Method and system for generating and distributing document sets using a relational database

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BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to a method and system for creating and distributing sets of related documents.

Traditionally, documents are considered as discrete paper records representing textual or other information. In recent years, a broader definition of documents has been adopted that incorporates storage of the underlying document information in electronic form. That can include graphic or other information displays derived from separate computer programs and exported into a computer word processor program and stored as a single computer file in word processor format. Many documents are functionally linked to other documents that deal with a particular business or academic function and can be referred to as `Document Sets`.

Conventional word processor documents store document information in a form fundamentally different from the form used for storage of much of the other data related to the documents (e.g., other data on a business project). Accordingly, integration of the information contained in these disparate documents, Document Sets and databases is difficult, and frequently involves repeated entry of the same information into multiple data storage devices. The Author of a document generated by a word processor does not have easy guidance on the format and content requirements of a given document type. The Author also lacks electronic access to relevant information contained in other documents or databases. Electronic transmission of a document (e.g., via computer networks) is performed by transmission of the entire electronic file for the document, regardless of whether some components of the electronic file are already present at the computer site receiving the document.

For example, Clinical Research Studies of a new drug for use in human disease require a Document Set for each Clinical Study. Each such Clinical Study requires a number of `documents` that are primarily text-based descriptions of various Clinical Study features, such as design and implementation agreements, instructions, and records of implementation of the Clinical Study. The central document for a Clinical Study is the `Protocol` which is a written description of how the Clinical Study will be conducted by an Investigator studying the drug in normal volunteers or patients with disease. In addition, other documents related to Clinical Studies are required. Documents in Clinical Study Document Sets are largely based on the underlying design of the Clinical Study, as represented by a series of actions performed at specified times.

It is therefore desirable to generate Document Sets in a manner that facilitates document creation, integration with other databases, efficient transfer of documents and related files between computers, linkage of related documents so as to access information from a common store, and enforcement of standards to be applied to such documents.

2. Description of the Prior Art

Documents are conventionally generated using either a typewriter or a computer word processor, but these methods have the disadvantage that they do not provide, or have limited capacity for, the following:

Relational Database: Storage within a relational database of document data, structural information, rules and Dependencies, so as to permit linking of comparable data residing in different sections of an individual document or in different documents, sophisticated searching, integration and analysis of the data, and analysis of data across multiple Document Sets. In addition, storage of document data in a relational database facilitates exchange of information between non-document relational databases that contain information functionally related to the information in the documents.

Time/Action Electronic Matrix: A central control mechanism for Document Sets based on an electronic matrix of time periods and associated actions.

Enhanced Electronic dissemination of Documents: Transfer of a document between computers by confining transmission to those portions of a document that are document-specific--i.e., those portions that are not shared by all other documents of the particular type.

Automatic regeneration of Dependent documents or document components: Dependency of a document or document section implies that it requires updating when a given data item shared within or across documents is changed.

Automatic updating and reconciliation of Data: Data from different documents within a Document Set or across multiple Document Sets can be automatically updated and reconciled.

Enforcement of Format and Content Requirements: Computer-controlled mechanism for avoiding document format violations and document information omissions.

For Clinical Research Studies, the following document types share linked information:

Clinical Study Protocol.

Investigator-Related Documents: Investigator Protocol Approval Forms, Correspondence, Telephone Contact Form, Site Visit Report Forms, Investigator Check Lists, Investigator Instructions.

Patient Documents: Patient Instructions, Documents to record Other Patient Data.

Regulatory Authority Documents: Clinical Study Summary; Integrated Summary of Safety; Integrated Summary of Efficacy; Other IND and NDA documents; Correspondence.

Serious Adverse Event (SAE) Documents: SAE Protocol Inventory Form, SAE Patient Report Form.

Budget Documents: Generic Budget, Investigator-specific Budget.

Informed Consent Form (ICF) Documents: Generic and Investigator-specific ICFs.

Other Internal Sponsor Documents: Memoranda; Internal Check Lists; Internal Approval Forms (for Protocol, ICF, budget, Case Report Form, drug supply request).

Other Document Types: Case Report Order Form, Drug Supply Order Form, Sample Size Estimation Form.

