Nicotinamide Treatment for Lupus-associated Skin Lesions in Lupus Erythematosus

An Open-label Study for Assessing the Efficacy and Safety of Nicotinamide Treatment for Lupus-associated Skin Lesions in Patients With Cutaneous Lupus Erythematosus or Systemic Lupus Erythematosus

This clinical study will test the efficacy and safety of nicotinamide for lupus-associated skin lesions refractory to the treatment of hydroxychloroquine plus low-dose corticosteroids in patients with cutaneous lupus erythematosus (CLE) or systemic lupus erythematosus (SLE).

Study Overview

• Status: Active, not recruiting
• Conditions: Cutaneous Lupus Erythematosus; Systemic Lupus Erythematosus Rash
• Intervention / Treatment: Drug: nicotinamide

Detailed Description

Backgrounds: Lupus erythematosus (LE) is an autoimmune disease affecting various organs. Lupus-associated skin lesions are the dominant clinical manifestations of cutaneous lupus erythematosus (CLE) and also occur in 70%~80% of patients with systemic lupus erythematosus (SLE), and usually involve the sunlight-exposure sites such as the face, neck and hands, which affects the personal appearance dramatically and causes substantial psychological impact to the patients.

While antimalarials such as hydroxychloroquine (HCQ) have been widely used as a first-line treatment for lupus-associated skin lesions, 30% of patients with lupus do not respond to this medication. Other available therapies such as corticosteroids and thalidomide can also be applied, however, their toxic side effects limit the clinical use. Recent studies by the investigators have shown that nicotinamide, a water-soluble vitamin whose side effects are considered as minimal, can protect MRL/lpr mice (a lupus-like mouse model) from skin lesions and autoantibody production. Thus it is hypothesized that nicotinamide treatment could be a novel therapy for lupus-associated skin lesions in patients with LE.

Design of Study: This is a single center, uncontrolled, open-label study to assess the efficacy and safety of nicotinamide for lupus-associated skin lesions refractory to the treatment of HCQ plus low-dose corticosteroids in patients with CLE or SLE.

Methods: For CLE or SLE patients with lupus-associated skin lesions scoring >=4 on the Revised Cutaneous Lupus Erythematosus Disease Area and Severity Index (RCLASI) that have been refractory to the treatment of HCQ plus low-dose corticosteroids (<=0.5 mg/kg/d) during the past two months, oral nicotinamide (500 mg twice daily) will be given consecutively for 3 months while the current regimen including HCQ and corticosteroids be maintained without change. The end points include clinical response and immunological changes, as well as safety.

• Study Type: Interventional
• Enrollment (Anticipated): 40
• Phase: Phase 2

Contacts and Locations

Study Locations

• China
  • Hunan
    • Changsha, Hunan, China, 410011
      • The second Xiangya Hospital of Central South University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Age: between 18 years and 65 years.
2. Patients clinically and histopathologically diagnosed as cutaneous lupus erythematosus (CLE) that have not respond to treatment with hydroxychloroquine (200-400 mg/day) plus corticosteroids at a dosage less than the equivalent of 0.5mg/kg/day of prednisone for the preceding two months or a longer period.
3. Patients diagnosed as SLE (meeting the 1997 American College of Rheumatology criteria for SLE) that present with lupus-associated skin lesions that have not respond to treatment with hydroxychloroquine (200-400 mg/day) plus corticosteroids at a dosage less than the equivalent of 0.5mg/kg/day of prednisone for the preceding two months or a longer period.
4. Revised Cutaneous Lupus Erythematosus Disease Area and Severity Index (RCLASI) ≥4; for patients with SLE, Safety of Estrogens in Lupus Erythematosus National Assessment version of the systemic lupus erythematosus disease activity index (SELENA-SLEDAI) is within the range between 0 and 9.
5. Written informed consent form.

