Decision Support Tool for Gonadotrophin Dose Selection in ART.
Condition: IVF
Study type: Interventional

Summary: 
      A multi-center randomized clinical trial is proposed to study the effectiveness of the
      advanced decision support tool Opt-IVF in reducing medication, testing, and improving
      outcomes.
    

Detailed description: 
      IAim: A Multi-center Randomized Clinical trial to determine the effectiveness of using the
      proposed decision support tool for each patient's customized optimal drug dosage profile.

      Subject Enrollment

      The recruitment plan designed is study-specific and site-specific. The investigators plan to
      recruit patients by reaching into the each center's own database of patients. Each center
      carries out on average 800 IVF cycles per year. PIs anticipate easier recruitment since they
      are not excluding any IVF patients, whether they are low, high, or average responders
      undergoing any protocol or patients with PCOS or not. The in-reach activities to be used
      include:

      Chart review from site patient database Establishing an internal referral network with all
      physicians within the site Educational meetings with providers and physicians Educational
      sessions with patients and relatives Financial assistance to patients undergoing the
      intervention Training staff to facilitate ICF process by o Effectively conveying risks and
      benefits Creating an open environment Monthly calls to site physicians and staff to convey
      success stories

      The retention activities include:

      Planning appointments with sites for initial/follow-up visits and providing
      flexible/convenient appointment times Spending extra time with patients to understand their
      concerns and address them effectively Providing a summary of laboratory results to patients
      to demonstrate progress Appointment reminder services Travel assistance for patients/family
      members/caregivers, and patient compensation services Identifying the warning signals for
      potential drop-outs and working closely with these patients to support them to continue on
      the study Study Design and Procedures

      This is a single-site cohort with two arms (one arm for the intervention and one arm for the
      traditional approach) clinical trial involving 200 patients.

      The main site for this task includes six Indira IVF centers all over India, and all the
      analysis will be carried out at the Stochastic Research site. Dr. Urmila Diwekar will be an
      investigator from the Stochastic Research Technologies LLC, and Dr. Bhoi will be an
      investigator from the Indira IVF. Apart from these two investigators, there will be a
      post-doctoral fellow from Stochastic Research Technologies LLC and medical personnel from the
      Indira IVF centers will be involved in this proposed clinical trial.

      In our study, Opt-IVF will be using the patient's age and day three serum day AMH and AFc
      levels to decide the starting dose for the patient's cycle. Opt-IVF will use the first day
      and day 5 data collected (Follicular size distribution, estrogen levels) for that patient to
      determine the optimal dosage profile for the entire cycle for that patient with the help of
      the decision support tool OPTIVF for this intervention in the clinical trial.

      Primary and secondary outcomes: The study's primary outcome measures will be: the proportion
      of women with an appropriate number of retrieved oocytes), total hormonal dosage employed
      during the cycle, and serum oestradiol concentrations on rHCG day, no.of ultrasounds, no. of
      M2s, no. of embryos obtained, no. of grade A embryos.

      The secondary outcome measures considered will be: the number of growing follicles (≥11 mm)
      on rHCG day; the number of large ovarian follicles ≥17 mm on rHCG day embryos transferred,
      fertilization rate, implantation rate, clinical pregnancy rate, OHSS rate, the number of
      cryopreserved embryos and the proportion of patients with cryopreserved embryos.

      Data sources

      Data Sources will be View Point (GE) and Syngo Dynamics (Phillips) for the sonographic images
      and Cerner for medical record information.

      Expected Risks/Benefits

      Current practice is to use every ultrasound and blood test every day to determine the dosage
      for that day that patient by the attending physician. The proposed decision support tool will
      be able to predict the patient's response to the hormonal dosage given each day of an IVF
      cycle using data from the first two days of that particular cycle. It will also provide a
      personalized optimal dosage profile for each patient, maximizing the outcomes and reducing
      medications, testing, and side effects. Based on earlier preliminary results, the tool use is
      expected to reduce the daily testing up to 75%, reduce the dosage up to 40%, thereby reducing
      the side effects like overstimulation, and is expected to provide equal or better outcomes
      for the patients. Dr. Diweakr's group have carried out retrospective studies with 150
      patients in the USA and India. The investigators also carried out a small prospective
      clinical trial in India. Both studies support the above conclusion about the methodology. In
      this study, the investigators will be conducting prospective clinical studies for this
      product in the United States. This will establish the efficacy of this tool for use in
      clinical practice. There is no additional risk with the use of this decision support tool
      other than the possibility of an unsuccessful cycle, a risk that exists with current practice
      also. The same medications are used at dosages 20-40% lower, thus reducing the side effects
      of the medications.

