Patient case: 54-year-old male with malignant hyperthermia; genetic feature: RYR1

Clinical trial: Improving Outcomes in HIV Patients Using Mobile Phone Based Interactive Software Support

Summary: PROTOCOL SUMMARY Abstract Current estimates point towards a huge increase in the number of people that are eligible to start ART in Uganda and globally. As many of the newly eligible patients are largely asymptomatic, there are concerns about adherence and retention of these individuals and especially those starting ART with a higher CD4 counts. Urgent information is required to plan for implementation of most recent WHO and National guidelines in the most cost effective manner as well as maximizing retention of HIV positive individuals in care and achieving virological suppression.
  We plan to undertake research designed to see if we can optimize adherence, virological outcomes and HIV knowledge, in order to give an overall increased quality of life in vulnerable populations starting or established on ART in Kampala, Uganda. We will test implementation of an open source software-based tool to send text messages and to give access to an interactive voice response system to support self-monitoring and provide health information using patients' mobile phones.
  We aim to undertake an open labeled randomised trial at two sites: the IDI which is an urban center of excellence in HIV care, and Kasangati Health Center, which is a peri-urban public health care facility. The project aims to enroll patients starting ART, already established on first line ART or switching to second line ART. We will include special populations including pregnant women, discordant couples and young people. The estimated length of the project is 30 months. The technology to be evaluated in this study is based on CONNECT FOR LIFETM m-health technology (CFL2015.01 or higher). CFL2015.01 provides text messages or Interactive Voice Response (IVR) functionalities, a technology that allows a computer to interact with humans through the use of voice and tones input via keypad, including pill reminders, clinic visit reminders, health tips and functionality to support symptom reporting.
  The Primary Objective of this study is to determine the effect of the CFL2015.01 tool on quality of life of HIV patients receiving care at IDI and Kasangati HCIV. At the start of the intervention, all patients will undergo quality of life assessment, which will be repeated at months 6, 12 and 24 months. The scores will be compared to assess the effect of the tool on quality of life. The Secondary Objectives are virological outcomes baseline, 6, 12 months and 24 months, retention in care, aversion of early treatment failure, disease knowledge, clinic attendance and cost analysis.

Detailed description: 5. DESCRIPTION OF INTERVENTION Call for Life UgandaTM Janssen Global Public Health Research and Development, in close collaboration with the Infectious Disease Institute Kampala (IDI), has developed Call for Life UgandaTM tailored to the needs of PLHIV in Uganda. Call for Life UgandaTM is based on the CONNECT FOR LIFETM technology (CFL2015.01 or higher version) and the MOTECH platform, an open source platform developed by Grameen Foundation and the University of Southern Maine with financial support from the Bill and Melinda Gates Foundation, and was released under the terms of the MOTECH open source license agreement.
  All patients consenting will;
  1. At enrolment receive detailed information from a nurse/counsellor on the Call for Life UgandaTM system and how it operates
  2. Receive calls or text messages from Call for Life UgandaTM will include recording of self-reported adherence (soliciting active feedback via keypad) and symptom management triggering alerts for the clinic.
  3. Participants with an undetectable viral load (after discussion with their counselors) will have the option chose the frequency of their calls, between daily to weekly to a minimum of an appointment reminder (every 1-2months) only.
  4. Participants with a detectable viral load at any time will receive daily calls or text messages. They will only be able to decrease the frequency of calls when their VL becomes undetectable and on discussion with their counsellor
  5. In addition all patients will receive
  1. an appointment reminder before their appointment (exact timing will be patients choice).
  2. health tips on HIV, ART and related conditions each week (or repeat of the old one if they wish).
  3. have the opportunity to report symptoms to the clinic at any point in time, which send an alert to the clinic (with a call back from clinic staff).
  After the 12 month interim analysis the study team and a trial steering group made of 3 independent member (a statistician, a mental health specialist and a clinical researcher) will review the data, and if there is no harm seen all of those on the control arm will be offered Call for Life Lite, which provides weekly adherence calls and appointment reminders only, as we plan to offer Call for Life Lite to all patients in the clinic by this time. Those on the full Call for Life arm will continue on this arm. If a positive benefit is seen full Call for Life will be offered to all in the clinic (as long as there are sufficient funding to allow for the phone connection aspect of the tool).
  6. STUDY PROCEDURES 6.1. Screening The subjects will be screened and enrolled over a period of 6 months These are the screening procedures
  -  All consecutive eligible patients will be approached for participation in the study.
  -  For patients interested in participating the inclusion and exclusion criteria will be ascertained.
