Relapsing Remitting Multiple Sclerosis
Conditions
Keywords
raltegravir, MS, RRMS, Charcot Project
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.
Interventions
DRUGRaltegravir
400mg twice daily for 3 months
Sponsors
Merck Sharp & Dohme LLC
Queen Mary University of London
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 55 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| The Number of New or Recurrent Gd-enhancing Lesions That Appear on Brain T1-weighted MRI | Baseline and at 6 months | Demonstrate in subjects with relapsing remitting multiple sclerosis a reduction in the number of new or recurrent Gd-enhancing lesions that appear on brain T1-weighted MRI over the period of treatment with raltegravir, compared to baseline. Within patient change in number of lesions was calculated by subtracting the after treatment period (3 months) minus before treatment period (3 months). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| The Cumulative Number of New or Enlarging T2 Weighted Lesions on Brain MRI. | Baseline and monthly for 6 months | Demonstrate a reduction in the cumulative number of new or enlarging T2 weighted lesions on brain MRI over the period of treatment with Raltegravir compared with baseline. Within-patient changes in lesion count calculated after-before. |
| 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. | Baseline and monthly until month 6. | Explore preliminary clinical responses in relapsing-remitting multiple sclerosis subjects treated with Raltegravir, compared with baseline as measured by Patient Reported Outcomes (Questionnaires). The MSFC is a composite score consisting of the standardly derived composite score from 9-hole peg test (9HPT), timed walk and PASAT scores. 9HPT is measured as timed speed to complete the task; higher scores indicate less disability. The 25-foot walk is measured as timed speed; higher scores indicate less disability. The Paced Auditory Serial Addition Test (PASAT) The PASAT is a measure of cognitive function that assesses auditory information processing speed and flexibility, as well as calculation ability. It is a timed speed test measured in seconds. In the PASAT a lower score indicates less disability. |
| Changes in Kurtzke Extended Disability Status Scale (EDSS) Score | Baseline and monthly to month 6 | The Kurtzke Expanded Disability Status Scale (EDSS) is a method of quantifying disability in multiple sclerosis. The scale has been developed by John F. Kurtzke. The EDSS quantifies disability in eight Functional Systems (FS) and allows neurologists to assign a Functional System Score (FSS) in each of these. 0 = Normal 1-1.5 = No disability, but some abnormal neurological signs 2-2.5 = Minimal disability 3-4.5 = Moderate disability, affecting daily activities, but you can still walk. A lower score indicates less disability. 5-8 = More severe disability, impairing your daily activities and requiring assistance with walking 8.5-9.5 = Very severe disability, restricting you to bed 10 = Death EDSS scores were measured monthly over 6 months and the mean of the measurements for the first three months (baseline) was recorded to use calculate the change from baseline compared with the mean of measurements taken monthly during the second three months (treatment). |
| Cumulative Number of Gd-T1 Enhancing Lesions | At Baseline and monthly for 6 months | This measure is the number of gadolinium-enhancing T1 lesions as determined by MRI taken on the monthly basis during the six months of the study. |
| Percent of Subjects With Scans Free From Enhancing Lesions in Raltegravir Treated Subjects vs. Baseline | Baseline to 6 months | This measure is the cumulative percentage of subjects who had scans free from Gd enhancing lesions during the first three months (baseline) compared with the second three months (treatment). These percentages are expressed as a total percentage for the baseline and for the treatment periods. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Mean Number of Adverse Events Per Patient | Screening to six months | This outcome will be assessed by blood and urine sampling; collection of patient reported symptoms and neurological and physical exams. This measure is the total number of adverse events recorded for each type of event during the study period. The number of participants is 31 which is the number screened and enrolled in the study. Eleven participants did not meet the criterion for baseline i.e. having a gadolinium enhancing lesion on MRI at the baseline visit and therefore did not continue to the baseline observation period. The adverse events for the 11 participants who did not begin the study observation period were recorded during the screening period and added to the 20 participants who were studied during the 6 months of the study. Adverse events are recorded as total number during the study period. Each patient may have had more than one adverse event. |
| Effect of Raltegravir Therapy on Specific Inflammatory Marker of MS Activity. | Baseline to 6 months | Measured by Human C-Reactive Protein (HCRP) which is a measure of general inflammation. The higher the value the more inflammatory response is present. The HCRP was measured monthly for six months. The mean value for the baseline three months was compared with the mean value taken for the second (treatment) three months. |
Countries
United Kingdom
Participant flow
Recruitment details
Patients 18-55 years of age with RRMS, as per McDonald Criteria 2010, EDSS up to 6.0, relapse within the past 12 months or at least one active Gd enhanced lesion on brain MRI within the 3 months prior to consent. All participants were recruited at the Clinical Research Centre of the Royal London Hospital and drawn from greater London.
Pre-assignment details
31 subjects screened. 8 had no evidence of Gd enhancing lesions in their baseline MRI and were screen failed. Of the 23 participants who were recruited into the study 3 were withdrawn prior to starting the treatment phase; one at the request of the participant and the remaining two due to MS relapse.
Participants by arm
| Arm | Count |
|---|---|
| Raltegravir All eligible patients will complete a 3 months observation period (no medications) followed by 3 months on treatment period. During the treatment period patients will be treated with open label raltegravir 400mg twice daily.
Raltegravir: 400mg twice daily for 3 months | 20 |
| Total | 20 |
Baseline characteristics
| Characteristic | Raltegravir |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 20 Participants |
| Region of Enrollment United Kingdom | 20 participants |
| Sex: Female, Male Female | 14 Participants |
| Sex: Female, Male Male | 6 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 31 / 31 |
| serious Total, serious adverse events | 1 / 31 |
Outcome results
Primary
The Number of New or Recurrent Gd-enhancing Lesions That Appear on Brain T1-weighted MRI
Demonstrate in subjects with relapsing remitting multiple sclerosis a reduction in the number of new or recurrent Gd-enhancing lesions that appear on brain T1-weighted MRI over the period of treatment with raltegravir, compared to baseline. Within patient change in number of lesions was calculated by subtracting the after treatment period (3 months) minus before treatment period (3 months).