A `Sponsor` of a Clinical Study is the organization responsible for filing the Clinical Study with the Food and Drug Administration (`FDA`) and is normally a pharmaceutical company. Most Sponsors use a word processor to write Protocols and other documents required in a Clinical Study, frequently by copying sections of previous documents and editing these. The `Author` (i.e., the person writing the Protocol) is not forced during Protocol writing to address all of the key items in writing a Protocol, so that major omissions and errors may be frequent. Even though a Sponsor may have a `standard format` for Protocols, this may not be followed by Authors--so that the task of those reviewing and approving the Protocol is more difficult. Photocopies of the Protocol are normally distributed for internal review and for hand-written comments to be written on the copy. The Protocol exists as a word processing file that limits search capabilities (e.g., dosage used across Protocols). Normally a separate form containing key Protocol items for the Sponsor's Serious Adverse Event database is hand-generated and these data are then entered into a separate computer database. Many disparate Clinical Study databases exist in pharmaceutical companies and integration of these databases has become a significant issue with the pharmaceutical industry and FDA--with significant medico-legal and regulatory implications.

SUMMARY OF THE INVENTION

It is an object of the present invention to provide enhanced methods and systems for creating Document Sets containing documents that share common information, and for providing more efficient electronic transfer of documents and other electronic files between computers.

In accordance with a preferred embodiment of the present invention, a method and system are used to format, define, generate, maintain, distribute and analyze documents. Document-specific data are stored in a relational database which allows dynamic two-way data exchange with document templates containing information common to all documents of a specific document type; a complete document is assembled by combining the data in the template and relational database.

In accordance with another embodiment of the present invention, Document Sets (groups of documents belonging to sets of related document types that share common information) are generated together and derive common information from a common data store.

In accordance with a further embodiment of the present invention, the creation of documents that relate to activities that require multiple actions at specified time points is driven by a unique Time/Action Electronic Matrix that serves as a central control mechanism for such a document set.

In another embodiment of the present invention, documents may be electronically transferred between computers by initial storage at each computer of assembly instructions and formatting information and content common to all documents in the document set, and subsequently transmitting only document-specific information for each document, with assembly of the document being performed by a receiving computer.

In a preferred embodiment of the present invention, the document data reside in a computer relational database that permits sophisticated information searching and creation of additional documents or reports. The document structure can be stored either in specialized word processor templates or as templates residing in the relational database. The relational database also stores Document Dependencies that determine which data items and documents are to be linked. The relational database also contains examples of generic text sections and text sections from other similar documents; these text sections can be selected by the Author and inserted into an active document and edited if necessary.

In a further preferred embodiment of the present invention, a template is initially generated for each document type and applied by all Authors. Each company can have a company-specific template with customized order of sections, level of section detail, `boilerplate` texts, etc. In addition, an individual project team can use a team-specific template. For example, a clinical research program in angina pectoris might routinely include a section on treadmill exercise testing.

In accordance with a preferred method incorporating the principles of the present invention, each Author is prompted to input the required information that is stored in a computer relational database. This database is used to generate the formatted documents, and to allow search capabilities of the information stored in the database. The document structure, data and text are stored. In addition, information on Dependencies between different documents is stored and this permits automatic regeneration of all Dependent documents or components. Each user (Author or reviewer) may be assigned a unique password that gives the user access to a specific level of permission for review, editing or deletion of a document. Different levels of password protection may be provided with different levels of access (from read-only to full editing and deletion privileges). Information shared between different sections of a document or between different documents is automatically maintained. In addition, additional information (e.g., on previous Protocols or on competitive drugs) can be linked to a document, and thus can be searched and incorporated in the document by the Author.

In accordance with a further preferred method incorporating the principles of the present invention, the company or other organization using the invention can specify rules for completion of individual sections or rules linking different sections; if so, error checks may be performed to make sure that these rules are being followed. Automatic consistency checking and error checking (including spell checking) can be provided. Revisions are tracked and individual versions may be designated as final and not editable.

A system incorporating the principles of the present invention automatically updates all electronically linked sections in the document or in other documents in the Document Set when an existing data item in a document is edited, Audit trails, different levels of access (editing, read only, etc.), and `frozen` archive copies of different versions may also be made available. Word processing computer files of existing documents not created by the method of the present invention may be converted to data files in the format used in the system of the present invention so that all examples of a Document Set will be in the same database format.

