RFP_No._NIHDA-2018-00198_-_Ammendment_1.pdf

NSN 7540 - 01 - 152 – 8070 STANDARD FORM 30 (REV. 10-83)

PREVIOUS EDITION UNUSABLE Prescribed by GSA

FAR (48CFR) 53.243

OMB No. 0990-0115 AMENDMENT OF SOLICITATION/MODIFICATION OF CONTRACT 1. CONTRACT ID CODE PAGE OF PAGES 1 15

2. AMENDMENT/MODIFICATION NO. 3. EFFECTIVE DATE 4. REQUISITION/PURCHASE REQ. NO. 5. PROJECT NO. (If applicable)

01 See Block 16C

6. ISSUED BY CODE tc 7. ADMINISTERED BY (If other than Item 6) CODE National Institute on Drug Abuse, NIH NIDA Section, Contracts Management Branch Blue Office of Acquisition, NIDA 6001 Executive Blvd, Room 4211 - MSC 9559 Bethesda, MD 20892-9559

8. NAME AND ADDRESS OF CONTRACTOR (No., street, county, State and ZIP Code)

To All Potential Offerors

9A. AMENDMENT OF SOLICITATION NO.

NIHDA-2018-00198

9B. DATED (SEE ITEM 11)

August 28, 2018

10A. MODIFICATION OF CONTRACT/ORDER NO.

10B. DATED (SEE ITEM 13)

CODE FACILITY CODE

11. THIS ITEM ONLY APPLIES TO AMENDMENTS OF SOLICITATIONS

The above numbered solicitation is amended as set forth in Item 14. The hour and date specified for receipt of Offer is extended is not extended.

Offers must acknowledge receipt of this amendment prior to the hour and date specified in the solicitation or as amended, by one of the following methods:

(a) By completing Item 8 and 15, and returning 1 copies of the amendment; (b) acknowledging receipt of this amendment on each copy of the offer submitted; or (c) By separate letter or telegram which includes a reference to the solicitation and amendment numbers. FAILURE OF YOUR ACKNOWLEDG- MENT TO BE RECEIVED AT THE PLACE DESIGNATED FOR RECEIPT OF OFFERS PRIOR TO THE HOUR AND DATE SPECIFIED MAY RESULT IN REJECTION OF YOUR OFFER. If by virtue of this amendment you desire to change an offer already submitted, such change may be made by telegram or letter, provided each telegram or letter makes reference to the solicitation and this amendment, and is received prior to the opening hours and date specified.

12. ACCOUNTING AND APPROPRIATION DATA (If required)

13. THIS ITEM APPLIES ONLY TO MODIFICATIONS OF CONTRACTS/ORDERS,

IT MODIFIES THE CONTRACT/ORDER NO. AS DESCRIBED IN ITEM 14.

A. THIS CHANGE ORDER IS ISSUED PURSUANT TO: (Specify authority) THE CHANGES SET FORTH IN ITEM 14 ARE MADE IN THE CONTRACT/ORDER NO. IN ITEM 10A.

B. THE ABOVE NUMBERED CONTRACT/ORDER IS MODIFIED TO REFLECT THE ADMINISTRATIVE CHANGES (such as changes in paying office, appropriation data, etc.) SET FORTH IN ITEM 14, C. THIS SUPPLEMENTAL AGREEMENT IS ENTERED INTO PURSUANT TO AUTHORITY OF:

D. OTHER (Specify type of modification and authority)

E. IMPORTANT: Contractor is not, is required to sign this document and return copies to the issuing office.

14. DESCRIPTION OF AMENDMENT/MODIFICATION (Organized by UCF section headings, including solicitation/contract subject matter where feasible.)

PURPOSE: To amend the Request for Proposal (RFP) to update clauses in Section C extend the deadline for response to the RFP. All other terms and conditions of the RFP remain unchanged.

Proposal Due Date: Wednesday, October 3, 2018, 2:00 PM EST (Changed)

Note: the Offeror should acknowledge on the cover page or first page of its business and technical proposals receipt of the RFP and this Amendment.

Except as provided herein, all terms and conditions of the document referenced in Item 9A or 10A, as heretofore changed, remains unchanged and in full force and effect.

