Study setting {9}
This trial aims to randomise 300 adult participants with Type 2 diabetes mellitus. Recruitment will be conducted across several research centres in the United States (US) and Ireland. Details of recruitment sites is described further in appendix 1. Several research sites were selected across the US to improve the generalisability of the study intervention.
SCREENING PROCEDURE
During the screening process, an independent clinical research organisation called Clinical Trial Mentors (CTM), will assist in participant recruitment.
PRE-SCREENING
If a participant expresses interest in the trial, they will be given a copy of the Participant Information Sheet (PIS) and Informed Consent Form (ICF) and allowed at least 48 hours to review before being contacted by researchers/CTM.
If recruited via online advertising, an online survey provider called Google Forms will be used to assess whether interested individuals are suitable for a pre-screening telephone call, which facilitates the identification of potential research participants, who meet the eligibility criteria for enrolment review. As this process will collect identifiable information (which includes protected health information) prior to obtaining consent to participate in the study a waiver of individual HIPAA authorization has been requested (US sites). This Privacy Rule Authorisation requests the participants permission to allow the study team to use any protected information disclosed within the pre-screening survey for the purposes of pre-screening/enrolment review.
Participants are eligible for a pre-screen call if they indicate they are willing to attend the clinical site during the trial and if they confirm that they are not taking insulin to treat their diabetes and have had no changes to their medications within the last 90 days. This call will be coordinated by either the study site or Clinical Trial Mentors.
The study will be conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki. Only eligible participants who have read the PIS/ICF will be included in the trial after written informed consent is obtained.
SCREENING ASSESSMENT
Potentially eligible participants will be screened to ensure that they meet the eligibility criteria. This will only be done after first obtaining informed consent and the participant signing the PIS/ICF. After giving informed consent, the following procedures will be conducted:
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• Completion of screening questionnaire
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• HIPAA (US sites only)
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• Confirmed HbA1c ≥ 6.5% and ≥ 9.5%
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• Height and weight to document BMI
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• Pregnancy test on urine (for women of childbearing potential)
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• Pass AMTAS Flex hearing assessment
Where a participant fails to fulfil the screening criteria, this will be documented, and the investigator will retain the signed consent form. The participant will not advance any further into this clinical investigation. The screening assessment will be merged with the Baseline Visit if they are deemed eligible.
Eligibility criteria {10}
Potential participants who are interested in taking part must meet the following eligibility criteria to be enrolled in the trial.
INCLUSION CRITERIA
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Male or female, age ≥ 22 years and ≤ 70 years a the time of signing informed consent (at the US sites). The non-US site will recruit participants aged ≥ 18 years and ≤ 70 years,
-
Diagnosed with Type 2 diabetes mellitus (DM) ≥ 90 days prior to day of enrolment,
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HbA1c (glycated haemoglobin) ≥ 6.5 and ≤ 9.5% (48-80mmol/mol),
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If taking medication to treat diabetes, a stable dose of no more than 3 anti-diabetic medications for at least 90 days prior to enrolment,
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Must be under care of physician for follow-up of their Type 2 DM
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Must agree to continue to participate with their diabetes care program
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Access to Wi-Fi.
-
BMI ≥ 25 kg/m2 (Ireland site only)
EXCLUSION CRITERIA
Key exclusion criteria include a history of vestibular dysfunction, Type 1 diabetes mellitus, participant is taking insulin, change in medications in previous 90 days, history of stroke or epilepsy and pregnancy. A full list of the comprehensive exclusion criteria for this trial is detailed in Appendix 2.
Who will take informed consent? {26a}
The study will be conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki. Only eligible participants who have read the Participant Information Sheet (PIS)/ Informed Consent Form (ICF) will be included in the trial after written informed consent is obtained.
