July 8, 2025
Welcome to the third issue of the MAGNITUDE-2 newsletter, containing important study-related information, updates, and data. Please file it in your Investigator Site File (ISF) binder because it is a study correspondence. If you have any comments or suggestions, contact your CRA, your Medpace regulatory submissions coordinator, or the study team.
There are currently 11 sites active in 6 countries. We are looking forward to activating more sites and countries before the end of Q3 2025.
• Countries with all sites activated: Australia, Brazil, New Zealand and Taiwan.
• Countries with active and non-active sites: Argentina and Singapore
• Countries pending site activation: Malaysia, Mexico, South Korea, Thailand and Turkey
We are on target for our enrollment projections. Thanks to all sites that have contributed to enrollment so far! Below you will see an overview of current enrollment status and recognition of our highest enrolling sites to date. Well done all, and we look forward to additional sites making their contributions!
1. Inclusion Criteria 2d (Abnormality (≥ 2 total points from > 1 nerve) among the following NCS attributes: fibular MNCV, tibial MNCV, ulnar MNCV, sural SNDL, ulnar SNDL.
2. Inclusion Criterion 2b (NIS of 10 to 130 (inclusive))
3. Exclusion Criterion 22e (Vitamin A < LLN)
We are closely tracking participant demographics and baseline characteristics. Please see below for a high-level summary of enrolled participants’ characteristics:
Median Age (Range) 51 (22-71)
Gender 11:1 (M:F)
Mutation Type A97S: 6 (50%) V30M: 5 (42%) Others: 1 (8%)
ATTRv-PN is a disease driven by > 100 variant type. Intellia is aiming to enroll a diverse population affected by ATTRv-PN, to enable the evaluation of nex-z in the broader affected patient population. Treated or screened participants to date have been predominantly men or carriers of V30M (V50M) or A97S (A117S) mutations. While these are predominant variants, Intellia would like to request considering women and additional types of variants when identifying potential participants for the study.
The following updates to EDC should be live soon:
1. PGIS field correction (will match Protocol Clarification Letter issued on 15-Nov-2024)
2. Notifications will be issued to site staff when Mayo Clinic uploads participant Eligibility Forms.
3. mNIS+7 upload forms will be available prior to other eligibility information being entered.
There is an upcoming update to the Requisition Form for Urinalysis to include a space to record the time of collection. The updated form should replace the previously provided forms for the following visits:
• Screening and Screening Retest
• Baseline
• Week 26
• Week 52
• Week 78
• Pre-TTR Tx
• Pre-crossover Period and Pre-crossover Period Retest
• Crossover Period Week 26
• Crossover Period Week 52
• Crossover Period Week 78
• EOS/ET
• Unscheduled
For the patients currently enrolled, queries will be posted in EDC and MRL ClinTrak to complete the forms. A new Lab Manual will be released to match a previous update on the QRC that was not reflected in the Lab Manual:
• Centrifugation speed was updated to 1800-2200g for 10 to 15 mins at 4°C for NTLA-2001 PK samples.
• Please make sure your site uses the most updated document version on each study visit.
To Avoid Incomplete Infusions
To avoid incomplete infusions, the unblinded team should be prepared to quickly troubleshoot any issues with IV tubing or infusion pump. Please see below some troubleshooting tips for IV filter failure.
1) Verify that you’ve been sent the correct size filter (1.2micron).
2) Ensure the filter is inserted in the infusion set in the correct direction—liquid can only flow one way—and in the correct position.
3) Follow the manufacturer guidelines included with filters for appropriately priming the filter. Many filters require holding the filter vertically while priming.
4) Administration with other IV solutions should be avoided—but ensure this is no “piggyback” solution (e.g., the flush) attached via a “Y” below the filter. This could allow retrograde flow into the filter.
5) Filters have a maximum pressure and flow rate. Ensure protocol and manufacturer guidelines are being followed when setting up and troubleshooting the IP infusion.
6) Never remove the filter and allow unfiltered IP to infuse!
7) Rule out other causes of infusion failure:
a. Trace the administration tubing from the IP bag to the patient, checking for kinks or pinched line.
b. Confirm all clamps are fully open.
c. Ensure that the IV or vascular access can flush easily.
If everything above was correct, it is reasonably likely that particulate matter is creating the clog.
8) A 1.2micron filter will filter particulate debris and air bubbles. Perform visual inspection of the IP container for evidence of particulate matter (e.g., enlarged lipid “droplets”), admixture issues or a lot of bubbles.
9) Is the IP solution in the correct temperature? When it’s cold, it’s possible the IP becomes more viscous and as it warms up and becomes less viscous, it passes through the filter more easily.
10) Always:
a. Remove clogged filter and replace it with a new filter.
b. Be alert for repeated episodes of occlusion.
c. Contact your unblinded CRA if you need further assistance.
Data Entry Reminder into Medidata RAVE EDC
Sites should enter data within 5 business days of the patient visit and respond to queries within 5 business days of the query issue date, or per site contract. The Data Management and Sponsor Oversight teams review the data on an ongoing basis and will raise queries if any entered data needs clarification or correction.
Data Entry of IRRs into Medidata RAVE EDC
If a participant experiences IRR symptoms, two eCRFs must be completed: 1) AE and 2) Infusion-Related Reaction (IRR). On the AE eCRF, do not enter multiple AEs under each IRR symptom. Instead, enter ONE line with the reported term as “Infusion-related-reaction”. Then, enter the details (including start-stop times) of each symptom on the separate eCRF “Infusion-Related Reaction”. Please see the eCRF Completion Guidelines, Sections 5.1 (Adverse Events) and 5.2 (Infusion Related Reactions) for further details on how to complete both forms.
AE/SAE – Assessment of Causality
When reporting an AE/SAE for the first time, please provide the causality assessment according to the criteria in Protocol Table 10. The assessment of causality must be made based on the initially available information and can be updated as new information becomes available.
Causal Relationship Criteria
Not Related A clinical event, including laboratory test abnormality, with a temporal relationship to administration of study intervention which makes a causal relationship improbable, and/or in which other drugs, chemicals, or underlying disease provide plausible explanations.
Possible A clinical event, including laboratory test abnormality, with a reasonable time sequence to administration of the study intervention, but which could also be explained by concurrent disease or otherdrugs or chemicals.
Probable A clinical event, including laboratory test abnormality, with a reasonable time sequence to administration of the study intervention, unlikely to be attributed to concurrent disease or other drugs or chemicals.
mNIS+7 Assessments Uploads Reminders
Prior to submitting the data from the assessments, please ensure the following:
• On each worksheet, all fields are completed clearly and as expected. There shouldn’t be any field that is blank. If something does not apply, “none” or “N/A” should be entered.
• Any corrections are annotated per Good Clinical Practice (GCP) guidelines with a single line through incorrect entry and initials/date next to the corrected value.
• Each component is scanned as a separate PDF (combine the worksheets and waveforms in one PDF for the NCS document).
• The naming convention for each file is: [Site-Subject]_[Visit]_[Date]_[Component]_Initial
• If corrections are needed to any of the worksheets, you will need to annotate using proper documentation practices and reupload the entire testing worksheet, not just the specific pages with corrections. A single line should be drawn through incorrect data. Corrections should be written near the incorrect data and initial/date near the correction. This will need to be resubmitted via RAVE.
• The naming convention for a reuploaded file is: [Site-Subject]_[Visit]_[Date]_[Component]_Query Response [Date]
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