Friday, October 05, 2012

Two new studies on BG 12 a new oral for MS

Gold R et al. Define Investigators.  Placebo-controlled phase 3 study of oral BG12 for relapsing multiple sclerosis. NEJM 367:1098-1107 , 2012

Fox et al.  CONFIRM investigators.  Placebo-controlled phase 3 study of oral BG-12 or glatiramer in multiple sclerosis.  NEJM 2012; 367: 1087-1097.

DEFINE  1234 patients were randomized and received at least one dose of meds (BG 12 , 240 bid, BG 12 240 tid, or placebo), about 400 per group.  Primary endpoint was number with relapse at 2 years.  Secondary endpoints were ANNUALIZED RELAPSE RATE, TIME TO CONFIRMED PROGRESSION OF DISABILITY, AND MRI FINDINGS. 

Results favored BG-12. Percent with relapses were 27 and 26 % in two BG 12 groups and 46 % with placebo, p<.001 for both.   ARR was .17, .19, and .36 again favoring BG 12. Percent with confirmed disability was 16 %, 18 %, and 27 % respectively favoring BG 12.  MRI  was also better. 

Patient selection:  age 18-55, EDSS ranging from 0-5, one relapse clinically or by MRI in period before entry into study.  198 sites in 28 countries participated with 1:`1:1 randomization. Baseline characteristics were similar in patients.  Patients could switch therapy if they completed 48 weeks of study or developed confirmed worse disability.Half in MRI study.  78 % completed study with similar rates of withdrawal in the 3 groups.  Time to first relapse was 37 weeks (placebo), 87 and 91 weeks in 2 BG 12 groups. 
Safety: key events were nausea, vomiting, abdominal pain, pruritus, flushing, and PROTEINURIA ( 12 %).  3 % had elevated LFT's esp first six months.

1430 patients were randomized, and patient 18-55, EDSS 0-5, one relapse or MRI change before initiation into study. 1:1:1:1 groups including bid and tid BG 12, placebo and  glatiramer.  Study went 96 weeks.  Primary endpoint was ARR, secondary endpoints were (in an MRI subcohort) new and enlarging lesions, enlarging T1 black holes, proportion of patients with relapse, and proportion with disability progression at two years. Dropout rates were higher in placebo group. 
ARR was 0.22, 0.2 and 0.44 favoring BG12 against placebo, and rate was .29 for glatiramer. 
Study was not powered to compare BG 12 and glatiramer.  Disability was not affected significantly in any group at 24 weeks.  All three non placebo groups had better outcome on MRI for new T1 black holes, number of new and enlarging lesions, and gado enhancing lesions. 

Exciting data.  CANNOT compare BG 12 and glatiramer.  Define but not Confirm showed benefit for disability.  Both studies showed benefit on relapse rates, and MRI although MRI was subgroup analysis in both studies. 

Saturday, September 29, 2012

Signals for many immunosuppressant drugs and PML

Signals of progressive multifocal leukoencephalopathy for immunosuppressants: a disproportionality analysis of spontaneous reports within the US Adverse Event Reporting System (AERS); Schmedt N, Andersohn F, Garbe E; Pharmacoepidemiology and Drug Safety (Jul 2012)
PURPOSE: Progressive multifocal leukoencephalopathy (PML) is a rare demyelinating disease of the central nervous system that has been reported as rare adverse drug reaction (ADR) of immunosuppressive drugs. We aimed to study signals of PML for immunosuppressants using a disproportionality analysis of spontaneous adverse event reports. METHODS: Within the US Adverse Event Reporting System, we analyzed all reports of ADRs submitted to the US Food and Drug Administration between January 1, 2004 and September 30, 2010. We used univariate and multivariate logistic regression analysis to calculate reporting odds ratios with 95% confidence intervals of PML for immunosuppressants according to the Anatomical Therapeutic Chemical classification system (L04), rituximab and cyclophosphamide compared to all other drugs. RESULTS: We identified 635 PML cases in a total of 1 978 706 patients eligible for analysis. Altogether, 21 out of 36 analyzed immunosuppressants were reported at least once with PML. In the univariate analyses, we found a signal for 11 of these drugs (azathioprine, cyclosporine, cyclophosphamide, efalizumab, leflunomide, methotrexate, mycophenolate mofetil, natalizumab, rituximab, tacrolimus and sirolimus). In the multivariate analysis, the signal was no longer present for sirolimus, leflunomide and methotrexate. DISCUSSION: Our study revealed signals of PML for a substantial number of immunosuppressants, including some drugs less considered so far as a risk factor of PML, especially when used for the treatment of autoimmune disorders. These drugs and possible interactions between different immunosuppressants should be studied more closely in future studies. Copyright © 2012 John Wiley&Sons, Ltd.

