Safety and Efficacy of the Xanomeline Transdermal Therapeutic System (TTS) in Patients with Mild to Moderate Alzheimer's Disease

The primary objectives of this study are

• To determine if there is a statistically significant relationship (overall Type 1 erroralpha=0.05) between the change in both the ADAS-Cog (11) and CIBIC+ scores, and drug dose (0, 50 cm2 [54 mg], and 75 cm2 [81 mg]).

• To document the safety profile of the xanomeline TTS.

The secondary objectives of this study are

• To assess the dose-dependent improvement in behavior. Improved scores on the Revised Neuropsychiatric Inventory (NPI-X) will indicate improvement in these areas.

• To assess the dose-dependent improvements in activities of daily living. Improved scores on the Disability Assessment for Dementia (DAD) will indicate improvement in these areas (see Attachment LZZT.5).

• To assess the dose-dependent improvements in an extended assessment of cognition that integrates attention/concentration tasks. The Alzheimer's Disease Assessment Scale-14 item Cognitive Subscale, hereafter referred to as ADAS-Cog (14), will be used for this assessment (see Attachment LZZT.2).

• To assess the treatment response as a function of Apo E genotype.

Patients with probable mild to moderate AD will be studied in a randomized, double-blind, parallel (3 arm), placebo-controlled trial of 26 weeks duration. The study will be conducted on an outpatient basis. Approximately 300 patients will be enrolled (see Schedule of Events for Protocol H2Q-MC-LZZT(c), Attachment LZZT.1).

Following informed consent, patients will be screened at Visit 1. At screening, patients will undergo complete neuropsychiatric assessment, psychometric testing, and general medical assessment (including medical history, pre-existing conditions, physical examination). In addition, vital signs, temperature, medication history, electrocardiogram (ECG), chest x-ray, and safety laboratories will be obtained. During the screening visit, patients will wear a placebo TTS to determine willingness and ability to comply with transdermal administration procedures. If patients have not had central nervous system (CNS) imaging in the previous 12 months, a computed tomography (CT) or magnetic resonance imaging (MRI) scan will be obtained. If patients are insulin dependent diabetics, a hemoglobin A 1c will be obtained. Screening exams and procedures may be performed after Visit 1; however, their results must be completed and available prior to randomization. The screening process should occur within 2 weeks of randomization (Visit 3 of the study).

Patients who meet enrollment criteria from Visit 1 will proceed to Visit 2 at which time they will undergo a 24-hour Ambulatory ECG. At Visit 3 the Ambulatory ECG will be removed and patients will be randomized to 1 of 3 treatment arms. The treatment arms will include a placebo arm, a low-dose xanomeline arm (50 cm 2 TTS Formulation E, 54 mg xanomeline), and a high-dose xanomeline arm (75 cm 2 TTS Formulation E, 81 mg xanomeline). All patients receiving xanomeline will be started at 50 cm 2 TTS Formulation E. For the first 8 weeks of treatment, patients will be assessed at clinic visits every 2 weeks and, thereafter, at clinic visits every 4 weeks. Patients who discontinue prior to Visit 12 (Week 24) will be brought back for full efficacy assessments at or near to 24 weeks, whenever possible.

A Data Safety Monitoring Board (DSMB), chaired by an external cardiologist, will meet after 75, 150, 225, and 300 patients have completed 1 month of treatment. The DSMB will review cardiovascular findings to decide if discontinuation of the study or any treatment arm is appropriate, if additional cardiovascular monitoring is required, if further cardiovascular monitoring is unnecessary, or if adjustment of dose within a treatment arm (or arms) is appropriate (see Section 3.9.4).

At Visits 3, 8, 10, and 12, efficacy instruments (ADAS-Cog, CIBIC+, and DAD) will be administered. NPI-X will be administered at 2-week intervals either at clinic visits or via a telephone interview. Vital signs, temperature, and an assessment of adverse events will

be obtained at all clinic visits. An electrocardiogram (ECG), and chemistry/hematology safety labs will be obtained at Visits 4, 5, 7, 8, 9, 10, 11, 12, and 13. Urinalysis will be done at Visits 4, 9, and 12. Use of concomitant medications will be collected at Visits 3, 4, 5, 7, 8, 9, 10, 11, 12, and 13. Plasma levels of xanomeline and metabolites will be obtained at Visits 3, 4, 5, 7, 9, and 11. At Visits 3, 4, 5, 7, 8, 9, 10, 11, and 12, medications will be dispensed to the patients.

