Efficacy and Safety of Oral Nicotinamide as an Adjunctive Therapy in Patients With Sepsis

Evaluation of the Efficacy and Safety of Oral Nicotinamide as an Adjunctive Therapy in Patients With Sepsis

Sepsis is a severe, life-threatening condition caused by an abnormal host response to infection, which includes systemic inflammation, oxidative stress, and increasing organ dysfunction. It is frequently associated with bacterial, viral, fungal, or parasite infections, as well as non-infectious illnesses like trauma and pancreatitis. It remains a primary cause of mortality in hospitals, with rates nearing 40% in severely ill patients. pathophysiological, excessive cytokine release (e.g., TNFα, IL-6, IL-1β) and reactive oxygen/nitrogen species lead to mitochondrial injury, immunosuppression, and multiple organ failure. Sepsis diagnosis is guided byNEWS2 & a SOFA score ≥2, hypotension, and elevated lactate, while worsening SOFA scores predict poor outcomes. Standard management focusses on early antibiotic therapy, fluid resuscitation, and vasoactive support. Standard anti-inflammatory methods using steroidal or non-steroidal medicines may show little efficacy to improve the patient's clinical outcomes. Adjunctive antioxidant therapies, including vitamins C and E, NAC, and melatonin, have demonstrated reductions in oxidative stress and organ dysfunction. Nicotinamide (NAM) (vitamin B3), a precursor of NAD+/NADP+ critical for energy metabolism and cellular repair, has emerged as a potential therapeutic candidate due to its ability to attenuate cytokine production, modulate immune responses, and mitigate oxidative damage. Usual dose of NAM (500mg-1500mg per day) is generally safe. A dose of 1000 mg was found to be safe and effective in reducing the circulating inflammatory cytokines showing a good profile as an anti-inflammatory adjunct therapy. Higher than usual NAM dose can increase the likelihood of adverse effects, such as diarrhea, increased liver enzymes (rarely occurring at doses exceeding 3 grams per day), symptoms of thrombocytopenia (including increased bruising and bleeding), and stomach upset.

Since the role of NAM as adjunct therapy in sepsis management is not yet established, further large-scale clinical studies are recommended to establish its efficacy and safety in sepsis management.

The aim of our study is to evaluate the efficacy and safety of the addition of Nicotinamide (1000mg oral tablet) as an adjunct therapy to improve the outcome of septic patients.

Study Overview

• Status: Not yet recruiting
• Conditions: Sepsis - to Reduce Mortality in the Intensive Care Unit
• Intervention / Treatment: Drug: Nicotinamide 1000 mg

Detailed Description

Sepsis is a life-threatening medical illness caused by the body's response to an infection, resulting in extensive inflammation. This inflammation can cause a series of changes in the body, leading to restricted blood flow to key organs, causing organ failure and eventually death. Sepsis can be caused by bacteria, viruses, fungi, or parasites, or it can develop due to noninfectious intra-abdominal causes, including severe trauma, pneumonia, pancreatitis, and urinary system infection. Despite advances in medical treatments, sepsis remains a major cause of death globally among hospitalized patients because of its complications. According to reports, Hospital mortality rates were 26% for hospital-wide sepsis and 40% for ICU sepsis. Sepsis was more common in the United States among men, non-white individuals, and the elderly (60 years and older) than among women and white persons.

Severe sepsis is characterized by one or more end-organ failures, while septic shock is characterized by hemodynamic instability despite intravascular volume replacement. The overwhelming immune response and the altered balance between pro-inflammatory and anti-inflammatory mediators contribute to the development of sepsis, making it particularly challenging to treat.

Some possible complications of sepsis include Acute/chronic renal injury, Mesenteric ischemia, Acute liver failure, Myocardial dysfunction, and Multiple organ failure. Previous studies showed that sepsis can cause the disturbance of immunological homeostasis, leading to immunosuppression in sepsis.

The SOFA (Sequential Organ Failure Assessment) score is currently advised for diagnosing both sepsis and septic shock. A diagnosis of sepsis is confirmed in the case of a (SOFA) score ≥ 2. The SOFA system is a simple technique that detects organ failure or dysfunction due to sepsis. Daily, the SOFA scoring scale allocates from 1 to 4 points for each of the following six organ systems, according to the level of dysfunction: The respiratory, circulatory, renal, hematological, hepatic, and central nervous systems. Sepsis is presented by a rise of two or more points in the SOFA score. Moreover, the SOFA score could be a method to assess morbidity in intensive care unit (ICU) sepsis patients.

