Case Study: Precise Data Management in Rare Liver Disease RNAi Trial

Alpha-1 Antitrypsin Deficiency (AATD) is a rare genetic disorder that affects approximately 1 in 2,500 individuals in Europe and 1 in 3,000–5,000 in the United States. It leads to progressive liver damage due to the accumulation of misfolded Z-AAT protein in hepatocytes.  

While lung disease is more commonly recognized, liver involvement—particularly hepatic fibrosis and cirrhosis—remains underdiagnosed and undertreated. With no approved therapies for liver manifestations, clinical trials targeting this indication face unique challenges in patient identification, biomarker screening, and long-term follow-up.  

This case study explores how a sponsor’s Phase 2 RNA interference (RNAi) program overcame operational hurdles through strategic data management, adaptive planning, and cross-functional collaboration—ultimately completing two trials across 8 countries and delivering critical interim analyses on time. 

Operational Complexity in Phase 2 RNAi Trials for AATD 

This multinational program faced four major hurdles: 

• Rare population with specific biomarker requirement: RNAi therapy required precise identification of patients with PiZZ confirmatory testing at Screening (PiMZ or PiSZ genotypes were not permitted) 

• Blinded data workflows: Interim analyses demanded strict separation of blinded and unblinded teams, systems, and communications. 

• Protocol amendments and form revisions: Critical updates to Pulmonary Function Test (PFT) and Magnetic Resonance Elastography (MRE) eCRF forms created cascading impacts on timelines and site burden. 
• COVID-19 disruptions: Enrollment and site activation were impacted by the pandemic, requiring site-by-site screening approvals and flexible monitoring strategies. 

To address these challenges, the sponsor partnered with Precision for Medicine to deploy a flexible data management strategy and proactive site engagement model. 

Initial planning included a detailed Data Management Plan (DMP) outlining freeze/unfreeze protocols, query workflows, and blinded team roles. As the trial progressed, real-time adjustments were made to accommodate evolving needs. 

Precision Strategies That Enabled Success in Autoimmune Liver Trials

Despite the complexity, the program achieved full enrollment across both studies:

• Study A: 40 patients randomized across 21 sites
• Study B: 16 patients randomized across 4 sites

Enrollment was completed in July 2021, with the majority of patients enrolled in North America. European sites faced delays due to COVID-related restrictions and holiday schedules, but ultimately contributed 11 patients to Study A and all 16 patients in Study B.

Key Milestones in a Rare Liver Disease RNAi Program

The sponsor’s RNAi program faced significant operational complexity, including blinded data workflows, form revisions, and pandemic-related disruptions. Precision deployed a phased database update strategy, reconfigured EDC roles, and maintained transparent communication with sponsor teams. Despite challenges, both interim analyses were delivered on time, and full enrollment was achieved across 8 countries covering North America and Europe.

Blinded Data Management Strategy Delivered Two On-Time Interim Analyses
The trial’s success hinged on a tightly controlled data management strategy that preserved blinding while enabling timely interim analyses. Precision implemented a phased data cleaning approach, supported by weekly sponsor meetings and a shared tracker that visualized progress. Despite complex form revisions and access restrictions, both Week 16 and Week 48 analyses were delivered on schedule. This was achieved through proactive planning, clear documentation, and a strong partnership between blinded and unblinded teams.

Phased Database Updates Minimized Disruption but Increased Site Burden
Mid-study revisions to the PFT and MRE eCRF forms required two rounds of database updates. To avoid delaying other critical amendments, Precision sequenced updates in phases—first implementing the revised forms, then rolling out broader protocol changes. While this approach preserved momentum, it placed additional demands on sites, which had to enter retrospective data and respond to new queries within tight timelines. CRA teams provided tailored support to help sites manage the dual workload and maintain compliance.

Site Activation and Enrollment Navigated Pandemic Disruptions
The trial launched in 2019, just months before COVID-19 halted global clinical operations. Precision worked with the sponsor to approve site-by-site screening based on local conditions, enabling enrollment to continue where feasible. Despite delays in Europe, North American sites maintained momentum, ultimately contributing the majority of patients to Study A. Enrollment was completed across both studies in July 2021, with 40 patients in Study A and 16 in Study B. The flexible site activation and controlled screening strategies proved essential in maintaining trial continuity.

Hyper-Granular EDC Role Configuration Required Late-Stage Remediation
The MRE Results eCRF form introduced unique access challenges due to its blinded nature. Initial EDC configurations restricted query management and form freezing capabilities, which were discovered during final data preparation. Precision rapidly updated user roles and permissions, but the timing—close to the interim analysis deadline—added pressure to already tight timelines. This experience highlighted the importance of early testing and validation of blinded workflows, especially for custom forms with restricted access.

