Risk and Benefit Assessment of Hypnotic Agents for Sleep Disorders Among Elderly (RABA-HASDE)

• ClinicalTrials.gov Identifier: NCT02648776
• Recruitment Status: Unknown
• First Posted: January 7, 2016
• Last Update Posted: January 11, 2016
• Sponsor: China Medical University Hospital
• Collaborator: National Health Research Institutes, Taiwan
• Information provided by (Responsible Party): Hsiang-Wen Lin, China Medical University Hospital

Study Description

Brief Summary:

The aims of this study are to (1) examine the medication use patterns of commonly prescribed hypnotics and the factors that were associated with the long-term and short-term use patterns among the elderly population in Taiwan; (2)investigate the associations of using hypnotics with the elderly patients' disease statuses, efficacy and safety, as well as its pharmacokinetic and pharmacogenetic characteristics;(3) determine the clinical, economic and humanistic outcomes of using hypnotics and the corresponding contributing factors for the elderly in Taiwan.

Condition or disease	Intervention/treatment
Sleep Disorders	Drug: Exposure to sedative-hypnotic drugs

Detailed Description:

Aging is associated with the changes in the sleep structure, continuity, and timing while it also affects the elderly's physiological and psychological health statuses. Despite the fact that hypnotics are beneficial for the short-term management of insomnia, it is inconclusive about the risk and benefit ratios of long-term use for the elderly. The objectives of this study are to (1)examine the medication use patterns of prescribed hypnotics and the factors that were associated with the use patterns among the elderly population; (2)investigate the associations of using prescribed hypnotics with the elderly patients' disease statuses, efficacy and safety, as well as their pharmacokinetic and pharmacogenetic characteristics;(3)determine the clinical, economic and humanistic outcomes and corresponding factors of using hypnotics for long-term and short-term use in Taiwanese elderly.

This proposed study is the second part of a larger project that consists of two main phases across four years. The first part will include a retrospective database analysis to examine the medication use patterns for sleep disorders and corresponding outcomes using three data sets. Elderly patients aged 65 or older and who received hypnotics for insomnia will be selected from Taiwan's National Health Insurance Research Database, National Health Interview Survey and China Medical University Hospital (CMUH) in-house databases. Focus will be placed on benzodiazepines (BZD) and BZD-receptor specific non-BZD agents (Z-drugs), but Chinese traditional medication used for insomnia will also be examined.

This study is the second part of the larger project. The investigators will conduct a longitudinal, prospective, observational cohort study over a period of two years. The focus of this study is the use of hypnotic BZD and Z-drugs on elderly insomnia patients. The study cohorts include elderly patients, aged 65 years or older, who have received services in the outpatient departments of China Medical University Hospital, Taichung, Taiwan, and who have been prescribed with a selected BZD or Z-drug for insomnia for at least one week. A control group cohort will also be recruited. Each recruited patient will be monitored and evaluated periodically for at least one year. Economic, clinical, and humanistic outcomes, as well as adherence to the hypnotics will be assessed and monitored. Safety and tolerability will be assessed by occurrence of adverse drug reactions. Pharmacokinetic properties and genotyping patterns will be also be evaluated using snapshot blood sampling after the 6th month of enrollment in the study. The clinical and humanistic outcomes measures will include changes in insomnia status, functional status changes, depression status, as well as over-all well-being using EuroQol 5D. Economic evaluation will compare total insurance and out-of-pocket expenses at baseline and at 12 months follow up.

Study Design

• Study Type: Observational
• Estimated Enrollment: 1400 participants
• Observational Model: Cohort
• Time Perspective: Prospective
• Official Title: Risk and Benefit Assessment of Hypnotic Agents for Sleep Disorders Among Elderly; A Prospective Cohort Study at a Taiwanese Academic Medical Center
• Study Start Date: January 2016
• Estimated Primary Completion Date: January 2018
• Estimated Study Completion Date: December 2018

