Thymosin Alpha-1 and Sepsis: The 1,106-Patient Double-Blind Trial That Came Back Null

Thymosin alpha-1 has been sold on sepsis data for years. TESTS, a double-blind phase 3 trial of 1,106 patients across 22 centres, reported 28-day mortality of 23.4% versus 24.1% on placebo: hazard ratio 0.99, P = 0.93. Null.

That result matters more than most negative findings, because thymosin alpha-1 is the best-credentialled compound in the immune support and longevity peptides category — a defined 28-residue molecule with a known mass, approvals in real countries and a pharmaceutical developer behind it. It had the kind of trial most research peptides never get, and the trial closed the question. Vendor listings and per-milligram pricing sit on the thymosin alpha-1 compound page.

Does thymosin alpha-1 reduce mortality in sepsis?

No. TESTS, a double-blind placebo-controlled phase 3 trial published in the BMJ in January 2025, randomised 1,106 adults with sepsis across 22 centres and found 28-day all-cause mortality of 23.4% on thymosin alpha-1 versus 24.1% on placebo — hazard ratio 0.99, 95% CI 0.77 to 1.27, P = 0.93. No secondary endpoint and no safety outcome differed significantly. It is the largest and only properly blinded trial the compound has had.

The trial (BMJ, PMID 39814420) randomised 552 patients to thymosin alpha-1 and 554 to placebo, dosed subcutaneously every 12 hours for seven days.

The authors' own words: "This trial found no clear evidence to suggest that thymosin α1 decreases 28 day all cause mortality in adults with sepsis."

Two subgroup interactions reached nominal significance, and both should be read as what they are. Patients under 60 did worse (HR 1.67, 95% CI 1.04–2.67). Diabetic patients did better (HR 0.58, 95% CI 0.35–0.99). These are hypothesis-generating post-hoc findings inside a trial with a null primary endpoint. Neither is a result.

What did the ETASS trial show before TESTS?

ETASS, published in Critical Care in 2013, was single-blind, ran across six Chinese tertiary hospitals and randomised 361 patients — 181 to thymosin alpha-1, 180 to saline control. 28-day all-cause mortality was 26.0% versus 35.0%, an absolute risk reduction of 9.0% with a 95% confidence interval of −0.5 to 18.5, and P = 0.062. That interval crosses zero, so ETASS was non-significant on its primary analysis, and it was nonetheless cited for a decade as though it were positive.

The dosing in ETASS (PMID 23327199) was 1.6 mg subcutaneously twice daily for five days, then once daily for two.

Read the intervals rather than the point estimates. The absolute risk reduction interval runs from −0.5 to 18.5, meaning the data are compatible with a small harm. The relative risk was 0.74 with a 95% CI of 0.54–1.02, which crosses one. A 9.0-percentage-point mortality gap is a large number and an appealing one to quote, but it arrived in a single-blind trial and did not reach significance.

Twelve years later, a double-blind trial four times the size returned a hazard ratio of 0.99. The sequence is the finding: the weaker design produced the encouraging number, the stronger design produced the null.

Why does the 2025 meta-analysis report a benefit TESTS did not find?

The 2025 meta-analysis pooled 11 randomised trials and 1,927 patients and reported an odds ratio of 0.73 for 28-day mortality, 95% CI 0.59 to 0.90, P = 0.003. Its own subgroups dissolve that headline: restricted to high-quality trials the odds ratio is 0.82, P = 0.09; restricted to multicentre trials it is 0.86, P = 0.20. The benefit lives in the smaller, weaker, single-centre studies, and its trial sequential analysis calls the sample size inadequate.

The 2025 meta-analysis (PMID 40969554) is the citation most often produced in defence of thymosin alpha-1 after TESTS, usually as the pooled odds ratio alone. Its trial sequential analysis states that "the current sample size is inadequate."

That pattern — a pooled benefit that survives in the weaker studies and evaporates in the better ones — is the classic signature of an effect driven by study quality rather than pharmacology. When a body of evidence looks like that, the prediction is that the next large, well-designed trial will be null. TESTS is exactly what the prediction called for.

What do the hepatitis B and COVID-19 citations actually say?

