Define kits for titrations

When subjects can titrate, you must define the titration rule by creating titrations. Create one titration for each treatment arm. Every kit type in the titration must contain the same product and should have the same distribution status (either blinded or unblinded). This procedure can also apply to rollover studies.

You must first create all required kit types for a study. For step-by-step instructions, see Define the kits for the investigational product.

If subjects titrate based on a predefined schedule, don't perform these steps. Instead, you can choose the appropriate kits when you define the dispensation schedule by choosing the appropriate kits for each visit. For step-by-step instructions, see Define the dispensation schedule.

To define how subjects titrate:

Task 1   Start creating the kit type titration

1. Access the Draft version of a study as described in Open a study's design.
2. Click Study Supplies.
3. Click the Kits tab.
4. Click Create Titration.

   Tip:

   If the button is grayed out, that means that you haven't created any kit types that can be titrated.

Task 2   Complete fields in the Titrations section

1. On the Create Titration dialog, on the Titration page, enter a title for your titration.

   Tip:

   If applicable, consider including the treatment arm and dose levelto ensure that you associate the titration with the correct treatment arm later.
2. Complete the table with all of the required fields:

   Caution:

   For each possible start dose, you must have a titration definition included on a separate row. If you don't define at least one row for each kit type or dose that subjects can titrate, site users won't be able to dispense these kits.

   Also, you must specify a value for every cell in every row of the table, even when a lower or higher dose isn't available. This means that you must have a row for each kit type (or dose when using calculated doses), and its respective up, down and maintain titration kits defined.

   Field	Description
   Title of Dose Level	Type a name that corresponds with a kit type titration's concentration. This label is optional but might be useful for blinded kits used in kit type titrations, so site users know if subjects are on a low, medium or high dose of the investigational product without unblinding the study.
   Start	Click + Add Kit Type for each kit that you want to include in a titration. If the kit type has calculated doses, then the system displays a right arrow so you can select a calculated dose.
   Down	Click + Add Kit Type, and choose the kit type that subjects should receive when they want to titrate down. If the kit type has calculated doses, then the system displays a right arrow so you can select a calculated dose. Tip: If there isn't a lower dose that subjects can move to, just select the same kit type that appears in the Start column to the left. You can combine kit types for a down titration, but only if they're different kit types. In other words, you can't dispense two or more kits of the same type when subjects titrate.
   Maintain	Click +Add Kit Type, and choose the kit type that subjects should receive when they want to maintain their dose. If the kit type has calculated doses, then the system displays a right arrow so you can select a calculated dose.
   Up	Click + Add Kit Type and choose the kit type that subjects should receive when they want to titrate up. If the kit type has calculated doses, then the system displays a right arrow so you can select a calculated dose. Tip: If there isn't a higher dose that subjects can move to, just select the same kit type that appears in the Start column to the left. You can combine kit types for an up titration, but only if they're different kit types. In other words, you can't dispense two or more kits of the same type when subjects titrate.

3. To reorder the rows in the table, such as to better show the progression through the study, click the three vertical dots on the left of a row, and drag the row up or down.
4. To add additional rows to the table (for instance, if you added a kit type after you created the kit type titration), click the plus sign (+) in the upper right, and specify values for each cell.
5. When you complete titration definitions for every kit type or dose that subjects can titrate, click Next.

Task 3   Complete fields in the Settings section

1. On the Create Titration dialog, on the Settings page, complete all of the required fields:

   Note:

   To view tips for completing a field, click into the field or choose an option.
   1. On the Maximum Dose Changes section, choose how you want to define restrictions:
      • Choose Total to restrict the total number titrations.
      • Choose Up and Down to restrict up titrations and down titrations separately.
   2. Complete the table under Maximum Dose Changes section:

      Tip:

      You can leave any of these fields empty if you don't want to limit dose changes in any particular way.

