VIP: FDA Declined the Emergency Authorization Twice, and the 473-Patient Trial Explains Why

FDA declined an Emergency Use Authorization for aviptadil twice, in November 2021 and again in 2022. The NIH's phase 3 trial then reported an odds ratio of 1.11 and a P value of 0.54. The regulator had been right in advance.

Vasoactive intestinal peptide had the best possible conditions for a clean answer: a synthetic form, aviptadil, tested in COVID-19 respiratory failure during a pandemic, under emergency pathways, with an NIH-run master protocol behind it. VIP sits in the immune support and longevity peptides category, and its VIP compound page carries 62 independent lab tests. What is sold today is mostly not aviptadil for COVID-19 — it is nasal spray for mould illness, and that use has never been trialled at all.

Did FDA authorise aviptadil for COVID-19?

No. FDA declined to issue an Emergency Use Authorization for aviptadil on 4 November 2021, citing "insufficient data regarding the known and potential benefits" after reviewing safety data in only 131 randomised patients. It declined a second time on 1 July 2022 for a narrower subgroup, having already declined Breakthrough Therapy Designation for ZYESAMI. FDA does not publish EUA declines, so the sponsor's own announcements are the primary record here.

The first decline is documented in the sponsor's own announcement, dated 4 November 2021. FDA was "unable to issue the EUA at this time due to insufficient data regarding the known and potential benefits" and "known and potential risks of ZYESAMI in patients suffering from Critical COVID-19 with respiratory failure." At that point the agency had reviewed safety data in 131 randomised patients — a small evidence base on which to make a decision, and the reason the decision looked contestable at the time.

The second decline, announced 1 July 2022, covered a narrower subgroup. The same announcement notes that FDA "had already recently declined Breakthrough Therapy Designation for ZYESAMI."

That FDA does not publish EUA declines is a limitation worth naming rather than glossing. The sponsor's statements are the primary record for both events, and a sponsor announcing its own regulatory setback is an unusual but not unreliable source — the incentive runs against overstating the refusal.

What did the TESICO trial find?

Nothing. TESICO, the NIH ACTIV-3b phase 3 trial of intravenous aviptadil published in The Lancet Respiratory Medicine in 2023 (PMID 37348524), carried 461 patients in its aviptadil modified intention-to-treat population and missed its primary endpoint: ordinal recovery at day 90 returned an odds ratio of 1.11, 95% CI 0.80 to 1.55, P = 0.54. Day-90 mortality was 38% on aviptadil versus 36% on placebo, and the safety composite ran numerically worse at 63% versus 56%.

Brown, Barkauskas, Grund et al., "Intravenous aviptadil and remdesivir for treatment of COVID-19-associated hypoxaemic respiratory failure in the USA (TESICO): a randomised, placebo-controlled trial," Lancet Respiratory Medicine 2023;11(9):791–803 (PMID 37348524). Part of the NIH ACTIV-3b programme, registered as NCT04843761.

The authors' conclusion, verbatim: "aviptadil did not significantly improve clinical outcomes up to day 90 when compared with placebo."

The safety composite deserves careful reading rather than either dismissal or alarm. At 63% versus 56% it is numerically worse on aviptadil and does not reach significance. That is not evidence of harm. It is the absence of a favourable safety signal in a trial that also found no benefit, which is a meaningfully worse position than a null efficacy result on its own.

One earlier trial remains unresolved. NCT04311697 (COVID-AIV), a phase 2b/3 study sponsored by APR Applied Pharma Research, enrolled 203 patients with a primary endpoint of being alive and free of respiratory failure at day 28. We could not locate posted results or a peer-reviewed publication of its primary endpoint, so we cannot say whether it met or missed. Anyone citing a result for that trial should be asked for the source.

What is VIP, and why are we not printing a molecular weight?

Vasoactive intestinal peptide is a 28-residue neuropeptide, HSDAVFTDNYTRLRKQMAVKKYLNSILN, of the secretin/glucagon superfamily, an agonist at the VPAC1 and VPAC2 receptors, with formula C₁₄₇H₂₃₇N₄₃O₄₃S and a C-terminal asparagine amide. Its synthetic form is aviptadil, branded ZYESAMI. We are not printing a molecular weight, because the Guide to Pharmacology lists 3,357.9 g/mol while the formula on the same record computes to roughly 3,326.8, and we could not resolve that against a second authoritative source.

We are not going to print a number we cannot stand behind. Publishing the formula and the sequence while omitting a precise mass is the honest position when the reference record disagrees with itself. Anyone verifying a certificate of analysis for VIP should establish the expected mass from the sequence and the amidation state rather than from a vendor's figure, which is in any case the more reliable method.

The amidation matters more than it sounds. A C-terminal free acid instead of the asparagine amide is a different molecule at a different mass, and it is a common synthesis shortfall — one that a purity percentage will not surface. See mass spectrometry for peptides.

Is intranasal VIP proven for chronic inflammatory response syndrome?

