VITAMINS trial (Vitamin C, Hydrocortisone and Thiamine in patients with septic shock)

The VITAMINS trial was a pilot, multicentre, randomised, open-label controlled, feasibility study to compare the administration of vitamin C, thiamine and hydrocortisone vs hydrocortisone alone in critically ill patients with septic shock.

Goal: To determine whether the intravenous administration of high-dose vitamin C (6 g/d), thiamine (400 mg/d) and hydrocortisone (200 mg/d) in patients with septic shock leads to a more rapid resolution of shock and shortens the duration of vasopressor dependence compared to hydrocortisone alone.

Rationale: Many experimental data have demonstrated that both corticosteroids and intravenous vitamin C attenuate the release of pro-inflammatory mediators and could, therefore, reduce the injury caused by the body's harmful response to sepsis.

Vitamin C is an essential water-soluble vitamin. Several studies have administered vitamin C in doses exceeding 100 g/day as adjuvant therapy in patients with cancer with no discernible side effects. A dose of 6 g/day (as used in our study protocol) will achieve a steady-state serum concentration of about 100 times less than the reported toxic dose. Furthermore, the recently published ADRENAL trial investigated the impact of 200 mg of intravenous hydrocortisone a day compared to placebo, in ICU patients with sepsis requiring mechanical ventilation. Despite finding no significant difference in mortality 3-months after ICU admission, administration of intravenous hydrocortisone resulted in a reduced duration of shock and vasopressor use, and a reduction in the intensive care length of stay. These findings justify the use of intravenous hydrocortisone in patients with septic shock, as standard care.

In a recent single centre before-after study, early use of intravenous vitamin C, together with corticosteroids and thiamine, was associated with significantly less organ dysfunction and reduced mortality in patients with severe sepsis / septic shock.

These results have generated debate in the critical care community, particularly given the inherent bias of such a study design, and a pragmatic randomised controlled trial is now essential to further this research question.

Registration: NCT03333278

Study results: The results were published on 17 January 2020 in the Journal of the American Medical Association

The VITAMINS trial found that treatment with intravenous vitamin C (1.5 g 6 hourly), hydrocortisone (50 mg 6 hourly), and thiamine (200 mg 12 hourly) does not lead to a more rapid resolution of septic shock compared with intravenous hydrocortisone (50 mg 6 hourly) alone.


VITAMINS Trial Statistical analysis plan for an interim analysis SAP sample size calculation. Version 3.0, 2 November 2018 (Uploaded 22 Jan 2019)

VITAMINS Trial Statistical analysis plan for the final sample size. Version 1.0, 15 February 2019 (Uploaded 21 Feb 2019)

Fujii T, Udy AA, Deane AM, Luethi N, Bailey M, Eastwood GM, Frei D, French C, Orford N, Shehabi Y, Young PJ, Bellomo R; VITAMINS Trial Investigators. Vitamin C, Hydrocortisone and Thiamine in Patients with Septic Shock (VITAMINS) trial: study protocol and statistical analysis plan. Crit Care Resusc 2019;21:119-125.

VITAMINS Trial Investigators, Fujii T, Luethi N, Young PJ, Frei DR, Eastwood GM, French CJ, Deane AM, Shehabi Y, Hajjar LA, Oliveira G, Udy AA, Orford N, Edney SJ, Hunt AL, Judd HL, Bitker L, Cioccari L, Naorungroj T, Yanase F, Bates S, McGain F, Hudson EP, Al-Bassam W, Dwivedi DB, Peppin C, McCracken P, Orosz J, Bailey M, Bellomo R. Effect of Vitamin C, Hydrocortisone, and Thiamine vs Hydrocortisone Alone on Time Alive and Free of Vasopressor Support Among Patients With Septic Shock: The VITAMINS Randomized Clinical Trial. JAMA. 2020 Jan 17. doi: 10.1001/jama.2019.22176.

Contact: For further information about this study, please contact the coordinating investigator Tomoko Fujii by email.