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An Observational Study of the Safety of Direct-acting Antivirals in Patients With Hepatitis C

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ClinicalTrials.gov Identifier: NCT03423641
Recruitment Status : Completed
First Posted : February 6, 2018
Last Update Posted : February 13, 2018
Sponsor:
Collaborators:
OneFlorida Clinical Research Consortium
Patient-Centered Outcomes Research Institute
Information provided by (Responsible Party):
Elizabeth A. McGlynn, Kaiser Permanente

Brief Summary:
The investigators will assess whether patients with the Hepatitis C virus (HCV) who are prescribed direct-acting antiviral (DAA) medications experience higher rates of adverse events than patients with HCV who are untreated. The investigators hypothesize that patients receiving DAAs do not experience higher rates of adverse events compared to patients who have not received DAAs. The study population is adults between the ages of 18 and 88 with any indication of a diagnosis of HCV. An intervention group (those receiving a DAA) and comparison group (those who are not treated) will be created using medication dispensing data. Eligibility for the study will be determined from January 1, 2011 through December 31, 2017. Covariates will be collected from January 1, 2011 through December 31, 2017. Individual study sites may have access to historical data prior to 2011 that can be used as covariates or to identify individuals with HCV. The primary outcomes of interest include acute myocardial infarction, neurological outcomes (e.g. acute stroke, intracranial bleed), acute kidney failure, acute on chronic liver failure, hepatic decompensation, multiple organ dysfunction syndrome, cancer, bradyarrhythmia, and death. The secondary outcomes include decompensated cirrhosis, hospitalization, emergency department visit, and arrhythmia. Outcomes will be assessed from January 1, 2011 through December 31, 2017. The investigators will use two different analytic approaches to answer the question of interest: a Poisson regression model and marginal structural modeling (MSM). The simpler Poisson model is an extension of tabular rate of event analysis. The more complicated MSM model incorporates modeling of the treatment decision to more flexibly control for confounding by indication. For each outcome, the investigators will only record the first date an outcome occurs. Each outcome will be modeled separately.

Condition or disease Intervention/treatment
Hepatitis C, Chronic Drug: Direct Acting Antivirals

Study Type : Observational
Actual Enrollment : 120000 participants
Observational Model: Cohort
Time Perspective: Retrospective
Official Title: Safety of Direct-Acting Antiviral Medications for Hepatitis C
Actual Study Start Date : January 1, 2011
Actual Primary Completion Date : December 31, 2017
Actual Study Completion Date : December 31, 2017

Resource links provided by the National Library of Medicine


Group/Cohort Intervention/treatment
Direct Acting Antivirals
Patients who receive a direct acting antiviral enter the DAA cohort at the time of initiation of the drug.
Drug: Direct Acting Antivirals
The time period during which a patient is dispensed the medication and for up to 180 days after initiation of the medication.

Comparison
The exposure time of patients who have not received a direct acting antiviral (patients can change from the comparison to the DAA group once they receive the medication)



Primary Outcome Measures :
  1. Acute Myocardial Infarction (AMI) [ Time Frame: Patient diagnoses collected from encounters will be examined for the duration that patients are untreated. For patients that receive DAAs, diagnoses will be examined for up to 180 days from the day the patient initiated a DAA. ]
    Encounter with an ICD-9 diagnosis code of 410.xx or ICD-10 diagnosis code of I21.xx.

  2. Acute on Chronic Liver Failure [ Time Frame: Labs and diagnoses collected from clinical encounters will be examined for the entire duration that patients are untreated. For patients that receive DAAs, labs and diagnoses will be examined for up to 180 days from the day the patient initiated a DAA. ]
    An acute change in MELD score of 5 or more and the change is deemed to have persisted (defined as meeting one of the following criteria: MELD continues to be elevated 3 months later, liver transplant, death).

  3. Acute Kidney Failure (AKF) [ Time Frame: Patient diagnoses collected from encounters will be examined for the duration that patients are untreated. For patients that receive DAAs, diagnoses will be examined for up to 180 days from the day the patient initiated a DAA . ]
    Encounters with an ICD-9 diagnosis code of 584.xx or ICD-10 diagnosis code of N17.xx.

  4. Neurological Events [ Time Frame: Encounter diagnoses will be examined for the duration that patients are untreated. For patients that receive DAAs, diagnoses will be examined for up to 180 days from the day the patient initiated a DAA. ]
    Encounters with ICD-9 diagnosis code of 43x.xx or ICD-10 code of I6x.xx or G45.xx.

  5. Multiple Organ Dysfunction Syndrome (MODS) [ Time Frame: Encounter diagnoses will be examined for the duration that patients are untreated. For patients that receive DAAs, diagnoses will be examined for up to 180 days from the day the patient initiated a DAA. ]
    Encounters with ICD-9 diagnosis code of 995.92, 995.94, 785.52 or ICD-10 code of R65.11 or R65.2x.

  6. Death [ Time Frame: Death dates will be examined for the duration that patients are untreated. For patients that receive DAAs, death dates will be examined for up to 180 days from the day the patient initiated a DAA. ]
    Date of death in one or more records. Death data comes from medical records, Social Security, or state databases.


Secondary Outcome Measures :
  1. Decompensated Cirrhosis [ Time Frame: Encounter diagnoses will be examined for the duration that patients are untreated. For patients that receive DAAs, diagnoses will be examined for up to 180 days from the day the patient initiated a DAA. ]
    A patient will be characterized as having decompensated cirrhosis from an encounter indicating hepatic encephalopathy, jaundice (ICD-9 diagnosis code of 782.4 or ICD-10 code of R17), ascites (ICD-9 diagnosis code of 789.5, 789.51, 789.59 or ICD-10 diagnosis code of R18.0, R18.8, K71.51, K70.11, or K70.31), or varices (ICD-9 diagnosis code of 456.0, 456.20 or ICD-10 diagnosis code of I85.01 or I85.11.