Visits 1 through 13 should be scheduled relative to Visit 3 (Week 0 - randomization). Visits 4, 5, 7, 8, and 13 should occur within 3 days of their scheduled date. Visits 9, 10, 11, and 12 should occur within 4 days of their scheduled date. At Visit 13 patients will be given the option to enter the open-label extension phase (see Section 3.10.3. Study Extensions).

Figure LZZT.1. Illustration of study design for Protocol H2Q-MC-LZZT(c).

Previous studies of the oral formulation have shown that xanomeline tartrate may improve behavior and cognition. Effects on behavior are manifest within 2 to 4 weeks of initiation of treatment. The same studies have shown that 8 to 12 weeks are required to demonstrate effects on cognition and clinical global assessment. This study is intended to determine the acute and chronic effects of the TTS formulation in AD; for that reason, the study is of 26 weeks duration. Dosage specification has been made on the basis of tolerance to the xanomeline TTS in a clinical pharmacology study (H2Q-EW-LKAA), and target plasma levels as determined in studies of the oral formulation of xanomeline (H2Q-MC-LZZA).

The parallel dosing regimen maximizes the ability to make direct comparisons between the treatment groups. The use of placebo allows for a blinded, thus minimally biased, study. The placebo treatment group is a comparator group for efficacy and safety assessment.

Two interim analyses are planned for this study. The first interim analysis will occur when 50% of the patients have completed Visit 8 (8 weeks). If required, the second interim analysis will occur when 50% of the patients have completed Visit 12 (24 weeks). (See Section 4.6, Interim Analyses.)

The name, title, and institution of the investigator(s) is/are listed on the Investigator/Contacts cover pages provided with this protocol. If the investigator is changed after the study has been approved by an ethical review board, or a regulatory agency, or by Lilly, this addition will not be considered a change to the protocol. However, the Investigator/Contacts cover pages will be updated to provide this information.

Commencing at Visit 1, all patients will be assigned an identification number. This identification number and the patient's three initials must appear on all patient-related documents submitted to Lilly.

When qualified for enrollment at Visit 3 the patient will be randomized to 1 of 3 treatment arms.

The study will be double-blind. To further preserve the blinding of the study, only a minimum number of Lilly and CRO personnel will see the randomization table and codes before the study is complete.

Emergency codes generated by a computer drug-labeling system will be available to the investigator. These codes, which reveal the patients treatment group, may be opened during the study only if the choice of follow-up treatment depends on the patient's therapy assignment.

The investigator should make every effort to contact the clinical research physician prior to unblinding a patient's therapy assignment. If a patient's therapy assignment is unblinded, Lilly must be notified immediately by telephone. After the study, the investigator must return all sealed and any opened codes.

Intermittent use of chloral hydrate, zolpidem, or lorazepam is permitted during this clinical trial as indicated for agitation or sleep. If medication is required for agitation for a period exceeding 1 week, a review of the patient's status should be made in consultation with the CRO research physician. Caregivers and patients should be reminded that these medications should not be taken within 24 hours of a clinic visit (including the enrollment visit), and administration of efficacy measures should be deferred if the patient has been treated with these medications within the previous 24 hours.

If an antihistamine is required during the study, Claritin® (loratadine) or Allegra® (fexofenadine hydrochloride) are the preferred agents, but should not be taken within 24 hours of a clinic visit. Intermittent use (per package insert) of antitussives (containing antihistamines or codeine) and select narcotic analgesics (acetaminophen with oxycodone, acetaminophen with codeine) are permitted during the trial. Caregivers and patients should be reminded that antihistamines and narcotics should not be taken within 3 days of a clinic efficacy visit (including enrollment visit). If an H 2 blocker is required during the study, Axid® (nizatidine) will be permitted on a case-by-case basis by the CRO medical monitor. For prostatic hypertrophy, small doses (2 mg per day) of Hytrin® (terazosin) or Cardura® (doxazosin) will be permitted on a case-by-case basis. Please consult the medical monitor. The calcium channel blockers Cardene® (nicardipine),

Norvasc® (amlodipine), and DynaCirc® (isradipine) are allowed during the study. If a patient has been treated with any medication within disallowed time periods prior to the clinic visit, efficacy measures should be deferred.