Saturday, September 08, 2012

Interferon B for SPMS: a systematic review

La Mantia L, Vacchi L, Rovaris M et al.  JNNP 2012

Cochrane analysis of placebo controlled trials 1995-2012. 5 trials, 3082 patients. IFN did not reduce disability progression, there was small decrease in relapses, cognition not studied.  More treated than placebo patients dropped out.  Conclusion: Only use IFN in selected patients with active disease to reduce risk of disabling superimposed relapses.

Comment (blogger).  If patients are relapsing they have RRMS.  SPMS is diagnosed and differentiated from RRMS as an art form.

Tuesday, September 04, 2012

Emerging therapies in MS AAN 2012 Mark Freedman

Random Notes
1.  Tereflunomide- blocks de novo synthesis of pyrimidine synthesis
"Nobody has a clue how these things really work"
2. TEMSO  2 doses used 7 and 14 mg decreased RR, time to attack, and EDSS progression at 2 years and disease activity free measure increased by 60 percent  with higher dose, decreased Gd+ lesions
3. Minor safety issues minor GI , hair thinning (reversible) ; decreased pain (???)
4.  TENERE  -- primary point not efficacy but effectiveness which comparator Rebif.  looked at time to treatment failure due to relapse or AE's leading to stop drug.  RR similar except low dose, but effectiveness was better with tereflunomide.LFT's only thing seen reliably.
5.  Add on therapy to IFN or GA, patients doing well, added on TFN, did not need attack, just stable dose of drug or placebo, added TFN.  Patients doing well, followed with monthly MRI's, half patients had a Gd+ lesions (.57) decreased 80 % when TFN added.  patients doing well were not doing so well, even without relapses.  Keracles is a phase 3 study of combined.  IFN + TFN > GA + IFN
6.  BG 12 blocks NF pathway.  - no effect of BG 12 until got to dose of 240 bid.  bid v tid (240 mg) improved RR , EDSS 9by 30-40 %).  Curves for rr split at 6 months, why ph 2 study (6 month trial) failed, but effect persists and sustains. 
7.  Confirm:  beats GA for RR and MRI. 
8. DEFINE -- 30 % dropout, mostly flushing and nausea.  Used in Germany for years
9.  Laquinomid-- Allegro and Bravo.  23 % reduction RR overall, 36 % reduction risk to progression, modest effect on MRI, well tolerated.  Rare LFT elevations.Did not beat avonex for rr.  EDSS progression "barely significant " for laquinomid.
10. alemtuzumab. 
Care MS I (naive patients).less than 5 years into disease, EDSS < 3. 
.39 RR, much better with alemtuzumab, EDSS progression, only 11 % progressed in IFN arm, not powered to see .  MRI affected positively at 2 years.  AE's: minor infections, infusion reactions. AI disease; Graves, mild to moderate, usually managed effectively with tapazole.  ITP picked up in 4 patients.  May be a biomarkers to predict ITP.
Care MS 2- breakthrough patients with activity. EDSS < 5, years of disease < 10.  2+ attacks in 24 months before entry. 1+ attack during therapy with IFN.  Was 49 % reduction in RR, 42 % risk reduction of sustained disability.
1. Daclizumab-- anti CD 25 effect-
Average duration of disease in initial trials was seven years, so there is a huge difference in timing of treatment

natalizumab Omar Khan AAN 2012 notes

These are random notes of interest
1  Natalizumab was originally used for MS relapses in the 1990s, published in Neurology; negative study but a secondary outcome , on gad enhancement was positive.
2. A later trial by David Miller, sequential trial was also positive and focus changed.  There also was a resurgence of disease activity noted even then when treatment ceased.
3.   Khan open label study sequential failure on GA/IFN then change to NAT with no change with first switch, but dramatic decline in RR after second switch to NAT with significant MRI findings as well. Old study, about to be published.
4.  Suggests usefulness in non aggressive "run of mill " disease.  Tissue repair study with voxel wise MTR imaging, tracking lesions longitudinally
5. Risk management: usually 5 issues: infusion reactions, NAB's, hepatotoxicity, malignancies, opportunistic infections.  Rare cases of toxo, lymphoma but PML is king
PML-- mean duration of dosing was 34.1 months, range 8-67 doses.  Overall incidence is 2.08/1000 (CI 95 % 1.8 to 2.39) 3 risk factors. 
42 patients have died, 159 alive (79 %) but 80 % plus have severe disability among survivors.
3-4 x rise in risk with prior IS use, even one dose, across board therapies.
JCV Ab conversion rate is approximately 2-3 percent per year
6.  "Not a clear path" how to treat patients when they come off natalizumab