Written and verbal versions of the PIS/ICF will be presented to the participants detailing no less than: the exact nature of the trial; what it will involve for the participant; the implications and constraints of the protocol; the known side effects and any risks involved in taking part. It will be clearly stated that the participant is free to withdraw from the trial at any time for any reason without prejudice to future care, without affecting their legal rights and with no obligation to give the reason for withdrawal.
The participant will be allowed as much time as wished to consider the information, and the opportunity to question the Investigator, their PCP/medical provider/GP or other independent parties to decide whether they will participate in the trial. Written Informed Consent will then be obtained by means of participant dated signature and dated signature of the person who presented and obtained the Informed Consent. The person who obtained the consent must be suitably qualified and experienced and have been authorized to do so by the Chief/Principal Investigator. A copy of the signed Informed Consent will be given to the participant. The original signed form will be retained at the trial site.
Additional consent provisions for collection and use of participant data and biological specimens {26b}
N/A – No ancillary studies will be performed in this trial
Interventions
Explanation for the choice of comparators {6b}
Comparators for this study include an active vestibular nerve stimulation headset and a device providing sham stimulation (i.e. not clinically meaningful) to allow for direct comparison in efficacy of active device compared to control.
Intervention description {11a}
Participants will be instructed to self-administer vestibular nerve stimulation (VeNS) or sham stimulation at home, one hour daily for 24 weeks, and will be trained on how to use the device by research study staff during their baseline visit.
Participants will be trained in the following:
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How to set up the headset and pair with the associated study app
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The application and placement of electrode pads
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How and when to wear the headset
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How to control the headset using the study app
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The sensation to expect when wearing the headset and potential side effects to be aware of
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How to care for and store the headset
INVESTIGATIONAL MEDICAL DEVICE
The proposed device (Vestal DM) uses vestibular nerve stimulation (VeNS) and consists of a battery-powered headset designed to deliver low level energy in the form of a neurostimulation waveform that modulates the activity of the vestibular cranial nerve. The device is placed on the head in a manner analogous to headphones and delivers a small electrical current to the skin through two self-adhesive electrode pads. These pads are placed on the skin overlaying each mastoid process (behind the ears – see Fig. 2.
Figure 2: Appearance of both the active and sham Non-Invasive electrical vestibular stimulation (VeNS) headset, with placement of electrode pads over the mastoid processes.
The Vestal DM device can only be used for a up to a total of one hour a day, after which it will automatically lock out for a period of 16 hours. To use the product, the participant should be sitting down and remain in this position for the duration of the session (maximum 60 minutes). When correctly positioned, the headset should be switched on using the on/off button. When initially switched on, the default stimulation is 0mA. The participant can then increase the stimulation in 0.1mA increments until the desired level is reached, which is determined by the participant beginning to experience a gentle sense of swaying, indicating modulation of the vestibular nerve. The participant should ideally remain at this level for the duration of the session. There is a total of 15 levels with the highest stimulation set to 1.5mA. Increasing the stimulation levels results in an increased intensity of stimulation for the participant which they are free to adjust based on their own level of comfort. Adjustments to the stimulation level may be made either via Bluetooth using the study app or via the up and down buttons on the headset, which are located just above the power button. The device can also be paused by pressing the pause button on the app or by pressing the power button on the headset twice. When finished, the user removes the headset and disposes of the electrode pads after each use.
SHAM DEVICE
A sham device has been created to appear identical in external appearance to the active device, to maintain participant and study coordinator blinding, while simultaneously not causing significant vestibular system stimulation in the control participants. This sham device follows this pattern by applying some stimulation to a user for a limited period (30 seconds) before tapering down to zero over a further 20 seconds, thus creating the impression of an active device. Moreover, participants will be informed during their training on how to use the device that it is normal for the sensation to be stronger initially on first turning on the device and then for it to, quite quickly, become less noticeable. It elaborates that this is because they “accommodate” to the stimulation.
