A novel oral nutraceutical formula of omega-3 and omega-6 fatty acids with vitamins (PLP10) in relapsing remitting multiple sclerosis: a randomised, double-blind, placebo-controlled proof-of-concept clinical trial

Abstract

Objective: To assess whether three novel interventions, formulated based on a systems medicine therapeutic concept, reduced disease activity in patients with relapsing-remitting multiple sclerosis (MS) who were either treated or not with disease-modifying treatment.

Design: A 30-month randomised, double-blind, placebo-controlled, parallel design, phase II proof-of-concept clinical study.

Settings: Cyprus Institute of Neurology and Genetics.

Participants: 80 participants were randomised into four groups of 20 each. A total of 41 (51%) patients completed the 30-month trial. The eligibility criteria were an age of 18-65; a diagnosis of relapsing-remitting MS according to the McDonald criteria; a score of 0.0-5.5 on the Expanded Disability Status Scale (EDSS); MRI showing lesions consistent with MS; at least one documented clinical relapse and either receiving or not a disease-modifying treatment within the 24-month period before enrolment in the study. Patients were excluded because of a recent (<30 days) relapse, prior immunosuppressant or monoclonal antibody therapy, pregnancy or nursing, other severe disease compromising organ function, progressive MS, history of recent drug or alcohol abuse, use of any additional food supplements, vitamins or any form of polyunsaturated fatty acids, and a history of severe allergic or anaphylactic reactions or known specific nutritional hypersensitivity.

Interventions: The first intervention (A) was composed of Ω-3 and Ω-6 polyunsaturated fatty acids at 1:1 wt/wt. Specifically, the Ω-3 fatty acids were docosahexaenoic acid and eicosapentaenoic acid at 3:1 wt/wt, and the Ω-6 fatty acids were linoleic acid and γ-linolenic acid at 2:1 wt/wt. This intervention also included minor quantities of other specific polyunsaturated, monounsaturated and saturated fatty acids as well as vitamin A and vitamin E (α-tocopherol). The second intervention (B, PLP10) was a combination of A and γ-tocopherol. The third intervention (C) was γ-tocopherol alone. The fourth group of 20 participants received placebo. The interventions were administered per os (by mouth) once daily, 30 min before dinner for 30 months.

Main outcome measures: The primary end point was the annualised relapse rate (ARR) of the three interventions versus the placebo at 2 years. The secondary end point was the time to confirmed disability progression at 2 years.

Results: A total of 41 (51%) patients completed the 30-month trial. Overall, for the per-protocol analysis of the 2-year primary end point, eight relapses were recorded in the PLP10 group (n=10; 0.40 ARR) versus 25 relapses in the placebo group (n=12; 1.04 ARR), representing a 64% adjusted relative rate reduction for the PLP10 group (RRR 0.36, 95% CI 0.15 to 0.87, p=0.024). In a subgroup analysis that excluded patients on monoclonal antibody (natalizumab) treatment, the observed adjusted RRR became stronger (72%) over the 2 years (RRR 0.28, 95% CI 0.10 to 0.79, p=0.016). The per-protocol analysis for the secondary outcome at 2 years, the time to disability progression, was significantly longer only for PLP10. The cumulative probability of disability progression at 2 years was 10% in the PLP10 group and 58% in the placebo group (unadjusted log-rank p=0.019). In a subgroup analysis that excluded patients on natalizumab, the cumulative probability of progression was 10% for the 10 patients in the PLP10 group and 70% for the 12 patients in the placebo group, representing a relative 86% decrease in the risk of the sustained progression of disability in the PLP10 group (unadjusted log-rank p=0.006; adjusted HR, 0.11; 95% CI 0.01 to 0.97, p=0.047). No adverse events were reported. Interventions A (10 patients) and C (9 patients) showed no significant efficacy.

Conclusions: In this small proof-of-concept, randomised, double-blind clinical trial; the PLP10 treatment significantly reduced the ARR and the risk of sustained disability progression without any reported serious adverse events. Larger studies are needed to further assess the safety and efficacy of PLP10.

Trial registration: International Standard Randomised Controlled Trial, number ISRCTN87818535.

Figure 1

Ω-6 and Ω-3 PUFAs, their respective metabolic derivatives and their possible effects on inflammation. After consumption, the PUFAs are metabolised via several pathways (not shown) to active compounds that mediate inflammation and to products that promote the resolution of inflammation. COX, cyclooxygenase; HETrE, hydroxyeicosatetraenoic acid; HPETE, hydroperoxyeicosatetraenoic acid; IFN-γ, interferon γ; IL-2, interleukin 2; LOX, lipoxygenase; LT, leukotriene; MMP, metalloproteinase; NFκB, nuclear factor kappa B; Nrf2, nuclear respiratory factor; PG, prostaglandin; PGE2, prostaglandin E2; PL, phospholipid; PPARγ, peroxisome proliferator-activated receptor γ; PUFAs, polyunsaturated fatty acids; RXR-γ, retinoid X receptor/γ; TGFβ, transforming growth factor β; TNF, tumour necrosis factor; TX, thromboxane.

Figure 2

Study flowchart.

Figure 3

(A) Demonstrates the ARR of the all-time on-study patients during the 24-month pretreatment (baseline ARR) and at different on-study intervals (6, 12, 18 and 24 months) per-treatment arm.* (B) Demonstrates the ARR of the all-time on-study population between the 0–6, 6–12, 6–18 and 6–24-month period intervals for the PLP10 versus placebo groups.* (C) Demonstrates the ARR of the all-time on-study population for the PLP10 versus placebo groups at baseline, during the first year, and during the second year on-treatment.* (D) Demonstrates the dispersion of relapses throughout the 2-year period of all-time on-study (excluding patients on natalizumab) for PLP10 (n=10) versus placebo (n=10). The placebo group showed an irregular dispersion of relapses compared with the PLP10 group, with a linear increasing trend, whereas the PLP10 group showed a stabilised linear trend. Using the per-protocol model in which the patients on natalizumab were excluded, the number of relapses could be compared on the same number of patients.* Including the patients on natalizumab.

Figure 4

(A) Demonstrates the Kaplan-Meier plot of the time to sustained progression of disability among the all-time on-study patients, excluding the patients on natalizumab, receiving interventions A, PLP10 and C compared with placebo. PLP10 reduced the risk of the sustained progression of disability by 86% over 2 years (p=0.006). Intervention formula A reduced the risk of the sustained progression of disability by 53% (p=0.266), and intervention formula C, by 67% (p=0.061). (B) Demonstrates the Kaplan-Meier plot of the time to sustained progression of disability among the intention-to-treat population receiving interventions A, PLP10 and C compared with placebo. PLP10 reduced the risk of the sustained progression of disability by 71% over 2 years (p=0.052, trend). Intervention formula A reduced the risk of the sustained progression of disability by 22% (p=0.727), and intervention formula C, by 40% (p=0.447).

Figure 5

Mean change in the expanded disability status scale score as a function of visit number. The values are expressed as the mean±SE of the mean (s.e.m.), ¶ Including patients on natalizumab and ¶¶ excluding patients on natalizumab.