Sunday, September 02, 2012

MS notes AAN meeting Gilenya 2012

Jeffrey Cohen on Gilenya
1. O.5 mg daily is only approved dose, lower doses are being tested
2. May take a month or more to completely clear out of system
3. Caution in patients with severe liver disease
4.  Drug interactions occur with inhibitors of liver metabolism, esp ketoconazole; drugs that lower heart rate (beta blockers and calcium channel blockers), drugs that affect QT interval esp amiodarone, other antiarryhtmics which could cause Q onT phenomenon and tachyarrythmias. 
5.  In their center they weight at least three months to switch onto gilenya from natalizumab, etanercept and other antiimmunosuppressants
6.  Freedoms, about 50 % decrease in relapses, slowing brain atrophy, disability v. avonex and placebo
7.  Musculoskeletal side effects including back pain and others is common.
8.  Lymphocyte counts come back within 1-2 months after stopping drugs, although it is longer in some patients.
9.  Relationship between lymphocyte count in blood and infections is tenuous or nonexistant, tend to ignore .
10.  Case of PML reported : details dx ms in 2007, treated with interferon, then natalizumab in 2008, found to be seropositive to JCV antibody in 2011 and changed to Gilenya.  MRI at that time showed one new lesion, which actually was likely first PML episode.  Later treated with steroids for a relapse, no benefit, visual changes led to stopping gilenya after fourteen weeks, PML found, but was there before starting drug.
11.  HR stays abnormal for up to a month and gradually returns to normal.
12.  Holter before hand is useless
13.  Patient death 23 hours after first dose in November 2011: details:  EMA (Europe) and FDA reviewed.  Recommendations are similar.  CHMP recommendations: stronger language for patients with contraindications, including prior cardiac and CVD which require overnight monitoring, not just overnight;caution in patients on certain drugs, liberal use of cardiology consultation.  First dose monitoring should now include VS and EKG prior to dosing, continuous monitoring during dosing.  Extend monitoring until HR has increased at least two consecutive hours, and if concern, monitor overnight. In USA, less tringent changes for first dose monitoring: EKG prior to dosing and prior to discharge; monitor at least six hours, do hourly VS during dosing.  D/C criteria similar to Europe.  Overnight monitoring for those with symptomatic bradycardia, QTc pronlongation or conditions that would predispose to QTc prolongation.
14.  In first two weeks, repeat induction if they skip one day; in second two weeks, if they skip a week; subsequently if they miss two weeks of therapy.
15.  HTN during gilenya beware of.
16.  Macular edema:  half time is symptomatic (blurring), half time asymptomatic.  Usually unilateral, may b bilateral.  Increased in diabetics, (excluded in ph 3 trial), higher dose, and those with uveitis and ? ON.  Reverses within several months if drug is discontinued.
17.  Cases exist of MI, CVA, PRES, others.  HA's seen in trials and is the most frequent reason to discontinue medication:  exacerbation of preexisting migraine.
18.  Sense of SOB or cough
Summary-- his opinion-- used in 800 patients.  Check  LFT's no CBCs, OCT repeated after 3 months
Using in RRMS Approved as first line therapy but actually use less often.

