A Pilot Study in Participants With Relapsing Remitting Multiple Sclerosis (RR-MS) (INCREASE)

Evaluation of clINical reCovery After a Relapse: a Pilot Study assEssing the Neuronal Effects of D-Aspartate in RR-MS Subjects Treated With IntErferon Beta 1a 44 mcg TIW (INCREASE)

The purpose of this study was to evaluate the improvement in spontaneous recovery from clinical deficits at the time of an acute relapse in RR-MS participants already receiving interferon (IFN) beta 1a with D-aspartate (versus placebo) as add-on therapy.

Study Overview

• Status: Terminated
• Conditions: Multiple Sclerosis, Relapsing-Remitting
• Intervention / Treatment: Dietary supplement: D-aspartate; Biological: IFN beta-1a; Drug: Methylprednisolone; Drug: Placebo

• Study Type: Interventional
• Enrollment (Actual): 7
• Phase: Phase 2

Contacts and Locations

Study Locations

• Italy
  • Cagliari, Italy
    • Ospedale Binaghi, Università di Cagliari,ASL 8
  • Chieti, Italy
    • Ospedale Clinicizzato SS. Annunziata
  • Gallarate, Italy
    • Azienda Socio Sanitaria Territoriale della Valle Olona (presidio di Gallarate)
  • Genova, Italy
    • Azienda Ospedaliero Universitaria San Martino
  • Genova, Italy
    • Ospedale P.A.Micone
  • Milano, Italy
    • Ospedale San Raffaele
  • Napoli, Italy
    • Seconda Università degli Studi di Napoli
  • Napoli, Italy
    • A.O.U. Federico II
  • Napoli, Italy
    • Azienda Ospedaliera di Rilievo Nazionale A. CardarelliAzienda Ospedaliera di Rilievo Nazionale A. Cardarelli
  • Padova, Italy
    • Azienda Ospedaliera di Padova
  • Pozzilli, Italy
    • I.R.C.C.S. Neuromed-Istituto Neurologico Mediterraneo
  • Roma, Italy
    • Azienda Ospedaliera San Camillo Forlanini
  • Roma, Italy
    • Policlinico Universitario Agostino Gemelli
  • Roma, Italy
    • Azienda Ospedaliera Sant'Andrea-Università di Roma La Sapienza
  • Rome, Italy
    • Azienda Ospedaliera Universitaria Policlinico Tor Vergata
  • Savona, Italy
    • Ospedale S. Paolo
  • Torrette Di Ancona, Italy
    • Azienda Ospedaliero Universitaria Ospedali Riuniti

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 55 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Participants with RR-MS, according to the revised McDonald Criteria (2010)
• Participants with an expanded disability status scale (EDSS) score between 0 and 3 before screening visit and before relapse
• Participants receiving treatment with IFN beta 1a 44 mcg three times a week for at least 6 months but for no more than 10 years before the screening visit
• Female participants must be neither pregnant nor breastfeeding and must lack childbearing potential
• Participants willing and able to comply with the protocol for the total duration of the study
• Participants able to understand the purposes and the risks of the study
• Participants have signed the appropriate written informed consent form, approved by the Independent Ethics Committee (IEC), prior to the performance of any study activities
• For MS participants with relapse:
• Deterioration of at least one step in a relevant Functional Systems Scale (FSS) or an increase in EDSS of 1 point or more compatible, according to physician's judgment, with the therapy prosecution
• Relapse started within maximum 5 days before the inclusion in the study
• MS participants without relapse with clinically stable RR-MS

Exclusion Criteria:

• Participants with diagnosis of primary progressive MS (PP-MS)
• Participants have any disease other than MS that could better explain his/her signs and symptoms
• Participants with any comorbidity with diseases that might alter synaptic plasticity (example Parkinson Disease, Alzheimer Disease, Stroke)
• Participants receiving concomitant treatment with drugs that may alter synaptic plasticity (example, cannabinoids)
• Participants with history or presence of any unstable medical condition (tumor or chronic infection or severe life threatening infection within the last 6 months)
• Participants who have received any corticosteroids therapy within 3 months prior to the screening
• Participants with any concomitant disease that may require chronic treatment with systemic corticosteroids or immunosuppressive agents during the course of the study
• Participants who have received any immunosuppressive agents other to corticosteroids, as monotherapy or combination therapy within 3 months prior to the screening visit
• Participants with history or currently active primary or secondary immunodeficiency
• Participants with inadequate liver function, defined by alanine aminotransferase (ALT) > 3 * upper limit of normal (ULN), or alkaline phosphatase (AP) > 2 * ULN, or total bilirubin > 2 * ULN if associated with any elevation of ALT or AP
• Participants with inadequate bone marrow reserve, defined as a white blood cell count less than 0.5 * lower limit of normal (LLN)
• Participants with moderate to severe renal impairment
• Participants unable to complete an magnetic resonance imaging (MRI) (contraindications for MRI include but are not restricted to weight >=140 kilogram (kg), pacemaker, cochlear implants, presence of foreign substances in the eye, intracranial vascular clips, surgery within 6 weeks of entry into the study, coronary stent implanted within 8 weeks prior to the time of the intended MRI, etc)
• Participants with contraindication to gadolinium (Gd) can be enrolled into the study but cannot receive Gd contrast dyes during their MRI scans
• Participants receiving supplements that, in the Investigator's opinion, may affect the evaluation of fatigue
• Participants with any known contraindications or hypersensitivity to D-aspartate or any excipient
• Participants with any other significant disease that in the Investigator's opinion would impede study assessments or endanger the participant
• Female participants with positive pregnancy test at baseline or participants with active project of pregnancy during the study
• Participants with legal incapacity or limited legal capacity
• Participants have participated in any other investigational study within 8 weeks before the screening visit

