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 – 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.

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