Neither says what it is used to say. Cochrane record CD014610, "Thymosin-α1 for people with chronic hepatitis B," is a protocol — a published plan for a review — so no Cochrane conclusions about thymosin alpha-1 exist. The COVID-19 trial most often cited is a single 105-patient randomised study from India whose abstract publishes no p-value, no confidence interval and no denominators, and whose serious-adverse-event count does not reconcile with its percentages.

The Cochrane point deserves emphasis because it is a fabrication magnet. Cochrane's own site labels CD014610: "This is a protocol for a Cochrane Review." A protocol sets out how a review will be conducted. It contains no findings, no pooled estimate and no conclusion. Any article citing Cochrane conclusions about thymosin alpha-1 in hepatitis B is citing a document that does not exist.

The COVID-19 trial (PMID 36042753) was a randomised placebo-controlled phase 3 study from India in 105 patients, reporting death rates of 11.1% versus 38.5%. The abstract publishes no p-value, no confidence interval and no denominators, and separately states that eight serious adverse events (deaths) occurred in the study — which does not reconcile with those percentages across 105 patients. We are not quoting the effect size, and neither should anyone else.

What is thymosin alpha-1?

Thymosin alpha-1 is a defined 28-residue peptide, Ac-SDAAVDTSSEITTKDLKEKKEVVEEAEN, N-terminally acetylated, with the formula C₁₂₉H₂₁₅N₃₃O₅₅ and a molecular weight of 3,108.3 g/mol. It carries two CAS numbers, is also called thymalfasin, and is sold under the brand ZADAXIN by SciClone. The acetyl group is part of the molecule rather than decoration: a non-acetylated version would be 42 Da lighter and a different compound.

It was originally isolated from thymic tissue. Mass spectrometry against 3,108.3 Da is the identity check, and it is a check that actually works here — see mass spectrometry for peptides.

One verification trap worth naming. PubChem CID 16130265 is not thymosin alpha-1 — it is a 14-residue peptide, C₈₁H₁₁₄N₁₆O₃₀, auto-titled "Tyifevefqkeedd." If a certificate of analysis or an article cites that CID for Tα1, it is wrong. The correct record is CID 16130571.

Is thymosin alpha-1 FDA-approved?

No. A query of FDA's drug application database for the active ingredient thymalfasin returns no matches, verified against a working control query to rule out a broken search. Thymosin alpha-1 does hold US and European orphan drug designation for hepatocellular carcinoma — a development incentive granted at the designation stage, not an approval and not a finding of efficacy. Ex-US approvals are real, but the commonly quoted country count is not sourceable.

Both halves of "approved in a number of countries and not in the United States" get distorted, in opposite directions.

Orphan designation is not approval. SciClone's own SEC filing records US and European orphan drug designation for hepatocellular carcinoma. Designation is granted at the development stage; it carries tax credits and market exclusivity if a drug is later approved. It involves no finding of efficacy, and it is routinely presented in marketing as though it were an approval.

The ex-US approvals are real, and the number attached to them is dated. SciClone's 2005 annual report states that ZADAXIN was "currently approved for sale in over 30 countries internationally, primarily in Asia, the Middle East and Latin America," principally for hepatitis B, with additional approvals in some countries for hepatitis C, as a vaccine adjuvant, or as a chemotherapy adjuvant. That is a twenty-year-old filing. We could not verify a current country-by-country list, and the specific figures circulating online are not traceable to any current source.

Where does thymosin alpha-1 sit on FDA's compounding lists and WADA's Prohibited List?

Thymosin alpha-1 is not on FDA's active Category 2 list; on the page current 22 April 2026 it sits in the second table, "Bulk drug substances nominated but withdrawn." It is not on the 503A bulks list, not on the 503B list and has no USP monograph, so it satisfies none of the three statutory routes for 503A compounding. WADA's 2026 Prohibited List does not name it anywhere.

FDA's retained language on the bulk drug substances page, verbatim: "Compounded drugs containing thymosin-alpha-1 (Ta1) may pose significant risk for immunogenicity for certain routes of administration and may have complexities with regard to peptide-related impurities and API characterization. The safety-related information is inadequate for the agency to sufficiently understand the extent of any safety issues raised by the proposed compounded drug."