15A. NAME AND TITLE OF SIGNER (Type or print) 16A. NAME AND TITLE OF CONTRACTING OFFICER (Type or print)

Tracy L. Cain, Contracting Officer, NID Section, CMB Blue

15B. CONTRACTOR/OFFEROR 15C. DATE SIGNED 16B. UNITED STATES OF AMERICA 16C. DATE SIGNED

(Signature of person authorized to sign) BY

(Signature of Contracting Officer)

Request for Proposal Amendment No. 1 NIHDA-2018-00198 Page 2 of 14

Request for Proposal (RFP) No. NIHDA-2018-00198 is amended as follows:

ARTICLE C.1. STATEMENT OF WORK, is superseded in whole as follows:

I. Introduction/Objectives

The objectives of this contract are to determine the effects of compounds in the following paradigms:

(1) drug discrimination test in nonhuman primates when tested alone or in combination with cocaine and (2) self- administration test in nonhuman primates when tested for ability to reduce cocaine self administration or to be directly self-administered.

Insofar as the Addiction Treatment Discovery Program (ATDP) is a screening and evaluation program that utilizes standardized protocols, the Contractor shall be willing to adopt the ATDP protocols in order to accommodate the needs of the program. However, NIDA recognizes that advances in the field of substance abuse research during the course of the Contract may require modification of the testing paradigms as specified in the Statement of Work. In addition, shifting priorities within NIDA may require this contract to support testing needs using other drugs of abuse, particularly opioids. If necessary, the Contracting Officer will issue a modification requiring introduction of these tests into the testing program, and appropriate options will be exercised to cover the cost. These options will cover animal purchases, laboratory supplies, and labor.

The NIDA Division of Therapeutics and Medical Consequences anticipates that, based on promising findings in preliminary rodent studies and nonhuman primate studies, some potential treatment medications will require additional follow-up preclinical studies in nonhuman primates. These follow-up studies may be required so that the Addiction Treatment Discovery Program can decide whether to recommend these compounds as drug development candidates.

NIDA cannot accurately predict the need for these follow-up studies and the precise experimental design of the studies will depend upon initial findings. In part to address this uncertainty, options are included in this Statement of Work that may cover the labor hours for these studies. Separate options are included to cover purchases and laboratory supplies.

II. Services to be Performed

A. General Requirements

1. Independently, and not as an agent of the Government, the Contractor shall furnish all necessary labor, materials, supplies, equipment, and services (except as otherwise specified herein) and perform the work set forth below.

2. All work under this contract shall be monitored by the Government Contracting Officer's Representative (COR).

B. Specific Requirements

1. Task Requirements

NIHDA-2018-00198 Page 3 of 14

Task 1: The specific objectives of this task are to determine the efficacy (i.e., dose response evaluation) of ATDP compounds to substitute for the discriminative stimulus effects of cocaine and/or to inhibit or antagonize the discriminative stimulus effects of a cocaine injection. Within Task 1, the Contractor shall conduct two distinct experimental procedures referred to as the substitution protocol and the antagonism protocol. The Contractor shall conduct both of these protocols in monkeys trained to discriminate cocaine from saline according to the procedures and experimental specifications described in Subsection C. For Task 1, the Contractor shall utilize a maximum of eight monkeys and a minimum of three monkeys for each compound evaluation. At the time of award, all monkeys used for Task 1 shall be male rhesus monkeys (Macaca mulatta); however, over the life of the contract, if it becomes increasingly difficult for the Contractor to obtain virus-free rhesus monkeys, the NIDA Contracting Officer's Representative (COR) may authorize the use of a different type of monkey (e.g., cynomolgous Macaca fascicularis monkeys).

The Contractor shall perform all testing on compounds assigned by the COR.

The Contractor shall blind the identity of all standard compounds under evaluation to those conducting the assays. Any alterations in the described protocol design and conduct are subject to COR approval. Approximately 5-12 compounds will be evaluated each contract year.

Task 2: The specific objectives of this task are to determine the efficacy (i.e., dose response evaluation) of ATDP test compounds to alter cocaine-maintained responding (i.e., cocaine self-administration) as compared to food-maintained responding in nonhuman primates (pretreatment protocol), and/or to evaluate the efficacy of ATDP compounds to replace cocaine as the drug available for intravenous self-administration (substitution protocol). The pretreatment self-administration protocol shall be conducted by the Contractor according to the specifications described in Subsection D, and requires that the efficacy of ATDP compounds be evaluated at multiple (i.e., more than 2) doses, sufficient to characterize compound- induced alterations (shifts) in the cocaine dose-response curve. Likewise, the Contractor shall conduct the substitution self-administration protocol according to the specifications described in Subsection D and requires that the Contractor evaluate test compounds at multiple unit doses. Both of these protocols shall be conducted by the Contractor in male rhesus monkeys (Macaca mulatta) trained to self-administer food and cocaine (intravenous (i.v.) injection method) according to the training procedures and experimental specifications described in Subsection D. For Task 2, the Contractor shall utilize a minimum of eight monkeys with a minimum of four monkeys utilized for each compound evaluation. At the time of award, all monkeys used for Task 1 shall be male rhesus monkeys (Macaca mulatto); however, over the life of the contract, if it becomes increasingly difficult for the Contractor to obtain virus-free rhesus monkeys, the NIDA COR may authorize the use of a different type of monkey (e.g., cynomolgous Macaca fascicularis monkeys). The Contractor shall perform all testing on compounds assigned by the COR. The Contractor

