Double-blind, Randomized, Multi-Center Placebo-Controlled Trial of Varenicline in the Treatment of SCA-3 (Achantia) Theresa A. Zesiewicz, MD FAAN – PowerPoint PPT presentation
Title: Double-blind, Randomized, Multi-Center Placebo-Controlled Trial of Varenicline in the Treatment of SCA-3 (Achantia)
Double-blind, Randomized, Multi-Center
Placebo-Controlled Trial of Varenicline in the
Treatment of SCA-3 (Achantia)
- Theresa A. Zesiewicz, MD FAAN Professor of Neurology Director, Ataxia Research CenterUniversity of
South Florida Tampa, Florida
Authors
- Susan L. Perlman, MD (UCLA, California) Penny Greenstein, MD (Beth Israel, Harvard
University, Boston Massachusetts) Kelly L. Sullivan, Amber Miller, Israt Jahan, MD and University of South Florida
team
Protocol Development
- Tetsuo Ashizawa Khalef Bushara Christopher Gomez S. H. Subramony George Wilmot, III
Varenicline (Chantix)
- Varenicline is a drug made by Pfizer
Pharmaceuticals Developed for the sole purpose of helping patients quit smoking Other drugs used for this purpose include nicotine gum, nicotine patch Drugs designer thought that agonist at nicotinic
acetylcholine system would be beneficial
Varencline as a smoking aid
- Varenicline proved to be beneficial for the most
part in assisting people with stopping their
physostigmine There were also reports in the past about
Wellbutrin, and its anecdotal reports about
treatment of ataxia
Varenicline Reports
- In December 2007, a patient with FXTAS came to
clinic and stated that he took his wifes smoking
drug, Varenicline (Chantix) This is a syndrome related to fragile X that
causes ataxia and tremor, as well as parkinsonism
8
- He told me that he hadnt quite quit smoking, but
that his balance and gait were much improved First I doubted him Second, I took him off the drug and told him to Varenicline First Reports
- The patients balance and gait worsened off
varenicline, although his tremor was better The patient was prescribed varenicline again,
with similar benefit within about 3 weeks time.
Varenicline First Reports
- Reported the finding, using this patient as his
own control We decided to see if varenicline could improve
some additional ataxias, including the ADCAs and
ARCAs, like Friedreichs ataxia In March 2008, an SCA 3 patient and a patient
with SCA 14 also took varenicline, got up to
maximum dose of 1 mg BID Both had marked improvements in the SARA scores The SCA 3 patient used 2 crutch canes originally,
but was able to ambulate without them.
Varenicline First Reports
- The titration up was a bit rocky The patients complained of nausea and very vivid
dreams One patient took an antacid to help her, although some antacids may interfere with varenicline One patient had coronary artery disease and brain
ischemia, even a myocardial infarction in the
past
Varenicline First Reports
- The SCA 3 patient estimated that it took about 3
SCA 3 patient
- The patient with SCA type 3 had a 16-year history
of imbalance, gait dysfunction, and dysarthria. Her gait consisted of severe staggering and
ataxia, and she required the constant use of a
walker or the support of a cane to ambulate. The patient could not stand in a natural
position without falling, and she was unable to
tandem walk even with support.
Varenicline
- Upon examination 1 month after starting
varenicline, her gait dysfunction had improved
markedly, and she was able to walk independently
while only occasionally reaching for the wall for
stability. The total SARA score prior to the patient taking
varenicline 1 mg twice daily was 29, while the
score one month after starting varenicline was
13. The patient has remained on varenicline for 5
months with continued improvement.
Varenicline
- She remains the patient with the most improvement Has taken varenicline for 3 years on and off She notes that everytime she stops it and then
restarts the drug, it takes longer and longer for
her to feel the effects (3 weeks, 6 weeks)
Study Rationale
- Varenicline is a highly selective partial agonist
at the a4ß2 nicotinic acetylcholine receptor that
aids smoking cessation by reducing nicotine
withdrawal symptoms Nicotinic acetylcholine receptors also have a
harmful to developing cerebellum as evidenced by
Study Rationale
- Nicotinic acetylcholine receptors are very
numerous in the brain Cerebellar Purkinje cells express nicotinic
acetylcholine receptors including the a4 and a7
Cerebellum and nicotinic receptor subunits
- Using immunohistochemical localization of
nicotinic acetylcholine receptor subunits in
Study Sponsored By
- National Ataxia Foundation Bobby Allison Ataxia Research Alliance
Study Purpose
- The purpose of the study was to test the efficacy
and safety of varenicline (Chantix) in a
controlled study in SCA -3 patients This was a pilot trial to determine whether our
varenicline in SCA 3
Primary Objective
- To assess the effectiveness of varenicline on
SARA symptoms and severity (as measured by
clinical rating scales) at endpoint compared to
baseline. To assess the frequency and severity of
dose-limiting adverse events associated with
varenicline treatment.