Other classes of medications not stated in Exclusion Criteria, Section 3.4.2.2, will be permitted. Patients who require treatment with an excluded medication (Section 3.4.2.2) will be discontinued from the study following consultation with the CRO research physician.

To ensure both the safety of participants in the study, and the collection of accurate, complete, and reliable data, Lilly or its representatives will perform the following activities:

• Provide instructional material to the study sites, as appropriate.

• Sponsor a start-up training session to instruct the investigators and study coordinators. This session will give instruction on the protocol, the completion of the clinical report forms, and study procedures.

• Make periodic visits to the study site.

• Be available for consultation and stay in contact with the study site personnel by mail, telephone, and/or fax.

• Review and evaluate clinical report form data and use standard computer edits to detect errors in data collection.

To ensure the safety of participants in the study and to ensure accurate, complete, and reliable data, the investigator will do the following:

• Keep records of laboratory tests, clinical notes, and patient medical records in the patient files as original source documents for the study.

Lilly or its representatives may periodically check a sample of the patient data recorded against source documents at the study site. The study may be audited by Lilly Medical Quality Assurance (MQA) and/or regulatory agencies at any time. Investigators will be given notice before an MQA audit occurs.

In general, all patients will be included in all analyses of efficacy if they have a baseline measurement and at least one postrandomization measurement. Refer to Section 3.9.1.2. for a discussion of which specific efficacy data will be included in the primary analysis.

In the event that the doses of xanomeline TTS are changed after the study starts, the analysis will be of three treatment groups (high dose, low dose, and placebo), even though patients within the high dose treatment group, for example, may not all be at exactly the same dose. Also, if the dose is changed midway through the study, the mean dose within each group will be used in the dose response analysis described in Section 4.3.3.

All analyses described below will be conducted using the most current production version of SAS® available at the time of analysis.

All measures (for example, age, gender, origin) obtained at either Visits 1, 2, or 3, prior to randomization, will be summarized by treatment group and across all treatment groups. The groups will be compared by analysis of variance (ANOVA) for continuous variables and by Pearson's chi-square test for categorical variables. Note that because patients are randomized to 1 of the 3 treatment groups, any statistically significant treatment group differences are by definition a Type I error; however, the resulting p-values will be used as another descriptive statistic to help focus possible additional analyses (for example, analysis of covariance, subset analyses) on those factors that are most imbalanced (that is, that have the smallest p-values).

Although safety data is collected at the 24 week visit for retrieved dropouts, these data will not be included in the primary analysis of safety.

Pearson's chi-square test will be used to analyze 3 reasons for study discontinuation (protocol completed, lack of efficacy, and adverse event), the incidence of abnormal (high or low) laboratory measures during the postrandomization phase, and the incidence of treatment-emergent adverse events. The analysis of laboratory data is conducted by comparing the measures to the normal reference ranges (based on a large Lilly database), and counting patients in the numerator if they ever had a high (low) value during the postrandomization phase.

Additionally, for the continuous laboratory tests, an analysis of change from baseline to endpoint will be conducted using the same ANOVA model described for the efficacy measures in Section 4.3. Because several laboratory analytes are known to be nonnormally distributed (skewed right), these ANOVAs will be conducted on the ranks.

Several outcome measures will be extracted and analyzed from the Ambulatory ECG tapes, including number of pauses, QT interval, and AV block (first, second, or third degree). The primary consideration will be the frequency of pauses. The number of pauses greater than or equal to 2, 3, 4, 5 and 6 seconds will be tabulated. Primary analysis will focus on the number of pauses greater than or equal to 3 seconds. Due to possible outliers, these data will be analyzed as the laboratory data, by ANOVA on the ranks.

Treatment-emergent adverse events (also referred to as treatment-emergent signs and symptoms, or TESS) are defined as any event reported during the postrandomization period (Weeks 0 - 26) that is worse in severity than during the baseline period, or one that occurs for the first time during the postrandomization period.

