TARGET Protein — Augmented Enteral Protein in Critical Illness (2025 bridging)

⚠️ Bridging Reference (2025)

This trial was published in JAMA in July 2025, not 2026. It is included here as essential context for interpreting the 2026 mechanistic trial (Summers et al., AJRCCM 2026) in this same category, since both share senior authorship and address the same clinical question from different angles (mechanistic vs. pragmatic clinical outcome).

1. Publication

• Title: Augmented Enteral Protein During Critical Illness: The TARGET Protein Randomized Clinical Trial
• Acronym: TARGET Protein
• Year & Journal: JAMA, 2025;334(4):319-328 (published July 22, 2025)
• Citation: Summers MJ, Chapple LS, Karahalios A, et al; TARGET Protein Investigators; ANZICS CTG. Augmented enteral protein during critical illness: the TARGET Protein randomized clinical trial. JAMA. 2025;334(4):319-328. doi:10.1001/jama.2025.9110

2. Context & Rationale

Background: International clinical practice guidelines recommend augmenting protein (≥1.2 g/kg/day) during critical illness based on observational data, but impact on patient outcomes was uncertain. Critical illness causes severe catabolism, muscle wasting, and persistent functional disability among survivors — providing the physiological rationale for higher protein targets that this trial (and the related 2026 mechanistic trial in this handbook) tested at different levels of evidence.

Research Question/Hypothesis: In critically ill patients receiving enteral nutrition, does augmented protein delivery increase days alive and free of the index hospital at day 90, compared with usual-dose protein?

Why This Matters: TARGET Protein was the third major multicenter trial (after EFFORT Protein and alongside PRECISe) to test this widely-recommended but weakly-evidenced practice at a large, pragmatic, clinical-outcome level.

3. Design & Methods

• Study Type: Investigator-initiated, pragmatic, cluster-randomized, cross-sectional, double cross-over, open-label, registry-embedded trial
• Setting & Centers: 8 mixed adult ICUs, Australia and New Zealand; conducted May 23, 2022 – August 23, 2023 (final follow-up November 21, 2023)
• Population:
• Inclusion: Adults ≥18y receiving enteral nutrition within 72h of ICU admission
• Exclusions: Not detailed in available trial text
• Intervention: Augmented-protein isocaloric enteral formula (100 g protein/L)
• Comparator: Usual-protein isocaloric enteral formula (63 g protein/L)
• Design: Each ICU used each formula sequentially for 3-month periods over a 12-month period (staggered commencement: 4 ICUs started augmented, 4 started usual); 3412 patients enrolled
• Blinding: Open-label
• Statistical Power & Follow-Up: Primary outcome: number of days free of the index hospital and alive at day 90. Secondary: proportion alive at day 90, survivor-only hospital-free days, ventilation duration, ICU/hospital LOS, tracheostomy incidence, RRT, discharge destination.

4. Key Results

3412 patients enrolled across 8 ICUs.

5. Internal Validity Assessment

• Randomization & Allocation: Cluster-randomized (by ICU), cross-sectional, double cross-over design — each ICU serves as its own control across the two formula periods, a methodologically sophisticated design for a pragmatic nutrition trial, though cluster designs carry inherent limitations relative to individual-patient randomization.
• Protocol Adherence & Separation: Formula-based delivery (rather than individualized titration) ensures strong compliance/separation once a given ICU is in a given period, though actual protein delivery still depends on overall enteral nutrition volume delivered (variable in practice).
• Blinding & Detection Bias: Open-label; objective primary outcome (days alive/free of hospital, largely registry/administrative-data-derived) limits detection bias.
• Missing Data & Sensitivity Analyses: Large sample (3412 patients) with registry-linked outcome ascertainment.
• Overall Internal Validity Conclusion: Moderate-to-strong — large, pragmatic, cluster-cross-over design with registry-based objective outcome ascertainment provides robust evidence for the null primary result, though cluster (not individual) randomization and variable actual protein delivery in practice are relevant limitations.