NIHDA-2018-00198 Page 4 of 14 shall blind the identity of all standard compounds under evaluation to those conducting the assays. Any alterations in the described protocol design and conduct are subject to approval by the COR. The Contractor shall evaluate approximately 5-12 compounds.

Task 3: Approximately every 12 months (if options are exercised), the Contractor shall attend a meeting (up to 2 days each) with NIDA staff and possibly a group of consultants for the purpose of reviewing past, current and/or proposed work under this contract. Specific items for discussion will be subject to the approval of the NIDA COR. Prior to each meeting, the Contractor shall, if requested by the NIDA COR, prepare "pre-meeting packets" summarizing all data on test compounds to be presented and describing relevant protocol methods. The Contractor shall include summaries of:

proposals for optimization of existing protocols; progress in ongoing protocol development (Task 6, Task 7); proposals for new protocol development;

problems encountered in the implementation of tasks required by the contract;

and proposed solutions to problems encountered. The Contractor shall send this information to the NIDA COR at least three weeks in advance of each meeting for approval, and after approval is obtained, to each consultant at least two weeks prior to the meeting. The Contractor shall present this information at the meetings and subsequently prepare a report to summarize and synthesize the findings of each meeting. In most cases, the site of the meetings shall be in the Washington, D.C. area. However, in some special circumstances the NIDA COR may designate another meeting site, such as a professional meeting (e.g., College on Problems of Drug Dependence meeting, Society for Neuroscience meeting, etc.). This contract shall be responsible for payment of the Contractor's travel expenses (up to three persons) to all contract and/or consultant meetings. Another NIDA contract will pay all expenses for the consultants. The NIDA COR may specify which individuals will serve as consultants.

Task 4: The Contractor shall maintain a chronological list of compound authorization, receipt, usage, and evaluation. The Contractor shall maintain separate logs for compounds authorized for drug discrimination and self-administration testing. The following information shall be recorded in tabular form: (1) compound under study (the ATDP compound number with associated batch number or compound name if provided), (2) date when written authorization to evaluate a compound was obtained from the COR, (3) description of authorized protocol procedure (i.e., drug discrimination or self-administration utilizing substitution, antagonism or pretreatment protocol), (4) date when compound was received from distribution site, (5) date of study initiation (date that laboratory testing begins), (6) study completion date (date when Contractor deems laboratory testing to be complete), (7) date that resulting Final Study Report was sent to the NIDA COR, and (8) date of report revision, if requested. The Contractor shall maintain this table chronologically, by date of compound testing authorization. The Contractor shall update this

NIHDA-2018-00198 Page 5 of 14 table at least once each month, within 5 working days before the submission date of each Monthly Progress Report.

Task 5: The Contractor shall retain, for the duration of this contract, all laboratory notebooks (which shall include hard copies of raw data) and any electronic data files generated under this contract, as well as all coded ATDP compounds received for evaluation under this contract. Beginning on a date specified by the NIDA COR and continuing throughout the life of the contract, the Contractor shall maintain a cumulative data table in electronic spreadsheet format. The table shall contain, for each standard or test compound evaluated, all values (e.g., ED50 values) that the NIDA COR indicate will be entered into NIDA's internal medications development database in a format to be specified by the COR. The Contractor shall update the table at least monthly.

Simultaneous with table updates, the Contractor shall, if so instructed by the NIDA COR, electronically transfer all new data to NIDA. The NIDA COR will provide the Contractor with appropriate instructions for transferring data. In lieu of the above, the NIDA COR may require the Contractor to submit the updated table on a data storage device such as a USB flash drive, by mail. In addition, the Contractor shall label complete electronic data files and electronic files of all study reports according to ATDP compound number and date of evaluation.

