PICC is initially routine insertion at the time of admission of hospice-palliative care unit

PICC is inserted if 3 or more times of IV insertion trial per day is required for IV access

comparisons of the safety, efficacy, and patient-perceived satisfaction between the initially routine PICC insertion group (routine PICC group) and general IV access group (general IV group)

peripherally inserted central catheter (PICC)

Kwonoh Park, MD, PhD

To establish the IV access strategy for terminally ill cancer patients, using comparisons of the safety, efficacy, and patient-perceived satisfaction between the initially routine PICC insertion group (routine PICC group) and general IV access group (optional PICC group).

Reliable intravenous (IV) access is an important issue in terminally ill cancer patients, however, they have limited or no peripheral venous access due to edema or long period of IV therapy. Thus, intravenous access has been provided by Central venous catheter (CVC).

There are some options for applying CVC in cancer patients; subclavian venous catheter (SVC), chemo-port (CP), and the peripherally inserted central catheter (PICC).

When considering the characteristics of terminally ill cancer patients, such as poor general condition and a limited period of survival, PICC could be a safe and effective method for intravenous access.

There are two previous studies concerned about PICC study in terminally ill cancer patients. They showed that PICC might be overall safe and efficient in terminally ill cancer patients. However, these studies did not evaluate superiority of PICC insertion compared to no insertion and the appropriate time for PICC insertion due to limitation of their design, such as retrospective or single-arm observational study. Thus, strategies of PICC insertion for IV access in terminally ill cancer patients have not been determined until now.

Considering the favorable results of PICC insertion in previous studies and limited survival time of terminally ill cancer patients, the investigator postulated that routine PICC insertion at the time of admission for terminal care would be effective for IV access.

Thus, the investigator assumed that initially routine PICC insertion would be non-inferior in maintenance success rate / and complication rate compared to general IV access. In addition, it would be superior in patient-perceived satisfaction. The inveistigator will undertake a randomized phase II study to confirm the hypothesis.

Prospective, Single institution, Open-label, Randomized, Phase 2

Comparison Between Initial Routine PICC and General IV Access in Terminally Ill Cancer Patients

Comparison of Safety, Efficacy, and Patient-perceived Satisfaction Between Initial Routine Peripherally Inserted Central Catheters Insertion and General Intravenous Access in Terminally Ill Cancer Patients: A Randomized Phase II Study

rate of successful PICC maintenance until death or discharge/transfer

rate of any complication which is related with PICC

rate of premature removal such as self-removal or CRBSI before death or discharge

procedure-related distress during insertion of PICC

patient perceived comfort and convenience ("How do participants feel comfort and convenience about the IV access?" at 3th - 7th days after enrollment

Investigator evaluate the colonization of PICC using tip culture at the time of removal

Pusan National University Yangsan Hospital

Professor, clinical research

Symptoms and General Pathology

All Conditions

Nervous System Diseases

Cancer Pain

Pain

Neurologic Manifestations

Analgesics

Central Nervous System Depressants

All Drugs and Chemicals

Ketamine

Anesthetics

Anesthetics, Dissociative

Anesthetics, Intravenous

Anesthetics, General

Excitatory Amino Acid Antagonists

Neurotransmitter Agents

continuous intravenous infusion of ketamine

Application of ketamine using continuous intravenous infusion method during 5 days

* Ketamine 100mg/2ml + 5% Dextrose water or Normal saline 98 ml mixed fluid
* Dose schedule: 0.05mg/kg/hr -\> 0.10mg/kg/hr -\> ... -\> 0.5mg/kg/hr (increase dose at a rate of 0.05mg/kg/hr every 8 hours)

Mikyung Kang

So Yeon Oh

Sang-Bo Oh

Eun-Ju Park

To establish the role of ketamine in hospitalized terminally ill cancer patients with refractory cancer pain, using continuous intravenous infusion of ketamine