Participants using the sham device will be instructed to use the device in the same way as those with the active device. They will be instructed to connect to the study app and control their level of “stimulation” in this way or through the physical buttons on the headset. The sham device can be used for a total of one hour a day, after which it will automatically lock out for a period of 16 hours. To use the product, the participant should be sitting down and remain in this position for the duration of the session (maximum 60 minutes).
DIETARY & EXERCISE ADVICE
All participants taking part in the study with a BMI ≥ 25 kg/m2 must agree to try to lose weight and will be
provided with dietary advice for a hypocaloric diet in accordance with guidelines from the American Diabetes Association and the Food and Drug Administration. Exercise recommendations are also part of the lifestyle modification component, tailored to individual health conditions and capabilities, in line with the Guidelines for American Diabetes Association.
A patient’s Basal Metabolic Rate (BMR) is determined using TANITA BIA scales or the Harris-Benedict equation, and their total daily energy expenditure is calculated by multiplying their BMR by 1.3. A 500kcal deficit will be taken from the BMR calculation and the study coordinator will provide standard dietary advice to the participant and discuss a realistic approach to achieve the 500kcal deficit.
If a patient has a BMI of < 25 kg/m2, they will not be required to actively lose weight. However, their BMR may still be captured, and they will be provided with guidance on ensuring that their dietary intake is achieved throughout the course of the trial (i.e 2,500kcal/day for men and 2,000kcal/day for women). If a participant’s BMI was to increase to ≥ 25 at the 12-week follow-up visit, the participant should be considered for a hypocaloric diet. The dietary advice given to the participant would be reinforced. All participants will negotiate 3–5 realistic dietary/lifestyle goals for them to follow throughout the trial with their study coordinator.
Participants (irrespective of BMI) will be recommended to perform 150 minutes of moderate exercise every week. Participants not capable of achieving this will be asked to do as much as their abilities and capabilities allow. Participants will be advised to discuss any increase in activity levels with their healthcare provider.
Criteria for discontinuing or modifying allocated interventions {11b}
N/A – Participants are required to use the device as described. A failure to consistently use the device will result in withdrawal from the trial. If a participant’s usage over 2 weeks falls below 9 hours, study staff and CTM will be notified. The study staff and CTM can then monitor and discuss issues leading to non-compliance. If the usage falls below the determined threshold and a valid low usage reason is not given, the site will be required to consider the subject for withdrawal.
Strategies to improve adherence to interventions {11c}
Compliance with using the active or sham device is assessed via the study app, which will be monitored by Clinical Trial Mentors on a weekly basis. The data collected will include: the total usage each day; average intensity the device is used at; and average resistance. This will be stored on an encrypted server.
Monitoring will occur on a weekly basis. If a participant’s usage over the previous 2 weeks falls below 9 hours, then an email alert, containing the participant’s ID code and usage information will be sent to study coordinators, CTM staff and the PI. Study staff and CTM may contact the participants to discuss any issues that are leading to non-compliance and may consider study withdrawal if no valid reason is given for non-compliance.
Relevant concomitant care permitted or prohibited during the trial {11d}
It is not permitted for participants to take beta-blockers, insulin, anti-histamines (with the exception of fexofenadine), H2 receptor antagonists, medication that could cause iatrogenic type 2 diabetes or dietary supplements that may affect glycemic control.
Participants should continue to take medications for other conditions as normal. However, if it is anticipated that the participant will need any prohibited therapies during the intervention phase, they will be ineligible for the study.
Provisions for post-trial care {30}
No post-trial care will be provided to the participants
Outcomes {12}
All participants will attend a maximum of 4 site visits during the 24-week trial period: screening visit, baseline visit (week 0), visit 2 (week 12), and final visit (week 24). The schedule of events for this trial is summarised in Table 1.
PRIMARY EFFICACY OUTCOME
The primary efficacy outcome for this study is the change in HbA1c (%) from baseline (week 0) to week 24. Formal venous blood assays will be taken for HbA1c at 0, 12 and 24 weeks and analysed using a NGSP (National Glycohemoglobin Standardization Program) certified assay.