On or before the expiration date of this contract, the Contractor shall ship the laboratory notebooks and electronic files to the NIDA COR. On or before the expiration date of the Contract, the Contractor shall ship the test compounds, following authorization by the COR, to the NIDA-contracted compound distribution site.

Task 6: As directed by the NIDA COR, the Contractor shall conduct follow-up studies on compounds with particular promise as clinical candidates for treatment of drug dependence. These studies may necessitate the development and pharmacological characterization of a nonhuman primate model of drug dependence that is amenable to the evaluation of potential pharmacotherapeutic agents. Examples of such follow-up studies may include but are not limited to the following: (1) modification of the specified protocols in Subsections C and D that would allow for a more rapid evaluation of compounds and thus increase compound throughput; (2) development of a protocol that has features similar to the clinical situation of relapse to drug use; (3) development of a protocol that utilizes neuroendocrine, neurochemical and/or physiological endpoints that are relevant to drug dependence and/or withdrawal; and (4) development of individualized, specific protocols with regard to dosing, schedule of testing, or other parameters as needed for the evaluation of particular compounds. Study designs shall be subject to the prior review and approval of the NIDA COR.

Data reports and compound testing by the Contractor shall adhere to a format determined by the NIDA COR. Work under this task may or may not be authorized by the COR depending upon the needs of Program, and would require the exercise of options.

NIHDA-2018-00198 Page 6 of 14

Task 7: As directed by the NIDA COR the Contractor shall develop drug discrimination and self administration protocols using an opiate compound, THC, or possibly another drug of abuse as the training drug, and conduct assessments of potential treatment medications using these methods described under Tasks 1 and 2. Although the protocols may be similar to those used for cocaine, differences in pharmacokinetics or other factors may necessitate different training procedures, operant schedules and protocol differences that cannot be specified at this time. In addition, the use of other primate species may be considered depending upon the rationale. Through the exercise of options, protocols would be developed and approved, additional animals would be obtained, trained, and used for testing. Data reports prepared by the Contractor shall adhere to a format determined by the NIDA COR. Work under this task may or may not be authorized by the COR depending upon the needs of Program, and would require the exercise of options.

2. Schedule of Work

Base Period plus Option Periods 1-4 and Option Quantities (if options are exercised):

I. The Contractor shall evaluate up to 12 compounds as described under Task 1 and evaluate up to 12 compounds as described under Task 2. The Contractor shall also conduct the work described under Tasks 3 through 5.

II. Options (available each year):

Option 1: The Contractor shall devote up to 1000 person hours to the work described under Task 6 and/or Task 7.

Option 2: The Contractor shall devote up to 2000 person hours to the work described under Task 6 and/or Task 7.

Option 3: The Contractor shall devote up to 4000 person hours to the work described under Task 6 and/or Task 7.

Option 4: As required for the work described under Task 6 and/or Task 7, the Contractor shall pay for up to $20,000 (direct cost) in laboratory supplies, animal purchases, and/or animal per diem charges.

Option 5: As required for the work described under Task 6 and/or Task 7, the Contractor shall pay for up to $40,000 (direct cost) in laboratory supplies, animal purchases, and/or animal per diem charges.

Option 6: As required for the work described under Task 6 and/or Task 7, the Contractor shall pay for up to $60,000 (direct cost) in laboratory supplies, animal purchases, and/or animal per diem charges.

NIHDA-2018-00198 Page 7 of 14

C. Protocol Specifications for Task 1: Cocaine Discrimination Protocol

1. Subjects: The subjects will be six male rhesus monkeys (Macaca mulatta) weighing approximately 5.0 to 7.5 kg. The Contractor shall maintain each monkey on a diet of three to four monkey biscuits and one piece of fresh fruit per day. During the week, the Contractor shall deliver all food after the experimental session, whereas on weekends, the Contractor shall deliver food between 9 a.m. and noon. Water will be freely available for all monkeys at all times. The Contractor shall maintain the room in which the monkeys are housed on a 12-hour light/dark cycle, with lights on from 7 a.m. to 7 p.m.

The Contractor shall conduct animal maintenance and research in accordance with NIH guidelines provided by the Committee on Laboratory Animal Resources. The facility must be licensed by the United States Department of Agriculture, and protocols must be approved by the Institutional Animal Care and Use Committee. Consulting veterinarians shall periodically monitor the health of the monkeys. Monkeys will have visual, auditory, and olfactory contact with other monkeys throughout the study. Operant food and drug self-administration procedures will provide an opportunity for environmental manipulation and enrichment.