Groups and Cohorts

Group/Cohort	Intervention/treatment
Estazolam; Exposure to sedative-hypnotic drugs; Patients who have taken estazolam for at least one week before the first date of enrollment	Drug: Exposure to sedative-hypnotic drugs; These patients will have been prescribed a sedative-hypnotic drug for at least one week prior to enrollment.; Other Name: Medication Exposure
Lorazepam; Exposure to sedative-hypnotic drugs; Patients who have taken lorazepam for at least one week before the first date of enrollment	Drug: Exposure to sedative-hypnotic drugs; These patients will have been prescribed a sedative-hypnotic drug for at least one week prior to enrollment.; Other Name: Medication Exposure
Diazepam; Exposure to sedative-hypnotic drugs; Patients who have taken Diazepam for at least one week before the first date of enrollment	Drug: Exposure to sedative-hypnotic drugs; These patients will have been prescribed a sedative-hypnotic drug for at least one week prior to enrollment.; Other Name: Medication Exposure
Alprazolam; Exposure to sedative-hypnotic drugs; Patients who have taken Alprazolam for at least one week before the first date of enrollment	Drug: Exposure to sedative-hypnotic drugs; These patients will have been prescribed a sedative-hypnotic drug for at least one week prior to enrollment.; Other Name: Medication Exposure
Flunitrazepam; Exposure to sedative-hypnotic drugs; Patients who have taken Flunitrazepam for at least one week before the first date of enrollment	Drug: Exposure to sedative-hypnotic drugs; These patients will have been prescribed a sedative-hypnotic drug for at least one week prior to enrollment.; Other Name: Medication Exposure
Zolpidem; Exposure to sedative-hypnotic drugs; Patients who have taken Zolpidem for at least one week before the first date of enrollment	Drug: Exposure to sedative-hypnotic drugs; These patients will have been prescribed a sedative-hypnotic drug for at least one week prior to enrollment.; Other Name: Medication Exposure
Zopiclone; Exposure to sedative-hypnotic drugs; Patients who have taken Zopiclone for at least one week before the first date of enrollment	Drug: Exposure to sedative-hypnotic drugs; These patients will have been prescribed a sedative-hypnotic drug for at least one week prior to enrollment.; Other Name: Medication Exposure
Control Group; Patients not taking any of the included or any other anxiety-hypnotic agents

Outcome Measures

Primary Outcome Measures :

1. Changes from baseline in sleep quality at 12 months [ Time Frame: after 12 months of enrollment ]
   Clinical outcome, measured by a Chinese version of the Pittsburgh Sleep Quality Index
2. Number of participants with an occurrence of associated ADR [ Time Frame: after 12 months of enrollment ]
   Safety and tolerably, as measured by patients that experience falls, hip/limb fracture, cognitive impairment, etc. during the 12 months of enrollment

Secondary Outcome Measures :