* There are approximately 20 percent patients of refractory cancer pain, which is troubled with uncontrolled pain though treatment including opioids.
* Ketamine has been showed the performance of Ketamine, N-methyl-D-aspartate (NMDA) receptor blocker, in refractory cancer pain based on prior studies.
* We cannot yet confirm the role of Ketamine comparing the benefit and risk due to incompatible results of prior studies. Additionally, most of prior studies were studied in heterogenous groups, which are from beginning of palliative chemotherapy to terminal status, so role of ketamine was not assessed in homogeneous terminally ill cancer patients. And they has used mostly 'bolus intravenous infusion' or 'continuous subcutaneous infusion (CSCI)', relatively rare in continuous intravenous infusion (CIVI).
* The bolus intravenous method is convenient but is concerned with leading to relatively severe adverse events due to poor general condition of terminally ill cancer patients, the CSCI method is not recommended because of adverse events (AEs) such as skin irritation. On the contrary, the CIVI method using gradual increasing ketamine minimizes AEs and is free of skin irritation. Most of hospitalized terminally ill cancer patients has proper IV access using intravascular devices (chemoport or PICC). So, CIVI method is suitable to hospitalized terminally ill cancer patients.
* This study assess the efficacy and safety of 5-days CIVI gradual dose titration of Ketamine in terminally ill cancer patients with refractory cancer pain.

Prospective, Single institution, Open-label, Phase 2

Continuous IntraVenous Infusion of Ketamine in Terminally Ill Cancer Patients

A Phase II Study About Efficacy and Safety of the Continuous IntraVenous Infusion of Ketamine in Terminally Ill Cancer Patients With Refractory Cancer Pain

complete pain response plus partial pain response

* Complete pain response is defined as patient reported pain score using numerical rating scale (range 1-10) ≤ 3 or ≤ personalized pain goal (PPG) and receiving less than four rescue analgesic doses for 24 hours, without unacceptable toxicities
* Partial pain response is defined as receiving less than four rescue analgesic doses per day without a patient reported pain score using numerical rating scale (range 1-10) ≤ 3 or ≤ personalized pain goal for 24 hr, without unacceptable toxicities

Delineate changes of pain intensity daily, from the time baseline until 5th days after application of ketamine.

Pain intensity is defined as the mean of terdiurnal checked patient reported pain score during a day.

Dose and number of rescue analgesics for breakthrough pain

Satisfaction about pain control and Ketamine-related distress during application of ketamine was evaluated by questions as follows: "How do you feel satisfaction about ketamine?" (at 5th days or drop-out)

Rate of discontinuation due to Ketamine related AEs

Time from application of ketamine until death or discharge/transfer

Death

Interventions includes prognosis disclosure and discussions of EOL care as needed as in current clinical practices.

Interventions of the attention usual care arm include a consistent master prepared nurse on the study team will provide the attention portion of the care and a workbook and a video with educational materials. The initial meeting will occur before the patient discharges from hospital and the usual care nurse will give patients and family caregivers a workbook and a video with educational materials on how to manage common symptoms and a comprehensive list of resources available, including patient support organizations, support and financial assistance through the social work department.

The intervention aims at facilitating patients, families, and primary physicians to discuss the patient's wishes for EOL care by clarifying a terminally ill cancer patient's understanding of his/her prognosis and treatment options and her/his readiness for engagement in ACP, appropriately weighting the benefits and burdens of medical treatments at EOL, and clearly defining and documenting the patient's preferences so as to be readily available later for the patient's primary physician to guide EOL care decision-making which will honor the patient's preferences for EOL care.

The facilitator will begin each course of intervention by assessing the patient's and his/her family caregiver's readiness for engagement in ACP independently.

Providing participant-centered care tailored to the specific needs of participants at each stage of readiness for engagement in ACP.

Facilitating EOL care discussions throughout the dying process.

A workbook and a video decision aid that briefly describes ACP to enhance participants' understanding of the essential elements in ACP.

Interactive advance care planning

a consistent master prepared nurse on the study team will provide the attention portion of the care. The initial meeting will occur before the patient discharges from hospital and the usual care nurse will give patients and family caregivers a workbook and a video with educational materials on how to manage common symptoms and a comprehensive list of resources available, including patient support organizations, support and financial assistance through the social work department..