Time frame: Baseline and at 6 months
Population: ITT
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Raltegravir | The Number of New or Recurrent Gd-enhancing Lesions That Appear on Brain T1-weighted MRI | 0.12 lesions |
Secondary
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.
Explore preliminary clinical responses in relapsing-remitting multiple sclerosis subjects treated with Raltegravir, compared with baseline as measured by Patient Reported Outcomes (Questionnaires). The MSFC is a composite score consisting of the standardly derived composite score from 9-hole peg test (9HPT), timed walk and PASAT scores. 9HPT is measured as timed speed to complete the task; higher scores indicate less disability. The 25-foot walk is measured as timed speed; higher scores indicate less disability. The Paced Auditory Serial Addition Test (PASAT) The PASAT is a measure of cognitive function that assesses auditory information processing speed and flexibility, as well as calculation ability. It is a timed speed test measured in seconds. In the PASAT a lower score indicates less disability.
Time frame: Baseline and monthly until month 6.
Population: ITT
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Raltegravir | 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. | 25 foot walking test in seconds | -0.24 seconds | Standard Deviation 28.2 |
| Raltegravir | 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. | 9 hole peg test as a timed measurement | 0.05 seconds | Standard Deviation 0.01 |
| Raltegravir | 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. | PASAT. This is a TIMED measurement | 49.72 seconds | Standard Deviation 8.81 |
Secondary
Changes in Kurtzke Extended Disability Status Scale (EDSS) Score
The Kurtzke Expanded Disability Status Scale (EDSS) is a method of quantifying disability in multiple sclerosis. The scale has been developed by John F. Kurtzke. The EDSS quantifies disability in eight Functional Systems (FS) and allows neurologists to assign a Functional System Score (FSS) in each of these. 0 = Normal 1-1.5 = No disability, but some abnormal neurological signs 2-2.5 = Minimal disability 3-4.5 = Moderate disability, affecting daily activities, but you can still walk. A lower score indicates less disability. 5-8 = More severe disability, impairing your daily activities and requiring assistance with walking 8.5-9.5 = Very severe disability, restricting you to bed 10 = Death EDSS scores were measured monthly over 6 months and the mean of the measurements for the first three months (baseline) was recorded to use calculate the change from baseline compared with the mean of measurements taken monthly during the second three months (treatment).
Time frame: Baseline and monthly to month 6
Population: All patients enrolled in clinical trial
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Raltegravir | Changes in Kurtzke Extended Disability Status Scale (EDSS) Score | 2.55 units on a scale | Standard Deviation 0.92 |
Secondary
Cumulative Number of Gd-T1 Enhancing Lesions
This measure is the number of gadolinium-enhancing T1 lesions as determined by MRI taken on the monthly basis during the six months of the study.
Time frame: At Baseline and monthly for 6 months
Population: ITT
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Raltegravir | Cumulative Number of Gd-T1 Enhancing Lesions | 3.08 Gadolinium enhancing T1 lesions |
Secondary
Percent of Subjects With Scans Free From Enhancing Lesions in Raltegravir Treated Subjects vs. Baseline
This measure is the cumulative percentage of subjects who had scans free from Gd enhancing lesions during the first three months (baseline) compared with the second three months (treatment). These percentages are expressed as a total percentage for the baseline and for the treatment periods.
Time frame: Baseline to 6 months
Population: ITT
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Raltegravir | Percent of Subjects With Scans Free From Enhancing Lesions in Raltegravir Treated Subjects vs. Baseline | 15 percentage of subjects |
Secondary
The Cumulative Number of New or Enlarging T2 Weighted Lesions on Brain MRI.
Demonstrate a reduction in the cumulative number of new or enlarging T2 weighted lesions on brain MRI over the period of treatment with Raltegravir compared with baseline. Within-patient changes in lesion count calculated after-before.
Time frame: Baseline and monthly for 6 months
Population: ITT
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Raltegravir | The Cumulative Number of New or Enlarging T2 Weighted Lesions on Brain MRI. | 0.19 T2-weighted lesions |
Other Pre-specified
Effect of Raltegravir Therapy on Specific Inflammatory Marker of MS Activity.
Measured by Human C-Reactive Protein (HCRP) which is a measure of general inflammation. The higher the value the more inflammatory response is present. The HCRP was measured monthly for six months. The mean value for the baseline three months was compared with the mean value taken for the second (treatment) three months.
Time frame: Baseline to 6 months
Population: ITT
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Raltegravir | Effect of Raltegravir Therapy on Specific Inflammatory Marker of MS Activity. | 535.82 ng/mL |
Other Pre-specified
Mean Number of Adverse Events Per Patient
This outcome will be assessed by blood and urine sampling; collection of patient reported symptoms and neurological and physical exams. This measure is the total number of adverse events recorded for each type of event during the study period. The number of participants is 31 which is the number screened and enrolled in the study. Eleven participants did not meet the criterion for baseline i.e. having a gadolinium enhancing lesion on MRI at the baseline visit and therefore did not continue to the baseline observation period. The adverse events for the 11 participants who did not begin the study observation period were recorded during the screening period and added to the 20 participants who were studied during the 6 months of the study. Adverse events are recorded as total number during the study period. Each patient may have had more than one adverse event.
Time frame: Screening to six months
Population: ITT
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Raltegravir | Mean Number of Adverse Events Per Patient | 7.9 Adverse events |