Secondary Endpoints
- Change in T25-FW Change in 9-hole peg test (9HPT) Change in SF-36 quality of life rating scale Change in Depression rating scale Change in Anxiety rating scale Change in clinical global impression of
improvement (CGI) Change in activities of daily living scale
Inclusion Criteria
- Outpatients with SCA 3 diagnosed by a movement
disorder specialist and confirmed by genetic
testing (of the patient or in a first degree
relative of the patient). Age 18 years to 80 years. Women of child-bearing potential must use a
reliable method of contraception and must provide
a negative pregnancy test at entry into the
study. Serum creatine kinase, complete metabolic panel,
complete blood count, liver function tests, renal
function tests, platelets and EKG are within
normal limits (results obtained from primary care
physician and dated within the past 6 months
Inclusion Criteria
- Stable doses of all medications for 30 days prior
to study entry and for the duration of the study. Ability to ambulate with or without assistance. Score of 10 or higher (worse) on the SARA total score. Score of 3 or higher (worse) on the gait
subsection of the SARA rating scale.
Exclusion Criteria
- Any unstable illness or concomitant medical
condition that, in the investigators opinion,
precludes participation in this study. This
includes other disorders that may affect gait or
balance (stroke, arthritis, etc). Pregnancy or lactation. Concurrent participation in another clinical study. Patients with a history of substance abuse. Patients who currently smoke or have smoked within the past 12 months. Presence of psychosis, bipolar disorder,
untreated depression (BDI greater than or equal
to 21), or history of suicide attempt.
Exclusion Criteria
- Concurrent treatment with any MAOIs, Wellbutrin,
or nicotine patches. Dementia or other psychiatric illness that
prevents the patient from giving informed consent
(Mini Mental Status Exam score less than 24). Presence of severe renal disease (BUN 50 greater
than normal or creatinine clearance lt60 mL/min)
or hepatic disease. Abnormal creatine kinase and/or platelet count in
the past 6 months (as determined by lab reports
obtained from primary care physicians or
placebo daily over a 5 week period Stable dose maintained for an additional 4 weeks. The primary efficacy measure was the change in
SARA scores from baseline to the end of the first
arm (week 9).
RESULTS
- Nineteen subjects with SCA 3 were enrolled in the
study (placebo n10, varenicline n 9).
(Originally had 20 patients, one patient was
given study drug, but the travel was too
extensive and there were no scores The mean age of patients was 51.7 10.7 years The mean total SARA score at baseline was 16.2
4.6.
RESULTS Phase I RESULTS Phase I
variable baseline mean chantix locf mean chantix baseline mean placebo locf mean placebo p-value (wilcoxon)
sara gait 4.1 3.4 5.2 4.9 0.0313
sara stance 2.2 2 3.4 2.8 0.0728
sara sitting 0.3 0.3 0.9 1.1 0.7539
sara speech 2.4 1.9 2.3 2.3 0.3213
sara finger chase 1.2 1.1 1.2 1.7 0.3159
sara finger nose 0.8 0.8 1 1.2 0.7102
sara rapid alternating movements 2 1.4 2.1 1.7 0.0034
sara heel shin 1.4 1.5 1.8 2 0.5976
sara total 14.4 12.5 17.8 17.5 0.1563
9hpt dominant average 41.3 36.5 57.7 57.9 0.3124
9hpt nondom average 43.7 39.3 66.5 65.5 0.1447
25' walk avg 15.7 12.2 31 21.3 0.0496
becks depression 7.4 3.7 8.6 6.2 0.0313
Drop Outs
- 6 of 19 patients 4 of 19 patients took placebo, and dropped out in
Phase I These adverse events included urosepsis, muscle
pain, 1 non-compliant patient and 1 patient with
Drop Outs
- The patient with auditory hallucinations was a
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DOUBLE BLIND DOUBLE DUMMY PLACEBO CONTROLLED RANDOMIZED CLINCAL TRIAL OF IMPLANTABLE NALTREXONE (PRODETOXONE) FOR HEROIN ADDICTION
Evgeny Krupitsky, MD, PhD, D. Med. Sci.
Background
Pharmacokinetics of Prodetoxone(data from the manufacturer)
METHODS
- 306 male and female heroin addicts after detoxification, giving informed consent and passing a Naloxone challenge had been randomly assigned to one of three treatment groups (102 PATIENTS EACH).
Three cell study design:1.В Naltrexone Implant (1000 mg) (3 times, every 2 months) + Oral Placebo (OP+NI).
2. Oral Naltrexone (50mg/day) + Implant Placebo (3 times, every 2 months)(ON+PI).3. Implant Placebo(3 times, every 2 months)+ Oral Placebo (OP+PI).
All patients received biweekly clinical management / compliance enhancement counseling.
Treatment lasted 6 months.
Control of abstinence, compliance, psychiatric symptoms, and side effects – every other week.
All patients had at least one family member who was able to supervise medication compliance.
Study design: Double blind double dummy placebo controlled randomized clinical trial.
Assessments
- Assessments have been done at baseline, at each biweekly appointment, and at 3 and 6 months following the end of treatment.
Assessments included: Psychiatric rating scales, Riboflavine control of compliance, Urine drug tests, Naloxone challenge.
Secondary outcomes: Opiate negative urines, HIV risk, psychiatric symptoms, and other measures of adjustment.
