The trial is an open-label, parallel-group, single-center randomized controlled trial to evaluate the effectiveness of an EHR-nested reminder system for serum lithium level monitoring. The trial program in the EHR system automatically prompts for eligibility screening, conducts the random allocation, outputs reminders, and collects outcomes.
Participants, interventions, and outcomes
The trial will be conducted at Toyooka hospital, which is a tertiary care hospital with 518 beds in Toyooka City, Hyogo, Japan, which has a population of 85,000.
Participants will be recruited in accordance with the eligibility criteria described below.
The participant must fulfill all the following:
1. Age ≥18 years on the day of informed consent
2. Has recurrent major depression, bipolar I disorder, or bipolar II disorder according to Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5)
3. Has been taking lithium carbonate for 6 months or longer
4. Has been judged by the treating physician judged to need a prescription of lithium carbonate for the next 18 months
The participant must not meet any of the following criteria:
1. Prescribed lithium carbonate for an indication other than mood disorders
2. A primary diagnosis of schizophrenia
3. Judged to have an imminent high risk of suicide by the treating physician
4. Suspected to have lithium intoxication
5. Women who are pregnant or breastfeeding
6. Cohabiting family members of study staff personnel
7. Inability to understand written Japanese
8. Contraindications for lithium carbonate
9. Participating in another clinical trial
10. Currently hospitalized
11. Terminal physical disease
12. No serum lithium concentration available within 7 days of informed consent
13. No appointment between 4 and 8 months after informed consent
14. Written informed consent is unavailable
15. Judged as inappropriate for participation by the treating physician
(Conditions 12 and 13 may be confirmed after informed consent, but before randomization.)
The trial program outputs two-step reminders of serum lithium level monitoring to the treating physician as specified by the algorithm (Table). We anticipate that the two-step reminders will improve both the physician’s awareness and the participant’s adherence.
· Reminder A
The text of reminder A is as follows: “Please notify the participant of the need for a blood test for serum lithium level at the next outpatient visit. If the next visit will be 8 months or further from the previous blood test, please notify the participant of the need to conduct a blood test today. The participant and the treating physician can decide whether to conduct the blood test.”
· Reminder B
The text of reminder B is as follows: “Please notify the participant about notify the participant of the need for a blood test for serum lithium level today. The participant and the treating physician can decide whether to conduct the blood test.”
Concurrent treatment and concerns about contamination
There are no restrictions on concurrent treatments in the trial.
At the first scheduled visit, between 18 and 24 months after informed consent, the program will output a reminder for the final evaluation. The treating physician will conduct a blood test within 7 days of the visit.
The primary outcome is the achievement of therapeutic serum lithium concentration between 0.4 and 1.0 mEq/L after 18 months after informed consent. If a participant withdraws during the follow-up period or the result of the final blood test is not available, he/she will be not be regarded to have achieved the primary outcome.
1) The number of blood tests for serum lithium concentration in the 18 months period after the date of informed consent.
2) Exacerbation of major depression or bipolar disorder in the 18 months period from the date of informed consent, defined by at least one of the following: hospitalization; increase in lithium dose; addition of antipsychotics or mood stabilizer (valproic acid, carbamazepine, lamotrigine); or addition of, or increase in, antidepressants.
3) Proportion of days covered (PDC) of lithium carbonate prescription during the 18 months from informed consent.(26)
4) Abnormalities in thyroid, renal, and liver functions at the final evaluation
The timeline for the study participants is shown in Figure 1 and the enrollment, intervention and assessment schedule is shown in Figure 2.
Screening by the trial program
The trial program screens candidates who fulfill all of the following criteria, based on the EHR:
1. Age ≥18 years
2. Have active diagnostic codes of mood disorders by International Classification of Diseases (ICD), 10th Revision F3x.
3. First prescription of lithium carbonate more than 6 months previously
4. Lithium carbonate was prescribed more than twice in the previous 6 months
5. No results of serum lithium concentration available within the previous 4 months
The participant will not be screened if he/she has been already registered as “not eligible”, “refused participation”, or “withdrawal after participation”.
Eligibility check and registration
Primary Care Evaluation of Mental Disorders (PRIME-MD) is a semi-structured diagnostic tool to assist primary care physicians in the diagnosis of common mental disorders based on DSM-5.(27) The treating physician conducts the PRIME-MD and confirms the diagnosis of depression, bipolar I, or bipolar II. If the candidate meets the eligibility criteria and written informed consent is obtained, the treating physician registers the participant through the EHR. If the candidate is not eligible, refuses participation, or withdraws after participation, the treating physician enters the status through EHR. The treating physician will conduct a baseline blood test within 7 days of informed consent. If the candidate does not receive the baseline blood test or a result for serum lithium level is not available within 7 days, he/she will be excluded from the study.
