MINERAL (Magnetic-resonance Image of Nutraceutical Efficacy on Relapsing-ms Autoimmune Lesions) study: a novel nutraceutical formula NEUROASPIS PLP10® for the treatment of relapsing-remitting multiple sclerosis

• Register: ISRCTN
• Last refreshed on: 21 November 2022
• Main ID: ISRCTN06166891
• Date of registration: 19/03/2013
• Prospective Registration: Yes
• Primary sponsor: Ministry of Commerce, Industry and Tourism (Cyprus)
• Public title: MINERAL (Magnetic-resonance Image of Nutraceutical Efficacy on Relapsing-ms Autoimmune Lesions) study: a novel nutraceutical formula NEUROASPIS PLP10® for the treatment of relapsing-remitting multiple sclerosis
• Scientific title: Novel oral nutraceutical intervention NEUROASPIS PLP10® for the treatment of relapsing-remitting multiple sclerosis: A multicenter, parallel-group, phase III, double-blind, randomized, placebo-controlled, add-on with Interferon Beta, trial of efficacy and safety
• Date of first enrolment: 01/02/2016
• Target sample size: 200
• Recruitment status: Completed
• URL: https://www.isrctn.com/ISRCTN06166891
• Study type: Interventional
• Study design: Multicenter Phase III interventional randomized double-blind placebo-controlled parallel clinical trial of efficacy and safety (Treatment)
• Phase: Phase III

Countries of recruitment

Cyprus, Greece

Contacts

• Name: Ioannis Patrikios

Key inclusion & exclusion criteria

Inclusion criteria:
1. Men and women
2. Aged between 18 and 55 years
3. Diagnosis of relapsing remitting multiple sclerosis (RRMS) according to revised McDonald criteria
4. A score of 0.0 to 5.0 on the Expanded Disability Status Scale (EDSS)
5. At least one medically documented relapse within the 18 months before enrolment
6. Cranial MRI scan demonstrating lesion(s) consistent with MS
7. On interferon beta (IFN-ß) treatment for the last 6 continuous months or more

Note: If a clinical documented relapse (see primary outcomes) is reported during the 'normalization' period the entry baseline EDSS for that patient will be reported as the EDSS score documented at least 4 weeks after the last relapse during this period.

Exclusion criteria:
1. Prior immunosuppressants or monoclonal antibodies therapy (prior or concomitant use of cladribine, mitoxantrone, copaxone, or other immunosuppressant agents such as azathioprine, cyclophosphamide, cyclosporin, methotrexate, mycophenolate, fingolimod or natalizumab [Tysabri]) or Tecfidera/BG-12)
3. Prior use in the 3 months preceding randomization of cytokine therapy, glatiramer acetate or intravenous immunoglobulins, or concomitant use of these treatments
3. Pregnancy or nursing
4. A clinically significant infectious illness within 30 days prior to randomization
5. Primary progressive, secondary progressive or progressive relapsing MS
6. Patients known to have a history of recent drug or alcohol abuse
7. Any severe disease other than MS compromising organ function, meaning: history of or abnormal laboratory results indicative of any significant cardiac, endocrinologic, hematologic, hepatic, immunologic, metabolic, urologic, pulmonary, gastrointestinal, dermatologic, renal and/or other major disease, that in the opinion of the investigator would preclude the administration of PLP10 for 30 months.
8. History of severe allergic or anaphylactic reactions or known specific nutritional hypersensitivity.

As of 31/03/2016 the following exclusion criteria have been added:
9. Consumption of any additional food supplement formula (prior use in the 3 months preceding randomization, of any type of vitamin including vitamin D, or 6 months preceding randomization, of any form of polyunsaturated fatty acid (PUFA), or concomitant use of these treatments)
10. Prior or concomitant use of statins

Note: During intervention treatment it is strongly suggested for the patients to continue only on the interferon beta treatment. If a patient changes therapy to immunosuppressant or monoclonal antibody or fingolimode or any other treatment on physicians? decision then he/she will be considered as a drop-out, but will continue to be medically followed for the purpose of the intention-to-treat analyses.


