Chronic Hepatitis C Virus
Conditions
Keywords
HCV genotype 1 (GT-1), HCV, Sustained Virologic Response, Direct Acting Antiviral, Combination Therapy, GS-7977, GS-5885, Ribavirin, Open Label, Sofosbuvir, Additional relevant MeSH terms:, Hepatitis, Hepatitis, Chronic, Hepatitis C, Hepatitis C, Chronic, Liver Diseases, Digestive System Diseases, Hepatitis, Viral, Human, Virus Diseases, Enterovirus Infections, Picornaviridae Infections, RNA Virus Infections, Flaviviridae Infections, Antiviral Agents, Anti-Infective Agents, Therapeutic Uses, Pharmacologic Actions, Antimetabolites, Molecular Mechanisms of Pharmacological Action
Brief summary
This study is to evaluate the safety, tolerability, and antiviral efficacy of ledipasvir/sofosbuvir fixed dose combination (FDC) with or without ribavirin (RBV) administered for 12 or 24 weeks in treatment-experienced subjects with chronic genotype 1 hepatitis C virus (HCV) infection.
Interventions
DRUGLDV/SOF
Ledipasvir (LDV) 90 mg/sofosbuvir (SOF) 400 mg fixed-dose combination (FDC) tablet administered orally once daily
DRUGRBV
Ribavirin (RBV) tablets administered orally in a divided daily dose according to package insert weight-based dosing recommendations (\< 75 kg = 1000 mg and ≥ 75 kg = 1200 mg)
Sponsors
Gilead Sciences
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Age \> 18, with chronic genotype 1 HCV infection * HCV treatment-experienced, including patients who have previously failed a nonstructural protein (NS)3/4A protease inhibitor plus pegylated interferon (PEG)/RBV regimen * HCV RNA \> 10,000 IU/mL at screening * Cirrhosis determination; a liver biopsy may be required * Screening laboratory values within defined thresholds * Use of two effective contraception methods if female of childbearing potential or sexually active male
Exclusion criteria
* Pregnant or nursing female or male with pregnant female partner * Coinfection with HIV or hepatitis B virus * Current or prior history of clinical hepatic decompensation * Hepatocellular carcinoma or other malignancy (with exception of certain resolved skin cancers) * Chronic use of systemic immunosuppressive agents * History of clinically significant illness or any other medical disorder that may interfere with subject treatment, assessment or compliance with the protocol
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Sustained Virologic Response (SVR) 12 Weeks After Discontinuation of Therapy (SVR12) | Posttreatment Week 12 | SVR12 was defined as HCV RNA \< the lower limit of quantitation (LLOQ; ie, 25 IU/mL) 12 weeks following the last dose of study drug. |
| Incidence of Adverse Events Leading to Permanent Discontinuation From Any Study Drug | Up to 24 weeks | The percentage of participants who experienced an adverse event leading to permanent discontinuation from any study drug was summarized. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With HCV RNA < LLOQ at Week 2 | Week 2 | — |
| Percentage of Participants With HCV RNA < LLOQ at Week 4 | Week 4 | — |
| Percentage of Participants With HCV RNA < LLOQ at Week 8 | Week 8 | — |
| Percentage of Participants With HCV RNA < LLOQ at Week 12 | Week 12 | — |
| Percentage of Participants With HCV RNA < LLOQ at Week 24 | Week 24 | — |
| Percentage of Participants With SVR at 4 and 24 Weeks After Discontinuation of Therapy (SVR4 and SVR24) | Posttreatment Weeks 4 and 24 | SVR4 and SVR24 were defined as HCV RNA \< LLOQ at 4 and 24 weeks following the last dose of study drug, respectively. |
| Change From Baseline in HCV RNA at Week 2 | Baseline; Week 2 | — |
| Change From Baseline in HCV RNA at Week 4 | Baseline; Week 4 | — |
| Change From Baseline in HCV RNA at Week 8 | Baseline; Week 8 | — |
| Percentage of Participants With Virologic Failure | Baseline to posttreatment Week 24 | Virologic failure was defined as on-treatment virologic failure or virologic relapse. * On-Treatment Virologic Failure was defined as * Breakthrough (confirmed HCV RNA ≥ LLOQ after having previously had HCV RNA \< LLOQ while on treatment), or * Rebound (confirmed \> 1 log10 IU/mL increase in HCV RNA from nadir while on treatment), or * Non-response (HCV RNA persistently ≥ LLOQ through 8 weeks of treatment) Virologic relapse was defined as confirmed HCV RNA ≥ LLOQ during the posttreatment period having achieved HCV RNA \< LLOQ at last on-treatment visit. |
| Change From Baseline in HCV RNA at Week 1 | Baseline; Week 1 | — |
| Percentage of Participants With HCV RNA < LLOQ at Week 1 | Week 1 | — |
Countries
United States
Participant flow
Recruitment details
Participants were enrolled at a total of 64 study sites in the United States. The first participant was screened on 03 January 2013. The last participant observation occurred on 20 February 2014.