Further features of the present invention are a Time/Action Electronic Matrix document controller, and a method for more effective electronic transmission of documents or other electronic files:

Time/Action Electronic Matrix:

In accordance with further embodiments of the present invention, Document Sets are generated using, as a central control mechanism, a Time/Action Electronic Matrix representing time (the period during which actions take place) and actions (evaluations, interventions or other actions taken or performed during the project to which the Document Set relates). The full data in the Time/Action Electronic Matrix may be visually represented in a `Flow Chart` table that can be incorporated directly into another document. The various documents in the Document Set utilize the information in this matrix. The matrix is represented as a set of electronic data locations. The intersection of each time-point/action pair is represented by a `cell`. The cell indicates whether or not the action is to be performed at the specified time point. When the Time/Action Electronic Matrix has been designed by the Author, the Dependent components of the various documents in the Document Set (i.e., those text sections which are dependent on the entered matrix data) are automatically available. The document text sections are independently accessed by the Author for insertion of the remaining text.

Electronic Transmission of Documents or Other Files:

According to a further embodiment of the present invention, data storage in a relational database can be used to provide a more efficient method of transmitting files electronically by computer networks or by physical transfer of copies residing in electronic storage media. Computer networks such as the Internet (a publicly available worldwide network of computers) and Intranets (organization-specific proprietary computer networks that may also access the Internet) have a significant and increasing problem of `bandwidth` creating a bottleneck in the speed of data transmission. Other workers have developed methods for compacting the information within an individual computer file (e.g., a word processor file) but have not addressed the possibility of eliminating redundant information across documents of a particular document type. Documents of a specific document type may all contain common formatting information or common text sections that substantially increase the size of the electronic document file. The example of a document provided as Protocol Document Listing I has file sizes of 66 kilobytes (KB) as a conventional Microsoft Word file, 26 KB as a simple text (ASCII) file, and 16 KB as a file confined to the document-specific components of the file (i.e., eliminating both formatting information and text segments shared by the Protocol document type). Even greater file size savings can be obtained by eliminating redundant information stored at multiple document locations at which shared information is placed (i.e., common information stored in the document database and inserted in multiple places within the document). Utilizing the present invention, the document-specific information stored in the relational database can also be stored and transmitted in a more compact data format using the C++ computer software classes that can be used in the method and system of the present invention to link the data in the relational database to the word processor templates that will generate the complete documents.

In accordance with the present invention, similar methods can be used to enhance the efficiency of transfer of non-document electronic files that belong to a particular file type that shares common formatting or content between all files of that type. The standard formatting and content for a particular file type can be transmitted to a remote computer on a single occasion, and thereafter this computer will be able to assemble a file of that type by combining the file-specific information subsequently transmitted with the standard format and content information already stored in the computer for the file type. Accordingly, major reductions in data transmission requirements can be achieved using the present invention.

The aforementioned objects, features and advantages of the present invention will become more apparent from the following detailed description, taken in conjunction with the accompanying drawings in which:

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a block diagram of the hardware components of a preferred embodiment of the system according to the present invention;

FIG. 2 is a block diagram of the main functional components of a preferred embodiment of the present invention;

FIG. 3 is a block diagram of a design engine used for a Clinical Study according to the method and system of a preferred embodiment of the present invention;

FIG. 4 is a block diagram for electronic transmission of documents according to the method and system of a preferred embodiment of the present invention;

FIG. 5 is a block diagram for electronic transmission of other file types according to the method and system of a preferred embodiment of the present invention; and

FIG. 6 is a Clinical Study Flow Chart showing the results of using the method and system embodying the present invention.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

As previously mentioned, Clinical Study documents are necessary features of investigations of the effects of drugs or other therapeutic modalities in the treatment or evaluation of human disease. The method and system according to the present invention generates Clinical Study documents and utilizes the information in such documents during the execution, analysis and reporting phase of clinical investigation.

Referring to the drawings:

FIG. 1 is a block diagram of the hardware components of a preferred embodiment of the system according to the present invention. In this figure,

Block 1 is a processor such as a computer microprocessor. Block 2 and Block 3, respectively, represent the CPU and Memory components of the microprocessor in Block 1. Block 4 is a computer hard disk. Block 5 is a computer floppy disk. Block 6 is a computer floppy disk drive. Block 7 is a network that may optionally contain some software components of the invention. Block 8 is a keyboard for data entry. Block 9 is a computer mouse. Block 10 is a video display device. Block 11 is a printer for paper copies of documents.