SECONDARY EFFICACY OUTCOMES
A full description of secondary outcomes is detailed in Appendix 3. In brief, several secondary outcomes have been outlined to further evaluate the effects of VeNS treatment on participants. This will include responder rates to HbA1c changes, weight and body composition measurements, laboratory endpoints, vitals, quality of life measures and assessment of medication and healthcare resource use.
SAFETY OUTCOMES
The primary safety outcome of the study is the frequency of all device-related serious adverse events (SAEs) from the start of the study (week 0) to week 24. Secondary safety outcomes will assess the overall frequency of adverse events, including SAEs, over the same period.
Additional secondary safety measures involve monitoring the frequency of hypoglycemic episodes, episodes resulting in HbA1c exceeding 10%, and any changes in hearing as determined by the GSI AMTAS Flex device from baseline to week 24.
Participant timeline {13}
Table 1: Schedule of study events
Sample size {14}
The sample size calculation was based on %HbA1c data obtained from a small pilot study in India (McGeoch, McKeown et al. 2020) looking at the use of VeNS treatment using the 1mA Vestal device on patients with type 2 DM. Using a difference between groups mean in %HbA1c (SD) of 1.81 (1.68) and factoring in a superiority margin = 0.5% (requested by the FDA) the true difference in the experimental and control means is 1.31%.
Consequently, a total of 36 experimental subjects and 36 control subjects will be required to be able to reject the null hypothesis that the population means of the experimental and control groups are equal with probability (power) 0.95. Inflating for 15% dropout out at a 95% power gives 52 per group. However, as the Indian pilot trial was carried out in a rural Indian population and in order to maximize the probability of success in a Western population, as well as accrue an adequate amount of safety and usage data we propose using a sample size of n = 200 (100 per group). Power calculation was generated using G*Power Statistical Analysis software (ver. 3.1.9.4)
Recruitment {15}
Recruitment of participants started in May 2021 with one EU site (University College Dublin, Ireland). Three more sites in the United States joined later in 2021, bringing the total to 4. Five more sites were added in 2022 and a further 7 started recruiting in 2023 bringing the total number of research sites to 16. The trial is continuing to recruit participants and is planned to continue recruiting until the second quarter of 2024. Figure 2 is a diagram showing the RCT’s timeline.
Clinical sites in the US will recruit participants via the following:
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Research Match (a NIH-sponsored national registry of volunteers who have indicated a willingness to learn more about research studies
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Clinical practice patient/research database (only if applicable)
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Social media advertising (e.g. Facebook) in the local areas where the clinical sites are located
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Recruitment flyers and posters in medical clinics; the study site; and diabetes support groups
The clinical site in the Ireland will recruit participants via the following:
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Approved study posters amongst; GP clinics; the hospital/university site; and diabetes support groups
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Advertisement on Diabetes Ireland/UK website
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Through routine obesity and diabetes clinics conducted at site
Assignment of interventions: allocation
Sequence generation {16a}
At baseline, eligible participants will be randomized into one of the two arms: 1. Active VeNS group + lifestyle modification; or 2. Sham VeNS group + lifestyle modification. Allocation of devices to enrolled participants at the study site will be stratified by sex assigned at birth. Randomization of device active or placebo/sham status using device serial numbers is performed by designated unblinded member(s) of staff within the manufacturing team at the Sponsor organization.
Concealment mechanism {16b}
Internet-based randomization software (https://www.randomizer.org) will be used to allocate the study participants (1:1 ratio). Treatment assignments to active or sham devices will be generated using a blocked randomization process via a 2 per block method (i.e. an active and sham device will be allocated to each block). Status allocation by gender will be achieved using an alternate block method (e.g. males will use block 1, females will use block 2, males will use block 3 etc) Randomization will be conducted based on device serial numbers, with all devices being randomized prior to shipping to site. Stratification is performed by a member of staff at site.
