A PHASE 3, MULTI-CENTER, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED 26-WEEK TRIAL TO EVALUATE THE EFFICACY AND SAFETY OF DIMEBON (LATREPIRDINE, PF-01913539) IN PATIENTS WITH MODERATE-TO-SEVERE ALZHEIMER’S DISEASE

• Register: EUCTR
• Last refreshed on: 28 January 2013
• Main ID: EUCTR2009-012456-25-DE
• Date of registration: 07/10/2009
• Prospective Registration: Yes
• Primary sponsor: Pfizer Inc, 235 East 42nd Street, New York, NY 10017
• Public title: A PHASE 3, MULTI-CENTER, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED 26-WEEK TRIAL TO EVALUATE THE EFFICACY AND SAFETY OF DIMEBON (LATREPIRDINE, PF-01913539) IN PATIENTS WITH MODERATE-TO-SEVERE ALZHEIMER’S DISEASE
• Scientific title: A PHASE 3, MULTI-CENTER, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED 26-WEEK TRIAL TO EVALUATE THE EFFICACY AND SAFETY OF DIMEBON (LATREPIRDINE, PF-01913539) IN PATIENTS WITH MODERATE-TO-SEVERE ALZHEIMER’S DISEASE
• Date of first enrolment: 21/12/2009
• Target sample size: 576
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2009-012456-25
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes Randomised: yes Open: no Single blind: no Double blind: yes Parallel group: yes Cross over: no Other: no If controlled, specify comparator, Other Medicinial Product: no Placebo: yes Other: no

Countries of recruitment

Czech Republic, Germany, Hungary, Portugal, Spain

Key inclusion & exclusion criteria

Inclusion criteria:
1. Are men and women =50 years of age with a diagnosis of probable AD according to the following criteria:
a. Diagnostic and Statistical Manual of Mental Disorders IV Text Revision (DSM IV TR)as listed in Appendix 1 of the protocol
b. National Institute of Neurological and Communicative Disorders and Stroke -Alzheimer’s Disease and Related Disorder Association’s Criteria (NINCDS ADRDA) for probable AD
c. MMSE score between 5 and 14 inclusive
d. Modified Hachinski Ischemic Score =4
2. Are willing and able to give informed consent. If the patient is deemed to not have capacity to provide consent, a mentally competent legally acceptable representative must provide informed consent on their behalf, and the patient must provide assent
3. Have had brain imaging such as magnetic resonance imaging (MRI) and/or computed tomography (CT) approximately within twelve months of Screening, consistent with a diagnosis of probable AD without any other clinically significant co morbid pathologies found. If there has been a significant change in clinical status suggestive of stroke or other possible central neurological disease with onset between the time of the last MRI or CT and the Screening evaluation, the scan should be repeated if considered appropriate by the Investigator
4. Must be on background anti-demtia monotherapy only with the NMDA receptor antagonist, memantine, for a minimum of six (6) months preceding the Screening MMSE and at a stable dose and regimen orally daily for at least four (4) months with no intent to change this regimen while participating in the study
5. Must be or have previously (in pre AD condition) been literate, and capable of reading, writing, and communicating effectively with others
6. Have a caregiver who assists the patient at least five days per week for at least three hours per day and has intimate knowledge of the patient’s cognitive, functional, and emotional states, and of the patient’s personal care. The caregiver must be willing to accompany the patient to all study visits and to supervise study drug administration, as well as report adverse events. The caregiver must be willing and able to give informed consent for their own participation, be able to read and write, and be capable of providing responses to the CIBIC plus, ADCS ADLsev, NPI, EQ 5D, and RUD Lite assessment tools
7. If female, is either a) of reproductive potential and compliant in using adequate birth control or b) not of reproductive potential. Adequate birth control is defined as consistent practice of an effective and accepted method of contraception (hormone based, intrauterine device, or double barrier contraception, ie, condom and diaphragm, diaphragm and spermicidal gel or foam) throughout the duration of the study. Abstinence is an acceptable method of contraception. Female patients not of reproductive potential may be patients who have undergone menopause, hysterectomy, bilateral oophorectomy, or bilateral tubal ligation. Menopause is defined as 1 year without menses. If the patient’s menopausal status is in question, a follicle stimulating hormone (FSH) level of >40 milli international units per milliliter (mIU/mL) must be documented. Hysterectomy, bilateral oophorectomy, or bilateral tubal ligation must be documented; and
8. If male, is either a) of reproductive potential and compliant in using adequate birth control or are b) not of reproductive potential. Surgical sterilization must be documented. Adequate birth control
Exclusion criteria:
1. Have clinically important structural brain disease (eg, ischemic infarcts, subdural
hematoma, hemorrhage, etc.);
2. Have any major medical illness or unstable medical condition within six months of
Screening that, in the opinion of the investigator, may interfere with the patient’s ability to comply with study procedures and abide by study restrictions, or with the ability to interpret safety data, including:
a. Any physical disability that would prevent completion of study procedures or
assessments
b. A history of cancer within five years of enrollment with the exception of
non-melanoma skin cancers or prostate cancer that has been stable for at least six
months or Grade 0 or Grade 1 cancers that have a remote probability of recurrence,;
c. The following cardiovascular parameters:
• Hypotension - systolic blood pressure <86 millimeters of mercury (mmHg) or
bradycardia with heart rate less than 50 beats per minute;
• Uncontrolled hypertension as indicated by a resting systolic blood pressure >170 mmHg or diastolic blood pressure >105 mmHg;
• A corrected QT interval by the Fridericia correction formula (QTcF) of greater than 470 milliseconds (msec) on an electrocardiogram (ECG) at the Screening Visit based on value from central over-read;
• Active cardiovascular disease..
d. A history of traumatic brain injury with remaining neurological deficit;
e. A diagnosis of a dementing central nervous system disease other than AD;
f. A history of epilepsy or seizure disorder requiring ongoing treatment, or any seizure or unexplained loss of consciousness within the six months preceding Screening;
g. Any current psychiatric diagnosis according to DSM-IV-TR that may interfere with
the patient’s ability to perform the study and all assessments;.
3. Are pregnant or lactating females;
4. Reside in a nursing home or assisted care facility with need for direct continuous medical care and nursing supervision;
5. Have a caregiver who is paid to care for more than two patients, unless that caregiver is clinically trained;
6. Have a history of previous exposure to dimebon or who have participated in a previous dimebon clinical trial;
7. Have known human immunodeficiency virus (HIV) seropositivity.;
8. Have any of the following laboratory abnormalities at the Screening visit:
a. Clinically significant Vitamin B12 levels less than the lower limit of normal (LLN) or
on replacement Vitamin B12 for less than three months prior to enrollment;
b. Clinically significant folate levels less than the lower limit of normal or on
replacement folate therapy for less than three months prior to enrollment;
c. Thyroid-stimulating hormone (TSH) levels greater than the upper limit of normal
(ULN) AND a free thyroxine lower than the lower limit of normal;
d. Positive Rapid Plasma Reagin (RPR) confirmed by Fluorescent Treponemal
Antibody - Absorption [FTA-ABS]);
e. Total bilirubin (Tbili), alanine aminotransferase (ALT), or aspartate aminotransferase (AST) levels greater than two times the upper limit of normal;
f. Renal impairment with a serum creatinine (Cr) >133 µmol/L (1.5 mg/dL);
g. Hematocrit, absolute neutrophil count, and/or platelet count below the LLN indicating clinically significant anemia, neutropenia, and/or thrombocytopenia.
9. Taken or plan to take prescribed anti-dementia agents besides memantine, from 2 months prior to the screening MMSE through the End of Study;
10. Have taken a prescription medical food or prescription nutriceuticals marketed for AD;
11.

Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Alzheimer's Disease
MedDRA version: 12.0 Level: LLT Classification code 10001896 Term: Alzheimer's disease

Intervention(s)

Product Name: Dimebon
Product Code: PF-01913539
Pharmaceutical Form: Film-coated tablet
CAS Number: 97657-92-6
Current Sponsor code: PF-01913539
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 5-
Pharmaceutical form of the placebo: Film-coated tablet
Route of administration of the placebo: Oral use

Product Name: Dimebon
Product Code: PF-01913539
Pharmaceutical Form: Film-coated tablet
CAS Number: 97657-92-6
Current Sponsor code: PF-01913539
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 20-
Pharmaceutical form of the placebo: Film-coated tablet
Route of administration of the placebo: Oral use

Primary Outcome(s)

Main Objective: The co-primary objectives of this study are:
1. To determine the effect of dimebon, as compared to placebo, on the primary measure of cognition, the Severe Impairment Battery (SIB) in patients with moderate to severe Alzheimer’s disease (AD)

2. To determine the effect of dimebon, as compared to placebo, on the primary measure of self-care and daily function, the Alzheimer’s Disease Cooperative Study -Activities of Daily Living (severe) (ADCS-ADLsev) scale in patients with moderate-to-severe AD

Primary end point(s): The co primary endpoints in this trial are change from baseline in the SIB and ADCS ADLsev as cognitive and functional measures, respectively at Week 26 (LOCF).

Secondary Objective: To determine the effect of dimebon, as compared to placebo on the following efficacy and safety measures in patients with moderate-to-severe AD:

Key Secondary Objectives:
1. Neuropsychiatric Inventory (NPI) total score (behaviour);
2. Sum of the delusions and hallucinations subdomain scores of the NPI (a measure of AD-related psychosis);
Other Secondary Objectives:
1. Clinician’s Interview-Based Impression of Change plus caregiver input (CIBIC+, global function);
2. Mini-Mental State Examination (MMSE, cognition);
3. Resource Utilization in Dementia (RUD-Lite) and quality of life (EuroQol 5-domain);
4. Influence of patient covariates on dimebon pharmacokinetics and PK/PD
5. Safety and tolerability assessments, including AEs, labs, and ECGs

Secondary ID(s)

B1451006