Life Sciences, Vol. 58, No. 15, pp. 1201-1207, 1996
`Copyright o 1996 Elsevier Science Inc.
`Printed in the USA. All rights reserved
`0024-3205 f96 $15.00 + .00
`
`PII S0024-3205(96)00081-l
`
`SAFETYffOLERABILITY TRIAL OF SDZ ENA 713
`IN PATIENTS WITH PROBABLE ALZHEIMER'S DISEASE
`
`; Thomas S. Wardle1
`John J. Sramek 1; Ravi Anand2
`
`;
`Peter Irwin2
`; Neal R. Cutler1.3
`; Richard D. Hartman2
`
`1 California Clinical Trials, Beverly Hills, California 90211; 2Sandoz Pharmaceuticals
`Corporation, East Hanover, New Jersey 07936
`
`(Received in final form February 1, 1996)
`
`Summary
`
`SDZ ENA 713 (ENA 713) is an acetylcholinesterase inhibitor being developed
`as a potential treatment for Alzheimer's disease (AD). A prior Phase II safety
`and efficacy study used an upper dose limit of 6 mg/day ENA 713. The present
`study was designed to assess the safety and tolerability of higher doses of ENA
`713 in probable AD patients. Fifty AD patients (22M; 28F, mean age 68 yrs,
`range 45-90) were assigned to a fixed, nine-week dose escalation schedule in
`which they were randomized to receive up to 12 mg/day of ENA 713 bid (n=20)
`or tid (n=20), or placebo (n=10) followed by a one-week washout. Mg/day dose
`escalation for the bid and tid ENA 713 groups was identical, beginning with 2
`mg/day on Days I to 3 and escalating to 12 mg/day in Weeks 8 and 9. Doses
`through 12 mg/day were well tolerated. Most adverse events were mild to
`moderate in severity and of limited duration, most commonly headache, nausea,
`dizziness, and diarrhea. Three offorty patients on ENA 713 discontinued, all due
`to adverse events. Two experienced nausea and vomiting; the third experienced
`an unrelated mild atrial fibrillation.
`
`Key Words: SDZ ENA 713, Alzheimer's disease, bridging study, Phase I trials
`
`Although multiple neurotransmitter deficits have been documented in the brains of patients
`with Alzheimer's disease (AD) (for a review see Bowen eta! 1995 [1]), the most prominent
`deficits described to date have been in presynaptic cholinergic markers (2,3) and the loss of
`cholinergic cell bodies ( 4 ). This has led to the hypothesis that cholinergic substitution therapy
`may be beneficial in AD (I).
`
`(+)(S)-N-ethyl-3-[(1-dimethyl-amino)ethyl]-N-methyl(cid:173)
`SDZ ENA 713 {ENA 713 or
`phenylcarbamate hydrogentartrate} is a brain-selective carbamate acetylcholinesterase (AChE)
`inhibitor which prevents the degradation of acetylcholine in the synaptic cleft, thereby
`It inhibits AChE more potently in the cortex and
`facilitating cholinergic transmirsion.
`
`3 Author to whom correspondence should be addressed at 8500 Wilshire Blvd, 7th
`Floor, Beverly Hills, California 90211.
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`hippocampus, both main targets for symptomatic treatment of AD, than in other brain regions
`(5). ENA 713 represents a potential improvement over the AChE inhibitor tacrine for several
`reasons. As a carbamate, ENA 713 has a different mechanism of enzyme inhibition than
`tacrine, resulting in a longer duration of cholinesterase activity blockade: up to ten hours in
`animals after a single dose (data on file, Sandoz Pharmaceuticals). ENA 713 has also been
`shown to potentiate central cholinergic transmission at doses not associated with peripheral
`cholinergic effects, which could permit greater tolerance at effective doses than that seen with
`tacrine. Furthermore, ENA 713 appears to have little potential for organ toxicity, as the major
`drug metabolite seen in both animals and man is a phenolic cleavage product, and there is no
`further metabolism through classical metabolic pathways.
`
`Studies in healthy volunteers showed that multiple doses of ENA 713 up to 3 mg/day were
`well tolerated. In early safety/tolerability studies in Alzheimer's patients, doses up to 3 mg
`bid were also well tolerated. Adverse events, including headache, dizziness, nausea, and
`diarrhea, were generally mild and short-lived and did not result in dose reduction or
`discontinuation. A placebo-controlled efficacy and tolerability trial was performed at doses
`of 2 and 3 mg bid in 402 AD patients, but primary efficacy variables showed no evidence of
`a statistically significant effect after 13 weeks, though two of six secondary efficacy variables
`showed greater improvement in patients receiving ENA 713 than in placebo patients (data on
`file, Sandoz Pharmaceuticals Corporation). Thus, the present study was designed to determine
`the maximum tolerated dose (MTD) of ENA 713 in Alzheimer's patients, in order to
`maximize the potential for demonstrating efficacy in subsequent extended clinical trials.