Age minimum:
Age maximum:
Gender: Both

Health Condition(s) or Problem(s) studied

Relapsing-remitting multiple sclerosis
Nervous System Diseases
Multiple sclerosis

Intervention(s)

Update as of 26/09/2018:
In case where there are changes and alteration of the local clinical practice guidelines, making difficult the enrolment due to difficulties to find patients in accordance to the designed protocol inclusion criteria, to participate in a reasonable time (meaning the study participants' recruitment rates for these centers are severely hindered) the study should continue to completion and be ended according to the protocol if the total enrolled number of patients can be considered as able to produce statistically meaningful results by the independent statistician of the project, positive or negative.

1. The daily oral liquid formula dose of intervention PLP10, is a mixture of:
1.1. EPA (about 1650 mg)
1.2. DHA (about 4650 mg)
1.3. GLA (about 2000 mg)
1.4. LA (about 3850 mg)
1.5. Total other omega-3 (about 600 mg)
1.6. Total monounsaturated fatty acids (MUFA) (about 1700 mg)
1.7. Total saturated fatty acids (SFA) (18:0 about 160 mg, 16:0 about 650 mg)
1.8. Vitamin A (about 0.6 mg)
1.9. Vitamin E (about 22 mg)
2. Pure ?-tocopherol (760 mg)
3. Placebo is composed of virgin olive oil (16930 mg).
4. Food grade lemon-aroma is in each intervention formula to make up a total dosage of 20 ml of solution per day once daily for a total of 30 months
5. The first 6 months of the study is used as a normalization period for the interventions? agents to exert their beneficial effect
6. All preparations and the placebo have identical appearance and smell
7. The bottles containin

Primary Outcome(s)

Primary outcome measures as of 31/03/2016:
At 2 years the primary end points will be the annual relapse rate (ARR)

1. The study is designed to end 30 months after enrollment (plus 12-month washout period) and neurological and clinical assessments should be scheduled at entry baseline (6 months after enrollment, the end of normalization period) and at 6, 12, 18 and 24 months on-treatment. Another assessment should be scheduled 6 months after the end of the study if a patient is reported with an increased EDSS score during the 24th month assessment , otherwise at 12 months after the end of the study.
2. Patients should be examined within 48 hours after the onset of new neurological symptoms for the treating physician to confirm and record a relapse as per protocol


Original primary outcome measures:
At 2 years the primary end points will be the annual relapse rate (ARR) and the number of new or enlarging brain lesions (evaluated by MRI)

1. The study is designed to end 30 months after enrollment (plus 12-month washout period) and neurological and clinical assessments should be scheduled at entry baseline (6 months after enrollment, the end of normalization period) and at 6, 12, 18 and 24 months on-treatment. Another assessment should be scheduled 6 months after the end of the study if a patient is reported with an increased EDSS score during the 24th month assessment.
2. Patients should be examined within 48 hours after the onset of new neurological symptoms for the treating physician to confirm and record a relapse as per protocol.
3. MRI scans should be scheduled at enrollment and at the end (completion) of the study.
4. Number of T1 gadolinium-enhancing lesions, proportion of patients free from gadolinium-enhancing lesions, number of new or enlarged lesions on T2-weighted MRI scans, proportion of patients free from new or enlarged lesions on T2-weighted scans, volumes of hyperintense lesions on T2-weighted scans and hypointense lesions on T1-weighted scans, change in brain volume between baseline and 24 months, and safety and tolerability measures.
5. Magnetization transfer (MTR) and diffusion-weighted images (the total enrolled population will be investigated by these techniques to demonstrate possible remyelination) for proportion of patients exhibiting remyelination.

MRI
MRI protocol should include a dual-echo, a 3D T1w and a post-contrast T1- and T2-weighted sequence, for quantification of disease activity (number of new T2 lesions, gadolinium-enhancing lesions) and magnetization transfer and diffusion images for remyelination.

Relapses are defined as new neurologic symptoms or worsening of pre-existing symptoms (that are stable for at least 1 month) not associated with fever or infection that lasts for at least 24 hours and characterized by new or worsening neurological signs on examination.