Sample size calculation
The sample size was estimated as follows. In a database owned by Real World Data. Co. Ltd, 1,464 patients were prescribed lithium carbonate in a 6 months period. Of those, the serum lithium level was kept between 0.4 mEq/L and 1.0 mEq/L for 818 (55.9%) patients. In the trial, we assumed that 80% of participants in the intervention group and 55% of patients in the control group will achieve the goal. As 49 participants are needed for each group, assuming a dropout rate of 10%, a total of 120 participants is required to detect this difference with a type I error of 5% and a type II error of 10% using a two-sided hypothesis test.
Assignment of intervention
The participants will be stratified into nine strata in accordance with the following two conditions and randomized by the trial program at their first scheduled visit between 4 and 8 months from the informed consent, using permuted block randomization.(28)
· Diagnosis based on PRIME-MD (major depression, bipolar I disorder, or bipolar II disorder)
· Lithium blood level (between 0.4 mEq/L and 1.0 mEq/L; < 4.0 mEq/L; or > 1.0 mEq/L)
The random allocation sequence will be generated by an independent trial statistician but will not be notified to other researchers and participants.
Allocation status will not be masked to the treating physician and the participant. Allocation status will be masked to the data manager, the trial statistician, and the steering committee until the steering committee finalizes the interpretation report with masked data.
Stopping rules for participants and trial
Stopping trial intervention
If the participant meets any of the following conditions, the treating physician will stop the trial intervention and record the date and the reason. However, the participant is not considered to have dropped out of the study at this stage and will receive the protocol assessments.
1) The participant wishes to withdraw from the trial intervention and/or lithium carbonate.
2) The treating physician judges that it is difficult to continue the trial intervention and/or lithium carbonate owing to the occurrence of serious adverse events.
3) The treating physician judges that the trial intervention and/or lithium carbonate should be stopped for clinical reasons other than serious adverse events.
4) The Steering Committee judges that the trial intervention or lithium carbonate should be stopped for any reason.
If the participant withdraws their consent to the protocol assessments, the participant will be excluded from analyses regardless of whether he/she continues the trial intervention and/or lithium carbonate.
The participant will be excluded from analyses if, after informed consent, it is found that the participant did not meet the eligibility criteria. In this case, the participant will not be considered to have stopped the trial intervention or the protocol assessments.
Stopping criteria for the trial
The Steering Committee will stop the trial upon advice or orders from the Ethics Committee if any of the following conditions are met.
1) Any serious problem in the quality, safety, and efficacy of the trial intervention and/or lithium carbonate.
2) When changing orders to the study protocol from the Ethics Committee is unacceptable.
The decision to stop the trial, and the reason for this, will be reported to the Ethics Committee and research staff as soon as possible.
Data collection and management
A password-protected trial program on a local server will collect baseline and follow-up data automatically.
All analyses will be conducted based on the intention-to-treat principle. The primary outcome will be analyzed from the full analysis set with a logistic regression analysis and reported with the odds ratio, p-value, and 95% confidence interval. The model includes the primary diagnosis based on PRIME-MD (major depression, bipolar I disorder, or bipolar II disorder) and baseline serum lithium level (0.4 mEq/L to 1.0 mEq/L; < 0.4 mEq/L; or > 1.0 mEq/L). Secondary analyses and subgroup analyses will be conducted to supplement the primary analysis and explore a deeper understanding of the study questions. As secondary and subgroup analyses are exploratory, we will not adjust the significance level for multiple testing. All statistical tests will be two-sided and p values of < 0.05 will be considered statistically significant. The details of the statistical analysis will be decided within the statistical analysis protocol, which will be reviewed and approved by the trial statistician before the analysis is undertaken. No interim analyses will be conducted in this trial.
The data manager, in conjunction with the clinical management team, will conduct on-site monitoring every 6 months after registration of the first case.
No formal site auditing will be conducted because the trial comprises only a minimally invasive intervention.
Adverse events are defined as follows: any undesirable or unintended signs including anomalies in clinical laboratory evaluations, symptoms, or diseases that occurred to participants, regardless of the causal relationship with the treatment. The treating physician will provide and/or arrange appropriate treatments, including hospital admission if necessary. Because adverse events, including toxicities of lithium carbonate, are monitored as part of routine care, study specific monitoring will not be required.
When a serious adverse event occurs, the treating physician must take all the necessary and appropriate measures to ensure the safety of the participant. The treating physician must also notify the principal investigator and file a report with the chief study investigator at Toyooka Hospital within 24 hours. The principal investigator must notify the Ethics Committee of the Graduate School of Medicine, Kyoto University Graduate School of Medicine within 72 hours. The chief study investigator at Toyooka Hospital must make a report to its own IRB and, if it concerns an unforeseeable serious adverse event, must make a report to the Ministry of Health, Labour and Welfare (MHLW). A serious adverse event is defined as one that may lead to death or to continuous severe impairment, depending on the patient’s conditions and circumstances.