Implementation {16c}
All participants who give consent for participation and who fulfil the inclusion criteria will be randomized. Allocation of devices to enrolled participants at the study site will be stratified by gender by carried out by site study staff using the alternate block method as described above.
Assignment of interventions: Blinding
Who will be blinded {17a}
Both the participants and the site researchers will be blinded to the randomization process. Externally the active and sham devices appear identical. They can only be distinguished by a unique serial number that is known only to the manufacturing team at Neurovalens who are independent from the study team. At the end of the study once the dataset has been locked, the master code will be passed to the study statisticians.
Procedure for unblinding if needed {17b}
To maintain the overall quality of the trial, code breaking will only occur in exceptional circumstances when knowledge of the group allocation is essential in a medical emergency for further management of the participant or where information is required for expedited safety reporting. The Chief Investigator will decide if it is necessary to unblind the participant. On the occurrence of any such event, the local Principal Investigator will contact the manufacturing team at Neurovalens to request emergency unmasking of the participant via the randomization system. If unmasking occurs, the participant may discontinue the study.
Data collection and management
Plans for assessment and collection of outcomes {18a}
Responder HbA1c
This includes both the responder rate and actual achievement of participants reaching an HbA1c of either less than 7.0% or less than or equal to 6.5%, benchmarks set by the American Diabetes Association (ADA) and the American Association of Clinical Endocrinologists (AACE) respectively. Another focus will be on the magnitude of HbA1c reduction, with a specific goal set at achieving at least a 0.5% reduction in at least half of the participants. Formal venous blood assays will be taken for HbA1c at 0, 12 and 24 weeks and analysed using a NGSP certified assay.
Weight and body composition
Body weight, BMI and body composition (including body fat percentage, muscle mass and visceral fat) will be assessed at baseline, week 12 and week 24. Waist circumference and hip circumference will be measured at baseline and week 24. Body composition analysis will be analysed using Bioelectrical Impedance Analysis (BIA) scales (Tanita BIA scale).
Laboratory endpoints
Venous blood assays will be carried out at baseline and week 24 for a fasted lipid profile assessment (to assess total non-HDL cholesterol, HDL to total cholesterol ratio, laboratory tests will include total cholesterol, triglycerides, VLDL cholesterol, HDL cholesterol and LDL cholesterol).
Venous blood assays will also be carried out at 0, 12 and 24 weeks at the sites for fasting plasma glucose. At Visit 1 (timepoint 0 weeks), participants will be provided with a blood glucose (BG) meter (US sites - AgaMatrix Presto; Ireland – AgaMatrix Wavesense JAZZ) including auxiliaries as well as instructions on how to use it. This device is to be used for the following: for the participants to carry out 7-point SMBG assessments; and to measure their blood glucose should they experience symptoms of hypoglycemia (< 72mg/dl or < 4mmol/l).
Participants will be instructed to perform two 7-point SMBG assessments during the study. These will be done: the day following enrolment into the study and after which they can start regular device usage; and one day in the week before Visit 3 at 24-weeks. Participants will be instructed at the site on how to undertake this and will also be provided with take home instructions. They will record the readings from these 7-point SMBGs onto the take home SMBG reporting form.
Vitals
Heart rate and blood pressure will be measured at baseline and week 24 by an automated monitor.
Quality of Life measures
The following quality of life measures will be assessed:
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EuroQol − 5 Dimension − 5 Level Questionnaire (EQ-5D-5L) – Baseline, week 12 & week 24 (19)
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Audit of Diabetes Dependent QoL (ADDQoL) – Baseline & week 24 (20)
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Diabetes Treatment Satisfaction Questionnaire (DTSQ) - Baseline & week 24 (21)
Medication and Healthcare Resource use
On enrolment, participants will be asked to continue with their currently prescribed anti-diabetic medication dosages for the during of the trial. If, for clinical reasons, a participant is initiated on a new anti-diabetic medication or their current dosage is increased, they will be withdrawn and asked to attend a close-out visit as soon as possible after this event.