Pre-assignment details
551 participants were screened.
Participants by arm
| Arm | Count |
|---|---|
| LDV/SOF 12 Weeks LDV 90 mg/SOF 400 mg FDC tablet once daily for 12 weeks | 109 |
| LDV/SOF+RBV 12 Weeks LDV 90 mg/SOF 400 mg FDC tablet once daily plus RBV tablets (1000-1200 mg daily based on weight) for 12 weeks | 111 |
| LDV/SOF 24 Weeks LDV 90 mg/SOF 400 mg FDC tablet once daily for 24 weeks | 109 |
| LDV/SOF+RBV 24 Weeks LDV 90 mg/SOF 400 mg FDC tablet once daily plus RBV tablets (1000-1200 mg daily based on weight) for 24 weeks | 111 |
| Total | 440 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Lack of Efficacy | 7 | 4 | 0 | 1 |
| Overall Study | Randomized But Not Treated | 0 | 0 | 1 | 0 |
| Overall Study | Withdrew Consent | 0 | 0 | 1 | 0 |
Baseline characteristics
| Characteristic | LDV/SOF 12 Weeks | LDV/SOF+RBV 12 Weeks | LDV/SOF 24 Weeks | LDV/SOF+RBV 24 Weeks | Total |
|---|---|---|---|---|---|
| Age, Continuous | 56 years STANDARD_DEVIATION 6.9 | 57 years STANDARD_DEVIATION 8 | 56 years STANDARD_DEVIATION 8.3 | 55 years STANDARD_DEVIATION 7.8 | 56 years STANDARD_DEVIATION 7.8 |
| HCV Genotype Genotype 1a | 86 participants | 88 participants | 85 participants | 88 participants | 347 participants |
| HCV Genotype Genotype 1b | 23 participants | 23 participants | 24 participants | 23 participants | 93 participants |
| HCV RNA | 6.5 log10 IU/mL STANDARD_DEVIATION 0.44 | 6.4 log10 IU/mL STANDARD_DEVIATION 0.54 | 6.4 log10 IU/mL STANDARD_DEVIATION 0.57 | 6.5 log10 IU/mL STANDARD_DEVIATION 0.6 | 6.5 log10 IU/mL STANDARD_DEVIATION 0.54 |
| HCV RNA Category < 800,000 IU/mL | 6 participants | 13 participants | 16 participants | 15 participants | 50 participants |
| HCV RNA Category ≥ 800,000 IU/mL | 103 participants | 98 participants | 93 participants | 96 participants | 390 participants |
| IL28b Status CC | 10 participants | 11 participants | 16 participants | 18 participants | 55 participants |
| IL28b Status CT | 70 participants | 77 participants | 68 participants | 68 participants | 283 participants |
| IL28b Status TT | 29 participants | 23 participants | 25 participants | 25 participants | 102 participants |
| Prior HCV Treatment IFN-alfa-2b+RBV | 0 participants | 0 participants | 1 participants | 1 participants | 2 participants |
| Prior HCV Treatment PEG-IFN-alfa-2a or PEG-IFN-alfa-2b+RBV | 43 participants | 47 participants | 58 participants | 59 participants | 207 participants |
| Prior HCV Treatment PI+PEG-IFN-alfa-2a or PEG-IFN-alfa-2b+RBV | 66 participants | 64 participants | 50 participants | 51 participants | 231 participants |