FIG. 2 is a block diagram of the main functional components of a preferred embodiment of the present invention.

Block 1 represents a document template that defines a preferred document format and standard text of a specific Sponsor, that is located either in a relational database or in word processor template file, and in which reside:

Block 2 which represents `Boilerplate` text that is used in most documents. Such text can be required to be used `as is` in the document (and this may be achieved by incorporation within a word processor template). It can also be used as default text that can be optionally selected by the Author.

Block 3 which represents the different sections and fields of a given document.

Block 4 represents the input elicited from the document Author, and which includes:

Block 5 which represents the overall design of the Clinical Study elicited from the Author via the Time/Action Electronic Matrix.

Block 6 which represents Author selection of `Boilerplate` text.

Block 7 which represents other text provided by the Author.

Block 8 which represents numerical data provided by the Author.

Block 9 represents a Time/Action Electronic Matrix that drives the Clinical Study design, and is associated with a graphical display on the screen of the video display device.

Block 10 represents the relational database for an individual document and which contains tables containing various functional components, including the Time/Action Electronic Matrix data and other information provided by the Author.

Block 11 represents a word processor computer software program that may participate with the relational database in two-way exchange of information, and may also be used to control assembly and printing of a completed document.

Block 12 represents the document assembly process whereby the data in the relational database is combined with the document template information. Document assembly may be done either by the word processor in Block 11 (by combining the document template stored in word processor format with the Author-entered information stored in the relational database), or from special software used in the present invention that can combine template and Author-entered information to provide either direct printout of the document, or generation of a Rich Text Format (RTF) file that can be used by a word processor to print the document.

Block 13 represents the transfer of an assembled document to another device.

Block 14 represents the transfer of a document to another computer using the special electronic transfer process used in the present invention.

Block 15 represents the transfer of document information to a printing device that can generate a hard copy of the document.

Block 16 represents the Dependency information stored with the Clinical Study template, and which determines which documents or document sections share common data.

Block 17 represents different linked documents for an individual Clinical Study.

Block 18 represents linked documents for different Clinical Studies.

Block 19 represents non-document databases that can be linked with documents generated using the present invention. Examples include a patient database of results obtained during the Clinical Study, and a commercial database of marketed drugs such as the Physicians' Desk Reference (Medical Economics Data Production Company).

Block 20 represents the search, analysis and reporting functions for multiple Clinical Studies, and the resulting compound documents.

FIG. 3 is a block diagram of a design engine used for a Clinical Study according to the method and system of a preferred embodiment of the present invention.

Block 1 represents the Time/Action Electronic Matrix that drives the Clinical Study design, and which has the following two axes:

Block 2 which represents the Actions axis, and which contains Classes of actions such as criteria for Dosing, Entry/Retention of patients, efficacy assessment, safety assessment, pharmacokinetic/pharmacodynamic assessment (PK/PD) and other (miscellaneous) actions. Each Class of actions contains a number of Items that fall within the Class.

Block 3 which represents the Times axis, and which contains Stages (Block 4), each of which contains one or more Periods (Block 5), each of which contains one or more patient Visits (Block 6).

Block 7 which represents cells in the matrix that represent Time/Action pairs, and which represent which actions are to be performed at a specific time.

An example of Clinical Study document utilizing the techniques of FIG. 3 will be subsequently reviewed.

FIG. 4 is a block diagram for transmitting a document between computers according to the method and system of a preferred embodiment of the present invention.

Block 1 represents a computer that transmits a document to a separate computer.

Block 2 represents the document assembly instructions, and the format and content information applicable to all documents of a particular document type.

Block 3 represents the document-specific content for an individual document stored in the relational database.

Block 4 represents the process whereby an electronic file is created to store the document-specific content in a condensed format using well known computer principles and techniques.

Block 5 represents a computer network or a physical or other standard computer mechanism for transferring an electronic file from one computer to another computer.

Block 6 represents a computer that receives a document transmitted from a separate computer.

Block 7 represents a process whereby the data represented in Blocks 2 and 4 are combined to assemble a complete document identical to that assembled in the computer that transmitted the data.