6. External Validity Assessment

• Population Representativeness: Broad, pragmatic ICU population across 8 Australian/New Zealand ICUs receiving enteral nutrition — highly representative of general ICU nutrition practice in these health systems.
• Practice Context: Formula-based (not individually titrated) protein delivery reflects a genuinely deployable, real-world nutrition strategy.
• Overall External Validity Conclusion: Good — large, pragmatic, multicenter design with broad ICU inclusion supports strong generalizability to similar health systems' general ICU populations.

7. Strengths & Limitations

Strengths:

• Large sample (3412 patients), among the largest ICU protein-dosing trials to date
• Pragmatic, registry-embedded, cluster cross-over design minimizing research infrastructure burden
• Clear, well-powered null result consistent with EFFORT Protein and PRECISe

Limitations:

• Open-label, cluster (not individual-patient) randomization
• Variable actual protein delivery depending on overall enteral nutrition volume in practice
• Formula-based approach does not allow individualized protein titration

8. Interpretation & Practice Impact

• Clinical Implications: Augmenting enteral protein delivery does not improve days alive and free of hospital at day 90 — joining EFFORT Protein and PRECISe as a third major trial finding no clinical benefit from higher protein targets in critical illness.
• Mechanistic Coherence: Directly complements the 2026 mechanistic trial (Summers et al., AJRCCM) in this same handbook category, which found that higher protein doses do not even further augment muscle protein synthesis at the physiological level — together, these two trials (same senior authorship) provide a coherent "bench to bedside" null result: no mechanistic benefit at the muscle-synthesis level, and no clinical benefit at the patient-outcome level.
• Systems-Level Takeaway: Reinforces a shift away from routine protein-dose escalation as an ICU nutrition strategy, consistent with contemporary reviews suggesting increasing protein delivery has not consistently improved outcomes and may even be harmful in specific subgroups (e.g., AKI).

9. Controversies & Subsequent Evidence

• Editorial Commentary/Debates: A JAMA correspondence exchange (Berris & Elango; Summers et al. reply, October 2025) followed publication, indicating active post-publication discussion of the trial's methodology and interpretation.
• Guideline Integration: Alongside EFFORT Protein and PRECISe, TARGET Protein contributes to a now-consistent pattern of null-to-harmful findings for higher protein dosing in unselected critically ill populations, likely to inform reconsideration of guideline protein-dose recommendations that had been based on observational data.

10. Summary & Executive Takeaway

Summary: TARGET Protein, a cluster-randomized, cross-sectional, double cross-over trial across 8 Australian/New Zealand ICUs, randomized 3412 patients (by ICU-period) to augmented (100 g/L) versus usual (63 g/L) enteral protein formula. Augmenting protein did not improve days alive and free of the index hospital at day 90, nor secondary outcomes including mortality or length of stay.

Overall Takeaway: TARGET Protein is the third major trial (after EFFORT Protein and PRECISe) to find no clinical benefit from augmented enteral protein delivery in critically ill patients — a pattern now mechanistically supported by the companion 2026 physiological trial showing higher protein doses do not even further augment muscle protein synthesis, together arguing against routine protein-dose escalation as an ICU nutrition strategy.

11. Bibliography

• Heyland DK, Patel J, Compher C, et al; EFFORT Protein Investigators. The effect of higher protein dosing in critically ill patients with high nutritional risk (EFFORT Protein). Lancet. 2023;401(10376):568-576.
• Bels JLM, Thiessen S, Van Gassel RJJ, et al. Effect of high versus standard protein provision on functional recovery (PRECISe). Lancet. 2024;404:659-669.
• Summers MJ, Kouw IWK, Asser IE, et al. Increasing protein dose does not further augment muscle protein synthesis in critical illness. Am J Respir Crit Care Med. 2026;212(5):964-971.