Attention usual care

Siew Tzuh Tang, DNSc

The purpose of this 5-year interventional study is to design, implement, and evaluate the effectiveness of an intervention aimed at facilitating prognosis communication and end-of-life care decision-making to increase the extent of congruence between the patient's preferred and actual EOL care received and patients' and family caregivers' QOL and psychological well-being, reduce futile aggressive healthcare resources utilization at end-of-life, and facilitate bereavement adjustment.

A randomized controlled trial with a tailored, multifaceted intervention will be conducted on a convenience sample of 231 dyads of terminally ill cancer patients and caregivers with the same number of attention controlled group to evaluate the intervention's effectiveness.

Sample size calculation: There was no interventional study directly investigating the effectiveness in increasing the extent of congruence between patient preferred and actual end-of-life (EOL) care received by terminally ill cancer patients; therefore sample size estimation will be based on the effectiveness of holding EOL care discussions between patients and physicians on the extent to increase congruence between the patient's preferred and actual EOL care received. Patients who reported having EOL care discussions with their physicians significantly more likely to receive EOL care consistent to their preferences (OR=2.26; p\<.0001) and received significantly fewer aggressive medical interventions near death, with lower rates of CPR (0.8% vs 6.7%; AOR, 0.16; 95% CI, 0.03-0.80), mechanical ventilation support (1.6% vs 11.0%; AOR, 0.26; 95% CI, 0.08-0.83), and ICU care (4.1% vs 12.4%; AOR, 0.35; 95% CI, 0.14-0.90), respectively. A sample size of 124-195 dyads per group achieves 80% power to detect a difference between the interventional and control group by a two-sided hypothesis test with a significance level of 0.05. In compensating the 18.5% of attrition rate found in our previous longitudinal study, 147-231 dyads per group are needed. The proposed sample size will be targeted on 231 dyads per group to ensure adequate power to detect the hypothesized effects of the proposed intervention.

Approximately 8-10 new dyads of terminally ill cancer patients and their family caregivers were recruited in each month. In order to recruit the targeted 462 dyads (231 dyads in each treatment group) of subjects, after development of detailed study protocol, subjects will start to enter into the study at the beginning of the 6th month of the study through the 54 th month and be followed through the 5th year of the proposed study period. We will enroll and randomly assign eligible dyads of terminally ill cancer patients and their family caregivers into intervention or attention controlled group in a 1:1 fashion without stratification.

Data collection procedures: Assessments will be performed prospectively and continue until patient death, loss to follow-up, study withdrawal, or when the patient can no longer be interviewed. An every-3-week time frame will be used in this study for repeated QOL and other outcomes assessments for both patients and their family caregivers bases on the review of literature to cover the most rapid change of patient physical conditions and demanding period of caregiving until the death of the patient. After each patient's death, a chart review and postmortem interview with patients' caregivers will be performed to confirm the type of medical care received at the EOL. Bereavement interviews will be conducted 1, 3, 6 and 13 months after the time of death in order to avoid contamination on the basis of anniversary grief reactions.1

Several strategies will be taken to ensure research fidelity.