FIG. 5 is a block diagram for transmitting between computers an electronic file that contains formatting information or content shared among files of a specific file type according to the method and system of a preferred embodiment of the present invention. An example of such a file is one containing the assembly instructions for a document.

Block 1 represents a computer that transmits a file to a separate computer.

Block 2 represents the file assembly instructions, and the format and content information applicable to all files of a particular file type.

Block 3 represents the file-specific content for an individual file. Such a file may store data using any of a variety of standard computer principles and techniques.

Block 4 represents the process whereby an electronic file is created to store the file-specific content in a condensed format using well known computer principles and techniques.

Block 5 represents a computer network or a physical or other standard computer mechanism for transferring an electronic file from one computer to another computer.

Block 6 represents a computer that receives a file transmitted from a separate computer.

Block 7 represents a process whereby the data represented in Blocks 2 and 4 are combined to assemble a complete file identical to that stored in the computer that transmitted the data.

FIG. 6 is a Clinical Study Flow Chart that is a visual representation of a Time/Action Electronic Matrix representing time (top three rows) and actions (left hand column). The time axis represents the duration during which a patient participates in the Clinical Study, and is divided into Stages, that are divided into Periods, that are divided into Visits. The actions axis includes various action groups (drug dosing; criteria for entering or retaining a patient in the study; assessment of the clinical and laboratory efficacy of the drugs; assessment of the clinical and laboratory safety of the drugs; pharmacokinetic assessments; and other assessments) and each action group may include zero, one, or multiple action items. The `cell` located at each time/action intersection indicates whether or not the specified action is to be performed at the specified time. As an example, the action item "Physical Exam" in the Entry/Retention Criteria action group is to be performed at a single Visit (Visit -4), and Footnote 1 explains that this action is to be a "Complete Physical Examination, including height, weight and funduscopic examination". The `Flow Chart` table can be incorporated directly into another document such as the Protocol for the Clinical Study.

It is clear that the interaction between the various components of the above described blocks of the block diagrams follows well known computer principles and techniques and need not be further described in order to avoid unnecessarily complicating the drawings and specification. Thus, the computer or computers may be IBM.TM.PC-compatible personal computers using an Intel microprocessor of the 80386 or later CPU series and running the Microsoft Windows.TM. operating environment. The database program may use the Microsoft Access.TM. file format.

File transfer between computers may use a standard digital network. The Open Data Base Connectivity (ODBC) standard may be used to facilitate connection with other Sponsor or regulatory authority databases. The generation of the formatted documents may be by transfer of document-specific information to word processor templates including special field types created by the present invention; this approach allows the Authors to use their preferred word processor with all the normal functions of this word processor, together with special functions added by the present invention--for example, by providing a dynamic link library (DLL) provided as part of the invention.

Alternately, the documents may be generated by creating a Rich Text Format (RTF) file that can be utilized by any of the major computer word processors--in this alternative case, a visually appealing interface that may be written in Microsoft Visual Basic.TM. makes the system simple to use by Authors with limited computer knowledge. Communication of information between the relational data base and the word processor can be achieved by a separate component of the present invention, e.g., a set of C++ classes based on the Microsoft Visual C++.TM. computer program and the Microsoft Foundation Classes.TM.. It is of course understandable that any other computer, database program, word processor or other software may be utilized to achieve the same functional results.

A preferred embodiment of the present invention creates sets of documents for Clinical Studies. In this embodiment (see FIG. 3), the Time/Action Electronic Matrix uses as the time axis the period during which the study staff and patients participate in the Clinical Study, and as the actions axis the patient evaluations, interventions or other actions taken by study staff or patients. A Clinical Study can be considered as a sequence of time points, each of which is associated with one or more required actions--such as determining if a patient meets entry criteria, what therapy or other interventions should be prescribed for the patient, or what patient evaluations or tests should be performed.

In the Clinical Research embodiment of the present invention (see FIG. 3), the Time/Action Electronic Matrix has each axis of the matrix divided into separate classes of time or action. The Time axis of the matrix is divided into various nested levels--Stages (Pre-Therapy, Therapy, Post-Therapy), Periods (functionally discrete components within a Stage), and Visits. The Action axis is also divided into nested levels--i.e., various Categories of Evaluation/Intervention (e.g., Dosing Groups, Entry/Retention Criteria, Efficacy, Safety, Pharmacokinetics, Other) and individual Items within a Category. The Time/Action Electronic Matrix provides a flexible and simple means of performing the initial outline phase of the Clinical Study design, and of driving the subsequent format and content of the Clinical Study documents.

