The Randomized Controlled Trial

The Randomized Controlled Trial
By: Rakhi Naik, MD

Eltrombopag for Thrombocytopenia in Patients with Cirrhosis Associated with Hepatitis C

STUDY OUTLINE
* Hypothesis: Eltrombopag can increase platelet counts in patient with hepatitis C cirrhosis.
* Design: Randomized controlled trial
* Setting: Multicenter trial in US & Europe
* Participants: 74 patients w/Hepatitis C cirrhosis
* Data Collection: Measurement of platelet counts before and after eltrombopag administration for 4 weeks; measurement of platelet counts after standard hepatitis C treatment with peg-interferon/ribavirin
* Outcome: Platelet counts, safety

BACKGROUND
* Chronic liver disease secondary to hepatitis C cirrhosis is often associated with significant thrombocytopenia.
* Thrombocytopenia in chronic hepatitis C infection is multifactorial in origin & is thought to be caused by:
o splenic sequestration (2/2 portal hypertension/hypersplenism)
o decreased thrombopoetin production (2/2 impaired hepatic synthetic function)
o bone marrow suppression (2/2 direct toxic effect of the hepatitis virus itself).

* Platelet counts below 75,000 are often not eligible for treatment with pegylated interferon & ribavirin because treatment itself leads to cytopenias in almost 100% of cases.

BACKGROUND
* Eltrombopag is an oral thrombopoetin receptor agonist that increases megakaryocyte proliferation and differentiation in animal models.

* Research questions:
o Can eltrombopag increase platelet levels in patients with untreated chronic hepatitis C cirrhosis?
o Can continued use of eltrombopag during hepatitis C treatment reduce treatment-related thrombocytopenia?
o What dose of eltrombopag is most effective for achieving these goals?

METHODS

* 22 centers in the United States & Europe were involved in recruitment.
* Inclusion criteria:
o 18 years of age or older
o Presence of serum HCV antibody levels
o Detectable serum HCV RNA levels
o Compensated liver disease (which is not defined explicitly)
o Thrombocytopenia with platelet levels between 20,000-70,000.
o Evidence of cirrhosis defined as: liver biopsy c/w cirrhosis, radiographic evidence of cirrhosis, or endoscopic evidence of varices

* Exclusion criteria:
o Pregnancy
o History of thrombosis
o HIV co-infection
o Hepatitis B co-infection

METHODS
Patients randomly assigned to placebo or eltrombopag (30mg, 50mg, 75mg daily) x 4 weeks
Any patient with plt count >70k or >100k was eligible for treatment with peg-interferon α-2a or peg-interferon α-2b, respectively. The decision to treat was left to the physician & patient.
Patients continued with their previous dose of eltrombopag during treatment.
Study designed by GlaxoSmithKline & academic principal investigator.
Daily eltrombopag doses were held if platelet count rose >200,000 and would be resumed when counts dropped to around 100,000

RESULTS
Approximate bilirubin (converted) 1.5+/- 1mg/dL. INR and creatinine not reported.
5 of total 74 patient listed here were excluded for baseline plt counts >75k but were ultimately eligible for the treatment phase.
Uneven number of patients in each arm because this was a mulicenter trial & not all sites contributed to all 4 arms.

RESULTS
Only 18 patients completed treatment. Only 1 placebo patient completed tx even though 7 were eligible.
Median platelet values prior to inferon treatment and % responders had significant p values compared to placebo

RESULTS
Pre-treatment platelet values, especially in the 50mg and 75mg eltrombopag arms, were statistically significant.
Platelet levels decreased with hep C treatment in all arms. P values for the eltrombopag groups vs. placebo were not statistically significant.
More patients in the eltrombopag arms completed treatment.

CONCLUSIONS/ IMPLICATIONS
* Eltrombopag increases platelet counts in a dose-dependent manner in patients with untreated chronic hepatitis C cirrhosis.
* Eltrombopag can be used to boost platelet counts in patients being considered for peg-interferon & ribavirin treatment.

STRENGTHS
* Clinical relevance: Thrombocytopenia is a very common complication of hepatitis C infection and ineligibility for treatment is a significant public health concern.
* Efficacy: Eltrombopag is extremely effective in increasing pre-interferon platelet counts (i.e. the study was able to demonstrate efficacy even though the sample size was low).
* Ease of use: Eltrombopag can be taken orally and has an easy daily dosing schedule.
* Safety: Eltrombopag has minimal side effects, which do not seem to be dose-dependent, and are not associated with significant morbidity.