| Race/Ethnicity, Customized Asian | 1 participants | 0 participants | 0 participants | 0 participants | 1 participants |
| Race/Ethnicity, Customized Black or African American | 24 participants | 16 participants | 17 participants | 20 participants | 77 participants |
| Race/Ethnicity, Customized Hawaiian or Pacific Islander | 0 participants | 1 participants | 0 participants | 1 participants | 2 participants |
| Race/Ethnicity, Customized Hispanic/Latino | 7 participants | 12 participants | 11 participants | 11 participants | 41 participants |
| Race/Ethnicity, Customized Not Disclosed | 2 participants | 0 participants | 0 participants | 1 participants | 3 participants |
| Race/Ethnicity, Customized Not Hispanic or Latino | 100 participants | 99 participants | 98 participants | 99 participants | 396 participants |
| Race/Ethnicity, Customized Other | 0 participants | 0 participants | 1 participants | 1 participants | 2 participants |
| Race/Ethnicity, Customized White | 84 participants | 94 participants | 91 participants | 89 participants | 358 participants |
| Sex: Female, Male Female | 35 Participants | 40 Participants | 35 Participants | 43 Participants | 153 Participants |
| Sex: Female, Male Male | 74 Participants | 71 Participants | 74 Participants | 68 Participants | 287 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 73 / 109 | 96 / 111 | 87 / 109 | 100 / 111 |
| serious Total, serious adverse events | 0 / 109 | 0 / 111 | 6 / 109 | 3 / 111 |
Outcome results
Primary
Incidence of Adverse Events Leading to Permanent Discontinuation From Any Study Drug
The percentage of participants who experienced an adverse event leading to permanent discontinuation from any study drug was summarized.
Time frame: Up to 24 weeks
Population: Safety Analysis Set
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| LDV/SOF 12 Weeks | Incidence of Adverse Events Leading to Permanent Discontinuation From Any Study Drug | 0 percentage of participants |
| LDV/SOF+RBV 12 Weeks | Incidence of Adverse Events Leading to Permanent Discontinuation From Any Study Drug | 0 percentage of participants |
| LDV/SOF 24 Weeks | Incidence of Adverse Events Leading to Permanent Discontinuation From Any Study Drug | 0 percentage of participants |
| LDV/SOF+RBV 24 Weeks | Incidence of Adverse Events Leading to Permanent Discontinuation From Any Study Drug | 0 percentage of participants |
Primary
Percentage of Participants With Sustained Virologic Response (SVR) 12 Weeks After Discontinuation of Therapy (SVR12)
SVR12 was defined as HCV RNA \< the lower limit of quantitation (LLOQ; ie, 25 IU/mL) 12 weeks following the last dose of study drug.