  -  The patients will receive information about the study by the study nurse or counselor Patients who agree to participate in the study will sign the informed 6.3. Follow-up Visit The participants will come to the clinic monthly or 2 monthly to pick up their ART and concomitant medications (non-study visits).
  The participants will come for their study follow up visits every 6 months Every 6 months The patients will be assessed by the study staff.
  -  The study doctor will collect General Medical History and perform Physical Examination and enter it in an electronic CRF.
  -  The counselor will collect the Quality of life and Knowledge questionnaires and enter them in an electronic CRF.
  At baseline, 6, 12 and 24 months the following samples will be collected;
  • Viral load
  -  Storage plasma (1 aliquot) serum (3 aliquots)
  In case of death
  • Verbal autopsy by phone or by visiting the home of the deceased
  • Review of the clinical information in the clinic and study file to identify a presumptive cause of death
  Additional procedures Resistance testing: It will be done on stored samples
  • Baseline. Resistance testing will be carried out if subsequent viral failure in order to investigate transmitted resistant virus
  • Biological samples will also be stored at 6, 12 and 24 months and resistance testing carried out in case of viral load >1,000 copies/ml
  On stored sample Additional procedures on stored samples may be conducted during the course of the study if deemed to be relevant to improve clinical care will be made available to the clinicians and the study participants.
  6.4. Subject Withdrawal Subjects may withdraw from the study at any time at their own request, or they may be withdrawn at any time at the discretion of the investigator for safety or behavioral reasons, or the inability of the subject to comply with the protocol required schedule of study visits or procedures.
  If a subject does not return for a scheduled visit, every effort should be made to contact the subject. In any circumstance, every effort should be made to document subject outcome, if possible. The investigator should inquire about the reason for withdrawal and follow-up with the subject regarding any unresolved adverse events (AEs).
  If the subject withdraws from the study, and also withdraws consent for disclosure of future information, no further evaluations should be performed, and no additional data should be collected. IDI may retain and continue to use any data collected before such withdrawal of consent.
  7. ASSESSMENTS 7.1. Safety Safety monitoring for this study will focus on unanticipated problems involving risks to participants, including unanticipated problems that meet the definition of a serious adverse event.
  7.1.1. Unanticipated Problems
  Unanticipated problems involving risks to participants are defined as, any incident, experience, or outcome that meets all of the following criteria:
  • Unexpected in terms of nature, severity, or frequency given (a) the research procedures that are described in the protocol-related documents, such as the IRB-approved research protocol and informed consent document; and (b) the characteristics of the participant population being studied;
  -  Related or possibly related to participation in the research (possibly related means there is a reasonable possibility that the incident, experience, or outcome may have been caused by a procedures involved in the research); and
  -  Suggests that the research places participants or others at a greater risk of harm (including physical, psychological, economic, or social harm) than was previously known or recognized.
  7.2. Pregnancy Testing Pregnancy testing will be performed if required as standard of care at IDI, i.e. at the woman's request or missed menstrual period. Pregnant women will not be withdrawn from the study.
  7.3. Post-Recruitment Illness Patients with post-recruitment illness will be managed in accordance with standard of care in Uganda's public health sector.
  8. ADVERSE EVENT REPORTING 8.1. Adverse Events During each study visit the study clinician will assess AEs which may have occurred since the previous visit. ART toxicities and opportunistic infections will be entered in the electronic medical records as per standard of care, as well as other outcomes (e.g: death, hospitalization).
  The investigators will generate and submit annual reports summarizing these adverse events.
  8.2. Serious Adverse Events
  An SAE is any untoward medical occurrence at any dose that:
  Results in death; Is life-threatening (immediate risk of death); Requires inpatient hospitalization or prolongation of existing hospitalization; Results in persistent or significant disability/incapacity (substantial disruption of the ability to conduct normal life functions); Results in congenital anomaly/birth defect, 8.3. Severity Assessment This is not an intervention study and no specific drug will be investigated. Patients will be enrolled in the study to document in details the outcomes occurring during their care at the IDI clinic.
  8.4. Causality Assessment Since we are not testing any specific intervention/drug/device causality cannot be assessed 8.5. Reporting Requirements The investigators will generate and submit annual reports summarizing AEs. Since the study does not test any investigational drug or intervention, and causality assessment is not applicable, SAEs will also be reported to the SRC, IRB and the Uganda National Council of Science and Technology (UNCST) annually in aggregate.