WEAKNESSES
* Small sample size, especially in interferon treatment group (underpowered)
* Failed to standardize the protocol for initiation and cessation of interferon treatment phase.

* Lack of generalizability
o The investigators may have referred only patients with cirrhosis without portal hypertension to the study in order to select for a group who was more likely to benefit from treatment.
o Similarly, HCV viral loads were not taken into account.
* ? Clinical utility
o Could not ultimately answer question of whether pre-treatment with eltrombopag resulted in successful clearance of hepatitis C with treatment (i.e. whether the fact that more patients can receive interferon treatment actually leads to more patients who benefit from treatment).

The Randomized Controlled Trial.ppt

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From mice To Men

From mice To Men

Jumpstarting A Laboratory Research Career
December 6, 2007
By: Elizabeth M. Jaffee, M.D.
The Dana and Albert “Cubby” Broccoli Professor of Oncology


Issues to Consider
* Stay where you trained or go elsewhere
* Identifying mentors
* Deciding on a research focus
* Leveraging small grants, getting the big one
* Building a team to work for you
* Balancing the work versus home life

Should you stay where you trained or should you take your first job at another institution?
* Pros for staying
o Implies you have a supportive mentor
o Implies you have a project of interest to others in your institution
o Experience with the institutional systems
o Experience with who might be good colleagues
* Start Up Time Is Shorter
* Pros for leaving
o Cuts the apron strings so that you are not in competition with your mentor at same place
o Likely to get more space and resources due to negotiations
o Likely able to get good students with less competition in your field
* No Identity Complex

Identify a mentor(s) for the most difficult stage in your career

* Cheer leader, promoter, encourager
* Sounding board for fine tuning ideas
* Devil’s advocate whose not afraid to give you the opposite view
* Editor of paper’s, grants, and presentations
* Guidance counselor to help you navigate through tough issues
* Referral Agent who sends you qualified student/postdoctoral fellow applicants
* Introduces you to leaders in your field
Your parent in the workplace

Develop A Five-Year Plan
Time interval goal between Assistant and Associate Professor
* What research questions do you want to focus on?
* What do you need to get you to where you want to be at 5-years
* Is it feasible now? At 1, 2, 3, and 4 years later?
* Revisit each year with your mentor to make sure you are on track
* How many grants and papers do you plan to submit?

Considerations in choosing how to focus your research
* Choose areas that make you want to come to work
o Desire, Desire, Desire!
* Choose a 5-year plan that will help you develop an identity separate from your mentor’s
* Consider several related areas - one high risk and and one or more low risk
* Choose areas that have more than one funding source

Grants: If only it were the 1990’s Again!
* Apply for more than one
o Can submit same grant to several funding agencies or similar ones that overlap
* Apply for career development grants first
* Pursue institutional grants and foundations if appropriate
* Spend 3 or more months writing your first grant
o Have a draft available 1-2 months before due date
o Ask mentor and other colleagues to review
o Have a scientist in a related but different field read the grant for clarity of presentation of ideas
* Go for the R01 by the end of the 5-year plan

Building a Team That Works For You, Literally!
* Learn to lead
o You will make mistakes - learn from them
o Take leadership development courses
o Listen to your team
o Show trust and faith in your team members!
o Mistakes are made by all of us. Be forgiving and continue to trust.
o Don’t let emotions or sense of insecurity get in the way of doing the right thing for your team (we all have this starting at all stages of our career).
* Lead by example
* Identify individuals you can influence
o Make sure they have the personality to take direction from you
o Make sure they have qualities you value
o Make sure you can lead them to be the best they can be

Get the right people on the bus!
Key Point
* There are no special deals when it comes to people resources. Make sure they have the right experience to contribute to your team

* People resources are the single most important ingredient to success
* Develop a healthy work environment
* If you can’t do it on your own, hire someone to be your lab ambassador
* Get as many references as possible
* Ask everyone in your group and others with successful labs to interview candidates
* Reward valued team members with lunches, meetings, etc.
* Provide career development to your valued team members.