2. Apparatus: The Contractor shall house each monkey individually in a well-ventilated, stainless steel chamber. The Contractor shall modify home cages of all monkeys to include an operant panel mounted on the front wall. The Contractor shall arrange three square translucent response keys in a horizontal row of the operant panel. Each key should be transilluminated by red, green, or white stimulus lights. In addition, the Contractor should design the operant panel to support an externally mounted pellet dispenser that delivers one gram of fruit-flavored food pellets to a food receptacle mounted on the cage beneath the operant response panel. The Contractor shall accomplish operation of the operant panels and data collection with appropriate computers located in a separate room.

3. Discrimination training - general procedures: The Contractor shall run all monkeys 5 days per week during daily sessions composed of multiple cycles. Each cycle will consist of a 15-minute time-out period followed by a 5-minute response period. During the time-out, all stimulus lights will be off and responding will have no scheduled consequences. During the response period, the right and left response keys will be transilluminated red or green and monkeys can earn up to 10 food pellets by responding under a fixed ratio (FR) 30 schedule of food presentation. For two of the four monkeys, the Contractor shall illuminate the left key green and the right key red. For the remaining four monkeys, the Contractor shall reverse the colors of the response keys. The Contractor shall not illuminate the center key at any time, and responding on the center key will have no scheduled consequences.

If all ten food pellets are delivered before the end of the 5-minute response period, the stimulus lights transilluminating the response keys will be turned off and responding will have no scheduled consequences for the remainder of the 5-minute period.

On training days, the Contractor shall give the monkeys an intramuscular (i.m.) injection of either saline or 0.40 mg/kg cocaine 5-minute into each time-out period (i.e., 10 min

NIHDA-2018-00198 Page 8 of 14 before the response period). Following the administration of saline, responding on only the saline-appropriate key will produce food, whereas following administration of 0.40 mg/kg cocaine; only responding on the drug-appropriate key will produce food.

Responses on the inappropriate key will reset the FR requirement on the appropriate key.

The Contractor shall run the monkeys for one to five cycles, and if the Contractor administers the training dose of cocaine, the Contractor shall administer it only during the last cycle. Thus, training days will consist of 0-5 saline cycles followed by 0-1 drug cycles.

4. Dependent Variables to be Measured: During each response period, three dependent variables will be determined using the following equations.

I. Percent injection-appropriate responding prior to delivery of the first reinforcer as defined by: (Injection-appropriate responses emitted prior to 1st reinforcer / Total responses emitted prior to delivery of 1st reinforcer) X 100

II. Percent injection-appropriate responding for the entire response period as defined by: (Injection-appropriate responses emitted during response period / Total responses emitted during response period) X 100

III. Response Rate as defined by: (Total responses emitted during response period / Total response period time in seconds*

*Total Response Period Time = either 5 min or the time from the start of the cycle to the time when the 10th reinforcer was delivered, if all 10 FRs were completed.

5. Criteria for discrimination: Monkeys shall have acquired cocaine discrimination when the following three criteria are met for seven of eight consecutive training sessions including the most recent session.

I. The percent injection-appropriate responding prior to delivery of the first reinforcer is greater than or equal to 80% for all cycles.

II. The percent injection-appropriate responding for the entire cycle is greater than or equal to 90% for all cycles.

III. Response rates during saline training cycles are greater than 1.0 responses per second.

6. Discrimination Testing:

a) General Procedure: Once monkeys meet criterion levels of cocaine discrimination, testing will begin. Test sessions will be identical to training sessions except that responding on either key produces food, and the Contractor shall administer compounds using either a substitution or a pretreatment protocol as described below. In general, the Contractor shall conduct training sessions on Mondays, Wednesdays and Thursdays, and the Contractor shall conduct test session on Tuesdays and Fridays. The Contractor shall run test sessions only if the three criteria listed above under "Criteria for Discrimination"

NIHDA-2018-00198 Page 9 of 14 are obtained during the training day immediately preceding the test day. If responding does not meet criterion levels of discrimination performance, then the Contractor shall continue training until criterion levels of performance are obtained for at least 2 consecutive days.

b) Test Compound Evaluation: Test compounds will be evaluated using the substitution test protocol, the antagonism pretreatment test protocol or both as directed by the COR. Doses, pretreatment times, and routes of administration for each new medication will be chosen in consultation with the COR based on information concerning pharmacokinetics, peak effect and duration of action.

The Contractor must be able to administer oral doses of test compound when specified by the COR. In general, the Contractor will use the following procedures:

(1). Substitution Protocol: In a substitution protocol, the Contractor shall administer the test compound alone using a cumulative dosing procedure. In this procedure, each monkey will receive a dose of the test compound five minutes into each cycle of a multiple cycle session.