  9. DATA ANALYSIS/STATISTICAL METHODS 9.1. Sample Size Determination Based on a pre and post ART assessment in Burkino Faso and Uganda we anticipate that the quality of life score (MOS-HIV) in ART naïve patients will increase at least by 15 points for physical health summary (PHS) between baseline and 12 months ART use (34, 35). We estimate there will be an additional 5 points improvement in those receiving C4LTM which would give 20 point improvement for those on C4LTM and 15 points for those not on call for Life. In those already on ART we estimate an improvement for those established on ART with a 5 point improvement for those on C4LTM and nil for those not accessing C4LTM. We also estimate a 5 point increase in mental health score in those receiving C4LTM compared to no change in those without C4LTM starting ART, and a lower improvement of 2 points in mental health score in those already on ART. The study is powered on the PHS for QOL. For a power of 0.9 and precision of 0.05 we would need a minimum of 273 in each arm (overall 546) patients, if the mean PHS among patients with C4L was 58.2 compared to 55.2 among patients without C4L. We will include a 10% LTFUP/mortality rate to give a sample size of 600.
  The composition of the study participants is estimated as 300 patients at Kasanagati and 300 patients at IDI.
  With the proposed sample size, the numbers above depict over 90% power to test even the smallest differences in mean PHS at 12 months in the group of patients with and without C4L. We also anticipate that we will be able to detect changes in MHS QOL with this sample size.
  9.2. Analysis of Endpoints 9.2.1. Analysis of Primary Endpoint Scales to measure quality of life There are numerous measures of quality of life. For this study we have chosen to use the Medical Outcomes Study (MOS-HIV) Health Survey which is the most widely used health related HRQoL measure in PLHIV(36).
  A recent review of the HRQoL measures currently in use in HIV/AIDS clinical trials found the MOS-HIV to be one of the two most suitable HIV targeted HRQoL measures [2]. The other measure was the Functional Assessment of HIV Infection (FAHI)(37). The MOS-HIV scale was chosen because it has been validated in various settings including Uganda, has a Luganda language version, and was found to be useful in assessing HRQoL in PLHIV(38-40). In an HIV population in Uganda the MOS-HIV was reported to have Crohnbach's α coefficients > 0.70 for five out of the eight multi-item scale and factor analysis supported the underlying physical and mental health dimensions (38). In addition, the measure can be self-administered in ≤10 minutes.
  The MOS-HIV measures HRQoL in 11 areas: health perceptions, bodily pain, physical function, role function, social function, mental function, vitality, health distress, cognitive function, QoL, and health transition. One scores scale in a range from 0-100 with a higher score implying better health (41). In addition to these subscales, a Physical Health Summary score (PHS) and Mental Health Summary score (MHS) can be calculated.
  Intra patient in QoL scores will be compared using Paired T-tests and overall change will be investigated. The effect of calendar time on QoL life scores will be accounted for during analysis. Furthermore, the changes and or effect of the intervention on different sub-groups of HIV positives patients will be carried. For example, subgroups group analysis by type and duration of ART exposure, time from ART initiation, gender differences and other categories. All analysis will use robust standard errors to account for individual patient level variances/correlations, as well as cluster (facility) correlation. The effect of the intervention will also be compared between IDI and Kasangati sites. All analysis will be conducted using STATA, USA.Analysis of Secondary Endpoints.
  Analysis of secondary endpoints
  1. We will undertake analysis of MHS as discussed in the primary endpoint (PHS) above
  2. We will undertake an intention to treat analysis of virological outcomes (logistic regression) at 6, 12 and 24 months. A viral load >50 c/ml will be considered to be virological failure
  3. We will undertake an intention to treat analysis of lost to follow up (Cox regression). Lost to follow will be defined as not attending appointment for >3 months.
  4. We will compare knowledge about HIV, ART and associated health conditions which will be delivered as messages in the health tips section of Call for Life UgandaTM in both arms at 6, 12 and 24 months of Call for Life UgandaTM use. We will add additional questions to the MOSHIV tool will be adapted for each key population.
  5. We will assess perceptions and attitudes to the Call for Life UgandaTM tool thorough focus group discussions and Key informant interviews, targeting each special population. We will use purposeful sampling and will continue until no new themes emerge. We will use NVIVO software for coding of themes.
  6. Cost analysis along with the study evaluation; appropriate and detailed cost evaluation will also be performed. It is anticipated that if the intervention is proved effective, a cost effective analysis would contribute to developing a sustainable scale up strategy for similar service across Uganda.
  The overarching research questions addressed by this evaluation would be :
  A) From a societal and health care perspective, is the Call for Life UgandaTM intervention, in comparison with usual care, preferable in terms of costs, effects and utilities? B) What is the incremental cost-effectiveness ratio (ICER) of Call for Life UgandaTM in comparison with usual care? C) In comparison with usual care, is the Call for Life UgandaTM intervention preferable in terms of cost and utilities during the remaining life expectancy of the study population?(model based economic evaluation).