The Flow Chart (see FIG. 6) is displayed on the computer screen or as a paper printout in the final document, and includes an array of cells by which a given measurement, intervention or other action to be performed in the Clinical Study is linked to a given time point during the study at which the evaluation or intervention will be performed. In FIG. 6, the column on the far left lists the evaluations or interventions to be performed in Clinical Study patients; and the upper rows represent the Stages of the Clinical Study (e.g., Pre-Therapy, Therapy, and Post-Therapy), the Periods within each Stage, and the timing of Visits within each Period. Special formatting is used for Visits at which one Period ends and the next Period begins so as to describe which of the measurements or interventions at that visit represent the Period just completed or the Period just beginning. A footnote dialog box on the computer screen provides a mechanism for specifying footnotes to be associated with a given cell.

EXAMPLE

An example of utilizing the method and system of the present invention is explained using the Protocol Document Listing I as an example of a generated Clinical Research document. The Flow Chart of FIG. 6 is a visual representation of the Time/Action Electronic Matrix of the document.

PROTOCOL DOCUMENT LISTING I

ABC DRUG COMPANY CLINICAL RESEARCH PROTOCOL

DOUBLE BLIND PARALLEL STUDY OF ZALOPINE AND PLACEBO IN PATIENTS WITH MILD HYPERTENSION RECEIVING ADJUNCTIVE HYDROCHLOROTHIAZIDE

PROTOCOL NUMBER: 011-33-234-123

STUDY DRUGS: Zalopine and Placebo

DOSAGE FORM: Tablets

INVESTIGATOR: Margaret Smith, MD

STUDY LOCATION: Cardiology Division, Hippocrates School of Medicine, 1500 Broad way , New York, N.Y. 10036

MEDICAL MONITOR: Donald Kemp, M. D., 212 573-1234 Associate Medical Director, ABC Drug Company

VERSION DATE: Aug. 25, 1995

I have reviewed this Protocol and I agree to conduct this study according to the Protocol requirements.

Investigator Signature: .sub.---------- Date: .sub.------

This protocol is made available on a confidential basis to you and your staff in your capacity as an investigator or potential investigator for this clinical study. You may provide the protocol to your for the purpose of obtaining institutional approval to conduct the study. You may provide limited information to potential study patients, but only to the extent necessary for their participation in the study. The information must not be disclosed to others without written approval from ABC Drug Company.

Department of Clinical Research, ABC Drug Company, 235 East 76th Street, New York, N.Y. 10021.

I. SUMMARY

This study will be a 24-patient, 14-week, double blind, parallel comparison of zalopine and placebo in patients with mild hypertension. The Pre-Therapy Stage will have a 2-week washout Period and a 2-week single blind placebo run-in Period. The Therapy Stage will have an 8-week double blind Period. The Post-Therapy Stage will have a 2-week follow-up Period. All patients will receive adjunctive hydrochlorothiazide 50 mg qd. Patients will be assigned to zalopine or placebo in a 2:1 zalopine:placebo ratio. Zalopine dosage will be 5 mg.-20 mg qd. Efficacy (blood pressures), safety (Adverse Events and laboratory safety tests) and zalopine pharmacokinetics will be evaluated. Treatment groups will be analyzed for baseline comparability, and for differences between treatments in effects on blood pressure. Pharmacokinetic parameters will be AUC, Cmax, Tmax, and T 1/2. Descriptive statistics will be reported on other study variables.

II. OBJECTIVES

(1) Determine the efficacy of zalopine in reducing blood pressure.

(2) Determine the safety and toleration of zalopine in short term therapy.

(3) Evaluate the pharmacokinetics of zalopine in a setting of adjunctive hydrochlorothiazide therapy.

III. NUMBER OF PATIENTS

A total of 24 evaluable patients will be recruited from two sites. The sample size is based on Power of 90%, p<0.05, and a detectable difference between treatment groups of 2 mmHg. Each site will recruit approximately 12 patients.

IV. DURATION OF STUDY

The Study Duration is the time from the screening Visit until the last follow-up Visit (i.e., Week 4 through Week 10) and will be 14 weeks for each patient. The duration of double blind therapy will be 8 weeks.