Time frame: Posttreatment Week 12
Population: Full Analysis Set: participants who were randomized and received at least one dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| LDV/SOF 12 Weeks | Percentage of Participants With Sustained Virologic Response (SVR) 12 Weeks After Discontinuation of Therapy (SVR12) | 93.6 percentage of participants |
| LDV/SOF+RBV 12 Weeks | Percentage of Participants With Sustained Virologic Response (SVR) 12 Weeks After Discontinuation of Therapy (SVR12) | 96.4 percentage of participants |
| LDV/SOF 24 Weeks | Percentage of Participants With Sustained Virologic Response (SVR) 12 Weeks After Discontinuation of Therapy (SVR12) | 99.1 percentage of participants |
| LDV/SOF+RBV 24 Weeks | Percentage of Participants With Sustained Virologic Response (SVR) 12 Weeks After Discontinuation of Therapy (SVR12) | 99.1 percentage of participants |
p-value: <0.001Binomial test
p-value: <0.001Binomial test
p-value: <0.001Binomial test
p-value: <0.001Binomial test
Secondary
Change From Baseline in HCV RNA at Week 1
Time frame: Baseline; Week 1
Population: Participants in the Full Analysis Set with available data were analyzed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| LDV/SOF 12 Weeks | Change From Baseline in HCV RNA at Week 1 | -4.57 log10 IU/mL | Standard Deviation 0.501 |
| LDV/SOF+RBV 12 Weeks | Change From Baseline in HCV RNA at Week 1 | -4.50 log10 IU/mL | Standard Deviation 0.54 |
| LDV/SOF 24 Weeks | Change From Baseline in HCV RNA at Week 1 | -4.47 log10 IU/mL | Standard Deviation 0.569 |
| LDV/SOF+RBV 24 Weeks | Change From Baseline in HCV RNA at Week 1 | -4.50 log10 IU/mL | Standard Deviation 0.575 |
Secondary
Change From Baseline in HCV RNA at Week 2
Time frame: Baseline; Week 2
Population: Full Analysis Set
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| LDV/SOF 12 Weeks | Change From Baseline in HCV RNA at Week 2 | -5.08 log10 IU/mL | Standard Deviation 0.443 |
| LDV/SOF+RBV 12 Weeks | Change From Baseline in HCV RNA at Week 2 | -4.94 log10 IU/mL | Standard Deviation 0.52 |
| LDV/SOF 24 Weeks | Change From Baseline in HCV RNA at Week 2 | -4.99 log10 IU/mL | Standard Deviation 0.571 |
| LDV/SOF+RBV 24 Weeks | Change From Baseline in HCV RNA at Week 2 | -4.99 log10 IU/mL | Standard Deviation 0.617 |
Secondary
Change From Baseline in HCV RNA at Week 4
Time frame: Baseline; Week 4
Population: Full Analysis Set
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| LDV/SOF 12 Weeks | Change From Baseline in HCV RNA at Week 4 | -5.16 log10 IU/mL | Standard Deviation 0.439 |
| LDV/SOF+RBV 12 Weeks | Change From Baseline in HCV RNA at Week 4 | -5.02 log10 IU/mL | Standard Deviation 0.543 |
| LDV/SOF 24 Weeks | Change From Baseline in HCV RNA at Week 4 | -5.06 log10 IU/mL | Standard Deviation 0.571 |
| LDV/SOF+RBV 24 Weeks | Change From Baseline in HCV RNA at Week 4 | -5.04 log10 IU/mL | Standard Deviation 0.779 |
Secondary
Change From Baseline in HCV RNA at Week 8
Time frame: Baseline; Week 8
Population: Participants in the Full Analysis Set with available data were analyzed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| LDV/SOF 12 Weeks | Change From Baseline in HCV RNA at Week 8 | -5.16 log10 IU/mL | Standard Deviation 0.439 |
| LDV/SOF+RBV 12 Weeks | Change From Baseline in HCV RNA at Week 8 | -5.02 log10 IU/mL | Standard Deviation 0.544 |
| LDV/SOF 24 Weeks | Change From Baseline in HCV RNA at Week 8 | -5.06 log10 IU/mL | Standard Deviation 0.571 |
| LDV/SOF+RBV 24 Weeks | Change From Baseline in HCV RNA at Week 8 | -5.08 log10 IU/mL | Standard Deviation 0.605 |
Secondary
Percentage of Participants With HCV RNA < LLOQ at Week 1
Time frame: Week 1
Population: Full Analysis Set
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| LDV/SOF 12 Weeks | Percentage of Participants With HCV RNA < LLOQ at Week 1 | 26.6 percentage of participants |
