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| [ Print-friendly version ] |
| MINERAL (Magnetic-resonance Image of Nutraceutical Efficacy on Relapsing-ms Autoimmune Lesions) study: A novel nutraceutical formula PLP10 for the treatment of relapsing-remitting multiple sclerosis |
| ISRCTN | ISRCTN06166891 |
| DOI | 10.1186/ISRCTN06166891 |
| ClinicalTrials.gov identifier | |
| EudraCT number | |
| Public title | MINERAL (Magnetic-resonance Image of Nutraceutical Efficacy on Relapsing-ms Autoimmune Lesions) study: A novel nutraceutical formula PLP10 for the treatment of relapsing-remitting multiple sclerosis |
| Scientific title | Novel Oral Nutraceutical Intervention PLP10 for the Treatment of Relapsing-Remitting Multiple Sclerosis (MINERAL study): A Multicenter, Parallel-group, Phase IIIa, Double-blind, Randomized, Placebo-Controlled, Add-on with Interferon Beta, Trial of Efficacy and Safety. |
| Acronym | MINERAL |
| Serial number at source | N/A |
| Study hypothesis |
1. Docosahexaenoic acid (DHA)/ Eicosapentaenoic acid (EPA)/ Gamma-Linolenic Acid (GLA)/ linoleic acid (LA) polyunsaturated fatty acids along with specific monounsaturated fatty acids, minor quantity of specific saturated fatty acids and specific antioxidant vitamins (E and A) and gamma-tocopherol within a specific ratio, quantity and quality can possibly interfere with all known pathophysiological mechanisms in multiple sclerosis (MS)
2. This could result in increased treatment efficacy, reduction of annual relapses rate (ARR) and T1/T2 MRI lesions and disability accumulation and can possibly trigger remyelination and neuroprotection. This is for efficacy and safety of PLP10, composed and formulated based on natural structural and functional bio-molecules such as docosahexaenoic acid (DHA), eicosapentaenoic acid (EPA), linoleic acid (LA) and gamma (γ)-linolenic acid (GLA), gamma-tocopherol and other specific omega-3, monounsaturated, saturated fatty acids and antioxidant vitamins compared to placebo, on multiple sclerosis (MS) patients when it is used for a 6 month normalization period (oral essential fatty acids need about 6 months to exert their beneficial effect) until entry baseline plus 24 months on-treatment period (total 30 months). Trial Questions? 1. Whether the interventions are effective for those patients who adhere to the assigned treatment, the per-protocol analysis? and 2. What happened to all MS patients who are placed on the interventions, the effect of assignment, the intention to treat (ITT) analysis? |
| Lay summary | Lay summary under review 2 |
| Ethics approval | The protocol will be submitted for approval to the Cyprus National Bioethics Committee (CNBC) . Submission is planned for March 13th 2013. |
| Study design | Multicenter Phase IIIa interventional randomized double-blind placebo-controlled parallel clinical trial of efficacy and safety |
| Countries of recruitment | Cyprus, Greece |
| Disease/condition/study domain | Relapsing-Remitting Multiple Sclerosis |
| Participants - 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-β) treatment for the last 6 continuous months or more Note If a clinical documented relapse (see primary outcomes) is reported during “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. |
| Participants - 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))
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. Note During on 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 continue to be medically followed for the intention to treat analyses purposes. |
| Anticipated start date | 01/04/2013 |
| Anticipated end date | 31/12/2016 |
| Status of trial | Ongoing |
| Patient information material | Not available in web format, please use the contact details below to request a patient information sheet |
| Target number of participants | The target number of participants across all arms and all sites is 200. |
| Interventions |
1. The daily oral liquid formula dose of intervention PLP10, is a mixture of:
1.1. EPA (about 1650mg) 1.2. DHA (about 4650mg) 1.3. GLA (about 2000mg) 1.4. LA (about 3850mg) 1.5. Total other omega-3 (about 600mg) 1.6. Total monounsaturated fatty acids (MUFA) (about 1700mg) 1.7. Total saturated fatty acids (SFA) (18:0 about 160mg, 16:0 about 650mg) 1.8. Vitamin A (about 0.6mg) 1.9. Vitamin E (about 22mg) 2. pure γ-tocopherol (760mg) 3.Placebo is composed of Polyethylene Glycol (16930mg). 4. Food grade lemon-aroma is in each intervention formula to make up a total dosage of 20ml of solution per day once daily for a total of 30 months 5. The first 6 months of the study is used as 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 containing the syrup are labeled with medication code numbers unidentifiable for patients as well as investigators The intervention dosage: 20 ml, per os, daily, 30 minutes before dinner, for the six months normalization period and for the 24 months on-treatment period (total 30 months). A 12-month extension, free of drug (washout) period is included in the clinical trial design. Note: The design of the study includes six months normalization (essential fatty acids and antioxidant vitamins) period: Specifically the normalization period begins at enrolment and continues for six months with regular consumption of the assigned intervention (for both study arms). The end of this period is denoted as the entry baseline. The period between entry baseline and the 24 months of treatment until the study completion (end) is the “on treatment” period. “Normalization period” will be a 6-month period between enrolment and entry baseline (the first 6 months of the trial that patients will be on the intervention treatment for only normalization purposes). For the result analyses this 6 month period will be considered as a period before entry baseline for both treatment arms. Due to the nature of the intervention ingredients/agents the protocol of the clinical study is considering a normalization period for the interventions’ agents to exert their beneficial effect. |
| Primary outcome measure(s) |
At two years the primary end points will be the annual relapse rate (ARR) and the number of new or enlarging Brain lesions (evaluated by MRI)
• 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, six months after the end of the study if a patient is reported with an increased EDSS score during the 24th month assessment. • 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. • MRI scans should be scheduled at baseline and at the end (completion) of the study. • 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. • 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, Gd 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 outcome measure(s) |
Secondary end points at two 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-months 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-month (total of 30 months including normalization) for specific pharmacodynamic/pharmacokinetics experimental investigations (markers in the blood). • Evaluation of the Hematological (full blood count) and Biochemical analyses at enrollment, baseline (6 months after enrollment), 12 months and 24months on treatment and compared to enrollment and baseline. • Compare changes of inflammatory markers, cytokines, chemokines, adhesion molecules and lipid metabolites markers in plasma at enrollment, baseline, 12, 24 months on treatment and compared to enrollment and baseline. • Specific antioxidant vitamin counts in serum at enrollment, baseline, 12, 24 months on treatment compared to enrollment and baseline. • 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 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. |
| Sources of funding | Cyprus Ministry of Commerce Industry and Tourism (Cyprus) |
| Trial website | |
| Publications | |
| Contact name | Dr Ioannis Patrikios |
| Address |
The Cyprus Institute of Neurology and Genetics
c/o Clinic C for PALUPA Medical Ltd. 6 International Airport Avenue Ayios Dometios |
| City/town | Nicosia |
| Zip/Postcode | 1683 |
| Country | Cyprus |
| Tel | +357 99097856 |
| Fax | +357 22772616 |
| i.patrikios@euc.ac.cy | |
| Sponsor | Ministry of Commerce Industry and Tourism (Cyprus) |
| Address | 6 Andreas Araouzos Street |
| City/town | Nicosia |
| Zip/Postcode | 1421 |
| Country | Cyprus |
| Tel | +357 22867100 |
| Fax | +357 22375120 |
| perm.sec@mcit.gov.cy | |
| Sponsor website: | http://www.mcit.gov.cy |
| Date applied | 09/03/2013 |
| Last edited | 19/03/2013 |
| Date ISRCTN assigned | 19/03/2013 |
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| © 2013 ISRCTN unless otherwise stated. | |
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