Tuesday, May 15, 2012

Drugs that affect or may affect qt interval

Biggest problem is the proven drugs to cause torsades (drugs we see a lot)
Citalopram Celexa® Anti-depressant / depression
Erythromycin E.E.S.® Antibiotic;GI stimulant / bacterial infection; increase GI motility
Haloperidol Haldol® Anti-psychotic / schizophrenia, agitation When given intravenously or at higher-than- recommended doses, 
Methadone Dolophine® Opiate agonist / pain control, narcotic dependence
Quinidine Nuedexta® for PBA
The possible list to cause torsades, which is in my mind, the same risk as those above (drugs we use a lot):
Amantadine Symmetrel® Dopaminergic/Anti-viral / Anti-infective/ Parkinson's Disease
Dolasetron Anzemet® Anti-nausea / nausea, vomiting
Escitalopram Lexapro® Anti-depressant / Major depression/ Anxiety disorders
Famotidine Pepcid® H2-receptor antagonist / Peptic ulcer/ GERD
Fosphenytoin Cerebyx® Anti-convulsant / seizure
Granisetron Kytril® Anti-nausea
Levofloxacin Levaquin® Antibiotic / bacterial infection
Quetiapine Seroquel® Anti-psychotic / schizophrenia
Risperidone Risperdal® Anti-psychotic / schizophrenia
Tizanidine Zanaflex® Muscle relaxant
Venlafaxine Effexor® Anti-depressant / depression
Ziprasidone Geodon® Anti-psychotic / schizophrenia
The conditional ones (which we see used sometimes) which given the right circumstances (OD, drug interactions) cause torsades
All tricyclics (amitriptyline, doxepin, despipramine, imipramine, nortriptyline, trazodone among others).
Cyclobenzaprine is a tricyclic.
All other SSRI paroxetine, fluoxetine (not enough data on duloxetine milnacipran)
All fluoroquinolone antibiotics and TMP SMX
And azole antifungal agents
So ALL antidepressants, ALL antipsychotics, most muscle relaxants, most antibiotics. Don't forget Pepcid! As well as beta blockers, clonidine, calcium channel blockers (verapamil, diltaizem and a few others), quinine, quinidine, amiodarone.

Wednesday, April 11, 2012

ordering free jcv antibody test through quest

jc virus antibodywith reflex to inhibition assay
1 866 my quest call to get order sheet for test

Saturday, February 11, 2012

Risk factors for multiple Sclerosis

D'hooge MB, Nagels G, Bissay V, De Keyser J .  Modifiable factors influencing relapses and disability in multiple sclerosis. Modifiable facors influencing  relapses and disability in multiple sclerosis.  Multiple Sclerosis 2010; 16: 773-785.

Review paper.
Strong evidence suggest relapses can be triggered by infections, the postpartum period and stressful life events.  Hormone fertility treatment may trigger relapses.

Disease progression may occur due to stressful life events,radiotherapy to the head, low levels of physical activity and low vitamin D levels.  Smoking affects disease progression clinically and by MRI.  TNF inhibitors induce exacerbation.  GCF colony stimulator factor for stem cells induces worsening in 4/10 patients. Add on statin to Betaseron may trigger relapses, larger trial is underway.

Vaccinations against influenza, tetanus and hepatitis B appear safe as are surgery, general and epidural anesthesia, and physical trauma. 

Associations with lower relapses include pregnancy, exclusive breastfeeding, sunlight and higher vitamin D exposure. 

Childbirth does not increase relapse rate.  Protective effect of ETOH remains to be confirmed. 

Thursday, February 09, 2012

Re: [seMSc] Case - Gilenya

Please be aware of this paper:
Espinosa PS, Berger JR.  Delayed fingolimod associated asystole.  Multiple Sclerosis 2011; 17:1387-9.
A patient with MS developed asystole and sustatined bradycardia 21 hours after the first dose of fingolimod.  Patient was a 20 yo male with no prior treatment with DMT's, no personal or family history of cardiac disease.He had mild mental retardation and was taking risperidone.  He received IVMP and on day 4 began fingolimod.  The period of asystole lasted only seven seconds, was associated with brief LOC and convulsive like activity and was captured.  He remained bradycardic for two more days.  The f. was discontinued.  Authors suspect a synergistic response between fingolimod and risperidoneand possibly other psychotropic medication.

Early onset natalizumab related PML

Multiple Sclerosis 2011; 17: 1397-98 (letter)
23 year old with MS with EDSS of 5, failed GA, then azathioprine, then natalizumab.  After 6 doses he developed ataxia and was diagnosed with PML, confirmed by CSF. 

2 minute walk test in MS

Gijbels D, Eijnde BO, Feys P.  Comparison of the 2 and 6 minute walk test in multiple sclerosis.  Mulitple Sclerosis 17: 1269-72, 2011.
Authors state the shorter 2mwt is a practical alternative to the standard 6mwt in a disabled population.  40 subjects with MS, mean EDSS of 3.5, some walking with a cane, and analysis showed 2mwt was within 5 +/- 4 % of 6mwt.  Authors believe can substitute 2mwt for 6mwt based on results.

Components of Rao's brief repeatable battery of Neuropsychological tests

 selective reminding test
Spart- Spatial recall test
World List Generation
multiple forms used
also can be used with
MADRS (depression scale)