The effect of age, gender, origin, baseline disease severity as measured by MMSE, Apo E, and patient education level upon efficacy will be evaluated if sample sizes are sufficient to warrant such analyses. For example, if all patients are Caucasian, then there is no need to evaluate the co-factor origin. The ANCOVA and ANOVA models described above will be supplemented with terms for the main effect and interaction with treatment. Each co-factor will be analyzed in separate models. The test for treatment-bysubgroup interaction will address whether the response to xanomeline, compared with placebo, is different or consistent between levels of the co-factor.

Two interim efficacy analyses are planned. The first interim analysis will occur when approximately 50% of the patients have completed 8 weeks; the second interim analysis is to be conducted when approximately 50% of the patients have completed 24 weeks of the study. The purpose of these interim analyses is to provide a rationale for the initiation of subsequent studies of xanomeline TTS, or if the outcome is negative to stop development of xanomeline TTS. The method developed by Enas and Offen (1993) will be used as a guideline as to whether or not to stop one treatment arm, or the study, to declare ineffectiveness. The outcome of the interim analyses will not affect in any way the conduct, results, or analysis of the current study, unless the results are so negative that they lead to a decision to terminate further development of xanomeline TTS in AD. Hence, adjustments to final computed p-values are not appropriate.

Planned interim analyses, and any unplanned interim analyses, will be conducted under the auspices of the data monitoring board assigned to this study. Only the data monitoring board is authorized to review completely unblinded interim efficacy and safety analyses and, if necessary, to disseminate those results. The data monitoring board will disseminate interim results only if absolutely necessary. Any such dissemination will be documented and described in the final study report. Study sites will not receive information about interim results unless they need to know for the safety of their patients.

An analysis of the cardiovascular safety monitoring (see section 3.9.4) will be performed when approximately 25 patients from each treatment arm have completed at least 2 weeks at the treatment arms' respective full dosage (Visit 5). If necessary, this analysis will be repeated every 25 patients per arm. This analysis will be conducted under the auspices of the DSMB. This board membership will be composed of 3 external cardiologists who will be the voting members of the board, a Lilly cardiologist, a Lilly statistician, and the Lilly research physician in charge of the study. Only the DSMB is authorized to review completely unblinded cardiovascular safety analyses and, if necessary, to disseminate those results. The outcome of the cardiovascular safety analyses will determine the need for further Ambulatory ECGs.

Plasma concentrations of xanomeline will be determined from samples obtained at selected visits (Section 3.9.2). The plasma concentration data for xanomeline, dosing information, and patient characteristics such as weight, gender and origin will be pooled and analyzed using a population pharmacokinetic analysis approach (for example, NONMEM). This approach preserves the individual pharmacokinetic differences through structural and statistical models. The population pharmacokinetic parameters through the structural model, and the interindividual and random residual variability through the components of the statistical models will be estimated. An attempt will also be made to correlate plasma concentrations with efficacy and safety data by means of population pharmacokinetic/pharmacodynamic modeling.

In the United States and Canada, the investigator is responsible for preparing the informed consent document. The investigator will use information provided in the current [Clinical Investigator's Brochure or product information] to prepare the informed consent document.

The informed consent document will be used to explain in simple terms, before the patient is entered into the study, the risks and benefits to the patient. The informed consent document must contain a statement that the consent is freely given, that the patient is aware of the risks and benefits of entering the study, and that the patient is free to withdraw from the study at any time.

As used in this protocol, the term “informed consent” includes all consent and/or assent given by subjects, patients, or their legal representatives.

In addition to the elements required by all applicable laws, the 3 numbered paragraphs below must be included in the informed consent document. The language may be altered to match the style of the informed consent document, providing the meaning is unchanged. In some circumstances, local law may require that the text be altered in a way that changes the meaning. These changes can be made only with specific Lilly approval. In these cases, the ethical review board may request from the investigator documentation evidencing Lilly's approval of the language in the informed consent document, which would be different from the language contained in the protocol. Lilly shall, upon request, provide the investigator with such documentation.

1. “I understand that the doctors in charge of this study, or Lilly, may stop the study or stop my participation in the study at any time, for any reason, without my consent.”

2. “I hereby give permission for the doctors in charge of this study to release the information regarding, or obtained as a result of, my participation in this study to Lilly, including its agents and contractors; the US Food and Drug Administration (FDA) and other governmental agencies; and to allow them to inspect all my medical records. I understand that medical records that reveal my identity will remain confidential, except that they will be provided as noted above or as may be required by law.”