`
`Methods
`
`Outpatients with probable AD were selected to participate in this double-blind, prospective,
`randomized, parallel-group safety/tolerability study.
`Patients must have met NINCDS(cid:173)
`ADRDA criteria for probable AD (6), have had a Mini-Mental Status Examination (7) score
`between 10 and 26 inclusive, and not have had medical, neurological or psychiatric disorders
`(other than AD) which might confound assessment of the dementia. Patients were excluded
`if they had severe cardiovascular or pulmonary disease, unstable diabetes, peptic ulceration
`within five years, evidence of alcohol or substance abuse, or disease of any organ system
`which could affect study results or place patients at risk. Patients were also excluded if they
`had taken any other investigational drug within four weeks, any drug known to cause toxicity
`in a major organ system (including tacrine) within three months, tranquilizers within the past
`two weeks, antidepressants in the past month, or neuroleptics in the past two months, or if the
`patients would require concomitant medication with potential for interaction with ENA 713.
`All patients and their caregivers gave written and oral informed consent before participating,
`and the protocol was approved by a local investigational review board.
`
`Patients were randomized to receive ENA 713 bid, ENA 713 tid, or placebo for nine weeks
`of fixed dose escalation followed by a one-week washout period. All patients received three
`doses of study medication per day, with patients in the ENA 713 bid group receiving placebo
`at the midday dose. The schedule of dose escalation was identical in the two ENA 713
`treatment groups: 2 mg/day on Days 1-3, 3 mg/day on Days 4-7, 4 mg/day in Week 2,
`5 mg/day in Week 3, 6 mg/day in Week 4, 7.25 mg/day in Week 5, 8.5 mg/day in Week 6,
`10 mg/day in Week 7, and 12 mg/day in Weeks 8 and 9. In the event of poor dose toleration,
`patients were permitted to skip up to six doses at each dose level, but no more than three in
`sequence. The treatment-free washout period occurred in Week 10.
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`Patients were evaluated during screening, at baseline, and weekly through Week 4 (6 mg/day)
`as outpatients. Since doses above 6 mg/day had not previously been tested in AD patients,
`patients were hospitalized for the first nine doses (minimum three days) of each dose
`In Weeks 9 and 10,
`escalation in weeks 5-8 and were evaluated prior to each discharge.
`patients returned for evaluations as outpatients.
`
`Safety assessments included a physical examination at screening, baseline, and follow-up; vital
`signs, electrocardiogram (ECG), clinical laboratory evaluations, and volunteered and observed
`adverse event reports at screening, baseline, and weekly thereafter; and a diary of adverse
`events maintained by patients or their caregivers. Other data obtained at screening to support
`the patient's health status and diagnosis included medical and treatment histories, a modified
`Hachinski ischemic score (8), drug and hepatitis screens, a chest X-ray, computerized
`tomography or magnetic resonance imaging, and an electroencephalogram.
`
`Chi-square tests and Fisher's Exact tests were used to test homogeneity of treatment groups
`at baseline. Significance of treatment group differences in adverse event profiles and the
`proportions of abnormal ECG, clinical laboratory, and vital sign measurements were assessed
`by Fisher's Exact test. At each post-baseline time point, one-way ANOVA and pairwise t(cid:173)
`tests were used to assess between-treatment differences in ECG, clinical laboratory, and vital
`sign changes from baseline.
`
`Results
`
`Fifty probable AD patients (22M; 28F, mean age 68 yrs, range 45-90) were randomized to
`receive ENA 713 bid (n=20), ENA 713 tid (n=20), or placebo (n=lO). Two patients on
`placebo discontinued the study: one was called out of town; one misdosed himself and elected
`to discontinue. Three patients on ENA 713 discontinued, all due to adverse events. One was
`an 82-year old female who discontinued at 4mg/day (tid regimen) after experiencing mild
`atrial fibrillation. This patient was later found to have had a history of atrial arrhythmias,
`including atrial tachycardia, and the event was judged unrelated to study medication. The
`second was a 57-year old female on the bid regimen who, after experiencing intermittent mild
`to moderate nausea and vomiting beginning at 5 mg/day, discontinued at 8.5 mg/day. The
`third was a 47-year old female on the tid regimen who discontinued after experiencing nausea
`and severe vomiting at 12 mg/day.