Exclusion Criteria:

1. Severe comorbidities including heart failure (≥grade III NYHA), respiratory failure, renal insufficiency (creatinine clearance ≤30 ml/min), hepatic insuf¬ficiency (alanine aminotransferase or aspartate aminotransferase ≥2 times of the upper limit of the normal range), or active severe neuropsychiatric manifestations of SLE.
2. Acute severe infection such as sepsis and cellulitis, or a history of infection of hepatitis B or C virus, Mycobacterium tuberculosis, or human immunodeficiency virus (HIV).
3. A history of treatment with nicotinamide, niacin, or multi-vitamins in the recent month.
4. A history of treatment with rituximab or other biologics; or a history of treatment with high-dose corticosteroids (≥1.5 mg/kg/d), immunosuppressants, tripterygium glycosides, or intravenous immunoglobin G (IVIG) in the preceding three months.
5. Patients not suitable for using nicotinamide due to comorbidities including pruritic skin diseases such as atopic dermatitis and urticaria, vertigo, dizziness, headache, hyperglycemia, and hyperuricemia; patients not suitable for using hydroxychloroquine due to conditions including retinopathy or hypersensitivity to hydroxychloroquine.
6. Patients with drug abuse, alcohol abuse, or mental disorders that are unable to cooperate or adhere to treatment.
7. Pregnancy or lac¬tation in females.
8. Participants in other clinical trials.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: nicotinamide; Patients will receive 10 nicotinamide tablets orally twice daily (nicotinamide 500 mg, p.o., Bid) for a period of 3 months. Each tablet contains 50 mg of nicotinamide.	Drug: nicotinamide; Drug: nicotinamide; Pharmaceutical form: tablet; Route of administration: oral; Other Names: Niacinamide