  7. We will undertake an intention to treat analysis of attendance (Cox regression). Failure to attend will be defined as not attending appointment within 3 working days of scheduled attendance in each arm.
  8. For the primary outcome, we will undertake sub-analysis for the following groups;
  1. Pregnant women already receiving ART or starting ART .
  2. Male and female positive partners in discordant couples already receiving ART or starting ART with Call for Life UgandaTM
  3. Male and female young people (aged 15 to 24 years) already receiving ART or starting ART with Call for Life UgandaTM
  4. Male and female patients already receiving second line ART or starting second line ART with Call for Life UgandaTM
  5. Adult patients starting ART
  We intend to report the study by using standard reporting methods for randomized trials (COHORT) but also to follow the newly published mERA guidelines for reporting mHealth tools which include the outcomes in the table below(33).
  Radomisation Patients will randomly be assigned to either one of the two arms, that is, with and without CDL. To ensure that all patients in each of the arms are represented and equally balanced out in both arms, the study will use stratified randomization where each of the categories of patients at the start of the study will form the strata on interest. Within each stratum, the patients will randomly assigned to C4L or no C4L. Randomization lists wil be generated by an independent statistician and kept under lock and key in the two sites.
  9.3. Interim Analysis Interim analyses will be undertaken at the 6 month and one year visits to inform the study team on change in QOL and assess the impact of the intervention. However, the study will continue to collect information to the 24 month time point, unless there is a negative effect of the intervention at 6 or 12 months.
  10. QUALITY CONTROL AND QUALITY ASSURANCE During study conduct periodic monitoring may be conducted to ensure that the protocol and Good Clinical Practices (GCPs) are being followed. The monitors may review source documents to confirm that the data recorded on CRFs is accurate. Additionally, the study site may be subject to review by the Institutional Review Board (IRB) and/or to inspection by appropriate regulatory authorities.
  11. DATA HANDLING/RECORD RETENTION 11.1. Case Report Forms (CRF)/Electronic Data Record A CRF is required and should be completed for each included subject at enrolment and during study visits.
  The investigator has ultimate responsibility for the collection and reporting of all clinical, safety and laboratory data entered on the CRFs and any other data collection forms (source documents) and ensuring that they are accurate, authentic / original, attributable, complete, consistent, legible, timely (contemporaneous), enduring and available when required. The CRFs must be signed by the investigator or by an authorized staff member to attest that the data contained on the CRFs is true. Any corrections to entries made in the CRFs, source documents must be dated, initialed and explained (if necessary) and should not obscure the original entry.
  11.2. Record Retention To enable evaluations and/or audits, the investigator agrees to keep records, including the identity of all participating patients (sufficient information to link records, for example CRFs and hospital records), all original signed informed consent documents, copies of all CRFs, safety reporting forms, source documents, and detailed records of treatment disposition, and adequate documentation of relevant correspondence (for example letters, meeting minutes, telephone calls reports).
  Investigator records must be kept for as long as required by applicable local regulations (UNCST generally requires a minimum of 5 years). When more than one requirement can be applied, records must be maintained for the longest period provided.
  11.3. Confidentiality Clinical data will be entered into a study specific database by designated staff on a regular basis from completed Case Record Forms (CRF). Case Record Forms and other source documents will be kept in locked cabinets. Data will be entered on a regular basis to ensure that it is up to date. The database will be entered on regular basis on a secure PC, as will the pharmacokinetic database that will be received by from the laboratories. Access to database will be given to authorized personnel only (members of the immediate study team) and a log of authorized personnel will be stored in the trial master file. CRF and trial documents will be kept in locked cabinets. No participant identifying information will be disclosed in any publication or at any conference activities arising from the study.
  12. ETHICS 12.1. Institutional Review Board (IRB) It is the responsibility of the investigator to have prospective approval of the study protocol, protocol amendments, informed consent documents, and other relevant documents from the IRB. All correspondence with the IRB should be retained in the regulatory or trial master file. Copies of IRB approvals should be filed with other study documents.
  12.2. Ethical Conduct of the Study The study will be conducted in accordance with legal and regulatory requirements, as well as the general principles set forth in the International Ethical Guidelines for Biomedical Research Involving Human Subjects and the Declaration of Helsinki.
  In addition, the study will be conducted in accordance with the protocol, GCP guidelines, and applicable local regulatory requirements and laws.
  12.3. Subject Information and Consent All parties will ensure protection of subject personal data and will not include subject names on any forms, reports, publications, or in any other disclosures, except where required by laws.