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: D-aspartate + IFN beta-1a + Methylprednisolone; Participants received D-aspartate 2660 milligrams (mg) once daily in the form of oral solution for 24 weeks along with IFN beta-1a subcutaneously (sc) at a dose of 44 microgram (mcg) three times a week (TIW) in participants without relapse and IFN beta-1a sc TIW plus Methylprednisolone 1000 mg intravenously once daily for 5 consecutive days in participants with relapse.	Dietary supplement: D-aspartate; D-aspartate 2660 milligram (mg) once daily in the form of oral solution for 24 weeks.; Biological: IFN beta-1a; IFN beta-1a was administered subcutaneously at a dose of 44 microgram (mcg) three times a week for 24 weeks.; Drug: Methylprednisolone; Methylprednisolone 1000 mg was administered intravenously once daily for 5 consecutive days.
Placebo Comparator: Placebo + IFN beta-1a + Methylprednisolone; Participants received placebo matched to D-aspartate once daily in the form of oral solution for 24 weeks along with IFN beta-1a subcutaneously (sc) at a dose of 44 microgram (mcg) three times a week (TIW) in participants without relapse and IFN beta-1a sc TIW plus Methylprednisolone 1000 mg intravenously once daily for 5 consecutive days in participants with relapse.	Biological: IFN beta-1a; IFN beta-1a was administered subcutaneously at a dose of 44 microgram (mcg) three times a week for 24 weeks.; Drug: Methylprednisolone; Methylprednisolone 1000 mg was administered intravenously once daily for 5 consecutive days.; Drug: Placebo; Placebo matched to D-aspartate once daily in the form of oral solution for 24 weeks.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Change From Baseline in Multiple Sclerosis Related Disability Measured by Expanded Disability Status Scale (EDSS) at Week 8	EDSS is an ordinal scale in half-point increments that qualifies disability in participants with Multiple Sclerosis (MS). It assesses the 8 functional systems (visual, brainstem, pyramidal, cerebellar, sensory, bowel/bladder, cerebral and other) as well as ambulation. EDSS overall score ranging from 0 (normal) to 10 (death due to MS).	Baseline, Week 8