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
A change in Revised Cutaneous Lupus Erythematosus Disease Area and Severity Index (RCLASI) activity score	The higher the RCLASI score, the worse of the lupus-associated skin lesion is.	from baseline (at visit 0) to 3 months treatment (at visit 3)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
A change in RCLASI activity score	The higher the RCLASI score, the worse of the lupus-associated skin lesion is.	from baseline (at visit 0) to 1, 2, 4, and 6 months treatment (at visit 1, 2, 4, and 5), respectively
Response Rate and Remarkable Response Rate at 1, 2, 3, 4, and 6 months, respectively	Response is defined as a ≥ 4-point reduction or a ≥20% reduction in RCALSI activity score. Remarkable Response is defined as a ≥50% reduction in RCALSI activity score.	1 month, 2 months, 3 months, 4 months, and 6 months
Number of Relapses	Relapse means that if the patient's RCLASI activity score has a ≥ 4-point reduction or a ≥20% reduction than at baseline during the 3-month treatment, and then the RCLASI activity score increase to be no lower than at baseline after stopping using nicotinamide in the following 3 months.	4 months, 6 months
A change in Dermatology Life Quality Index (DLQI) score	DLQI reflect the quality of life related to skin manifestations.	from baseline (at visit 0) to 1 month, 2 months, 3 months, 4 months, and 6 months (at visit 1, 2, 3, 4, and 5), respectively
A change in Physician's Global Assessment (PGA) score		from baseline (at visit 0) to 1 month, 2 months, 3 months, 4 months, and 6 months (at visit 1, 2, 3, 4, and 5), respectively
A change in the percentage of different T helper cell (Th) subsets among CD4+ T lymphocytes	At each time point, the percentage of Th1, Th2, Th17, regulatory T cell (Treg), and follicular helper T cell (Tfh) subsets among CD4+ T lymphocytes in peripheral venous blood of the patient will be measured by flow cytometry. 5 ml of peripheral venous blood will be collected from the patient at each time point, of which 4.5 ml will be used in this flow cytometry assay.	from baseline (at visit 0) to 1 month, 2 months, 3 months, 4 months, and 6 months (at visit 1, 2, 3, 4, and 5), respectively
A change in the serum level of cytokines interferon (IFN)γ, interleukin (IL)-4, IL-17A, transforming growth factor (TGF)-β, IL-10, IL-21, and IL-6	At each time point, the serum level of cytokines IFNγ, IL-4, IL-17A, TGF-β, IL-10, IL-21, and IL-6 in the patient's venous blood will be measured using enzyme linked immunosorbent assay (ELISA) or Bio-Plex methods. 5 ml of peripheral venous blood will be collected from the patient at each time point, of which 0.5 ml will be used in this ELISA or Bio-Plex assay.	from baseline (at visit 0) to 1 month, 2 months, 3 months, 4 months, and 6 months (at visit 1, 2, 3, 4, and 5), respectively
A change in serum levels of complement 3 (C3), C4, and C1q	This is for evaluation of the potential effects of nicotinamide on serum levels of complements that are associated with lupus activity	from baseline (at visit 0) to 1 month, 2 months, 3 months, 4 months, and 6 months (at visit 1, 2, 3, 4, and 5), respectively
A change in the results of urine sediment test	This is for evaluation of the potential effects of nicotinamide on renal damage.	1 month, 2 months, 3 months, 4 months, and 6 months
Dose reduction of concomitant corticosteroids		from baseline (at visit 0) to 3 months, 4 months, and 6 months (at visit 3, 4, and 5), respectively
A change in SELENA-SLEDAI (Safety of Estrogens in Lupus Erythematosus National Assessment version of the systemic lupus erythematosus disease activity index)	This outcome is only evaluated for patients with SLE.	from baseline (at visit 0) to 1 month, 2 months, 3 months, 4 months, and 6 months (at visit 1, 2, 3, 4, and 5), respectively
A change in British Isles Lupus Assessment Group 2004 Index (BILAG-2004)	This outcome is only evaluated for patients with SLE.	from baseline (at visit 0) to 1 month, 2 months, 3 months, 4 months, and 6 months (at visit 1, 2, 3, 4, and 5), respectively
Incidence of side effects	Possible side effects of nicotinamide include flushing and itching of the skin, cardiac arrhythmia, dizziness, nausea, epigastric discomfort, loss of appetite, elevated blood glucose, and elevated blood uric acid. The major side effects of HCQ that need to be monitored include retina toxicity.	3 months
Incidence of side effects	Possible side effects of nicotinamide include flushing and itching of the skin, cardiac arrhythmia, dizziness, nausea, epigastric discomfort, loss of appetite, elevated blood glucose, and elevated blood uric acid. The major side effects of HCQ that need to be monitored include retina toxicity.	6 months

Collaborators and Investigators

• Sponsor: Second Xiangya Hospital of Central South University
• Collaborators: National Natural Science Foundation of China; Hunan Provincial Natural Science Foundation of China; National Key Clinical Specialty Construction Project of China
• Investigators: Principal Investigator: Qianjin Lu, MD, PhD, Central South University

Study record dates

Study Major Dates

• Study Start (Actual): August 31, 2017
• Primary Completion (Actual): January 1, 2020
• Study Completion (Anticipated): July 1, 2021

Study Registration Dates

• First Submitted: August 10, 2017
• First Submitted That Met QC Criteria: August 21, 2017
• First Posted (Actual): August 24, 2017

Study Record Updates

• Last Update Posted (Actual): February 2, 2021
• Last Update Submitted That Met QC Criteria: January 31, 2021
• Last Verified: January 1, 2021

More Information

Terms related to this study

• Keywords: nicotinamide; lupus-associated skin lesion; lupus erythematosus
• Additional Relevant MeSH Terms: Skin Diseases; Immune System Diseases; Autoimmune Diseases; Connective Tissue Diseases; Lupus Erythematosus, Systemic; Lupus Erythematosus, Cutaneous; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Vasodilator Agents; Antimetabolites; Micronutrients; Hypolipidemic Agents; Lipid Regulating Agents; Vitamins; Vitamin B Complex; Nicotinic Acids; Niacinamide; Niacin
• Other Study ID Numbers: PFK201707

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
• product manufactured in and exported from the U.S.: No