Total MRI scans will be centrally analyzed (Medical School, University of Vita-Salute San Raffaele, Milan, Italy, Massimo Philippi).

Secondary Outcome(s)

Secondary end points at 2 years will be the time to confirmed disability progression and quantity changes of inflammatory/anti-inflammatory markers in the blood

Time to confirmed disability progression is defined as an increase of 1.0 on the EDSS from a baseline score of 1.0 or more or an increase of 1.5 or more from a baseline score of 0.0, confirmed after 6 months, with an absence of an ongoing relapse at the time of assessment (progression cannot be confirmed during a relapse) and with no documented relapse during the 6-month period needed for the confirmation. Under the same conditions as previously discussed, the final EDSS score should also be confirmed 6 months after the end of the study.

Blood samples should be collected at enrollment, baseline, 12 and 24 months (total of 30 months including normalization) for specific pharmacodynamic/pharmacokinetic experimental investigations (markers in the blood).

1. Evaluation of the hematological (full blood count) and biochemical analyses at enrollment, baseline (6 months after enrollment), 12 months and 24 months on treatment and compared to enrollment and baseline.
2. Compare changes of inflammatory markers, cytokines, chemokines, adhesion molecules and lipid metabolite markers in plasma at enrollment, baseline, 12, 24 months on treatment and compared to enrollment and baseline.
3. Specific antioxidant vitamin counts in serum at enrollment, baseline, 12, 24 months on treatment compared to enrollment and baseline.
4. Changes of antioxidant activity and fatty acids in the serum and red blood cells at enrollment, baseline, 12, 24 months on treatment and compared to enrollment and baseline.

Safety adverse events:
Hematological (full blood count) and biochemical analyses at enrolment, baseline, 12 months and at study completion.
Serious adverse events are defined as those that result in admission to hospital, cause prolonged disability or death, or are judged to be life threatening or otherwise medically significant.

Drop outs:
The drop outs, at any time and even the drop outs that never received the assigned interventions should be followed like all other participants as required for intention-to-treat analyses (ITT).

Missing data handling:
All patients who prematurely discontinue the study drug will be encouraged to continue in the study until the end of the planned treatment period, regardless of the treatments received. The data collected will be included for analyses. The main analysis of ARR will include all confirmed relapses during the study, including relapses reported after study drug discontinuation.

As of 31/03/2016, the following secondary outcome measures have been added (originally primary outcome measures):
1. MRI scans should be scheduled at baseline and at the end (completion) of the study
2. Number of T1 gadolinium-enhancing lesions, proportion of patients free from gadolinium-enhancing lesions, number of new or enlarged lesions on T2-weighted MRI scans, proportion of patients free from new or enlarged lesions on T2-weighted scans, volumes of hyperintense lesions on T2-weighted scans and hypointense lesions on T1-weighted scans, change in brain volume between baseline and 24 months, and safety and tolerability measures
3. Magnetization transfer (MTR) and diffusion-weighted images (the total enrolled population will be investigated by these techniques to demonstrate possible remyelination) for proportion of patients exhibiting remyelination

MRI
MRI protocol should include a dual-echo, a 3D T1w and a post-contrast T1- and T2-weighted sequence, for quantification of disease activity (number of new T2 lesions, gadolinium-enhancing lesions) and magnetization transfer and diffusion images for remyelination.

Relapses are defined as new neurologic symptoms or worsening of pre-existing symptoms (that are stable for at least 1 month) not associated with fever or infection that lasts for at least 24 hours and characterized by new or worsening neurological signs on examination.

Total MRI scans will be centrally analyzed (Ayios Therissos Radiology Center, Nicosia Cyprus).

Secondary ID(s)

N/A

Source(s) of Monetary Support

Cyprus Ministry of Commerce Industry and Tourism (Cyprus)

Ethics review

Status:
Approval date:
Contact:

Cyprus National Bioethics Committee (CNBC), 27/03/2014, ref: EEBK/E?/2013/18

Results

• Results available: Yes
• Date Completed: 31/12/2018