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Change From Baseline in Multiple Sclerosis Related Disability Measured by Expanded Disability Status Scale (EDSS) at Week 12 and 24	EDSS is an ordinal scale in half-point increments that qualifies disability in participants with Multiple Sclerosis. It assesses the 8 functional systems (visual, brainstem, pyramidal, cerebellar, sensory, bowel/bladder, cerebral and other) as well as ambulation. EDSS overall score ranging from 0 (normal) to 10 (death due to MS).	Baseline, Week 12 and 24
25-foot Timed Walk (25-FWT) to Measure Multiple Sclerosis Related Disability and Cognitive Impairment	The Timed 25-Foot Walk is a quantitative measure of lower extremity function. The participants is directed to one end of a clearly marked 25-foot (7.62 m) course and is instructed to walk 25 feet (7.62 meter) as quickly as possible, but safely. The task is immediately administered again by having the participant walk back the same distance. Participants may use assistive devices when doing this task. The test scores were the time in seconds it took to walk the 25 feet. The data for the 25-FWT is reported for the 2 completed trials. Participant wise data was reported for this outcome.	At Week 8, 12 and 24
9 Hole Peg Test (9HPT) to Measure Multiple Sclerosis Related Disability and Cognitive Impairment	The 9HPT is a brief, standardized, quantitative test of upper extremity function. The participant picks up 9 pegs puts them in a block containing nine empty holes, and, once they are in the holes, removes them again as quickly as possible one at a time. The total time to complete the task is recorded. Two consecutive trials with the dominant hand are immediately followed by two consecutive trials with the non-dominant hand. The data for the 29HPT is reported for the 2 completed trials. Participant wise data was reported for this outcome.	Week 8, 12 and 24
Symbol Digit Modalities Test to Measure Multiple Sclerosis Related Disability and Cognitive Impairment	Symbol digit modalities test is to evaluate neurocognitive functions. This measure involves a coding key consisting of 9 abstract symbols, each paired with a number ranging from 1 to 9. The participants is required to scan the key and write down the number corresponding to each symbol as fast as possible. The number of correct substitution within 90 seconds is recorded. In the written version of the test the participants fills in the numbers that correspond to the symbols. The score is the number of correctly coded items from 0-110 in 90 seconds. A higher score indicates better performance. Participant wise data was reported for this outcome.	At Week 8, 12 and 24
Low Contrast Letter Visual Acuity Test to Measure Multiple Sclerosis Related Disability and Cognitive Impairment	Visual acuity is measured under low contrast conditions (10% contrast relative to the chart background) at object testing distances of 10 feets and is reported as the number of letters read correctly (ranging from 0 to 10 letters). The lower the number of letters read correctly on the eye chart, the worse the vision (or visual acuity). An increase in the number of letters read correctly indicates that vision has improved. Participant wise data was reported for this outcome.	Week 8, 12 and 24
Modified Fatigue Impact Scale (MFIS) Score to Measure Fatigue at Week 8, 12 and 24	MFIS is a structured, self-report questionnaire consisting of 21 items assessing the effects of fatigue. All 21 items are scaled 0 to 4, with higher scores indicating a greater impact of fatigue on participant's activities. The Total MFIS score ranges from 0 to 84. A score of 0 indicates fatigue has no impact on activities and the high-end score indicates fatigue has extreme impact on activities. Participant wise data was reported for this outcome.	Week 8, 12 and 24
Fatigue Severity Scale (FSS) Score to Measure Fatigue by at Week 8, 12 and 24	Fatigue Severity Scale (FSS) is a method of evaluating fatigue in multiple sclerosis and is designed to differentiate fatigue from clinical depression, since both share some of the same symptoms. The Fatigue Severity Scale is a 9-item questionnaire developed to assess the level of fatigue due to neurological disease, were each assessed on a 1-7 scale (1= no fatigue and 7= severe fatigue). The total score was calculated as the average of individual 9-items and ranged from 1 to 7 with a higher value indicating greater impairment due to fatigue. Participant wise data was reported for this outcome.	Week 8, 12 and 24
Long Term Potentiation Measured by Transcranial Magnetic Stimulation (TMS)	TMS is an electrophysiological technique that was used to measure neurologic changes associated with recovery from stroke via alterations in the excitability of the motor system. Motor threshold measures reflect global excitability of the corticospinal pathway, including large pyramidal cells, excitatory/inhibitory interneurons, and spinal motor neurons. Long term potentiation can be measured non invasively and painlessly, in awake humans through transcranial magnetic stimulation (TMS). TMS uses high intensity, brief duration, magnetic fields that, when applied on the scalp, can activate neurons within a small focal region of the cerebral cortex, through electromagnetic induction. Motor Evoked Potentials (MEP) amplitudes elicited by single TMS pulses of increasing intensity (110, 120 and 130% of the Resting Motor Threshold [RMT]) will be measured to calculate recruitment curves of the motor cortex. Participant wise data was reported for this outcome.	Baseline (0 minute) and Post-Baseline (15 minutes) at Week 8
Number of Treated Participants With Immune-metabolic Response of Lymphocytes	Treated participants with immune-metabolic response (glycolysis, mitochondrial respiration, fatty acids oxidation and circulating adipocytokines) of lymphocytes were to be reported.	Baseline, Week 8 and 12

Collaborators and Investigators

• Sponsor: Merck KGaA, Darmstadt, Germany

Study record dates

Study Major Dates

• Study Start (Actual): March 26, 2018
• Primary Completion (Actual): January 11, 2019
• Study Completion (Actual): January 11, 2019

Study Registration Dates

• First Submitted: December 22, 2017
• First Submitted That Met QC Criteria: December 22, 2017
• First Posted (Actual): December 29, 2017

Study Record Updates

• Last Update Posted (Actual): February 10, 2020
• Last Update Submitted That Met QC Criteria: February 6, 2020
• Last Verified: February 1, 2020

More Information

Terms related to this study

• Keywords: Relapsing remitting multiple sclerosis; interferon beta-1a; D-Aspartate
• Additional Relevant MeSH Terms: Pathologic Processes; Nervous System Diseases; Immune System Diseases; Demyelinating Autoimmune Diseases, CNS; Autoimmune Diseases of the Nervous System; Demyelinating Diseases; Autoimmune Diseases; Multiple Sclerosis; Sclerosis; Multiple Sclerosis, Relapsing-Remitting; Physiological Effects of Drugs; Autonomic Agents; Peripheral Nervous System Agents; Anti-Inflammatory Agents; Antineoplastic Agents; Antiemetics; Gastrointestinal Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Neuroprotective Agents; Protective Agents; Prednisolone; Methylprednisolone Acetate; Methylprednisolone; Methylprednisolone Hemisuccinate; Prednisolone acetate; Prednisolone hemisuccinate; Prednisolone phosphate
• Other Study ID Numbers: MS200136_0041

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No