V. PATIENT SELECTION CRITERIA

A. Inclusion Criteria

1. Age

At least 18 years.

2. Gender

Males, or Females without childbearing potential (see Exclusions V.B.I. below).

3. Race/Ethnicity

Patients may be of any racial or ethnic background.

4. Primary Disease

Mild hypertension (Phase V diastolic BP 90-104 mmHg) documented on at least 2 occasions and for a duration of at least 3 months prior to the study.

5. Outpatient/Inpatient Status

Outpatients.

6. Screening History, Physical Examination and Laboratory testing

A medical history, physical examination, and laboratory safety screening (see Section VIII) must be performed prior to study entry.

7. Informed Consent

All patients must give written informed consent prior to study entry.

8. Blood Donation

Patients must agree not to donate blood during the study or for 30 days after the study.

9. Adjunctive therapy required by Protocol

Hydrochlorothiazide therapy must have been taken for at least 3 months prior to the study and dosage will be 50 mg/day throughout the study.

10. Other Inclusion criteria

None.

B. Exclusion Criteria

1. Childbearing potential/pregnancy/lactation

Females must not be of child bearing potential based on prior surgery, current use of IUD or cervical cap, or post-menopausal status. Lactating women must not enter the study. See Inclusions V.A.2. above.

2. Concurrent or Previous Medical or Surgical conditions

Significant hematologic, renal, hepatic or cardiac disease.

Systemic lupus erythematosis.

Hypokalemia (see V.B.4. below).

Systolic BP>180 mmHg.

3. History of Hypersensitivity or Lack of Toleration with Drugs in Study

History of hypersensitivity reactions or severe adverse reactions to zalopine or related drugs.

4. Abnormal Laboratory Test Results

Serum potassium<3.8 mEq/L.

5. Prohibited Drug Therapy

Beta blockers, ACE inhibitors, calcium channel blockers and other antihypertensive drugs are prohibited during the study, and for 30 days prior to the study. Other investigational drugs are prohibited during the study, and for 30 days before and after the study.

6. Prohibited Non-Drug Interventions

General anesthesia or hospitalization within 30 days prior to the study or anticipated need for these interventions during the study. Blood donation within 30 days prior to the study.

7. Inability to Give Informed Consent

Patients incapable of providing fully informed consent.

8. Other Exclusion Criteria

None.

VI. STUDY DESIGN

A. Methods

1. Design

This study will be a double blind, parallel comparison of zalopine and placebo in patients with mild hypertension. Patients will be titrated to maximum permitted dosage based on efficacy and safety findings.

The Protocol is divided into the following Stages, Periods and Visits:

PERIOD EVALUATION STAGE PERIOD START/END VISITS Pre-Therapy Screening/ Week -4/ Weeks -4, -2 (Pre Rx) Washout Week -2 SB Placebo Week -2/Week 0 Weeks -2, 0 Run-In Therapy (Rx) Double Blind Week 0/Week 8 Weeks 0, 1, 2, 4, 8 Post-Therapy Follow-Up Week 8/Week 10 Week 10 (Post Rx)

Clinic Visits will be at Weeks -4, -2, 0, 1, 2, 4, 8 and 10. At the Week 8 Visit, patients will remain in the clinic for the 2, 4, 8 and 12 hours post-dosing blood pressures, in a room set aside for study patients; they may then return home and come back the following day for the 24 hours post-dosing pharmacokinetic and blood pressure evaluations. At the other Visits, patients will remain in the clinic until after the 2 hours post-dosing blood pressure evaluation.

The timing of study evaluations and treatments is shown in the flowchart in Appendix I.

2. Study Medication Instructions and Blinding Procedures

Instructions for medication handling and dispensing will be included with the shipment of the study medications to the Investigator (also see XII.B. below). The medications provided by ABC Drug Company will be the Study Drugs (zalopine and double blind placebo), run-in placebo medication, and adjunctive hydrochlorothiazide.

Tablets of zalopine and placebo will be identical in appearance. Patients will be assigned to treatment according to a computer-generated randomization list, with assignment to double blind medications being based on a 2:1 zalopine:placebo ratio. Commercially available hydrochlorothiazide tablets will be used.

3. Premature Disconti