No. There is no randomised controlled trial of intranasal VIP for chronic inflammatory response syndrome. PubMed's entire indexed literature at the intersection of VIP and CIRS is two records: a retrospective observational cohort of 188 patients (PMID 42077435) that is not primarily about VIP, and a single 2016 case report (PMID 27165859) in which VIP replacement was one of five simultaneous interventions. This is the dominant consumer use of VIP.

VIP nasal spray is marketed extensively for CIRS — the mould-illness protocol — across the English-speaking world. The literature behind that market is two records in total.

We should be clear about what that does and does not establish. It does not prove intranasal VIP is ineffective for anything. It establishes that a treatment protocol in widespread commercial use has never been tested in a controlled study, and that the published record amounts to one case in which the patient received five treatments at once and one cohort study whose subject is something else.

On FDA enforcement, we hit a wall and are saying so. We attempted to search FDA's warning letter database for VIP and aviptadil. Both FDA's site search and its warning-letter table render results via JavaScript and returned no rows to our tooling. We therefore cannot say whether FDA has issued warning letters about VIP nasal spray, and we are not claiming it has not.

Is aviptadil approved anywhere?

We could not resolve that, and we are saying so rather than guessing. Aviptadil is not FDA-approved — the two EUA declines establish that, and no approval followed. Secondary sources report a UK approval from October 2000 as Invicorp, aviptadil combined with phentolamine for erectile dysfunction, and an Indian clearance in April 2022 for severe COVID-19 ARDS. The UK electronic Medicines Compendium returned "No search results for Invicorp"; the MHRA products database returned no populated rows.

So the accurate statement is the uncomfortable one: we could not verify that aviptadil is approved anywhere, and we could not verify that it is not. Both database searches failed to return the record, and a failed search is not a disproof.

That matters more than it might seem, because it is the fact on which the anti-doping question turns. We also found no evidence of approval for pulmonary arterial hypertension or sarcoidosis anywhere.

Where does VIP stand on FDA's compounding lists?

Nowhere. VIP and aviptadil do not appear anywhere on FDA's compounding pages — not in the active Category 2 list, not in the "nominated but withdrawn" table, not on the 503A or 503B bulks lists. They were never nominated, so FDA has never evaluated them. That absence is not clearance: without a USP monograph or status as a component of an FDA-approved drug, VIP satisfies none of the three statutory routes for 503A compounding under 21 U.S.C. § 353a(b)(1)(A).

The distinction is easy to get backwards. A compound that appears on FDA's Category 2 list has been examined and flagged. A compound that appears in the "nominated but withdrawn" table was put forward and then pulled. VIP is in neither position — nobody ever asked, so the agency never looked. For how those categories came about and what movement between them means, see our FDA peptide regulation timeline.

Is VIP banned in sport?

Genuinely unresolved. Neither VIP, vasoactive intestinal peptide, nor aviptadil appears anywhere in the 2026 WADA Prohibited List by name. The S0 catch-all prohibits substances "with no current approval by any governmental regulatory health authority for human therapeutic use," so whether it captures aviptadil depends entirely on whether the reported UK and Indian approvals are real — and we could not verify them. If Invicorp is a genuine UK marketing authorisation, S0 does not apply. If not, it does.

We are flagging that as unresolved rather than picking a side, because picking a side would be guessing on a question with a real consequence attached. Any athlete should seek a ruling from their national anti-doping organisation rather than rely on either reading of S0. See are peptides legal for how approval status varies by jurisdiction and why that variation is decisive here.

Which VIP claims survive the evidence?

Not one of nine. FDA never granted an EUA — it declined twice. TESICO refuted the COVID-19 efficacy claim at OR 1.11, P=0.54. Aviptadil is not FDA-approved, intranasal VIP for CIRS is untested with zero randomised trials, and there is no favourable safety signal, the TESICO composite running 63% versus 56%. Two claims sit unresolved rather than refuted: the reported erectile-dysfunction approval, and whether WADA's S0 catch-all applies.

The two unresolved rows are unresolved for the same reason. Both depend on whether a UK marketing authorisation for Invicorp exists, and neither the emc nor the MHRA database would confirm it.

What do 62 lab tests and a twenty-fold price spread show?

VIP tests well and prices chaotically. The Purity Index records VIP at 99.37% average across 62 independent tests (verified May 2026), across 221 shops, in the "Excellent" tier. VIP price data shows 41 shops in stock, median $7.20/mg, with prices spanning $2.26 to $46.50 per milligram and vial sizes from 5 mg to 1000 mg (verified 10 August 2026). That is a twenty-fold spread at nominally comparable purity, one that a single implausible listing largely creates.

Those figures exclude shipping, taxes and customs, coupon codes, bulk tiers, multi-vial kits and account-gated pricing. They sit inside a platform tracking 530 shops and 11,852 independent lab tests across 118 peptides, with 1,283 community reviews (verified August 2026).