      Data Collection and Management Procedures

      Collecting the de-identified patient data without any PHI. All the information will be
      digitized and managed securely (as needed), so it can be analyzed and researched. Proprietary
      file formats may be used in this process.

      Data Protection Throughout the research work of this project, a large volume of data at
      various levels of detail. All research members will adhere to the highest standards for
      protecting subjects' privacy and the confidentiality of any information collected. Only
      properly trained and authorized individuals may access data with personal identifiers at each
      Indira IVF center. Nobody from stochastic research technologies will have access to personal
      identifiers.

      Backups The company provide automated computer backups. Web Server It has been planned to
      disseminate and maintain project information through Stochastic webservers. These are all
      hosted on a Windows Server, a VMware virtual machine instance.

      Data Analysis Data analysis will be performed by the co-PI using SPSS software.

      Quality Control and Quality Assurance Data is recorded and coded in an electronic database.
      Categorical data will be compared using Chi-square or Fischer exact test and ANOVA for
      frequency table of baseline characteristics. Odds ratios and 95% confidence intervals will be
      calculated, as well as 2-sided p values. A value less than 0.05 will be chosen for
      significance without adjustment for multiple comparisons. A biostatistician will be consulted
      for any statistical analysis beyond the scope of the PI or co-investigators.

      1 Data and Safety Monitoring De-identified data collected is in an excel spreadsheet in a
      password-protected computer.

      Statistical Considerations Sample size: Earlier clinical trial shows that for obtaining
      statistically significant outcomes for comparing dosage and grade A embryos a small sample 22
      patients in each arm was sufficient. However, for other outcomes like number of M2s higher
      samples size may be needed. Based on earlier results, the number of samples size is
      calculated to be 60 patients in each arm. Therefore, a sample size of 100 in each arm will be
      used in this trial.

      Analysis Methods: Between the groups, differences in continuous variables will be assessed
      with parametric or non-parametric statistics, as appropriate. Z-tests will be conducted
      comparing the proportion of individuals who reported an optimal outcome response.

      Regulatory Requirements Informed Consent The OPTIVF trial will be registered with Clinical
      Trials.Gov as per ACTG guidelines. PIs have established IRB-approved consent forms. This
      consent form is based on regular or long-form. The form presents detailed information about
      the treatments, risks, and benefits, mitigation of risks, etc., in summary, complete details
      on all elements of consent. Dr. Bhoi is responsible for this.

      Subject Confidentiality The confidentiality of participants will be safeguarded by the use of
      a de-identified dataset. A master data spreadsheet including any necessary PHI will be kept
      in a locked file on a secure drive. All data analysis will be performed on the de-identified
      dataset. The key for the identification will be kept in a third locked file separate from the
      data. Only the co-PI will have access to these files. Data will be entered into SPSS or other
      statistical software programs for analysis without subject identifiers.

      Unanticipated Problems Any unanticipated problems will be reported to the IRB as soon as they
      are discovered.
    

Intervention name(s): OPTIVF dosage; traditional drug treament
Intervention type(s): Device; Device
Intervention description(s): Opt-IVF dosage; Traditional drug treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: This is a multi-centric randomized clinical trial study with two arms (one arm for OPTIVF and one arm for the conventional approach) . In our study, the tool will be using the patient's age and day three serum AMH and FSH levels to decide the starting dose for the patient's cycle. Tool will use the first two days of data collected (Follicular size distribution, estrogen levels) for that patient to determine the optimal dosage profile for the entire cycle for that patient with the help of the decision support tool (OPTIVF )for this intervention in the clinical trial.
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: IVF; Opt-IVF