  The informed consent document used in this study, and any changes made during the course of the study, must be prospectively approved by the IRB.
  The investigator, or a person designated by the investigator, will obtain written informed consent from each subject or the subject's legal representative before any study-specific activity is performed. The investigator will retain the original of each subject's signed consent document.
  12.4. Data Privacy Any and all data generated in IDI's use of Call for Life UgandaTM shall be owned solely by IDI. Janssen and Grameen shall not be able to directly access or utilize patient data and information. Therefore IDI will take all reasonable steps to restrict disclosure of personal data including patient-identifiable to third parties.
  In addition the following Security Measures are in place to protect Patient's privacy when using Call for Life UgandaTM • Call for Life UgandaTM database hosted locally at IDI Kampala • Call for Life UgandaTM Web access is password protected • Inactivity of 30 minutes on Call for Life UgandaTM web interface will log the web user out. The user will have to re-login into Call for Life UgandaTM • Study sponsor has no access to patient level data
  • Data at Call for Life UgandaTM backend is maintained in encrypted format
  • History of Changes made by investigator via web interface are tracked
  • History of all web access by investigator and Admin - login/logout events is maintained
  -  Patients calling on Call for Life UgandaTM IVR are authenticated by their registered mobile number and the PIN they enter
  -  Call for Life UgandaTM will initiate calls to patients only on their registered mobile numbers and authorize Call for Life UgandaTM usage only when the called person will authenticate himself with his personal PIN
  -  Call for Life UgandaTM does not ask the person calling its own identity till the person has been authenticated himself as a registered patient (only Call for Life UgandaTM signature music is played)
  13. DEFINITION OF END OF TRIAL The trial will be considered ended at the time of the "Database Lock" 14. PUBLICATION OF STUDY RESULTS We aim to publish in high-impact, peer-reviewed journals with focus on open-access. Full anonymity of subject's details will be maintained throughout.
  We will present data at national, regional, and international congresses (poster or oral presentation) e.g. CROI (Conference on Retroviruses and Opportunistic Infections) or IAS conferences (International AIDS Society).
  The study results will also be presented to officials in charge of the antiretroviral treatment program at the Ministry of Health. Study summaries will be communicated to health care workers in Uganda through the AIDS Treatment Information Centre newsletter which is published by the IDI and distributed to all health workers in the public and not-for profit sectors in Uganda.
  The study will be registered on Clinicaltrials.gov.
  15. CAPACITY BUILDING We will be employing one clinical trial co-ordinator who will be trained in clinical trials management as a result of the study. This study will also build capacity in social science by Dr Rachel King who is a senior social scientist mentoring our junior research staff. Janssen will assist our statisticians at IDI with cost analysis and so build capacity in this regard.
  16. FUNDING Funding has been foreseen by Janssen Global Public Health which would be made available by the Johnson & Johnson Corporate Citizenship Trust through a grant to the Uganda Academy for Health Innovation and Impact .
  Project Timeline
  IRB approvals / protocol training Collection of baseline data - questionnaires Launch of Call for Life Uganda Enrolment of Call for Life patients IDI Follow up of Call for Life patients IDI Enrolment of Call for Life patients Kasangati Follow up of Call for Life patients Kasangati Interim data analysis Final data analysis primary outcome Observational data collection Call for Life patients IDI Observational data collection Call for Life patients Kasangati Analysis of observational 24 month data

Eligibility: Inclusion Criteria:
  -  Subjects must meet all of the following inclusion criteria to be eligible for enrollment into the study:
  1. Evidence of a personally signed and dated informed consent document indicating that the subject (or a legal representative) has been informed of all pertinent aspects of the study.
  2. Patients who are willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures.
  3. Patients having the ability to use basic cell phone functions (e.g., being able to make and receive phone calls).
  4. Patients with access to a mobile phone (need to be able to answer the phone at a predetermined time slot and to be able to call the clinic if they are sick)
  5. Patients who are able to understand Luganda or Runyankole or English (as these are the languages of the overwhelming majority of patients at IDI and Kasangati and so will be used for the trial. If any other language has more than 30 patients who require it, the tool will be adapted to include this new language before the roll out of the tool to the entire clinic population
  Exclusion Criteria:
  -  4.2. Exclusion Criteria
  1. Patient whose clinical condition interferes with appropriate use of cell phone (e.g., deafness, severe cognitive impairment)
  2. Patients < 15 years unless emancipated minors as defined by Ugandan National Research Ethics Committee guidelines.
  3. Patients who are enrolled in an interventional study at IDI
  4. Patients who are not receiving standard first and second line treatment
  5. Patients who are critically ill.

Relevance to patient case: not relevant