Participants will also be asked to record their health care resource usage in the last 6 months. This will include a log of the following: hospital visits, hospital admissions, doctors’ visits (including unscheduled visits) and allied health service use. They will also be asked to recall employment status and number of days off work sick as well as any lost earnings owing to ill health or health-care visits, and, if so, the estimated cost of this.
The tolerability of the treatment will be analysed using data such as duration of exposure and device usage data, which will be captured by the study app. Mentor support group usage (Clinical Trial Mentors) will also be assessed to offer a comprehensive understanding of the VeNS treatment's impact on type 2 DM.
Plans to promote participant retention and complete follow-up {18b}
Study participants are followed up with on a weekly basis by Clinical Trial Mentors who can discuss any issues the participant is having during the trial. During these calls, the mentor team will also provide encouragement to the participant for attending the study visits.
Each participant at the US sites will receive $300 for their complete participation in this study ($100 for each visit). Each participant at the Ireland site will be eligible to receive up to €300 in travel expenses for their participation in this study.
Data management {19}
Sites will prepare and maintain adequate source documents designed to record all observations and other pertinent data for each enrolled participant. Data will be entered from source documentation into a protocol-specific Case Report Form (CRF). Participants shall not be identified by name in the study database or on any study documents but will be identified by a site participant number. The de-identified data will be entered into a validated database. The following databases will be used to capture study data: REDCap, Real-Time & CRIO. Once all the quality assurance steps have been completed and the data integrity verified the database shall be locked. The handling of all data on the CRF will be the responsibility of the PI.
Confidentiality {27}
The participants will be identified by a unique trial specific participant number on study CRFs and within the database. The name and any other identifying detail will not be included in any trial data electronic file. All essential documentation and trial records will be stored securely at the site and access will be restricted to authorised personnel. Data collected in the study will be kept for 10 years as part of the study’s archiving process.
Plans for collection, laboratory evaluation and storage of biological specimens for genetic or molecular analysis in this trial/future use {33}
N/A – No genetic or molecular analysis will be conducted in this trial
Statistical methods
Statistical methods for primary and secondary outcomes {20a}
The statistical aspects of the study are summarized below with details to be fully described in the statistical analysis plan (SAP). All participants enrolled into the study who meet the requirements for the Intention To Treat (ITT) or Safety Analysis Set population will be included in the analyses. This will include those participants who withdrew from the study prematurely or have missing data. Single (LOCF) and multiple imputation methods will be used to deal with missing data.
PRIMARY ANALYSIS
The primary analysis will be conducted using a linear regression model adjusted for covariates (ANCOVA) with change from baseline in %HbA1c at 24 weeks as the dependent variable and treatment group, gender, age, race and baseline %HbA1c and region (USA vs Ireland) as independent variables. The treatment effect will be presented as a difference in least squares means (lsmeans) between arms with corresponding 95% confidence interval and p-value. P-values will be generated for both the test of superiority and the test of no difference. Individual lsmeans for each arm will also be estimated. The reduction in %HbA1c should be a superiority margin of ≥ 0.5% in the active group compared to sham group to be considered clinically meaningful.
PRIMARY SAFETY ANALYSIS
For the safety analysis, descriptive summaries of safety data for the Vestal DM group and the sham control group will be evaluated. Specifically, an overview summary will be produced reporting the number (%) of participants and number of events for each of the following categories:
-
AEs
-
Device related AE (determined as causally related)
-
Adverse Device effect (defined based on selected PT terms)
-
SAEs
-
Device related SAEs
-
Serious ADE
-
Unanticipated Device effects
SECONDARY ANALYSIS
For secondary outcomes, two-sample t-tests and Fisher's exact tests will be undertaken for continuous and categorical variables at each time point, respectively. Summary statistics (mean, standard deviation, counts, and percentages) will be produced for all demographic and study outcomes depending on the scale of measurement and distribution.
