In this proof-of-concept, randomised, double-blind clinical trial assessing the safety and efficacy of three variations of a novel nutritional formula in RRMS, we observed a significant association for a formula containing a balanced mixture of specific Ω-3 and Ω-6 PUFAs, MUFAs, SFAs, vitamin A, vitamin E and γ-tocopherol (PLP10) compared with the placebo for both the ARR and the progression of disability in the per-protocol analysis. Our results included analyses pertaining to a total of 42 months of study-collected data, including the 12-month intervention-free treatment extension period. We also observed a high dropout rate that was mostly the result of formula palatability, a common phenomenon in trials using oily interventions. Interestingly, a statistically significant reduction in the ARR and disability progression was also observed when comparing the ARR of the PLP10 patients in the 24-month period prior to the study with the ARR of the 24 months on-study; the observed differences became larger when the patients who received natalizumab (currently the most potent disease modifier) were excluded. The ARR decreased within a year on PLP10 and remained stable until the study's completion. The statistically significant difference in the ARR between patients on PLP10 and those on placebo continued for the 12-month extended period (persistent effect) without a significant difference on the DMT. These clinical findings are supported by the results from the MRI analysis, in which the proportion of patients free from new or enlarging brain T2 lesions was also higher in the PLP10 group than the placebo group. No severe side effects have been reported.
To the best of our knowledge, this study is the first randomised clinical trial assessing the proposed combination of active ingredients in a standardised proportion and dosing scheme for MS treatment designed according to the SM approach. Nutrition is commonly accepted as one of the possible environmental factors involved in the pathogenesis of MS, but its role as a complementary MS treatment is unclear and largely disregarded.51
It is well known that the majority of the patients suffering from MS do use dietary supplements for a variable length of time.52
Dietary antioxidants and fatty acids may influence the disease process in MS by reducing immune-mediated inflammation, oxidative stress and excitotoxic damage.12
Published data have revealed that healthy dietary molecules have a pleiotropic role and are able to change cell metabolism and downregulate inflammation by interacting with enzymes, nuclear receptors and transcriptional factors.51
Currently available treatments are the products of reductionism, partially effective and associated with severe side effects. Interferons and glatiramer acetate, the most widely used first-line MS drugs available today, are associated with the least severe side effects among the MS therapies, but they are reported to reduce the ARR only by about one-third and with no significant effect on the progression of disability.53
Natalizumab reduces the ARR by 68% and decreases the possibility of disability progression by 43%, with 57% of patients free of new or enlarging T2 lesions on MRI scans, compared with 15% on placebo.54
Fingolimod is associated with a 54% ARR reduction (without a significant benefit on the progression of disability). Both natalizumab and fingolimod are second-line drugs associated with severe side effects.55
In a review paper in 2009, Mehta reported different clinical studies on interventions formulated based on the individual aforementioned molecular ingredients or on a specific ratio of the aforementioned molecular ingredients for MS treatment, although no one was reported to be using the antioxidant vitamin γ-tocopherol.56
In our study, the choice of the ingredient proportion and dosing scheme was based upon evidence derived from in vivo and in vitro data. In the Western diet, the ratio of Ω-3 to Ω-6 is approximately 1:20–30; in populations that consume fish-based diets, the ratio is approximately 1:1–2.57
The intervention daily dose was aiming to be, and believed to be, high enough to restore/amplify body-efficient antioxidant activity and ensure cellular membranes lipid profile normalisation (PUFA content) and simultaneously potentiate the involvement of the ingredients in the anti-inflammatory and recovery mechanisms. Dietary fatty acid molecules need an approximately 6-month period to exert their beneficial effect, and this essential parameter was under consideration for the first time in our study design (normalisation period).46
This chronotherapy parameter might be of major importance and is in line with the SM treatment philosophy. We believe that the persistent effect within the poststudy period is in agreement with the very long washout phase reported for Ω-3 fatty acids, especially DHA, to return to the pretreatment values.46
Considering that Ω-3 PUFA supplementation can promote the replacement of AA within the cellular membranes, we can speculate that an increased inflammatory activity can possibly result during the first 6 months of supplementation.