`
`Adverse events that occurred in at least 15% of patients on either ENA 713 regimen are listed
`in Table 1. The most common adverse events experienced by patients on ENA 713 were
`headache (65%), nausea (48%), dizziness (40%), diarrhea (38%), vomiting (28%), and fatigue
`(28%). Nausea appeared sporadically at all dose levels, occurring at a greater incidence
`(p<0.05) in the ENA 713 tid group than in the placebo group. There were trends for patients
`treated with ENA 713 to show greater incidences of agitation (bid regimen) and fatigue (tid
`regimen) than patients on placebo (0.05<p<O.l 0). Except for the three patients who
`discontinued, adverse events associated with ENA 713 were generally short-lived and were
`easily managed by withholding up to three doses before resuming treatment. Once an adverse
`event had been tolerated, it did not reappear at a higher dose level. There was no apparent
`pattern for emergence of adverse events over the dose escalation period. Overall, there was
`no difference in treatment tolerability between patients on bid and tid regimens of ENA 713.
`
`There were no clinically significant changes in laboratory values, ECGs, or vital signs during
`the study.
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`Table 1.
`
`Number and percentage of patients having adverse events occurring in > 15%
`of either ENA 713 group.
`
`ENA 713
`BID
`n=20
`
`ENA 713
`TID
`n=20
`
`Placebo
`
`n=10
`
`Adverse
`event
`
`ANY EVENT
`headache
`nausea
`dizziness
`diarrhea
`vomitingt
`flatulence
`agitation
`fatigue
`abdominal pain
`rhinitis
`coughing
`myalgia
`urinary incontinence
`dyspepsia
`sweating
`asthenia
`hot flushes
`
`20 (100)
`13 ( 65)
`8 ( 40)
`8 ( 40)
`8 ( 40)
`6 ( 30)
`6 ( 30)
`6 ( 30)t
`5 ( 25)
`5 ( 25)
`4 ( 20)
`4 ( 20)
`4 ( 20)
`4 ( 20)
`3 ( 15)
`2 ( 10)
`2 ( 10)
`0
`
`18 (90)
`13 (65)
`11 (55)*
`8 (40)
`7 (35)
`5 (25)
`3 (15)
`0
`6 (30)t
`5 (25)
`5 (25)
`3 (15)
`1 ( 5)
`0
`5 (25)
`5 (25)
`5 (25)
`4 (20)
`
`13 (65)
`14 (70)
`8 (40)
`7 (35)
`13 (65)
`9 (45)
`2 (10)
`7 (35)
`5 (25)
`4 (20)
`
`10 (100)
`7 ( 70)
`1 ( 10)
`3 ( 30)
`3 ( 30)
`2 ( 20)
`1 ( 10)
`0
`0
`4 ( 40)
`4 ( 40)
`3 ( 30)
`0
`0
`3 ( 30)
`0
`0
`0
`
`9 (90)
`7 (70)
`3 (30)
`6 (60)
`4 (40)
`6 (60)
`0
`1 (10)
`4 (40)
`0
`
`ADVERSE EVENTS BY BODY SYSTEM
`17 ( 85)
`gastrointestinal system disorders
`15 ( 75)
`central & peripheral nervous syst.
`13 ( 65)
`psychiatric disorders
`musculoskeletal system disorders
`11 ( 55)
`10 ( 50)
`body as a whole - general
`8 ( 40)
`respiratory system disorders
`7 ( 35)t
`urinary system disorders
`4 ( 20)
`autonomic nervous system dis.
`4 ( 20)
`skin & appendages disorders
`3 ( 15)
`vision disorders
`
`*p<0.05 compared to placebo according to Fisher's Exact Test, two-tailed
`tp<O.l 0 compared to placebo
`tOf 11 ENA 713 patients who vomited, all experienced nausea, whereas neither of the 2
`placebo patients who vomited experienced nausea.
`
`Discussion
`
`In this study, administration of ENA 713 to patients with probable AD appeared to be safe
`and well tolerated at doses up to 12 mg/day. Mild to moderate adverse events experienced
`by at least 30% of patients in either of the two ENA 713 treatment groups included headache,
`
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`nausea, dizziness, diarrhea, vomiting, flatulence, agitation, and fatigue. These adverse events
`were predicted by earlier studies of the compound and suggest that the potential liabilities of
`ENA 713 are primarily mechanism-related side effects associated with excessive cholinergic
`stimulation. The dose titration used in this and previous ENA 713 studies was relatively slow,
`in order to allow for development of tolerance to cholinergic symptoms, particularly nausea
`and vomiting; however, adverse events were similar (in type and frequency) in this study to
`those which appeared in an earlier titration study which used doses up to 3 mg bid in probable
`AD patients. Both bid and tid regimens of ENA 713 were equally well tolerated, suggesting
`that future efficacy studies can employ the less frequent dosing regimen to improve patient
`compliance with taking study medication.