Sponsor Collaboration Was Key to Navigating Complexity
Throughout the trial, Precision maintained a high-touch engagement model with the sponsor, ensuring alignment on timelines, expectations, and data strategy. Weekly meetings, shared documentation, and escalation protocols helped resolve issues quickly. While some delays were unavoidable, the collaborative approach enabled both teams to adapt and deliver critical milestones. The sponsor’s responsiveness and willingness to engage in process discussions were instrumental in overcoming challenges and maintaining trial integrity.

Insights from Blinded Data Execution in AATD Studies

Expectation Management Requires Proactive Transparency

Managing sponsor expectations around data cleaning and form freezing proved to be one of the most critical—and underestimated—elements of the trial. Sponsors often assumed that once forms are source-verified and free of queries, they can be frozen immediately. However, ongoing internal data management activities such as SAS checks and data reviews continue beyond initial verification. This disconnect led to delays, particularly during interim analysis preparation. Precision addressed this by implementing a data cleaning tracker and holding weekly meetings to walk through progress and clarify timelines. These efforts helped build trust and reduce friction, but the experience highlighted the need for earlier education and alignment.

• Weekly meetings with sponsor teams to review data cleaning status
• Use of a shared tracker to visualize progress and pending actions
• Clarification of freeze/unfreeze protocols in the Data Management Plan
• Early education on the difference between “clean” and “final” data
• Escalation pathways for resolving freeze-related disputes

Form Revisions Must Be Anticipated and Budgeted

Mid-study revisions to critical forms—especially the PFT and MRE eCRF forms—had a ripple effect across the trial. The revised PFT form took three months to finalize, delaying database updates and requiring retrospective data entry from sites. This created a dual burden: sites had to enter historical data quickly, then respond to new queries after the second round of updates. The timing overlapped with summer holidays in Europe, further complicating site availability. While the phased update strategy minimized disruption to other parts of the database, it increased costs and required additional CRA support. For future trials form revisions can be anticipated and contingency plans built into both budget and timeline.

• Phased database updates to isolate critical form changes
• Retrospective data entry support for sites
• Additional CRA hours allocated for SDV and query resolution
• Timeline buffers to accommodate sponsor-side delays in form finalization
• Early engagement with sites to prepare for dual-round updates

Blinded Team Coordination Needs Early Infrastructure

The separation of blinded and unblinded teams was essential for maintaining trial integrity, but it introduced significant operational complexity. The MRE Results eCRF form required hyper-granular EDC role configurations, which were not fully tested until close to the interim analysis deadline. This led to access issues, query bottlenecks, and delays in form freezing. Additionally, communication between blinded sponsor teams and blinded Precision teams often functioned as a relay to unblinded counterparts, creating inefficiencies and highlighting the need for clearer and moredefined communication pathways . While the team ultimately delivered on time, the experience underscored the importance of establishing infrastructure for blinded workflows before data collection begins.

• EDC role configuration tested and finalized before first patient in
• Kickoff meetings for unblinded teams to define roles and communication flow
• Documentation of query management responsibilities across blinded/unblinded teams
• Use of dedicated sFTP folders with pre-validated access protocols
• Contingency planning for third-party vendor involvement in data transfers

Key Learnings to Inform Future RNAi Trials in Rare Disease

This Phase 2 program surfaced practical insights for teams managing complex, blinded trials in rare indications. From biomarker-driven enrollment to phased database updates and site-level coordination, each challenge revealed opportunities to refine processes and improve sponsor-CRO alignment. These takeaways are designed to guide future planning, especially in RNA-based or autoimmune liver studies.

• Align Sponsor Expectations Early
  Use visual trackers and weekly meetings to clarify data cleaning timelines and avoid confusion around form freezing and interim analysis readiness.
• Plan for Form Revisions Proactively
  Build flexible timelines and budgets that anticipate mid-study updates, and prepare sites with early guidance and CRA support.
• Establish Blinded Infrastructure Before FPI
  Finalize EDC roles, query workflows, and communication pathways before data collection begins to avoid late-stage remediation.
• Support Sites Through Operational Complexity
  Allocate additional CRA resources and provide clear instructions for retrospective data entry and SDV during phased updates.
• Use Phased Updates Strategically
  Isolate critical changes to minimize disruption, but prepare for increased site burden and ensure timelines account for dual-round data entry.

Strategic Impact of RNAi Trials in Autoimmune Hepatic Fibrosis

This Phase 2 RNAi program demonstrated the feasibility of conducting complex, multinational trials in rare liver disease populations. Operational learnings from two blinded interim analyses informed future protocol planning, data workflows, and sponsor engagement strategies. From phased database updates to site-level support, the program highlighted the importance of proactive communication, robust data governance, and adaptive planning in rare disease trials.

At Precision for Medicine, we specialize in navigating complexity—whether it’s biomarker-driven enrollment, blinded data workflows, or global site activation. Our integrated teams bring deep therapeutic expertise and operational agility to every engagement.

If you're planning a rare disease or RNA-based trial, let's talk about how Precision can help you deliver with confidence.