In addition to EPA, DHA, LA and GLA, PLP10 contained limited quantities of other structural/active PUFAs, specific MUFAs (mostly oleic acid) and SFAs (palmitic and stearic acids), specifically to provide a direct source for neuronal cell membrane rehabilitation and for (re)myelination and neuroprotection because these compounds are all major components, precursors and building blocks of any new physiological myelin and cellular membranes in general. Assembly of the correct molecules into the myelin membrane may be especially critical during active synthesis. If these critical constituents are not directly or indirectly available, amyelination, dysmyelination or demyelination may ensue.59
The maintenance of myelin requires continued turnover of its components throughout life.60
Different factors and molecular entities appear to be part of the possible aetiology for MS, with specific PUFAs and antioxidants found to be key substances related to all known pathogenic and recovery mechanisms. In our study, we further propose that a holistic SM model approach can be applied by synchronised action. First, there is an obvious convenience in administering one formula containing different specific active ingredients. The currently available evidence supports that nutritional interventions would confer a small to medium treatment effect with an accompanying appropriate safety profile.12
Combining these specific active ingredients together with γ-tocopherol and other specific active molecules into one stable formulation is expected to enhance adherence while still offering an appropriate safety profile. A similar approach could not be adopted for pharmaceutical interventions with common and severe adverse events, such as those indicated today for patients with MS. Given the advantages of the simultaneous use and that all the included ingredients have proven individually a valid biological plausibility and have been tested in various settings and under various dose schemes, we also assessed the hypothesis that a novel mixture of these ingredients would have a postulated efficacy attained synergistically through different mechanisms of action.52
Interestingly, the observed magnitude of the treatment effect cannot be explained by adding up the postulated efficacy estimates of the individual ingredients. Findings from in vitro and in vivo studies support this notion of proposed synergy, although this hypothesis can only be taken forward when the observed treatment effect is validated in various settings and in a larger number of patients.
We acknowledge that our study has two considerable limitations: the small sample size and the high dropout rate. Regarding the sample size, one should bear in mind that this study is a small, phase II clinical trial assessing a novel intervention and thus has comparable size in the appropriate literature. Questions taken forward from this trial can be assessed in a larger randomised trial in which appropriate power calculations would be possible, taking into consideration the findings of this study. The adherence of the participants is another limitation of our study, but the total duration of the study that covers a total of 42 months follow-up adds power to the results.48
We acknowledge that we had to deliver the intervention in the way most frequently associated with low compliance, that is, an oral, liquid formula, thus triggering maximum intolerance due to taste. Nevertheless, the observed suboptimal compliance is in accordance with the published literature in which clinical trials assessing liquid fatty acid interventions show a weaker adherence compared with clinical trials of pharmaceutical interventions. Indeed, in our study, we consistently recorded the reasons for withdrawal: most of the participants did not discontinue due to safety issues, but rather due to palatability issues. Controlling non-compliance due to palatability issues is by far easier to address compared with non-compliance related to adverse events and can be resolved when optimisation of the formulation is achieved in future trials. At this stage of the development of the intervention, we would by far exceed the cost-effectiveness threshold if we were to invest in improving these features of the intervention. Moreover, we should also note that MS patients are participant to far more frequent and more serious adverse events related to the current standard treatments.
As a direct consequence of the low compliance and the loss of power, the performed ITT analysis was far less robust than intended, and we would then have to take into serious consideration the performed per-protocol analysis. We focused on the per-protocol data analysis because it is the appropriate method to best provide the answer for the proof-of-concept trial-addressed question.24
To validly incorporate the results of the per-protocol analysis into the interpretation of the overall results of the trial, we need to ensure that the randomisation was not seriously violated due to the exclusion of the non-compliers. The comparison between the baseline characteristics of the patients included in the per-protocol analysis did show a relative balance in the compared groups for known confounders. Nevertheless, the presence of unknown confounders introducing bias to the trial results cannot be excluded despite non-significant differences in the baseline characteristics. As an additional safeguard towards that end, we also performed adjusted analyses for the primary and secondary analyses for important clinical and demographic parameters, that is, relapses, EDSS, age and DMT.
The present preliminary, small-size, randomised, controlled phase II clinical trial provides evidence for a novel nutraceutical formula based on dietary, metabolic, immunological and neurobiological pathways possibly involved with disease progression in MS. This novel intervention showed signs of efficacy in the observed ARR and disability progression. We took the appropriate methodological measures to control for potential sources of bias and to enable a valid interpretation to be reached. We acknowledge that the presence of bias can only be minimised, not excluded, in any clinical research setting and also that random error is always a possible scenario in small trials. Thus, we present the observed results as an additional piece of randomised evidence and anticipate the replication of our study findings in a larger randomised controlled clinical trial.