1. The proposed intervention requires professionals skilled in the content, techniques, and delivery of the intervention. Built on her previous oncology and hospice care experiences, a competency-based educational approach will be used to train the facilitator. The training will include an overview of the study protocol and procedures, a review of the developed workbook and video, and instructions in motivational assessments. The principal investigator (PI) will serve as a role model for the facilitator to coach her how to assess and motivate participants at different stage of the readiness for engagement in ACP and cooperate with physicians in coordinating and facilitating EOL care discussions. The facilitator needs to successfully demonstrate predefined competencies and consistency to delivery of the ACP intervention after training and receipt of individual feedback from the PI before formal interventions can be conducted. Thereafter the study team will meet biweekly to review the facilitator's notes on interventional sessions and to provide feedback on difficult subject management issues.
2. Interventions provided to subjects assigned to the intervention group will be compared with those received by those who assigned to the control group every 3 months. Randomly selected dyads of terminally ill cancer patients and their family caregivers in each treatment group will be interviewed by the PI to check the extent to which treatments provided to them consistent with the protocol for each group.
3. To avoid bias, separate data collectors will be hired and trained for the study to collect data for the intervention and the control group independently. Training will include screening subjects, obtaining consents, and administering the project instruments without offering information; research assistants (RAs) will be blinded to treatment conditions. Procedures will be implemented to insure the standardization of data collection. RAs reliability will be established by comparing data collected by the RAs with that recorded by the PI on five pilot cases. Ninety-five percent agreements will be required before data collection for main study can begin. Failure to reach this agreement rate will require additional training until the acceptable reliability level is reached. Intermittent reliability checks will be carried out by the PI throughout the study to maintain a 95% agreement.
4. An independent Data and Safety Monitoring Board (DSMB) will be organized to ensure continuing patient safety as well as the validity and scientific merits of the trial. The DSMB will constitute a biostatistician experienced in statistical methods for clinical trials, a nursing researcher experienced in conducting RCTs, and a physician-scientist experienced in cancer care.

The DSMB will monitor and address the following issues: (1) sufficient and appropriate enrollment of subjects, including compliance with the eligibility criteria for each dyad of terminally ill cancer patients and family caregivers enrolled in the trial, (2) appropriate implementation of randomization, (3) comparability of baseline data between treatment groups, (4) protocol compliance, including treatments delivered to each treatment group and the data collection schemes,(5) adverse events (AEs), quality assurance for data validation and registry procedures for Clinical Trial registration at ClinicalTrials.gov.

A databet that records number of recruitment each month and the baseline information will be maintained to ensure sufficient and appropriate enrollment of subjects.

A dataset that captures the values the personnel used to randomize participants will be maintained, thereby allowing the process of treatment allocation to be reproduced and verified later. The DSMB will monitor the appropriate implementation of randomization by reviewing this dataset.

Interventions delivered to subjects assigned to the intervention and the attention-controlled group will be compared every 6 months by interviewing randomly selected dyads of terminally ill cancer patients and their family caregivers in each treatment group to check treatments provided to them.

AEs will be recorded and submitted by the study team in written to the DSMB monthly, with immediate reporting of serious AEs to the DSMB and an oncologist with expertise in cancer care. Site reports AEs/SAEs to its IRB will be dictated by local requirements.

No data will be analyzed before the study ended. Access to interim results, including results according to study arm will be limited to the DSMB members and the statistician who prepared the reports only. The DSMB will review study data every 6 months and the DSMB' summary recommendations will be directed to the PI. A summary of the review of reported AEs/SAEs will be sent to the local IRB to ensure that the participating center will be informed of any pertinent safety issues.

The biostatistician will be responsible for ensuring quality of data submitted to the registry against the predefined range of each independent and dependent variable and assessing the accuracy and completeness of registry data by comparing the submitted data to the original data.

Data analysis and interpretation:

1. All data will be scored and entered into a computer spreadsheet by an administrative assistant blinded to the group allocation of the participant.
2. In order to test for baseline group equivalence, differences between study groups in baseline characteristics and identified outcomes will be assessed with the use of two-sided Fisher's exact tests and chi-square tests for categorical variables and independent-samples Student's t-tests for continuous variables.
3. Intention-to-treat regression analyses will be performed with generalized estimating equations (GEE) to examine the effectiveness of intervention. In the intention- to-treat regression analyses, all participants will be analysed in the treatment group to which they are initially allocated regardless of whether they complete or withdraw from the treatment until the patient dies.
4. The extend of congruence of the terminally ill cancer patients' preferred and actual EOL care received will be obtained by comparing the agreement between the preferences of EOL care elicited at the last assessment and actual EOL care received by the patient by the percentage of overall agreement and kappa coefficients to assess the extent of congruence to correct for the amount of agreement that can be expected to occur by chance alone.
5. Multivariate logistic regression by the GEE will be used to examine the impact of intervention on improving the extend of congruence between terminally ill cancer patients' preferred and actual EOL care received, and secondary outcomes, namely increasing prognosis awareness, EOL care discussion, and the extent of patient-family agreement on preferences of EOL care, decreasing use of futile aggressive EOL care, and facilitating hospice use and early hospice referral, with simultaneously adjusting for confounding factors. The moderation effects of prognosis awareness, EOL care discussion, and patient-family agreement on preferences of EOL care on extend of congruence between terminally ill cancer patients' preferred and actual EOL care received, decreasing use of futile aggressive EOL care, and facilitating hospice use and early hospice referral between interventional group and the attention controlled group also will be examined in the GEE model.

