Thymosin-α1 for Recurrent Implantation Failure

Official title

Thymosin-α1 for Recurrent Implantation Failure Following Transfer of PGT-a Tested Embryo: A Randomized, Double-Blind, Placebo-Controlled Trial

Overview

Clinical trial evaluating the safety and efficacy of Thymosin-α1 (Tα1) as an adjunctive immunomodulatory therapy in women with unexplained recurrent implantation failure (RIF) undergoing IVF/ICSI cycles.

Detailed description

Despite significant advancements in assisted reproductive technologies (ART), recurrent implantation failure (RIF) remains a persistent challenge. Growing evidence implicates dysregulation of both local endometrial and systemic immune components in the pathophysiology of RIF.

This has led to increasing attention on immune dysregulation, including aberrant cytokine signaling, altered Th1/Th2 balance, heightened NK cell cytotoxicity, and impaired maternal-fetal tolerance as possible contributors. These immunological pathways are critical for embryo implantation and pregnancy continuation; their disruption can create an environment hostile to the developing conceptus.

Thymosin-α1 (Tα1) is a naturally occurring thymic peptide with immune-modulatory properties. It has been historically used in the management of chronic viral infections and certain cancers, where it demonstrated the ability to enhance T-cell function, rebalance cytokine networks, and improve immune resilience. Its safety profile in non-obstetric conditions is well established.

Although comprehensive safety evaluation of thymosin alpha in pregnant women has not yet been completed, emerging evidence from observational studies, case reports, and proposed clinical trials suggests that thymosin alpha is generally regarded as safe during pregnancy, with no reported adverse effects linked to its use to date. Specifically, a published case report documented successful pregnancy following thymosin alpha administration in a woman with recurrent implantation failure, noting an absence of fetal anomalies or significant adverse events and emphasizing the need for further prospective trials to establish broader safety and efficacy. Preliminary clinical protocols continue to monitor for adverse events in patients undergoing reproductive treatments, and none have identified safety concerns thus far.

Emerging reproductive data suggest a potential role of Tα1 in implantation and pregnancy maintenance. Observational work reported lower maternal Tα1 levels in women whose pregnancies ended in miscarriage compared with those that continued to viability; this effect was not seen with thymosin-β4, suggesting specificity. Mechanistically, Tα1 enhances T-cell maturation, restores Th1/Th2 balance, and promotes regulatory T-cell activity-processes central to maternal immune tolerance during early pregnancy.

Taken together, these findings highlight a gap: Tα1 has biological plausibility and early signals but no definitive RCT evidence. This underlines the need for a rigorous, placebo-controlled study of Tα1 in women with RIF. To our knowledge, this is the first randomized placebo-controlled study looking at Tα1 in RIF patients undergoing treatment using PGT-a tested embryos.

Interventions

• Drug Thymosin Alpha1
  Start at luteal start in ART cycles and continue until 10+6 weeks' gestation.
• Other Placebo Control
  Matching placebo injections on the same schedule and duration.

Primary outcome measures

• Live birth more than 24 weeks [Time frame: Approximately 40 weeks]
• Determine whether Tα1 increases live birth versus placebo. [Time frame: Approximately 40 weeks]

Eligibility criteria

Inclusion criteria

• -Women 18-40 years
• -RIF- ≥2 failed embryo transfers with PGT-a tested euploid embryos
• \- Normal parental karyotypes
• \- Normal uterine cavity on imaging
• \- Negative antiphospholipid panel
• \- Thyroid and prolactin controlled within local reference standards

Exclusion criteria

• Identified/correctable non-immune cause of RPL (chromosomal, anatomic, endocrine)
• \- Active malignancy
• -Active infection
• \- Uncontrolled systemic disease
• \- Current systemic immunosuppression

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Quadruple blind

Primary purpose

Treatment

Study locations

United Arab Emirates · 1 center

• Fakih IVF — Abu Dhabi

Publications

• Graham JJ, Longhi MS, Heneghan MA. T helper cell immunity in pregnancy and influence on autoimmune disease progression. J Autoimmun. 2021 Jul;121:102651. doi: 10.1016/j.jaut.2021.102651. Epub 2021 May 18. PMID 34020252
• Dominari A, Hathaway Iii D, Pandav K, Matos W, Biswas S, Reddy G, Thevuthasan S, Khan MA, Mathew A, Makkar SS, Zaidi M, Fahem MMM, Beas R, Castaneda V, Paul T, Halpern J, Baralt D. Thymosin alpha 1: A comprehensive review of the literature. World J Virol. 2020 Dec 15;9(5):67-78. doi: 10.5501/wjv.v9.i5.67. PMID 33362999
• Kaufmann RA, Welch RA, Mutchnick MG. Low periconceptional maternal serum thymosin alpha 1 levels are associated with blighted pregnancies. Am J Reprod Immunol. 1993 Apr;29(3):171-5. doi: 10.1111/j.1600-0897.1993.tb00583.x. PMID 8373526
• Robertson SA. Immune tolerance in pregnancy. Nat Rev Immunol. 2020;20:67-82
• Garaci E, Favalli C, Pica F, Sinibaldi Vallebona P, Palamara AT, Matteucci C, Pierimarchi P, Serafino A, Mastino A, Bistoni F, Romani L, Rasi G. Thymosin alpha 1: from bench to bedside. Ann N Y Acad Sci. 2007 Sep;1112:225-34. doi: 10.1196/annals.1415.044. Epub 2007 Jun 28. PMID 17600290
• Lin, Y. et al. Maternal serum thymosin α1 and β4 levels in early pregnancy and risk of miscarriage. [Chinese study showing lower Tα1 in miscarriage]
• Romani L, et al. Thymosin alpha-1: a safe and effective immune modulator in clinical practice. Expert Opin Biol Ther. 2016;16(5):691-707.
• Goldstein AL, et al. Biological activities of thymosin alpha 1: clinical applications in disease modulation. Int Immunopharmacol. 2004;4(13):1781-1789.

Identifiers

NCT: NCT07675980 · FAKIH-2025-13 · DOH/ADHRTC/2026/345

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