The cumulative dose equals the sum of all doses administered during that session. In a typical cumulative dosing procedure, each dose will increase the total dose by 1/4 to 1/2 log units. In general, doses of the test drug will be evaluated from those that are inactive up to doses that either: a) increase the percent drug-appropriate responding for the entire response period to greater than or equal to 90%, or b) decrease response rates to less than 0.1 responses/sec. For each study, the Contractor shall test four monkeys.

(2). Antagonism Pretreatment Protocol: In a pretreatment protocol, the Contractor shall administer the test compound as a pretreatment at some time (usually 30 minutes) before the determination of a cumulative cocaine dose-effect curve. In general, the Contractor shall evaluate the test compound up to doses that either: a) produce a significant change in the cocaine dose-effect curve (to either the right or left), or b) decrease response rates to less than 0.1 responses/sec averaged over the entire session. For each study, the Contractor shall evaluate at least two monkeys.

For test compounds with short durations of action, it may be necessary to assess the full range of cocaine doses in two test sessions. This will ensure that the effects of the higher doses of cocaine are determined within a timeframe in which the test compound is active. In instances where a short duration of action is suspected by the Contractor, the COR will be notified and further testing instructions will be obtained. Similarly, in instances where a long duration of compound action is suspected by the Contractor, the COR will be notified and further testing instructions will be obtained. In these instances, the Contractor may conduct a supplementary test with each dose of the test compound, or

NIHDA-2018-00198 Page 10 of 14 conduct additional evaluations of response rate on days subsequent to compound administration.

In addition to collection of response rate measures, the Contractor shall note and systematically record observable pharmacological or toxicological effects following test compound administration for each monkey. The Contractor shall note these effects in the study report.

7. Generation of cocaine dose-effect curves: Cumulative cocaine dose-effect curves will be determined using the substitution protocol described above. Cocaine will be administered using cumulative dosing procedures in which each dose administration increases the total dose by 1/2 log unit. The Contractor shall obtain control cocaine dose-effect curves using the following cumulative dosing sequence: 0.013, 0.04, 0.13, 0.4, 1.3 mg/kg.

8. Route of administration: The Contractor shall administer all test compounds i.m. or p.o.

(nasal/oral gavage) as specified by the COR unless: (1) initial injections of a test compound cause unacceptable irritation at the injection site, (2) physical characteristics (i.e., particle size or pH) clearly indicate that a solution or suspension will cause unacceptable irritation at the injection site, or (3) the NIDA COR specifically requests an alternative route of administration. In cases where irritation at the injection site precludes the i.m. route of administration, the Contractor shall consult the NIDA COR before proceeding to an alternative route of administration, which may require a different pretreatment time.

9. Pretreatment time: Unless otherwise requested by the NIDA COR, the Contractor shall utilize a 30- minute pretreatment time for i.m. injections and a 90-minute pretreatment time for nasal/oral gavage administration.

10. Data analysis:

I. Test compound substitution protocol: For the substitution protocol, the Contractor shall plot individual subject graphs of the percent drug-appropriate responding for the entire response period and the response rate as a function of the dose of the test compound (log scale). Test compounds shall be considered to generalize to cocaine if some dose of the test compound produces at least 90% cocaine-appropriate responding. For compounds that generalize to cocaine, the slope of the test compound dose-effect curve and the slope of the cocaine dose- effect curve will be evaluated for parallelism using standard pharmacological procedures. In addition, the Contractor shall compare the relative potency of cocaine and the test compound. The Contractor will report ED50 values for those test compounds that generalize to cocaine. For each test compound that substitutes partially (>10% and <90%) for cocaine, the lowest dose that produces maximum cocaine-appropriate responding will be reported, as well as the associated maximum cocaine-appropriate responding value.

II. Test compound antagonism pretreatment protocol: For the pretreatment protocol, individual subject graphs of the percent drug-appropriate responding

NIHDA-2018-00198 Page 11 of 14 for the entire response period and the Contractor will plot response rate as a function of cocaine dose. The Contractor will evaluate the slopes and relative potencies of the cocaine dose-effect curves determined alone and following pretreatment with various doses of the test compound as above. For each test compound that significantly alters the cocaine dose-response curve, the Contractor will report ED50 values for cocaine curves determined in the presence of active doses of test compound, as well as for the corresponding control cocaine curves.