| LDV/SOF+RBV 12 Weeks | Percentage of Participants With HCV RNA < LLOQ at Week 1 | 33.3 percentage of participants |
| LDV/SOF 24 Weeks | Percentage of Participants With HCV RNA < LLOQ at Week 1 | 20.2 percentage of participants |
| LDV/SOF+RBV 24 Weeks | Percentage of Participants With HCV RNA < LLOQ at Week 1 | 29.7 percentage of participants |
Secondary
Percentage of Participants With HCV RNA < LLOQ at Week 12
Time frame: Week 12
Population: Participants in the Full Analysis Set with available data were analyzed.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| LDV/SOF 12 Weeks | Percentage of Participants With HCV RNA < LLOQ at Week 12 | 99.1 percentage of participants |
| LDV/SOF+RBV 12 Weeks | Percentage of Participants With HCV RNA < LLOQ at Week 12 | 100.0 percentage of participants |
| LDV/SOF 24 Weeks | Percentage of Participants With HCV RNA < LLOQ at Week 12 | 100.0 percentage of participants |
| LDV/SOF+RBV 24 Weeks | Percentage of Participants With HCV RNA < LLOQ at Week 12 | 100.0 percentage of participants |
Secondary
Percentage of Participants With HCV RNA < LLOQ at Week 2
Time frame: Week 2
Population: Full Analysis Set
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| LDV/SOF 12 Weeks | Percentage of Participants With HCV RNA < LLOQ at Week 2 | 81.7 percentage of participants |
| LDV/SOF+RBV 12 Weeks | Percentage of Participants With HCV RNA < LLOQ at Week 2 | 82.9 percentage of participants |
| LDV/SOF 24 Weeks | Percentage of Participants With HCV RNA < LLOQ at Week 2 | 81.7 percentage of participants |
| LDV/SOF+RBV 24 Weeks | Percentage of Participants With HCV RNA < LLOQ at Week 2 | 83.8 percentage of participants |
Secondary
Percentage of Participants With HCV RNA < LLOQ at Week 24
Time frame: Week 24
Population: Participants in the Full Analysis Set with available data were analyzed. Participants in the LDV/SOF 12 Weeks and LDV/SOF+RBV 12 Weeks groups did not continue treatment past Week 12 and are not included in the analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| LDV/SOF 24 Weeks | Percentage of Participants With HCV RNA < LLOQ at Week 24 | 100.0 percentage of participants |
| LDV/SOF+RBV 24 Weeks | Percentage of Participants With HCV RNA < LLOQ at Week 24 | 100.0 percentage of participants |
Secondary
Percentage of Participants With HCV RNA < LLOQ at Week 4
Time frame: Week 4
Population: Full Analysis Set
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| LDV/SOF 12 Weeks | Percentage of Participants With HCV RNA < LLOQ at Week 4 | 100.0 percentage of participants |
| LDV/SOF+RBV 12 Weeks | Percentage of Participants With HCV RNA < LLOQ at Week 4 | 99.1 percentage of participants |
| LDV/SOF 24 Weeks | Percentage of Participants With HCV RNA < LLOQ at Week 4 | 99.1 percentage of participants |
| LDV/SOF+RBV 24 Weeks | Percentage of Participants With HCV RNA < LLOQ at Week 4 | 99.1 percentage of participants |
Secondary
Percentage of Participants With HCV RNA < LLOQ at Week 8
Time frame: Week 8
Population: Participants in the Full Analysis Set with available data were analyzed.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| LDV/SOF 12 Weeks | Percentage of Participants With HCV RNA < LLOQ at Week 8 | 100.0 percentage of participants |
| LDV/SOF+RBV 12 Weeks | Percentage of Participants With HCV RNA < LLOQ at Week 8 | 100.0 percentage of participants |
| LDV/SOF 24 Weeks | Percentage of Participants With HCV RNA < LLOQ at Week 8 | 100.0 percentage of participants |
| LDV/SOF+RBV 24 Weeks | Percentage of Participants With HCV RNA < LLOQ at Week 8 | 100.0 percentage of participants |
Secondary
Percentage of Participants With SVR at 4 and 24 Weeks After Discontinuation of Therapy (SVR4 and SVR24)
SVR4 and SVR24 were defined as HCV RNA \< LLOQ at 4 and 24 weeks following the last dose of study drug, respectively.