1. Snapshot measurement of plasma drug and drug metabolite concentrations [ Time Frame: after 6 months of enrollment ]
   Pharmacokinetic evaluation by determining the levels of drug and metabolite in the patients plasma after established use
2. Snapshot measurement of urine drug and metabolite concentrations [ Time Frame: after 6 months of enrollment ]
   Pharmacokinetic evaluation by determining the levels of drug and metabolite in the patients plasma after established use -- and clearance after the sixth-month recruitments.
3. Calculation of drug clearance using snapshot plasma and urine concentrations [ Time Frame: after 6 months of enrollment ]
   Pharmacokinetic evaluation by determining the patient's clearance of the drug after established use
4. Proportion of patients with CYP3A5 mutations [ Time Frame: after 6 months of enrollment ]
   Pharmacogenetic evaluation and and genotyping of CYP3A5 enzyme for all enrolled patients with consent
5. Changes from baseline in sleep quality at 6 months [ Time Frame: after 6 months of enrollment ]
   Clinical outcome, measured by a Chinese version of the Pittsburgh Sleep Quality Index
6. Changes from baseline in Barthel Index at 6 months [ Time Frame: after 6 months of enrollment ]
   Clinical outcome, as a measure of independence, measured by Barthel Index
7. Changes from baseline in Barthel Index at 12 months [ Time Frame: after 12 months of enrollment ]
   Clinical outcome, as a measure of independence, measured by Barthel Index
8. Changes from baseline in IADL at 6 months [ Time Frame: after 6 months of enrollment ]
   Clinical outcome, as a measure of functional ability, measured by Instrumental Activities of Daily Living
9. Changes from baseline in IADL at 12 months [ Time Frame: after 12 months of enrollment ]
   Clinical outcome, as a measure of functional ability, measured by Instrumental Activities of Daily Living
10. Changes from baseline in EQ-5D-5L & EQ-5D-VAS at 6 months [ Time Frame: after 6 months of enrollment ]
    Changes in humanistic variables, as measured by the EuroQol 5D tool
11. Changes from baseline in EQ-5D-5L & EQ-5D-VAS at 12 months [ Time Frame: after 12 months of enrollment ]
    Changes in humanistic variables, as measured by the EuroQol 5D tool
12. Changes from baseline in MMAS-8 after 6 months [ Time Frame: after 6 months of enrollment ]
    Changes in medication adherence, as measured by the Morisky Medication Adherence
13. Changes from baseline in MMAS-8 after 12 months [ Time Frame: after 12 months of enrollment ]
    Changes in medication adherence, as measured by the Morisky Medication Adherence
14. Change from baseline in economic healthcare costs using NHI and out-of-pocket expenses at 12months [ Time Frame: At 12 months after enrollment ]
    NHI covered costs for inpatient and outpatient care taken from NHI data for the twelve months prior to enrollment, compared to the 12 months during enrollment. Added with patients' out of pocket expenses on health care.
15. Changes from baseline in insomnia at 6 months [ Time Frame: After 6 months of enrollment ]
    Clinical outcome, measured by a Chinese version of the Athens Insomnia Scale
16. Changes from baseline in insomnia at 12 months [ Time Frame: After 12 months of enrollment ]
    Clinical outcome, measured by a Chinese version of the Athens Insomnia Scale

Biospecimen Retention:   Samples With DNA

A single set of blood and urine samples taken in cohorts taking sedative-hypnotic medications, used to evaluate pharmacokinetic and pharmcogenetic parameters.

Eligibility Criteria

• Ages Eligible for Study: 65 Years and older (Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes
• Sampling Method: Non-Probability Sample

Study Population

Longitudinal prospective observational cohort study

Elderly patients receiving regular outpatient services at China Medical University Hospital

Criteria

• Inclusion criteria

  1. Patients who have received services in the outpatient departments in CMUH for at least six months persistently before the recruitment,
  2. who are diagnosed with any types of sleep disorders within the outpatient medical records, using ICD-9 codes to identify.
  3. who have been prescribed, for at least one week before the index date of observation, with one of the selected BZD or Z-drugs: estazolam, lorazepam, diazepam, alprazolam, flunitrazepam, zolpidem or zopiclone.
  4. who agree to participate in this observation study and have signed informed consent

• Exclusion criteria

  1. Those elderly patients who were diagnosed with cancers, seizures, specific psychiatric disorders (e.g., dementia, schizophrenia, panic disorder, alcohol withdrawal syndrome) and neurological disorders (e.g., Parkinson) in the baseline and during observation period

Contacts and Locations

Locations

Taiwan

China Medical University Hospital

Taichung, Taiwan

Sponsors and Collaborators

China Medical University Hospital

National Health Research Institutes, Taiwan

Investigators

• Principal Investigator: Hsiang-Wen Lin, PhD; Pharmacist, Associate Professor

More Information

• Responsible Party: Hsiang-Wen Lin, Associate Professor, China Medical University Hospital
• ClinicalTrials.gov Identifier: NCT02648776
• Other Study ID Numbers: DMR101-IRB1-083
• First Posted: January 7, 2016
• Last Update Posted: January 11, 2016
• Last Verified: January 2016

Keywords provided by Hsiang-Wen Lin, China Medical University Hospital:

hypnotic agents; sleep disorders; elderly

Additional relevant MeSH terms:

Sleep Wake Disorders; Parasomnias; Disease; Pathologic Processes; Nervous System Diseases; Neurologic Manifestations; Mental Disorders; Hypnotics and Sedatives; Central Nervous System Depressants; Physiological Effects of Drugs