3. “If I follow the directions of the doctors in charge of this study and I am physically injured because of any substance or procedure properly given me under the plan for this study, Lilly will pay the medical expenses for the treatment of that injury which are not covered by my own insurance, by a government program, or by any other third party. No other compensation is available from Lilly if any injury occurs.”

The investigator is responsible for obtaining informed consent from each patient or legal representative and for obtaining the appropriate signatures on the informed consent document prior to the performance of any protocol procedures and prior to the administration of study drug.

The name and address of the ethical review board are listed on the Investigator/Contacts cover pages provided with this protocol.

The investigator will provide Lilly with documentation of ethical review board approval of the protocol and the informed consent document before the study may begin at the site or sites concerned. The ethical review board(s) will review the protocol as required.

The investigator must provide the following documentation:

• The ethical review board's annual reapproval of the protocol

• The ethical review board's approvals of any revisions to the informed consent document or amendments to the protocol.

This study will be conducted in accordance with the ethical principles stated in the most recent version of the Declaration of Helsinki or the applicable guidelines on good clinical practice, whichever represents the greater protection of the individual.

After reading the protocol, each investigator will sign 2 protocol signature pages and return 1 of the signed pages to a Lilly representative (see Attachment LZZT.10).

Figure LZZT.1. Illustration of study design for Protocol H2Q-MC-LZZT(c).

Following informed consent, patients will be screened at Visit 1. At screening, patients will undergo complete neuropsychiatric assessment, psychometric testing, and general medical assessment (including medical history, pre-existing conditions, physical examination). In addition, vital signs, temperature, medication history, electrocardiogram (ECG), chest x-ray, and safety laboratories will be obtained. During the screening visit, patients will wear a placebo TTS to determine willingness and ability to comply with transdermal administration procedures. If patients have not had central nervous system (CNS) imaging in the previous 12 months, a computed tomography (CT) or magnetic resonance imaging (MRI) scan will be obtained. If patients are insulin dependent diabetics, a hemoglobin A 1c will be obtained. Screening exams and procedures may be performed after Visit 1; however, their results must be completed and available prior to randomization. The screening process should occur within 2 weeks of randomization (Visit 3 of the study).

Patients who meet enrollment criteria from Visit 1 will proceed to Visit 2 at which time they will undergo a 24-hour Ambulatory ECG. At Visit 3 the Ambulatory ECG will be removed and patients will be randomized to 1 of 3 treatment arms. The treatment arms will include a placebo arm, a low-dose xanomeline arm (50 cm 2 TTS Formulation E, 54 mg xanomeline), and a high-dose xanomeline arm (75 cm 2 TTS Formulation E, 81 mg xanomeline). All patients receiving xanomeline will be started at 50 cm 2 TTS Formulation E. For the first 8 weeks of treatment, patients will be assessed at clinic visits every 2 weeks and, thereafter, at clinic visits every 4 weeks. Patients who discontinue prior to Visit 12 (Week 24) will be brought back for full efficacy assessments at or near to 24 weeks, whenever possible.

At Visits 3, 8, 10, and 12, efficacy instruments (ADAS-Cog, CIBIC+, and DAD) will be administered. NPI-X will be administered at 2-week intervals either at clinic visits or via a telephone interview. Vital signs, temperature, and an assessment of adverse events will be obtained at all clinic visits. An electrocardiogram (ECG), and chemistry/hematology safety labs will be obtained at Visits 4, 5, 7, 8, 9, 10, 11, 12, and 13. Urinalysis will be done at Visits 4, 9, and 12. Use of concomitant medications will be collected at Visits 3, 4, 5, 7, 8, 9, 10, 11, 12, and 13. Plasma levels of xanomeline and metabolites will be obtained at Visits 3, 4, 5, 7, 9, and 11. At Visits 3, 4, 5, 7, 8, 9, 10, 11, and 12, medications will be dispensed to the patients.

Visits 1 through 13 should be scheduled relative to Visit 3 (Week 0 - randomization). Visits 4, 5, 7, 8, and 13 should occur within 3 days of their scheduled date. Visits 9, 10, 11, and 12 should occur within 4 days of their scheduled date. At Visit 13 patients will be given the option to enter the open-label extension phase (see Section 3.10.3. Study Extensions).