      Field	Description
      Maximum Dose Changes	This column displays either 1 or 2 fields, depending on how you chose to define restrictions in previous step. If you chose to restrict the Total number of titrations: Total: enter a number to limit maximum dose changes. If you chose to restrict Up and Down titrations separetely: Up Titration Limit: enter a number to limit maximum dose changes to a higher dose. Down Titration Limit: enter a number to limit maximum dose changes to a lower dose.
      Unscheduled Dose Changes	This column displays either 1 or 2 fields, depending on how you chose to define restrictions in previous step. If you chose to restrict the Total number of titrations: Total: enter a number to limit the total number of times a subject can titrate during unscheduled visits throughout a study. If you chose to restrict Up and Down titrations separetely: Up Titration Limit: enter a number to limit the total number of times a subject can titrate up during unscheduled visits throughout a study. Down Titration Limit: enter a number to limit the total number of times a subject can titrate down during unscheduled visits throughout a study.
      Minimum Time Between Dose Changes	For the Up Titration and Down Titration fields, enter a number in the box for the minimum time that must pass between up or down titrations respectively. Then select a unit of time: Days Hours Tip: The Days measurement is based on calendar days, not 24-hour increments. If your protocol has strict requirements on the time that must pass between titrations, consider choosing Hours instead. For instance, you can specify 48 hours if 2 whole days must pass between titrations. If you enter a value in any of the fields in this column, a check box to Set Exception appears. Select the check box to enter an extended time limit between changes from a specific starting dose to a specific ending dose. For instance, you can configure this setting when you want to allow a shorter time between titration of smaller doses, for example 5 to 10 mg, but enter an extended wait between titration to the highest dose, 10 to 15 mg. In this scenario, the minimum time between titration of the smaller doses, 5 to 10 mg, is configured as described in this table, and the extended wait will be defined as an exception having the highest dose of 15 mg as Ending Dose Level. This would prevent the subject from going too quickly to the highest dose. Exceptions are configured as part of Task 4, "Set exceptions to the titration restrictions".

   3. On the Highest Dose section, specify wether to Dispense When on Highest Dose and Site Wants Higher Dose or not:
      • Choose Yes to keep a subject on their current dose level when the subject is already on the highest dose and the site asks to titrate up.
      • Choose No to prevent dispensation when the subject is already on the highest dose and the site asks to titrate up. The subject remains in the study, and if subject decides to maintain their current dose, dispensation can still occur.
   4. Enter a Message for Site Users to display at dispensation when an up titration request occurs and the subject is already on the highest dose.

      Note:

      This field is required only when you set Dispense When on Highest Dose and Site Wants Higher Dose to No because dispensation isn't allowed. You can use this to inform site users of the possible next steps, but consider the blinding status of the kit type titration when determining the message to show.
   5. On the Lowest Dose section, specify wether to Dispense When on Lowest Dose and Site Wants Lower Dose or not:
      • Choose Yes to keep a subject on their current dose level when the subject is already on the lowest dose and the site asks to titrate down.
      • Choose No to prevent dispensation when the subject is already on the lowest dose and the site asks to titrate down. The subject remains in the study, and if subject decides to maintain their current dose, dispensation can still occur.
   6. Enter a Message for Site Users to display at dispensation when a down titration request occurs and the subject is already on the lowest dose.

      Note:

      This field is required only when you set Dispense When on Lowest Dose and Site Wants Lower Dose to No because dispensation isn't allowed. You can use this to inform site users of the possible next steps, but consider the blinding status of the kit type titration when determining the message to show.
2. Depending on how you configured these settings:
   • Click Finish to save your titration definition.
   • If you activated the checbox to Set Exception in the Minimum Time Between Dose Changes, click Next to continue.

Task 4   Set exceptions to the titration restrictions

Note:

This step is only required if, in a previous step, within Minimum Time Between Dose Changes, you chose to set exceptions to the standard time for either up titration, down titration or both.

1. If you chose to set up titration exceptions: On the Create Titration dialog, complete the table in the Up Titration Exceptions page:
   1. In the Starting Dose Level column, click + Add Dose Level and choose a kit type representing the starting dose for this titration.
   2. In the Ending Dose Level column, click + Add Dose Level and choose a kit type representing the ending dose for this titration.
   3. In the Minimum Time Between Dose Change column, enter a number in the box for the minimum time that must pass before the subject can titrate from the selected starting dose to the selected ending dose. Then select a unit of time:
      • Days
      • Hours

      Note:

      In the up-right corner of the screen, you can see the default minimum time between dose chaanges as previously configured in the Settings page.
   4. To add another exception, click the plus sign (+) next to the Default Minimum label and repeat the previous steps.
2. Depending on the Titration settings:
   • Click Finish to save your titration definition and exceptions.
   • Click Next to continue with Down Titration Exceptions.
3. If you chose to set down titration exceptions: On the Create Titration dialog, complete the table in the Down Titration Exceptions page as described in step 1.
4. Click Finish to save your titration definition and exceptions.

Your titration then appears among your kits in the Kits tab within Study Supplies. To view details about the allowed titrations for a kit type, hover over the titration icon to the right of the given kit type in the titration block as in the image below.

Figure 10-1 Doses in a kit type titration

Next up, you must add the titration to the visit schedule and decide when subjects can titrate. For step-by-step instructions, see Specify when subjects can titrate.