7. Multivariate multiple regression by the GEE will be used to test the effectiveness of intervention in improving patients' and family caregivers' QOL and psychological well-being (anxiety and depression), and family bereavement outcomes (including QOL, depression, and grief reactions), with simultaneously adjusting for confounding factors. The moderation effects of prognosis awareness, EOL care discussion, and patient-family agreement on preferences of EOL care on the differences in patients' and family caregivers' QOL and psychological well-being before the patient's death, and family bereavement outcomes between intervention group and the attention controlled group also will be examined in the GEE model. How limiting futile aggressive EOL care and the extent of congruence between terminally ill cancer patients' preferred and actual EOL care received will moderate the intervention's effectiveness on improving patients' and family caregivers' QOL and psychological well-being before the patient's death and family bereavement outcomes also will be examined in the GEE model.

An Interactive Advance Care Planning Intervention to Facilitate a Good Death for Cancer Patients

EOL care includes (1) life-prolonging or comfort-oriented EOL care, (2) CPR when life is in danger, (3) life-sustaining treatments, including cardiac massage, mechanical ventilation, ICU care, tube feeding, intravenous nutrition, and hemodialysis, and (4) hospice care.

McGill Quality of Life Questionnaire will be used to measure quality of life.

Depression and anxiety for terminally ill cancer patients.

Anxiety and depressive symptoms of terminally ill cancer patients will be measured by the Hospital Anxiety and Depression Scale.

Depressive symptoms will be measured by the Center for Epidemiological Studies-Depression Scale.

Quality of life for family caregivers while they provide end-of-life care will be measured by the Caregiver Quality of Life Index-Cancer.

Center for Epidemiological Studies-Depression Scale will be used to measure depressive symptom for bereaved family caregivers.

Complicated grief experience by family caregivers during their bereavement will be measured by the Inventory of Complicated Grief.

Terminally ill cancer patients' understanding whether their disease will be cured or not be cured and probability to die in the near future.

Family caregivers' understanding whether their relative's disease can be cured or not be cured and probability will die in the near future.

Discussions about the preferences for end-of-life care and advanced care planning.

The extent of patient-family agreements on preferences of cardiopulmonary resuscitation when life is in danger, life-sustaining treatments, including cardiac massage, mechanical ventilation, ICU care, tube feeding, intravenous nutrition, and hemodialysis, and hospice care.

Aggressive EOL care received by terminally ill cancer patients include cardiopulmonary resuscitation, life-sustaining treatments, including cardiac massage, mechanical ventilation, ICU care, tube feeding, intravenous nutrition, and hemodialysis, and hospice care.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Comparison Between Initial Routine PICC and General IV Access in Terminally Ill Cancer Patients	NCT03299868	Peripherally In... Intravenous Acc...	peripherally in...	18 Years -	Pusan National University Yangsan Hospital
Continuous IntraVenous Infusion of Ketamine in Terminally Ill Cancer Patients	NCT03362073	Ketamine Refractory Canc...	Ketamine	18 Years -	Pusan National University Yangsan Hospital
An Interactive Advance Care Planning Intervention to Facilitate a Good Death for Cancer Patients	NCT01912846	End Stage Cance...	Interactive adv... Attention usual...	20 Years - 95 Years	Chang Gung University
Comparison Between Initial Routine PICC and General IV Access in Terminally Ill Cancer Patients	NCT03299868	Peripherally In... Intravenous Acc...	peripherally in...	18 Years -	Pusan National University Yangsan Hospital

Spots Global Cancer Trial Database for terminally ill cancer patients