Cytokines are essential for the effective functioning of critical host immune systems because they regulate the body's reactions to infection, immunological responses, inflammation, and trauma. Modifying the cytokine response is an important aspect of therapy for many severe inflammatory disorders. In septic patients, it has been demonstrated that TNFα, IL-6, and IL-1β correspond with the severity of the disease and its outcome.

Oxidative stress (OS) damage plays a role in the pathogenesis of major disorders such as sepsis-induced multiple organ failure (MOF). Studies in animal models and septic shock patients have revealed an imbalance between the formation of reactive oxygen (ROS) and nitrogen (RNS) species and antioxidant defenses. ROS are produced by phagocytic cells, enzymes such as NADPH oxidase, xanthine oxidase, and iNOS, and enhanced inflammatory mediators via NFκB activation. OS-induced mitochondrial damage is part of the pathogenesis of MOF, subsequent sepsis.

To diagnose sepsis patients: SOFA score ≥ 2, mean arterial pressure (MAP) < 65 mmHg, and serum lactate level ≥ 2 mmol/L. Blood should be collected before initiating antibiotics to guide therapy and help determine the source of infection.

Effective sepsis management requires a combination of rapid interventions and supportive care. It involves different pathophysiological aspects, encompassing empirical antimicrobial treatment (which is promptly administered after microbial tests), fluid (crystalloids) replacement (to be established according to fluid tolerance and fluid responsiveness), and vasoactive agents (e.g., norepinephrine). Administering the appropriate medications on time has been linked to higher survival rates. Supportive care and adjuvant therapy, such as the use of corticosteroids, blood purification techniques, and immunomodulatory therapies, are still under investigation.

The inflammatory response in sepsis has played a significant role, and so, Standard therapy includes the use of steroidal and non-steroidal anti-inflammatory medicines, which have resulted in poor outcomes. Currently, antioxidant therapy in septic shock patients has been demonstrated to be effective in lowering Oxidative Stress (OS) indicators. Similarly, it was discovered that adding antioxidant therapy to the standard therapy in septic shock enhances total antioxidant capacity and reduces OS.

Many therapeutic strategies have focused on controlling the inflammatory response and managing oxidative stress, both of which are central to sepsis pathogenesis. Antioxidants and anti-inflammatory medications aim to counteract the overproduction of reactive oxygen species (ROS) and inflammatory cytokines, potentially reducing damage to tissues and organs. However, the complexity of sepsis, with its multifactorial nature and diverse responses among patients, continues to present challenges for developing more effective treatments.

Patients who receive antioxidants such as vitamin C, vitamin E, NAC, or MT in addition to traditional therapy demonstrate lower levels of pro-inflammatory cytokines and enhanced regulatory function in IL-2, IL-12, and IFN. The antioxidant capacity has improved, and indicators of oxidative stress have decreased, indicating that organ damage has reduced as determined by the SOFA score.

Nicotinamide (or nicotinamide) is a form of vitamin B3 that is often confused with its precursor nicotinic acid (or niacin) . Nicotinamide (NAM; niacin), nicotinic acid (niacin), and NAM riboside (NR) are the three vitamins that make up the components of the water-soluble vitamin B3 family. Nicotinamide is a precursor to two essential cofactors in cellular metabolism: Nicotinamide adenine dinucleotide (NAD) and its phosphate form, NADP. Nicotinamide adenine dinucleotide (NAD+) coenzymes are the primary regulators of cellular metabolism. While metabolic stress and age-related diseases can disrupt the NAD+ system, NAD is essential for several biological functions, such as DNA repair, energy synthesis, and cellular stress mechanisms.

Previous research suggests that NAM can effectively reduce cytokine release and inflammatory cell chemotaxis in skin disorders. Research indicates that NAM can reduce the number of inflammatory macrophages in chemically induced skin cancer. NAM has been shown to inhibit the secretion of cytokines and the chemotaxis of inflammatory cells in inflammatory skin diseases. This suggests that NAM might play a role in modulating immune responses, especially in conditions where excessive inflammation leads to tissue damage, like in psoriasis or eczema.

NAM may have therapeutic potential as a modulator of cytokine effects in inflammatory diseases since it significantly inhibits the proinflammatory cytokine response of IL-1β, IL-6, IL-8, and TNFα after endotoxin stimulation of human whole blood.