`
`No maximum tolerated dose (MTD) was reached in this study, nor was an MTD sought in any
`of the preliminary studies of ENA 713 performed in healthy elderly subjects or probable AD
`patients, though 3 mg was the highest well tolerated single dose in healthy young volunteers.
`Operationally, the MTD is defined as the dose immediately below the minimal intolerated
`dose (MID), based on multiple-dose administration of study drug to panels of at least six
`patients, with each panel receiving progressively higher doses. Our experience with MTD(cid:173)
`determining studies suggests that patients with probable AD frequently tolerate higher doses
`of cholinergic compounds than do normal subjects (higher than young normals: refs 9-12;
`higher than elderly normals: refs 13-15). Further evidence for differences in tolerability of
`cholinergic agents between AD and normal patients comes from recent reports that AD
`patients are hypersensitive to dilute amounts of the cholinergic antagonist tropicamide dropped
`into the eye (16). These differences suggest that traditional dose defining methods, which
`base clinical dosage constraints on the maximum well tolerated dose in healthy volunteers,
`may not predict dosages which will be useful for patients.
`
`In this study, the highest dose permitted was 12 mg/day, based on 50% of the no-toxic-effect
`level (NTEL) determined in animals. Dose levels above the NTEL produced cholinergic
`effects in animals (e.g. emesis, hypersalivation, diarrhea) but no permanent damage such as
`organ toxicity or changes in hematology or blood chemistry. In retrospect, establishing the
`upper human dosage based on the NTEL in animals was a handicap, since it did not allow us
`to determine the MTD for this compound in target patients. While animal studies should
`explore dosages well above any anticipated for use in humans in order to permit adequate
`characterization of the compound's toxicology, it is unclear how the NTEL can best be used
`to derive dose limits which may be useful in the development of cholinergic treatments for
`AD, since this patient population frequently tolerates doses well above those predicted.
`
`Tolerability differences between patients and healthy volunteers are an important reason to
`conduct phase I safety/tolerability studies ("bridging" studies) such as this one before initiating
`If healthy volunteers do not tolerate a compound as well as
`phase II efficacy trials (17).
`patients, and only the doses well tolerated in normals are used in Phase II, potentially useful
`agents may appear ineffective. A bridging study determines the MTD in the patient
`population before efficacy trials begin, thus permitting dose designs which maximize the
`potential to detect efficacy and save development time.
`
`Recent work with tacrine and xanomeline tartrate, showing that improvement with cholinergic
`agents is dose-proportional, further demonstrates the value of determining a patient MTD early
`in development. Large-scale trials of tacrine were conducted using low (80 mg/day) doses
`(18, 19), despite earlier evidence that 160 mg/day showed some benefit (20). Overall efficacy
`results in these two large trials were inconclusive, and a later study using doses up to 160
`
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`mg/day (21) was required to convince the scientific community of tacrine's efficacy. A
`bridging study of tacrine conducted in AD patients before Phase II may have permitted more
`rapid development by testing higher dosages earlier. Similarly, conduct of a bridging study
`appears to have been useful in the more recent development of the muscarinic agonist
`xanomeline tartrate. In a bridging study conducted by the authors, 1 00 mg tid was found to
`be the MTD in AD patients, compared to an MTD of 50 mg tid in healthy elderly subjects
`(15). In a subsequent placebo-controlled multicenter trial of 25, 50, and 75 mg tid doses of
`xanomeline in over 300 AD patients, only patients on 75 mg tid showed improvement over
`placebo-treated patients on several psychometric scales (p<0.05; see ref 15), again confirming
`the need to use the highest well-tolerated dose in patients.
`
`The high social and human cost of AD make the benefits of any pharmacologic therapy that
`could improve function in AD patients quite clear; the challenge, then, in designing bridging
`studies is to minimize risk to patients such that potential benefit outweighs potential risk.
`Clearly, it would be unethical to expose a large group of AD patients to a potentially toxic
`drug at doses tested only in normals when there is a possibility that this population will not
`tolerate the drug as well as normals. Bridging studies provide a compelling rationale to use
`particular dosages that will be tolerated and have maximum potential for efficacy. They
`represent a scientifically and ethically sound approach to drug development in the AD
`population provided that they are conducted by experienced investigators and nursing staff in
`fully-equipped hospital facilities (22).
`
`To conclude, a maximum tolerated dose was not determined in this bridging study of ENA
`713. However, doses up to 12 mg/day were well tolerated, with the majority of patients
`experiencing only mild to moderate adverse events. These doses are twice those that provided
`ambiguous results in a previous safety and efficacy study and will facilitate selection of a dose
`design which can provide a more definitive conclusion in future placebo-controlled efficacy
`trials.
`
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