D. Protocol Specifications for Task 2: Cocaine Self-Administration Protocol

1. Subjects: The subjects shall be eight male rhesus monkeys (Macaca mulatta). The Contractor shall maintain each monkey on a diet of three to four monkey biscuits and one piece of fresh fruit per day in addition to fruit flavored pellets delivered during operant sessions (see below). Water shall be freely available for all monkeys at all times. The Contractor shall house the monkeys in a humidity and temperature controlled room with a 12-hour light dark cycle.

The Contractor shall conduct animal maintenance and research in accordance with the guidelines provided by the NIH Committee on Laboratory Animal Resources. The facility must be licensed by the United States Department of Agriculture and protocols must be approved by the Institutional Animal Care and Use Committee. Consulting veterinarians periodically shall monitor the health of the monkeys. Monkeys shall have visual, auditory, and olfactory contact with other monkeys throughout the study. Operant food and drug self administration procedures will provide an additional opportunity for environmental manipulation and enrichment.

2. Training: All subjects shall be trained to respond for the delivery of 1-gm banana pellets by gradually increasing values of a fixed-ratio (FR) schedule until performance is maintained under the terminal FR 30-response schedule (FR 30). Monkeys shall be trained to perform this task either in their home-cage, modified to include an operant panel mounted on the front wall or while seated in a primate chair enclosed within a ventilated sound-attenuating chamber. Following initial operant training, home-cage monkeys shall be prepared with a double-lumen intravenous catheter that is surgically implanted under aseptic conditions. Chaired monkeys shall be implanted with a single-lumen intravenous catheter attached to a subcutaneous titanium access port. Subsequently, monkeys shall be trained to respond for cocaine.

Home cage monkeys shall be surgically implanted with double lumen Silicone rubber catheters to facilitate concurrent delivery of cocaine and treatment compounds. The Contractor shall implant catheters in the jugular or femoral vein, and the catheters will exit in the mid scapular region. All surgical procedures shall be performed under aseptic conditions. Monkeys shall initially be sedated and anesthesia will be induced. After surgery, monkeys shall be administered aspirin or acetaminophen (80 160 mg/day; p.o.) for 3 days. The antibiotic, Procaine Penicillin G (300,000 units/day, i.m.), shall be administered every day for 5 days. The Contractor shall protect the i.v. catheter by a tether system consisting of a custom fitted nylon vest connected to a flexible stainless steel cable and fluid swivel. This flexible tether system will permit monkeys to move freely. Catheter

NIHDA-2018-00198 Page 12 of 14 patency shall be evaluated periodically by i.v. administration of a short acting barbiturate.

Chaired monkeys shall be similarly implanted with a single-lumen intravenous catheter attached to a subcutaneous titanium access port.

3. Apparatus: The Contractor shall house each monkey individually in a well ventilated stainless steel chamber. The testing chamber (home cage or isolation chamber for chaired subjects) shall be modified to include an operant panel mounted on the front wall and fitted with response keys that will be transilluminated by colored stimulus lights (LEDs).

Additional stimulus lights shall be placed in a vertical column below the response keys.

The operant panel should also support an externally-mounted pellet dispenser delivering to a food receptacle mounted beneath the operant response panel. Two syringe pumps shall be mounted above each chamber for delivery of drug solutions or saline. Operation of the operant panels and data collection shall be accomplished with a computer located in an adjacent room.

4. Experimental sessions: Experimental sessions shall be two hours in length. At the start of each session, an illuminated response panel shall be activated to begin a two-hour session (see diagram below). Each session shall consist of three response components separated by five-minute timeout periods. A schematic diagram of the daily session is shown below.

During the first and last components (the food components), 1g banana flavored food pellets shall be available under an FR 30; TO 10 sec schedule for five minutes. During the second component (the drug component) intravenous injections of cocaine or saline shall be available under an FR 30; TO 60 sec or an FR 30; TO 45 sec schedule (for monkeys with relatively low response rates) for 100 minutes. The response key shall be illuminated with red lights during the food components and with green lights during the drug component. During the timeout following each reinforcer delivery, the response key shall be illuminated with yellow lights. During inter-component timeout periods, the lights illuminating the response key shall be turned off, and responding will have no scheduled consequences. The drug self-administration component shall be preceded by illumination of the yellow light for 10 sec together with the non-contingent delivery of a single "priming" injection of the dose of cocaine or saline that will be available during the ensuing test component. This priming injection will signal the magnitude of reinforcement provided by IV injections during the subsequent drug self-administration component and is expected to facilitate stable performance during sessions of saline or IV cocaine availability.

