Post-Authorisation Safety Study of Agomelatine and the Risk of Hospitalisation for Acute Liver Injury

Study type

• Study topic:
  Disease /health condition

  Human medicinal product
• Study type:
  Non-interventional study
• Scope of the study:
  Assessment of risk minimisation measure implementation or effectiveness

  Safety study (incl. comparative)
• Data collection methods:
  Secondary data collection

Non-interventional study

• Non-interventional study design:
  Case-control

  Cohort

  Other
• Non-interventional study design, other:
  Post-Authorization Safety Study (PASS)

Study drug and medical condition

• Anatomical Therapeutic Chemical (ATC) code:
  (N06AX22) agomelatine
• Medical condition to be studied:
  Major depression

Population studied

• Short description of the study population:
  The source population includes all individuals aged 18 years or older registered in each study data source since the date of the first-recorded prescription of agomelatine or any of the other study antidepressants.; All persons meeting the following criteria during the study period are eligible for study inclusion:; ­- First prescription or dispensing of one of the study antidepressants with no prescription of this medication during the prior 12 months (new users); ­- Aged 18 years or older; ­- Continuous registration or enrolment in the study data source for at least 12 months prior to the start date; Patients with any of the listed conditions recorded at any time before the start date will be excluded from the study:; - Acute and subacute liver disease including viral and other infectious or toxic hepatitis; - Chronic liver diseases, such as cirrhosis or fibrosis of the liver, alcoholic liver disease, chronic toxic liver disease, hemochromatosis, Wilson disease, deficit of alpha-1-antitrypsin, and Budd-Chiari syndrome; ­- Disorders of bilirubin excretion such as Gilbert’s syndrome and Crigler Najjar syndrome; - Chronic biliary or pancreatic disease; ­- Risk factors for liver disease: alcohol use disorder, heart failure; - Malignancy; ­- Human immunodeficiency virus (HIV) infection; ­- Organ transplant; ­- Drug abuse and dependence; ­- History of paracetamol intoxication; ­- Jaundice; ­- Hepatomegaly; ­- Other and unspecified disorders of the liver; ­- Non-specific elevation of levels of transaminases and lactic acid dehydrogenase (LDH)
• Age groups:
  Adults (18 to < 46 years)

  Adults (46 to < 65 years)

  Adults (65 to < 75 years)

  Adults (75 to < 85 years)

  Adults (85 years and over)
• Special population of interest:
  Hepatic impaired
• Estimated number of subjects:
  65000

Study design details

• Main study objective:
  Primary objective: to estimate, with the nested case-control analysis, the fully adjusted odds ratio of hospitalisation for ALI comparing patients initiating treatment with agomelatine and other antidepressants with patients initiating citalopram used as a common reference group.
• Outcomes:
  Primary endpoint: hospital diagnosis for ALI identified with specific ICD-9-CM or ICD-10-CM1 diagnosis codes (common in all the study data sources). Secondary endpoint : Hospital diagnosis for ALI identified with specific and non-specific ICD-9-CM or ICD-10-CM1 diagnosis codes evaluated only in Spain/Denmark in which validation of this less specific outcome will be possible.Tertiary endpoint : 1/specific and non-specific codes identified in both hospital and ambulatory settings. 2/evaluated in all data sources but validated in Spain/Denmark
• Data analysis plan:
  Cohort analysis 1/Crude and age- and sex-standardised incidence rates of hospitalisation for ALI for current use of agomelatine and each antidepressant.2/Kaplan-Meier to estimate crude cumulative incidence of ALI at monthly intervals after first dispensing of agomelatine and each antidepressant.3/Age- and sex-adjusted incidence rate ratios for agomelatine and each antidepressant during current use, compared with citalopram current use.Nested case-control analysis: 1/Cases and controls will be matched on age, calendar year of start date, and sex.2/Using density-based sampling, controls will have follow-up proportionate to cases and index date of case will be assigned to matched controls.3/For all endpoints, risk of ALI in current users agomelatine and current users other antidepressants will be compared with risk in current users of citalopram, adjusting for confounders using conditional logistic regression.4/Sensitivity analyses to include assessment recent/past use antidepressants

Documents

Study results

CLE-20098-094 Abstract EU-PASS Register

Study publications

Forns J, Cainzos-Achirica M, Hellfritzsch M, Morros R, Poblador-Plou B, Hallas …

Pladevall-Vila, M., Pottegård, A., Schink, T. et al. Risk of Acute Liver Injury…

M. Pladelvall, A. Pottegard, T. Schink, J. Reutfors, R. Morros, B. Poblador-Plo…

Forns J, Pottegård A, Reinders T, Poblador-Plou B, Morros R, Brandt L, et al. A…

Pladevall M, Hallas J, Schink T, Morros R, Poblador B, Forns J, Maja H, Reinder…