Interim analyses {21b}
N/A – no interim analysis is planned for this trial.
Methods for additional analyses (e.g. subgroup analyses) {20b}
The primary analysis population is defined to include all randomized subjects (i.e. an intention-to-treat population).
Methods in analysis to handle protocol non-adherence and any statistical methods to handle missing data {20c}
The primary analysis will be tested on the intent-to-treat population. Missing data will be clearly reported and included in tables. We will assess the assumption that the data is missing completely at random. For the primary effectiveness analysis of HbA1c as a continuous measure we will perform a multiple imputation analysis. We will include the same covariates in the multiple imputation model as in the linear regression, i.e. group, race, gender, age, study site. Supportive sensitivity analyses with different approaches to imputing missing data will also be performed using last observation carried forward (LOCF).
Plans to give access to the full protocol, participant level-data and statistical code {31c}
N/A – There are currently no plans for public dissemination of the trial protocol or trial-generated data. The full protocol and SAP will be uploaded to clinicaltrials.gov (NCT04595968)
Oversight and monitoring
Composition of the coordinating centre and trial steering committee {5d}
The sponsor agrees that a Trial Steering Committee is not required for this study.
In each participating centre a lead investigator will be identified, to be responsible for identification, recruitment, data collection and completion of CRFs, along with follow up of study participants and adherence to study protocol.
Composition of the data monitoring committee, its role and reporting structure {21a}
N/A - The sponsor agrees that there are no safety issues with the device that require an independent Data Monitoring Committee for safety monitoring in this study.
Adverse event reporting and harms {22}
This study defines an adverse event (AE) as an untoward medical occurrence, unintended disease or injury, or untoward clinical signs (including abnormal laboratory findings) in subjects, users or other persons, whether or not related to the investigational medical device/intervention.
All observed or volunteered adverse events (serious or non-serious) and abnormal laboratory findings will be recorded on an adverse event monitoring form and monitored in accordance with local adverse event reporting SOPs. The following information will be recorded: description, start date, stop date, severity, relationship, action taken, outcome, expectedness and further details deemed necessary. In accordance with SOPs and policies of the local ethics and FDA requirements, the PI will be required to record AEs accordingly.
An adverse event that meets the criteria for a serious adverse event (SAE) between study enrollment and hospital discharge will be reported to the local IRB [Institutional Review Board] as an SAE.
Frequency and plans for auditing trial conduct {23}
Regular monitoring will be performed according to the trial specific Monitoring Plan. Data will be evaluated for compliance with the protocol and accuracy in relation to source documents as these are defined in the trial specific Monitoring Plan. The data for the study will be monitored by Compliance Solutions (CS) Life sciences, a third-party medical device regulatory consultancy (https://cslifesciences.com/), who will verify that the clinical trial is conducted, and data are generated, documented, and reported in compliance with the approved protocol, study SOPs and relevant monitoring guidelines.
Plans for communicating important protocol amendments to relevant parties (e.g. trial participants, ethical committees) {25}
Any modifications to the protocol which may impact on the conduct of the study, potential benefit of the participant or may affect patient safety, including changes of study objectives, study design, participant population, sample sizes, study procedures, or significant administrative aspects will require a formal amendment to the protocol. Such amendment will be agreed upon by the Sponsor, and approved by Sterling IRB [institutional review board] and the National Office for Research Ethics Committees (NREC, Ireland) prior to implementation. Investigators and study site staff will be informed of any changes to the protocol.
Dissemination plans {31a}
Results from this study will be submitted for publication in a peer reviewed journal. Every attempt will be made to reduce to an absolute minimum the interval between the completion of data collection and the release of the study results. We expect to take about 3 to 4 months to compile the final results paper for an appropriate journal. The findings of this clinical trial will be used to support a FDA DeNovo application.