In general, Nicotinamide has fewer potential negative effects than other niacin supplements. There are expected mild side effects of NAM as (gastrointestinal upset, Headache, dizziness and Fatigue). However, a medication safety trial reported that consuming larger amounts of Nicotinamide than usual can increase the likelihood of adverse effects, such as diarrhea, increased liver enzymes (rarely occurring at doses exceeding 3 grams per day), symptoms of thrombocytopenia (including increased bruising and bleeding), which is a rare side effect. The severity of nicotinamide-induced adverse effects determines how they are managed. Antacids such as calcium carbonate, probiotics, or taking the dose with food can help ease gastrointestinal distress. Headaches can be treated with basic analgesics such as paracetamol or ibuprofen if not contraindicated. Although dizziness normally requires just supportive care, such as appropriate fluids or oral rehydration, it may be needed. Fatigue has no specific pharmacologic treatment, but improving sleep, staying hydrated, and taking a non-excessive B-complex supplement may assist. Diarrhea caused by large doses can be treated with oral rehydration salts and, if necessary, short-term loperamide, as well as lowering the nicotinamide dose.

Nicotinamide riboside (NR) increases NAD+ + levels and may help lower inflammation, even if metabolic stress and age-related disorders dysregulate the NAD+ + system. A previous Study Proves that NR markedly reduced the gene expression of IL-6 and IL-18 in peripheral blood mononuclear cells Moreover, it was found to reduce the incidence of RRT/death and improve the creatinine outcome in individuals with severe COVID-19-related AKI. Larger randomized trials are required to determine a causal link Given the high morbidity and mortality associated with septic patient, incorporating NAM as an adjunct to standard sepsis care could offer a novel therapeutic approach to improving survival and reducing long-term complications.

• Study Type: Interventional
• Enrollment (Estimated): 60
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Sarah Sabry, PhD; Phone Number: 00201068289698; Email: ssabry@ecu.edu.eg
• Study Contact Backup: Name: Basma Ahmed, Bachelor; Phone Number: 02201021975571; Email: baabdelsattar@ecu.edu.eg

Study Locations

• Egypt
  • Cairo, Egypt
    • El Demardash Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Patients older than 18 years of any gender who were admitted to the intensive care unit
• Diagnosed as sepsis patient with the Sequential Organ Failure Assessment (SOFA) Score described as an Increase in SOFA score ≥2 points due to infection.

Exclusion Criteria:

• Pregnant or lactating women
• Patients who had already been taking antioxidant supplements before recruiting.
• Patient with contraindications or reported allergies to Nicotinamide.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Supportive Care
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
No Intervention: Control Group; 30 Patients will receive the treatment alone according to the hospital management protocol
Active Comparator: Interventional Group; 30 Patients will receive 1000mg oral Nicotinamide tablets as an adjunct therapy to the treatment provided to the sepsis patients according to the hospital management protocol.	Drug: Nicotinamide 1000 mg; Nicotinamide 1000 mg Tablet; Other Names: Nicotinamide 1000 mg (Niacinamide)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The Change in SOFA Score	The SOFA (Sequential Organ Failure Assessment) score is a crucial ICU tool that quantifies organ dysfunction with score totaling 0-24, the higher score the worser Outcome	7 days of receiving treatment.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in IL-6 levels in serum	serum IL-6 level change will be calculated by subtracting the IL-6 level in Day 7 minus Baseline IL-6 level	At the 7th day of follow up
Change in NF-kB in serum	serum NF-kB level change will be calculated by subtracting the IL-6 level in Day 7 minus Baseline IL-6 level	At 7th day of follow up
Length of ICU stay (days)	Length of ICU stay measured in days from ICU admission until ICU discharge or death, obtained from patient medical records.	From ICU admission until ICU discharge or death, up to 28 days
28 day Mortality	to determine the mortality rate	At the 28th day of follow up
Length of hospital stay (days)	Change in length of hospital stay (days) measured from hospital admission to hospital discharge and obtained from patient medical records.	From hospital admission until discharge, up to 28 days
Assess the septic patients Mortality rate.	Assess effect of Nicotinamide on change of the Mortality rate in septic patient.	28 mortality day

Collaborators and Investigators

• Sponsor: Ain Shams University
• Collaborators: Egyptian Chinese University
• Investigators: Study Director: Sarah Farid, PhD, Clinical Pharmacy department Faculty of Pharmacy AIn SHams University