Foreseeable adverse events
No adverse events are foreseeable for the trial intervention itself, except for the potential burden and complications of blood tests. All drugs, including lithium carbonate, are within the approved dosages and indications by the MHLW.
The foreseeable side effects of lithium carbonate, as described in the package insert, are as follows:
Major side effects: Tremor (4.6%), dry mouth (2.4%), and diarrhea (1.2%). Serious side effects: Lithium intoxication (unknown frequency); malignant syndrome (unknown frequency); sick sinus syndrome and bradycardia (unknown frequency); nephrotic diabetes insipidus (unknown frequency); acute kidney injury, interstitial nephritis, and nephrotic syndrome (unknown frequency); hypothyroidism and thyroiditis (unknown frequency); hyperparathyroidism (frequency unknown); and dementia and impaired consciousness (frequency unknown).
Ethics and dissemination
Adherence to the study protocol
All researchers participating in the trial will place the safety and human rights of the participants at the highest priority and will adhere to the study protocol, as long as it does not compromise their safety and human rights.
Regulations to be adhered to
All researchers participating in the trial will abide by the Declaration of Helsinki and its amendments, as well as the Ethical guidelines for medical and health research involving human subjects (2017 revision, Ministry of Education, Culture, Sports, Science and Technology, and MHLW).
Approval by the institutional review boards
The trial has been approved by the Ethics Committee of the Kyoto University Graduate School of Medicine (registration number: C1401) and the Institutional Review Boards of Toyooka Hospital (registration number: 180).
Any changes to the study protocol will be reported to the Ethics Committee of the Kyoto University Graduate School of Medicine for approval. If approval is granted, approval for the study protocol change will subsequently be sought from the Institutional Review Board of Toyooka Hospital. Changes will then be disseminated to the research staff, and, where necessary to the study participants.
Procedures for informed consent
The treating physician must make sure that the participant has understood the contents of the trial and must obtain written informed consent from the participant. The treating physician must seek re-consent when the research protocol is revised, or a new invasion or any possible disadvantage is applied to the participant who has already consented.
All researchers and contractors of the trial must strictly manage participants’ personal information in adherence with the Ethics Guideline for Clinical Research and Act on the Protection of Personal Information. The data manager will delete site-specific patient IDs and add study-specific patient IDs at the time of data retrieval from Toyooka Hospital. Before the data manager retrieves the data, the data manager and the chief study investigator at Toyooka Hospital will ensure the data anonymity. The chief study investigator will keep the correspondence table up to date, including both the study-specific and the site-specific patient IDs at Toyooka Hospital. The data manager and the trial statistician will have access to only anonymized data but will not have access to the participants’ personal information. The media will be stored in a locked cabinet in the office of Department of Pharmacoepidemiology, School of Public Health, Department of Pharmacoepidemiology, Graduate School of Medicine/School of Public Health, Kyoto University, for 10 years after the publication of the main results and will then be discarded.
Access to the data
All members of the Steering Committee will have full access to all the final dataset.
Ancillary and post-trial care
All participants will receive standard care during and after the trial.
Exemption of medical expenses and rewards
As all the diagnostic tests and treatments in the trial are within the approved dosage and administration by the MHLW, medical expenses will be covered in the usual way through the participant’s health insurance and copayment. Participants will not receive any reward or exemption for any tests or treatments.
Compensation for adverse events
As all the diagnostic tests and treatments in the trial are conducted in accordance with the indications and dosage approved by the MHLW, the costs of care for any adverse events will be covered by the participant’s health insurance and copayment. We will not contract private health insurance for clinical research because the trial involves only a minimally invasive intervention.
The protocol will be published in an English academic journal and presented at a scientific conference. The synopsis will be available from the website of Department of Health Promotion and Human Behavior, Department of Pharmacoepidemiology, Graduate School of Medicine/School of Public Health, Kyoto University, and Toyooka Hospital. The trial results will be disseminated through academic journals and conference presentations. A summary of study results will be disseminated on the website listed above for dissemination to trial participants.
Authorship for the primary and secondary results will be determined by all members of the Steering Committee. If the chief study investigator, participating physicians, and other members of the Steering Committee do not appear as co-author, they will be listed at the end of the article. Such authors may be listed as co-authors in some journals, but not in others.
After the publication of the main findings, we will register the anonymized data set in UMIN-Individual Case Data Repository (ICDR) (http://www.umin.ac.jp/icdr/index-j.html). Only researchers who are certified by the Steering Committee will be allowed access the data.