Failing all three statutory routes means thymosin alpha-1 is not legally compoundable in the United States.

It was not reviewed at the July 2026 PCAC meeting. That meeting covered BPC-157, KPV, TB-500 and MOTS-c on 23 July, and DSIP, Semax and Epitalon on 24 July. Thymosin alpha-1 was not on the agenda. The full sequence of determinations is in our FDA peptide regulation timeline.

On WADA, one conflation causes most of the errors. Thymosin alpha-1 and thymalfasin do not appear anywhere on the 2026 Prohibited List. Thymosin beta-4 does: S2.3 names "Thymosin-β4 and its derivatives e.g. TB-500." Those are entirely different molecules, and content treating "thymosin" as one substance gets this wrong in both directions — see TB-500 and thymosin beta-4. We verified name-absence only. We did not assess whether the S0 catch-all could apply, so do not read this as a statement that Tα1 is permitted.

Which thymosin alpha-1 claims survive the evidence?

One of the nine claims below holds up: thymosin alpha-1 does hold US and European orphan drug designation, though marketing routinely presents designation as approval. The sepsis claim is refuted by TESTS at HR 0.99 and P = 0.93. The meta-analysis claim is an artefact of study quality, the FDA-approval claim is false, the 30-plus-countries figure rests on a 2005 filing, and no Cochrane conclusions exist at all.

Note the shape of the errors. Five of them are misread regulatory documents, three are misread statistics, and one cites a review that was never completed. None of them requires a conspiracy — they require nobody having opened the source.

How does thymosin alpha-1 compare with thymalin, TB-500 and LL-37?

Thymosin alpha-1 is the strongest of the four on every axis that matters for verification: a defined 28-mer of 3,108.3 Da, genuine approvals outside the United States, and real randomised trials. Thymalin is an undefined calf thymus extract with one non-randomised Russian cohort. TB-500 is thymosin beta-4, a different molecule that WADA names at S2.3. LL-37 is a defined 37-mer with two topical wound trials.

Thymalin is the instructive contrast, because it shares an organ of origin and a therapeutic story with thymosin alpha-1 and shares almost nothing else. It is an undefined calf thymus extract resting on a single non-randomised Russian cohort, so no trial of it could deliver what TESTS delivered here.

The general point is worth stating plainly: being a defined molecule is what made a definitive answer possible. Thymosin alpha-1 could be manufactured to a specification, measured in a vial, dosed reproducibly across 22 centres and compared against a matched placebo. The trials got run, and the biggest one was negative. That is a better outcome for buyers than permanent ambiguity.

How do you verify a thymosin alpha-1 vial?

Mass spectrometry against 3,108.3 Da is the check that matters, because it is what catches a missing N-terminal acetyl group — a des-acetyl form is 42 Da lighter and HPLC purity alone will not distinguish it. Ask for a batch-matched certificate carrying mass spectrometry, net peptide content and an endotoxin result, since immunogenicity and peptide-related impurities are FDA's own stated concerns for this substance.

Two of those rows are specific to this compound rather than generic advice. The acetyl group is the identity-critical feature, so a certificate reporting an HPLC purity figure and nothing else has not confirmed identity. And endotoxin is the exact issue FDA named in writing, which makes an LAL result on the batch the test that answers the regulator's own objection. A sourcing walkthrough with current vendor checks sits at where to buy thymosin alpha-1.

What does Peptigrity's platform data show for thymosin alpha-1?

The Purity Index records thymosin alpha-1 at 99.51% average HPLC purity across 217 independent tests from Kovera Labs, Janoshik, Freedom Diagnostics and others, across 224 verified shops (verified August 2026). The most recent test on file returned 99.95% on 31 July 2026. Price data shows 59 shops in stock, a median of $6.80/mg and a low of $2.50/mg on a 10 mg vial (verified 10 August 2026).

Those purity figures are among the strongest on the platform, which is what you would expect for a synthetically straightforward peptide with an established pharmaceutical version. The Purity Index draws on 11,852 independent lab tests across 118 peptides and 530 tracked shops (verified August 2026).

Quantity is where the variance lives. Measured content runs from −18.8% to +14.6% against label, most results within ±5%. One vendor's product labelled 13 mg tested at 10.56 mg, an 18.8% shortfall. Two others returned roughly +14% overages. Endotoxin results appear sporadically rather than routinely, with compliant samples passing at ≤0.05 EU/mL.

