%CI: -

2.32; 5.94))

o subjects who received RBV took longer to achieve significant improvements of PROs from baseline

than those who did not

DCV+SOF +/- RBV treatment was safe and well tolerated

o there were 5 deaths during the study (all non-related)

o frequency of SAEs and AEs, leading to treatment discontinuation was low (4% and 0.3%, respectively)

DATE OF REPORT: 16-Feb-2018

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