Healthy environments attract more good people to help you build and maintain a productive team!
Develop a reputation for leadership and fairness early!
You Are Your Best Advocate
* Promote yourself
o Discuss ideas with others
o Let colleagues know about your successes
o Offer to participate in meetings, etc
o Let colleagues know you are willing and available
* Let your boss know of your important successes
o Grant awards
o Accepted papers
o Abstract acceptances of high impact
* Develop a national reputation
o Get invited to national meetings by telling colleagues of interesting work
o Offer to present locally and at national meetings for visibility
o Get introduced to prominent individuals in your field

Senior scientists delight in interacting with enthusiastic, intelligient, honest, and creative young scientists who are the next leaders!

Women still have special issues (I can tell some stories!)
* My graduate student’s experience
* Women in science (am I the only one?)
* Postdoctoral fellows and junior faculty I know who get taken in by charming individuals disguised as mentors
* Our generation of men and women are making a difference

Pearls of Advise On How To Succeed in A Man’s World (from The Godfather)
* Just when I thought I was out, they pulled me back in!!!
* Keep your friends close, and your enemies closer!!!
* It ain’t personal, just business!!!

If you are going to fight for something, pick the right battles!
You can’t possible win them all!
If you don’t like someone, nominate them for something important!
If someone does something bad to you, don’t allow your emotions
to get in the way of how you deal with the situation!

HARDWORK
FOCUS
DETERMINATION
Don’t forget about a home life!
Physician-Scientist, Wife, and Mom
* Roadmap to successful

Inspiration
Role Models or Mentors
Hardwork
Focus
Determination
A balancing act!
Integrating a successful career with a home life
The road to success in anything is easier when you have a supportive partner!
Kids are the ultimate reminders of what is important in life!
Animals can be less demanding but loving substitutes!

Jumpstarting A Laboratory Research Career.ppt

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Insect Sting Allergy and Venom Immunotherapy

Insect Sting Allergy and Venom Immunotherapy
By: David B.K. Golden, M.D.
Johns Hopkins University, Baltimore


History of Reaction to Insect Stings (Skin Test Positive Patients)

No reaction
Large Local
Cutaneous Systemic
Anaphylaxis

Severe swelling 24 hrs after a sting should be treated with:
A. Antibiotics C. Antihistamine E. Epinephrine
B. Prednisone D. Venom immunotherapy

Venom immunotherapy:
A. Is not necessary (“He’ll outgrow it”) B. Is dangerous
C. is only partially effective D. Is forever E. None of the above

Diagnosis of Insect Sting Allergy (Indications for Venom Immunotherapy)
Symptoms and Signs of Insect Sting Anaphylaxis in Adults and Children
Symptoms or Sign
Cutaneous only
Urticaria/angioedema
Dizziness/hypotension
Dyspnea/wheezing
Throat tightness/
Hoarseness
Loss of consciousness

Epidemiology of Venom Allergy
* History of systemic reaction in 0.5%-3.0% of the population
* Positive venom skin test or RAST in 15%-25% of the population.
* Transient positive skin test or RAST may occur after uneventful sting.
* Presence of IgE venom antibody not necessarily predictive of clinical reactivity.

Correlation of Yellow Jacket Venom
RAST and Skin Tests
History Positive Patients with Negative Venom Skin Tests
Possible explanations:
Not true allergic reaction (no objective signs)
Allergy “outgrown”
Mastocytosis (~1 % of insect allergic patients)
Not detected:
Diagnostic Venom Test Reactivity after Systemic Sting Reaction
Venom Skin Test / RAST in History Positive Patients
Total history positive patients screened:
Diagnosis of Insect Allergy in Patients With Positive History (Systemic)
Skin test positive
ST negative /
Low Risk Sub-Groups of Patients With Positive Venom Skin Tests
Insect Sting Allergy in Children
Summary Of Sting Reactions
Natural History of Large Local Reactions
Repeat Systemic Reaction In Sting Allergic Patients
Risk of Systemic Reaction in
Untreated Skin Test Positive Patients
Controlled Trial of Venom Immunotherapy
Venom Immunotherapy Treatment Protocols
Dose Response of Venom Immunotherapy
Premedication During Venom Immunotherapy
Venom-IgE and Skin Test During
and After Venom Immunotherapy
Discontinuing Venom Immunotherapy:
Reported Studies and Criteria
Discontinuing Venom Immunotherapy

Insect Sting Allergy and Venom Immunotherapy.ppt

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