Thymosin alpha-1 price data shows the full spread across in-stock vendors. Those figures exclude shipping, taxes and customs, coupon codes, bulk tiers, multi-vial kits and account-gated pricing.

Every result behind those averages is browsable in the independent lab tests database, batch by batch.

Frequently Asked Questions

Is thymosin alpha-1 FDA-approved?

No. A search of FDA's drug application database for thymalfasin returns no results. It holds US and European orphan drug designation for hepatocellular carcinoma, which is a development incentive, not an approval and not a finding of efficacy. It is approved in a number of other countries, primarily in Asia, the Middle East and Latin America, mainly for hepatitis B.

Does it work for sepsis?

The largest and only double-blind trial — TESTS, published in the BMJ in 2025 with 1,106 patients across 22 centres — found 28-day mortality of 23.4% versus 24.1% on placebo, hazard ratio 0.99, P = 0.93. No secondary or safety outcome differed. The earlier ETASS trial was single-blind and also non-significant on its primary analysis at P = 0.062.

What about the meta-analysis showing a benefit?

The 2025 meta-analysis reports a pooled odds ratio of 0.73 across 11 trials. In its own subgroup analyses, the effect is not significant when restricted to high-quality trials (P = 0.09) or to multicentre trials (P = 0.20), and its trial sequential analysis states the sample size is inadequate. The benefit is concentrated in the weaker studies.

Is there a Cochrane review on thymosin alpha-1?

Cochrane record CD014610 for hepatitis B is a protocol — a published plan for a review — not a completed review. It contains no conclusions. Anything citing Cochrane findings on thymosin alpha-1 in hepatitis B is citing a document that does not exist.

Is thymosin alpha-1 the same as TB-500?

No. Thymosin alpha-1 is a 28-residue peptide of 3,108 Da. Thymosin beta-4 and its fragment TB-500 are entirely different molecules. The WADA 2026 Prohibited List names thymosin beta-4 at S2.3 and does not name thymosin alpha-1.

Is it on FDA's compounding risk list?

Not the active Category 2 list. As of the page current 22 April 2026 it sits in the "nominated but withdrawn" table, where FDA's retained language states the safety information "is inadequate for the agency to sufficiently understand the extent of any safety issues."

The trial that would settle this

No further sepsis trial is needed: TESTS answered that question at n = 1,106 with HR 0.99 and P = 0.93. What remains unanswered is whether thymosin alpha-1 does anything in the indications it is actually approved for elsewhere — chiefly hepatitis B, where a Cochrane protocol was published and the review was never completed. Any trial worth running would need double-blinding, multicentre recruitment outside the network that produced the positive signals, and a pre-registered clinical endpoint.

Where this leaves thymosin alpha-1

Thymosin alpha-1 is one of the better-credentialled compounds in this market: a defined, well-characterised peptide with real approvals in real countries, developed by a pharmaceutical company that ran real trials. Running those trials is what produced the answer. ETASS in 2013 came in at P = 0.062, close enough to be marketed as a win; twelve years later a double-blind trial four times the size returned HR 0.99 and P = 0.93.

The meta-analytic benefit turned out to live entirely in the studies with the weakest designs, which is the ordinary way this happens. It is less a failure of the compound than a demonstration of how a literature behaves before someone runs the definitive study.

Other indications remain genuinely open. Hepatitis B has an approval history in several countries and a Cochrane review that was planned and never completed. Sepsis does not remain open, and no amount of secondary citation will reopen it.

Browse the immune support and longevity peptides category, or our complete peptide guide with 118 compounds (verified August 2026). For reconstitution and per-injection volume, use the peptide dosing calculator alongside the reconstitution calculator. Compare shops through independent lab tests and community-verified shop reviews.

This article is for educational and informational purposes only and does not constitute medical advice. Peptides discussed may be investigational compounds not approved by the FDA (or equivalent regulators in your jurisdiction) for human use. Always consult a qualified healthcare provider before using any peptide or research compound. Peptigrity is an independent review platform and does not sell, endorse, or recommend specific products or vendors