Time frame: Posttreatment Weeks 4 and 24
Population: Full Analysis Set
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| LDV/SOF 12 Weeks | Percentage of Participants With SVR at 4 and 24 Weeks After Discontinuation of Therapy (SVR4 and SVR24) | SVR4 | 94.5 percentage of participants |
| LDV/SOF 12 Weeks | Percentage of Participants With SVR at 4 and 24 Weeks After Discontinuation of Therapy (SVR4 and SVR24) | SVR24 | 93.6 percentage of participants |
| LDV/SOF+RBV 12 Weeks | Percentage of Participants With SVR at 4 and 24 Weeks After Discontinuation of Therapy (SVR4 and SVR24) | SVR24 | 96.4 percentage of participants |
| LDV/SOF+RBV 12 Weeks | Percentage of Participants With SVR at 4 and 24 Weeks After Discontinuation of Therapy (SVR4 and SVR24) | SVR4 | 96.4 percentage of participants |
| LDV/SOF 24 Weeks | Percentage of Participants With SVR at 4 and 24 Weeks After Discontinuation of Therapy (SVR4 and SVR24) | SVR4 | 100.0 percentage of participants |
| LDV/SOF 24 Weeks | Percentage of Participants With SVR at 4 and 24 Weeks After Discontinuation of Therapy (SVR4 and SVR24) | SVR24 | 99.1 percentage of participants |
| LDV/SOF+RBV 24 Weeks | Percentage of Participants With SVR at 4 and 24 Weeks After Discontinuation of Therapy (SVR4 and SVR24) | SVR4 | 99.1 percentage of participants |
| LDV/SOF+RBV 24 Weeks | Percentage of Participants With SVR at 4 and 24 Weeks After Discontinuation of Therapy (SVR4 and SVR24) | SVR24 | 99.1 percentage of participants |
Secondary
Percentage of Participants With Virologic Failure
Virologic failure was defined as on-treatment virologic failure or virologic relapse. * On-Treatment Virologic Failure was defined as * Breakthrough (confirmed HCV RNA ≥ LLOQ after having previously had HCV RNA \< LLOQ while on treatment), or * Rebound (confirmed \> 1 log10 IU/mL increase in HCV RNA from nadir while on treatment), or * Non-response (HCV RNA persistently ≥ LLOQ through 8 weeks of treatment) Virologic relapse was defined as confirmed HCV RNA ≥ LLOQ during the posttreatment period having achieved HCV RNA \< LLOQ at last on-treatment visit.
Time frame: Baseline to posttreatment Week 24
Population: Full Analysis Set
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| LDV/SOF 12 Weeks | Percentage of Participants With Virologic Failure | On-Treatment Virologic Failure | 0 percentage of participants |
| LDV/SOF 12 Weeks | Percentage of Participants With Virologic Failure | Virologic relapse | 6.5 percentage of participants |
| LDV/SOF+RBV 12 Weeks | Percentage of Participants With Virologic Failure | Virologic relapse | 3.6 percentage of participants |
| LDV/SOF+RBV 12 Weeks | Percentage of Participants With Virologic Failure | On-Treatment Virologic Failure | 0 percentage of participants |
| LDV/SOF 24 Weeks | Percentage of Participants With Virologic Failure | On-Treatment Virologic Failure | 0 percentage of participants |
| LDV/SOF 24 Weeks | Percentage of Participants With Virologic Failure | Virologic relapse | 0 percentage of participants |
| LDV/SOF+RBV 24 Weeks | Percentage of Participants With Virologic Failure | On-Treatment Virologic Failure | 0.9 percentage of participants |
| LDV/SOF+RBV 24 Weeks | Percentage of Participants With Virologic Failure | Virologic relapse | 0 percentage of participants |