One listing deserves scrutiny before anyone anchors on the low end. The $2.26/mg figure comes from a 1000 mg vial priced at $2,263. A one-gram vial of VIP is not a plausible consumer presentation for a peptide dosed in microgram-to-milligram quantities, and it is dragging the floor price down by more than 25% relative to the next entry at $3.00/mg on a 10 mg vial. We are flagging that listing for verification and would not treat $2.26/mg as a real market price.

Even setting that entry aside, a spread from $3.00 to $46.50 per milligram at nominally comparable purity is worth noticing, across vial sizes running from 5 mg to 1000 mg. See how much do peptides cost.

Compare vendors on the VIP compound page, and read the wider body of independent lab tests for how this coverage compares with other immune compounds.

How does VIP compare with the other immune peptides that were properly tested?

VIP belongs to the group whose trials were actually run and came back null. Aviptadil's largest trial, TESICO, enrolled 461 patients and returned OR 1.11, P=0.54. Thymosin alpha-1's TESTS trial ran 1,106 patients double-blind for HR 0.99, P=0.93. Oxytocin's SOARS-B enrolled 290 and returned P=0.61. LL-37's largest human trial is Grönberg, n=34, topical, and positive. That is a more useful position than untested, because a null result converts uncertainty into information.

TESICO was a well-designed NIH trial in the population aviptadil was most plausible for, and it found nothing. A compound that has been asked a serious question and answered it is in a different epistemic position from one nobody has asked. The uncomfortable part, for VIP specifically, is that the question answered is not the question the product is sold to answer.

The trial that would settle this

The trial that would settle VIP is not another COVID-19 trial — TESICO answered that question. It is a randomised, placebo-controlled trial of intranasal VIP in chronic inflammatory response syndrome, using the marketed route rather than intravenous infusion, with a validated case definition as the entry criterion and a pre-specified objective endpoint. It would need to run for the months the commercial protocol claims. The case definition is the obstacle.

The diagnosis row is the real obstacle, and it is not a technicality. A controlled trial requires an entry criterion. Without a validated diagnostic definition there is no population to randomise — which is both why no trial exists and why one is unlikely to.

Frequently Asked Questions

Did FDA authorise aviptadil for COVID-19?

No. FDA declined to issue an Emergency Use Authorization in November 2021, citing insufficient data on benefits and risks after reviewing safety data in 131 randomised patients. It declined again for a narrower subgroup in 2022, having also declined Breakthrough Therapy Designation.

What did the big trial show?

TESICO, the NIH ACTIV-3b trial published in Lancet Respiratory Medicine in 2023, carried 461 patients in its aviptadil analysis population. The primary endpoint — ordinal recovery status at day 90 — returned an odds ratio of 1.11, 95% CI 0.80–1.55, P = 0.54. Day-90 mortality was 38% on aviptadil versus 36% on placebo.

Is VIP nasal spray proven for mould illness or CIRS?

No trial exists. PubMed's entire indexed literature on VIP and chronic inflammatory response syndrome is two records: one retrospective observational cohort of 188 patients that is not primarily about VIP, and one 2016 case report in which VIP was one of five simultaneous interventions.

Is aviptadil approved anywhere?

We could not resolve this. It is not FDA-approved. Secondary sources report a UK approval as Invicorp (with phentolamine, for erectile dysfunction) and an Indian clearance for COVID-19 ARDS, but the UK electronic Medicines Compendium and the MHRA products database returned no matching records when we searched. We are not claiming approval, and we are not claiming its absence.

Why does that unresolved question matter?

Because WADA's S0 clause prohibits substances with no current approval from any governmental health authority. If the UK or Indian approvals are real, S0 does not capture aviptadil; if they are not, it does. An athlete needs a ruling, not an inference.

What should I check on a VIP certificate of analysis?

Mass spectrometry confirming the 28-residue sequence with the C-terminal asparagine amide intact — a free-acid version is a different molecule — and no +16 Da oxidation adduct on the methionine. Also insist on a stated salt form and a batch endotoxin result.

Where VIP sits

VIP is a real neuropeptide with genuine VPAC1 and VPAC2 pharmacology, and aviptadil got a better test than almost any compound on this platform: an NIH-run, adaptive, blinded, placebo-controlled phase 3 trial in the exact population its mechanism pointed at. It returned an odds ratio of 1.11 and a P value of 0.54, with the safety composite running the wrong way. What is sold now is mostly intranasal VIP for a syndrome with no validated definition.

A pandemic removed every usual obstacle to running the trial — funding, urgency, recruitment, regulatory patience — and the trial still came back null. FDA had already declined twice on far less data, at a point when the declines looked harsh, and the larger dataset vindicated them.

The commercial reality has moved on regardless. Intranasal VIP for chronic inflammatory response syndrome has no randomised trial, no validated diagnostic definition, and a published evidence base of one case report from 2016 in which the patient received five interventions simultaneously.

The compound has been asked one serious question and answered it in the negative. The question it is actually being sold to answer has never been asked at all.

Browse the immune support and longevity peptides category, or our complete peptide guide with 118 compounds (verified August 2026). 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.