Publications and helpful links

General Publications

• Dolopikou CF, Kourtzidis IA, Margaritelis NV, Vrabas IS, Koidou I, Kyparos A, Theodorou AA, Paschalis V, Nikolaidis MG. Acute nicotinamide riboside supplementation improves redox homeostasis and exercise performance in old individuals: a double-blind cross-over study. Eur J Nutr. 2020 Mar;59(2):505-515. doi: 10.1007/s00394-019-01919-4. Epub 2019 Feb 6.
• Ungerstedt JS, Blomback M, Soderstrom T. Nicotinamide is a potent inhibitor of proinflammatory cytokines. Clin Exp Immunol. 2003 Jan;131(1):48-52. doi: 10.1046/j.1365-2249.2003.02031.x.
• Minne L, Abu-Hanna A, de Jonge E. Evaluation of SOFA-based models for predicting mortality in the ICU: A systematic review. Crit Care. 2008;12(6):R161. doi: 10.1186/cc7160. Epub 2008 Dec 17.
• Rello J, Valenzuela-Sanchez F, Ruiz-Rodriguez M, Moyano S. Sepsis: A Review of Advances in Management. Adv Ther. 2017 Nov;34(11):2393-2411. doi: 10.1007/s12325-017-0622-8. Epub 2017 Oct 11.
• Guarino M, Perna B, Cesaro AE, Maritati M, Spampinato MD, Contini C, De Giorgio R. 2023 Update on Sepsis and Septic Shock in Adult Patients: Management in the Emergency Department. J Clin Med. 2023 Apr 28;12(9):3188. doi: 10.3390/jcm12093188.
• Gyawali B, Ramakrishna K, Dhamoon AS. Sepsis: The evolution in definition, pathophysiology, and management. SAGE Open Med. 2019 Mar 21;7:2050312119835043. doi: 10.1177/2050312119835043. eCollection 2019.
• Raines NH, Ganatra S, Nissaisorakarn P, Pandit A, Morales A, Asnani A, Sadrolashrafi M, Maheshwari R, Patel R, Bang V, Shreyder K, Brar S, Singh A, Dani SS, Knapp S, Poyan Mehr A, Brown RS, Zeidel ML, Bhargava R, Schlondorff J, Steinman TI, Mukamal KJ, Parikh SM. Niacinamide May Be Associated with Improved Outcomes in COVID-19-Related Acute Kidney Injury: An Observational Study. Kidney360. 2020 Nov 20;2(1):33-41. doi: 10.34067/KID.0006452020. eCollection 2021 Jan 28.
• Hong G, Zheng D, Zhang L, Ni R, Wang G, Fan GC, Lu Z, Peng T. Administration of nicotinamide riboside prevents oxidative stress and organ injury in sepsis. Free Radic Biol Med. 2018 Aug 1;123:125-137. doi: 10.1016/j.freeradbiomed.2018.05.073. Epub 2018 May 24.
• Zhang Q, Li J, Zhong H, Xu Y. The mechanism of nicotinamide on reducing acute lung injury by inhibiting MAPK and NF-kappaB signal pathway. Mol Med. 2021 Sep 20;27(1):115. doi: 10.1186/s10020-021-00376-2.
• Camillo L, Zavattaro E, Savoia P. Nicotinamide: A Multifaceted Molecule in Skin Health and Beyond. Medicina (Kaunas). 2025 Feb 1;61(2):254. doi: 10.3390/medicina61020254.
• Snaidr VA, Damian DL, Halliday GM. Nicotinamide for photoprotection and skin cancer chemoprevention: A review of efficacy and safety. Exp Dermatol. 2019 Feb;28 Suppl 1:15-22. doi: 10.1111/exd.13819.
• Fontecha-Barriuso M, Lopez-Diaz AM, Carriazo S, Ortiz A, Sanz AB. Nicotinamide and acute kidney injury. Clin Kidney J. 2021 Sep 23;14(12):2453-2462. doi: 10.1093/ckj/sfab173. eCollection 2021 Dec.
• Huber R, Wong A. Nicotinamide: An Update and Review of Safety & Differences from Niacin. Skin Therapy Lett. 2020 Nov;25(5):7-11.
• Perez-Torres I, Aisa-Alvarez A, Casarez-Alvarado S, Borrayo G, Marquez-Velasco R, Guarner-Lans V, Manzano-Pech L, Cruz-Soto R, Gonzalez-Marcos O, Fuentevilla-Alvarez G, Gamboa R, Saucedo-Orozco H, Franco-Granillo J, Soto ME. Impact of Treatment with Antioxidants as an Adjuvant to Standard Therapy in Patients with Septic Shock: Analysis of the Correlation between Cytokine Storm and Oxidative Stress and Therapeutic Effects. Int J Mol Sci. 2023 Nov 22;24(23):16610. doi: 10.3390/ijms242316610.