  2. Hospitalization [ Time Frame: Inpatient hospital admissions will be examined for the duration that patients are untreated. For patients that receive DAAs, inpatient hospital admissions will be examined for up to 180 days from the day the patient initiated a DAA. ]
    An encounter in which the place of service is inpatient.

  3. Emergency Department Visit [ Time Frame: ED visits will be examined for the duration that patients are untreated. For patients that receive DAAs, ED visits will be examined for up to 180 days from the day the patient initiated a DAA. ]
    An encounter in which the place of service is an emergency department or urgent care center.

  4. Arrhythmia [ Time Frame: Encounter diagnoses will be examined for the duration that patients are untreated. For patients that receive DAAs, diagnoses will be examined for up to 180 days from the day the patient initiated a DAA. ]
    Encounters with an ICD-9 diagnosis code of 427.xx or 785.0 or an ICD-10 diagnosis code of I47.xx-I49.xx, R00.0, or R00.1.


Other Outcome Measures:
  1. Hepatocellular Carcinoma (HCC) [ Time Frame: Encounter diagnoses will be examined for the duration that patients are untreated. For patients that receive DAAs, diagnoses will be examined for up to 180 days from the day the patient initiated a DAA. ]
    Encounters with ICD-9 diagnosis code of 155.xx or ICD-10 code of C22.xx or confirmation of the diagnosis from a cancer registry.

  2. Cancers other than HCC [ Time Frame: Encounter diagnoses will be examined for the duration that patients are untreated. For patients that receive DAAs, diagnoses will be examined for up to 180 days from the day the patient initiated a DAA. ]
    Encounters with ICD-9 codes 140.xx through 239.xx, except 155.xx or ICD-10 coes C00-D48 except C22.xx or confirmation of cancer diagnosis in a cancer registry.

  3. Change in eGFR [ Time Frame: Labs collected from clinical encounters will be examined for the duration that patients are untreated. For patients that receive DAAs, labs and diagnoses will be examined for up to 180 days from the day the patient initiated a DAA. ]
    Clinically significant change between two adjacent testing periods based on creatinine labs.

  4. Change in HbA1c [ Time Frame: Labs collected from clinical encounters will be examined for the duration that patients are untreated. For patients that receive DAAs, labs and diagnoses will be examined for up to 180 days from the day the patient initiated a DAA. ]
    A change of 1 percentage point or more between two adjacent testing periods.

  5. HBV Reactivation [ Time Frame: Encounter diagnoses will be examined for the duration that patients are untreated. For patients that receive DAAs, diagnoses and labs will be examined for up to 180 days from the day the patient initiated a DAA. ]
    Clinically meaningful evidence of reactivation with indications such as an AST/ALT flare.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 88 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Sampling Method:   Probability Sample
Study Population
The groups/cohorts will consist of all HCV patients from Kaiser Permanente Southern California region, Kaiser Permanente Northern California region, and the OneFlorida Clinical Research Consortium.
Criteria

Inclusion Criteria:

  • HCV viral load
  • HCV genotype
  • HCV qualitative
  • HCV antibody
  • HCV drug
  • Continuously enrolled 12 months

Exclusion Criteria:

  • Each outcome will be analyzed separately as time to first event, thus people who experience an outcome prior to their study start date are ineligible for analyses related to that particular outcome.

The results will be examined for sensitivity to the following possible exclusion criteria:

  • Achieved SVR-12 prior to index date
  • HCV treatment experienced prior to index date
  • No visit in GI, Infectious Disease, or Liver Transplant / Hepatology
  • No positive HCV test (genotype, viral load, or qualitative)
  • No recent positive HCV test (genotype, viral load or qualitative)

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03423641


Sponsors and Collaborators
Kaiser Permanente
OneFlorida Clinical Research Consortium
Patient-Centered Outcomes Research Institute
Investigators
Principal Investigator: Elizabeth A McGlynn, PhD Kaiser Permanente

Responsible Party: Elizabeth A. McGlynn, Vice President, Kaiser Permanente Research; Executive Director, Center for Effectiveness and Safety Research, Kaiser Permanente
ClinicalTrials.gov Identifier: NCT03423641     History of Changes
Other Study ID Numbers: RI-RCR-1000
First Posted: February 6, 2018    Key Record Dates
Last Update Posted: February 13, 2018
Last Verified: February 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided
Plan Description: Current plan is to make a de-identified data set available to investigators under specified conditions.

Studies a U.S. FDA-regulated Drug Product: Yes

Keywords provided by Elizabeth A. McGlynn, Kaiser Permanente:
Drug-Related Side Effects and Adverse Reactions
Antiviral Agents / Adverse Effects
Antiviral Agents / Toxicity
Simeprevir
Sofosbuvir
Ledipasvir
Ombitasvir
Paritaprevir
Ritonavir
Dasabuvir
Daclatasvir
Elbasvir
Grazoprevir
Velpatasvir
Ribavirin

Additional relevant MeSH terms:
Hepatitis
Hepatitis A
Hepatitis C
Hepatitis C, Chronic
Liver Diseases
Digestive System Diseases
Hepatitis, Viral, Human
Virus Diseases
Enterovirus Infections
Picornaviridae Infections
RNA Virus Infections
Flaviviridae Infections
Hepatitis, Chronic
Antiviral Agents
Anti-Infective Agents