Clinical trial NCT01767701: Raltegravir (Isentress) Pilot Study in Relapsing Multiple Sclerosis
Official title: A Phase II Baseline Versus Treatment Study to Determine the Efficacy of Raltegravir (Isentress) in Preventing Progression of Relapsing Remitting Multiple Sclerosis as Determined by Gadolinium-enhanced MRI
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Relapsing Remitting Multiple Sclerosis
Keywords: raltegravir
MS
RRMS
Charcot Project
Lead sponsor: Queen Mary University of London
Sponsor class: OTHER
Collaborators: name: Merck Sharp & Dohme LLC
First posted: 2013-01-14
Enrollment: 23
Sex: ALL
Minimum age (years): 18
Maximum age (years): 55
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: The purpose of this study is to determine whether raltegravir is effective in preventing progression of relapsing remitting multiple sclerosis as determined by gadolinium- enhanced MRI.

Detailed description: There is accumulating research evidence that Human Endogenous Retrovirus (HERV) and herpes viruses (in particular Epstein-Barr Virus) are involved in the pathogenesis of multiple sclerosis. People with active MS have higher levels of HERVs than people either without MS or who have other neurological conditions. It has been shown that HERVs may produce neurotoxic proteins/antigens associated with MS activity and disease progression. This is the first clinical trial investigating the hypothesis that the antiretroviral drug raltegravir may suppress HERV activity and ameliorate progression of relapsing remitting MS. Raltegravir is an integrase inhibitor which blocks retroviral replication. A recent experimental study suggests that raltegravir may also be active against herpes viruses.

Eligible participants (see Inclusion/Exclusion Criteria) will be observed for 3 months having monthly brain Gadolinium enhanced MRIs and blood/urine/saliva sampling (baseline). Then they will be treated with raltegravir (one 400mg pill taken twice a day) for 3 months. During treatment period participants will continue to have monthly MRIs and blood/saliva/urine sampling. Participants will have monthly clinical and neurological examinations and they will complete questionnaires assessing response to treatment. Participants will have screening and study visits at The Royal London Hospital, Whitechapel. Monthly MRIs will be performed at the Institute of Neurology at Queens Square, London.

Eligibility criteria: Inclusion Criteria:

* Patients between 18-55 years of age.
* Diagnosis of MS, according to the revised McDonald Criteria 2010.
* EDSS score of 0-6.0 inclusive.
* Documented at least one relapse within the past 12 months or at least one Gd-enhanced lesion on the brain MRI detected within 3 months prior to screening date
* Gd-enhanced lesion on screening MRI (if MRI not used to meet screening criteria above).
* Female patients of childbearing potential will be expected to be on appropriate contraception (hormonal or barrier method of birth control; abstinence) from time of consent until 6 weeks after treatment discontinuation. (the repeated administration of gadolinium and MRI are not recommended during pregnancy). NOTE: Subjects are considered not of child bearing potential if they are surgically sterile (they have undergone a hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or they are postmenopausal.
* Females of childbearing potential must have a negative urine pregnancy test prior to every MRI scan/ within 7 days prior to being registered for protocol therapy.
* Must give written informed consent and authorize the release and use of protected health information, as required by local law.
* Able and willing to undergo blood, saliva and urine sampling at regular intervals as defined by the protocol.
* Able and willing to receive Gadolinium enhanced MRI's at regular intervals as defined by the protocol.
* Able to comply with study requirements.

Exclusion Criteria:

* Pregnant or breastfeeding or unwilling to use contraception.
* Treatment with immunosuppressive, immunomodulatory or experimental treatments within the last 6 months of enrolment in the study, but excluding pulsed intravenous or oral steroids for treatment of MS relapse.
* No pulsed intravenous or oral steroids in the 30 days preceding the baseline assessment.
* Patients presenting with medical disorder deemed severe or unstable by the CI such as poorly controlled diabetes or arterial hypertension, severe cardiac insufficiency, unstable ischemic heart disease, abnormal liver function tests (\>2.5 times ULN) and abnormal complete blood count (in particular leukopenia, as defined by a lymphocyte count \<500, neutrophil \<1.5 or platelet count \< 100, or thrombocytopenia \< 1.5 LLN), or any medical condition which, in the opinion of the chief investigator, would pose additional risk to the patient.
* Presence of human immunodeficiency virus antibodies.
* Patients receiving proton pump inhibitors (e.g. omeprazole/esomeprazole)
* Patients with active hepatitis B or/and C with liver function tests \>2.5 times ULN
* Exposure to any other investigational drug within 30 days of enrolment in the study.
* Prior history of malignancy unless an exception is granted by the Chief Investigator.
* History of uncontrolled drug or alcohol abuse within 6 months prior to enrolment into the study.
* Patients treated with Rifampicin in past four weeks.

Primary outcomes:
measure: The Number of New or Recurrent Gd-enhancing Lesions That Appear on Brain T1-weighted MRI
timeFrame: Baseline and at 6 months
Secondary outcomes:
measure: The Cumulative Number of New or Enlarging T2 Weighted Lesions on Brain MRI.
timeFrame: Baseline and monthly for 6 months
measure: Change in Score on Multiple Sclerosis Functional Composite (MSFC). This a Composite Score Based on the Measurement of Time in Seconds for the Three Separate Measurements.
timeFrame: Baseline and monthly until month 6.
measure: Changes in Kurtzke Extended Disability Status Scale (EDSS) Score
timeFrame: Baseline and monthly to month 6
measure: Cumulative Number of Gd-T1 Enhancing Lesions
timeFrame: At Baseline and monthly for 6 months
measure: Percent of Subjects With Scans Free From Enhancing Lesions in Raltegravir Treated Subjects vs. Baseline
timeFrame: Baseline to 6 months
Other outcomes:
measure: Mean Number of Adverse Events Per Patient
timeFrame: Screening to six months
measure: Effect of Raltegravir Therapy on Specific Inflammatory Marker of MS Activity.
timeFrame: Baseline to 6 months
Locations:
city: London
country: United Kingdom
facility: The Royal London Hospital
Study officials:
affiliation: Queen Mary University of London
name: Julian Gold, Prof
role: PRINCIPAL_INVESTIGATOR
affiliation: Queen Mary University of London
name: Gavin Giovannoni
role: PRINCIPAL_INVESTIGATOR
References:
citation: Christensen T. HERVs in neuropathogenesis. J Neuroimmune Pharmacol. 2010 Sep;5(3):326-35. doi: 10.1007/s11481-010-9214-y. Epub 2010 Apr 27.
citation: Perron H, Germi R, Bernard C, Garcia-Montojo M, Deluen C, Farinelli L, Faucard R, Veas F, Stefas I, Fabriek BO, Van-Horssen J, Van-der-Valk P, Gerdil C, Mancuso R, Saresella M, Clerici M, Marcel S, Creange A, Cavaretta R, Caputo D, Arru G, Morand P, Lang AB, Sotgiu S, Ruprecht K, Rieckmann P, Villoslada P, Chofflon M, Boucraut J, Pelletier J, Hartung HP. Human endogenous retrovirus type W envelope expression in blood and brain cells provides new insights into multiple sclerosis disease. Mult Scler. 2012 Dec;18(12):1721-36. doi: 10.1177/1352458512441381. Epub 2012 Mar 28.
citation: Farrell RA, Antony D, Wall GR, Clark DA, Fisniku L, Swanton J, Khaleeli Z, Schmierer K, Miller DH, Giovannoni G. Humoral immune response to EBV in multiple sclerosis is associated with disease activity on MRI. Neurology. 2009 Jul 7;73(1):32-8. doi: 10.1212/WNL.0b013e3181aa29fe. Epub 2009 May 20.
citation: Nadal M, Mas PJ, Blanco AG, Arnan C, Sola M, Hart DJ, Coll M. Structure and inhibition of herpesvirus DNA packaging terminase nuclease domain. Proc Natl Acad Sci U S A. 2010 Sep 14;107(37):16078-83. doi: 10.1073/pnas.1007144107. Epub 2010 Aug 30.