• Aisa-Alvarez A, Soto ME, Guarner-Lans V, Camarena-Alejo G, Franco-Granillo J, Martinez-Rodriguez EA, Gamboa Avila R, Manzano Pech L, Perez-Torres I. Usefulness of Antioxidants as Adjuvant Therapy for Septic Shock: A Randomized Clinical Trial. Medicina (Kaunas). 2020 Nov 17;56(11):619. doi: 10.3390/medicina56110619.
• Martinez ML, Plata-Menchaca EP, Ruiz-Rodriguez JC, Ferrer R. An approach to antibiotic treatment in patients with sepsis. J Thorac Dis. 2020 Mar;12(3):1007-1021. doi: 10.21037/jtd.2020.01.47.
• Marques A, Torre C, Pinto R, Sepodes B, Rocha J. Treatment Advances in Sepsis and Septic Shock: Modulating Pro- and Anti-Inflammatory Mechanisms. J Clin Med. 2023 Apr 15;12(8):2892. doi: 10.3390/jcm12082892.
• Liu D, Huang SY, Sun JH, Zhang HC, Cai QL, Gao C, Li L, Cao J, Xu F, Zhou Y, Guan CX, Jin SW, Deng J, Fang XM, Jiang JX, Zeng L. Sepsis-induced immunosuppression: mechanisms, diagnosis and current treatment options. Mil Med Res. 2022 Oct 9;9(1):56. doi: 10.1186/s40779-022-00422-y.
• Peivandi Yazdi A, Razavi M, Sheikh S, Boroumand N, Salehi M, Hashemy SI. Clinical Trial Assessment of Intermittent and Continuous Infusion Dose of N-Acetylcysteine on Redox Status of the Body in Patients with Sepsis Admitted to the ICU. J Intensive Care Med. 2020 Dec;35(12):1383-1388. doi: 10.1177/0885066618823152. Epub 2019 Jan 13.
• Rivers EP, Jaehne AK, Eichhorn-Wharry L, Brown S, Amponsah D. Fluid therapy in septic shock. Curr Opin Crit Care. 2010 Aug;16(4):297-308. doi: 10.1097/MCC.0b013e32833be8b3.
• Prauchner CA. Oxidative stress in sepsis: Pathophysiological implications justifying antioxidant co-therapy. Burns. 2017 May;43(3):471-485. doi: 10.1016/j.burns.2016.09.023. Epub 2016 Dec 27.
• Lei S, Li X, Zhao H, Xie Y, Li J. Prevalence of sepsis among adults in China: A systematic review and meta-analysis. Front Public Health. 2022 Oct 11;10:977094. doi: 10.3389/fpubh.2022.977094. eCollection 2022.
• Woznica EA, Inglot M, Woznica RK, Lysenko L. Liver dysfunction in sepsis. Adv Clin Exp Med. 2018 Apr;27(4):547-551. doi: 10.17219/acem/68363.
• Moschopoulos CD, Dimopoulou D, Dimopoulou A, Dimopoulou K, Protopapas K, Zavras N, Tsiodras S, Kotanidou A, Fragkou PC. New Insights into the Fluid Management in Patients with Septic Shock. Medicina (Kaunas). 2023 May 29;59(6):1047. doi: 10.3390/medicina59061047.

Helpful Links

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Study record dates

Study Major Dates

• Study Start (Estimated): July 1, 2026
• Primary Completion (Estimated): October 1, 2026
• Study Completion (Estimated): January 1, 2027

Study Registration Dates

• First Submitted: March 26, 2026
• First Submitted That Met QC Criteria: June 13, 2026
• First Posted (Actual): June 18, 2026

Study Record Updates

• Last Update Posted (Actual): June 18, 2026
• Last Update Submitted That Met QC Criteria: June 13, 2026
• Last Verified: March 1, 2026

More Information

Terms related to this study

• Keywords: anti-inflammatory; Sepsis; Mortality; IL-6; Nicotinamide; NF-kB
• Additional Relevant MeSH Terms: Pathologic Processes; Infections; Systemic Inflammatory Response Syndrome; Inflammation; Pathological Conditions, Signs and Symptoms; Sepsis; Pyridines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Acids, Heterocyclic; Nicotinic Acids; Niacinamide
• Other Study ID Numbers: FMASU MS 17 /2026

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No