NIHDA-2018-00198 Page 13 of 14

Diagram of drug self-administration protocol

5. Sequence and duration of training procedure: Subjects shall be initially trained in sessions with only two food components. During drug components, all lights shall be extinguished and responding will have no programmed consequences. This initial training will continue until responding for food pellets is reliably maintained under the FR 30 schedule. After food-maintained performance becomes stable, cocaine self-administration training shall be initiated. All subjects shall be trained to respond for cocaine under an FR 30-response schedule. Our cocaine training procedure shall include two phases described below.

Initially, subjects shall be trained to self-administer 0.1 mg/kg/inj cocaine during the daily session. In this phase of training, the number of available infusions shall be limited to twenty during the 100-min session to reduce the possibility of overdose in inexperienced subjects. If twenty infusions are self-administered prior to the elapse of 100-min, all lights shall be extinguished for the remainder of the session. When cocaine-maintained responding occurs reliably, the unit IV dose shall be reduced to 0.032 mg/kg of cocaine to limit the disruptive effects of each IV cocaine injection, thereby leading to higher levels of IV self-administration behavior throughout the session. Extinction training also shall begin during this initial phase by introducing sessions in which saline is substituted for 0.032 mg/kg IV cocaine during the entire session. Saline substitution shall be introduced on a double alternation basis (two session of cocaine self-administration followed by two sessions of saline availability; Coc-Coc-Sal-Sal). Saline shall be made available more frequently when extinction training is slow (see below for criterion). This extinction training procedure shall be introduced early in the training protocol to expedite the development of rapid and full extinction when saline is substituted for cocaine. Monkeys shall continue in this phase of training until they meet the following criteria for stable cocaine self-administration during three consecutive cycles of double alternation between cocaine and saline (i.e., Coc-Coc-Sal-Sal-Coc-Coc-Sal-Sal-Coc-Coc-Sal-Sal):

(a) The number of injections during each of the second days of IV cocaine availability differs by no more than 20% from the mean number of injections for those sessions;

and;

(b) Rapid saline extinction in each double alternation cycle as indicated by a marked fall-off in IV self-administration behavior on the first days of saline substitution, i.e., <20% of the mean number of injections of cocaine used for calculations in (a).

After reliable extinction, the training procedure shall be modified to permit self-administration of various unit doses ranging from 0.001 – 0.1 mg/kg of IV cocaine. Saline and different doses of cocaine shall continue to be available for IV self-administration under a double alternation schedule, and the priming dose of cocaine at the start of the component of IV self-administration shall be the same as the unit dose of cocaine that is available for IV self-administration. Occasionally, saline or a unit dose of IV cocaine shall be available for one or three consecutive sessions to limit the predictability of an unmodified double alternation schedule. When session values for IV self-administration of

NIHDA-2018-00198 Page 14 of 14 saline or a dose of cocaine in an individual monkey lie outside the range of values that are expected on the basis of previous training data, one or more additional sessions shall be conducted before continuing with the double alternation schedule. Under these conditions, the full dose-effect curve for IV cocaine self-administration shall be continually re-determined in all monkeys.

In addition to the food/drug/food session described above, home-cage monkeys shall also be given the opportunity to self-administer additional food pellets during supplementary food sessions. During these sessions, food is available under the same FR30/Timeout 10 sec schedule, and a maximum of 25 pellets per session shall be earned. These additional food sessions shall provide additional enrichment opportunities for the monkeys and behavioral information that may reveal health problems.

6. TESTING PROCEDURES: Two types of evaluation can be conducted as directed by the Project Officer.

a) Substitution procedure: In a substitution test, the test compound replaces cocaine as the drug available for IV self-administration. Various unit doses of the test compound, including saline control, shall be made available for self-administration for at least one test session in substitution for the peak dose of cocaine. Test compounds shall be evaluated up to doses that either: (1) go beyond the peak of the dose-effect curve to the descending limb of the dose-effect curve, or (2) eliminate rates of food-maintained responding during the second food component of the test session. At the conclusion of each substitution dose-condition, the monkeys shall resume training under the conditions described above.

b) Pretreatment procedure: Pretreatment tests will be conducted in two stages.

Test sessions during both stages of testing will be separated by at least three days.

In the first stage of the procedure, test sessions shall be conducted to determine the effects of a treatment compound on responding maintained by the peak unit dose of cocaine in individual monkeys (dose ranging). In these initial studies, the dose of test compound shall be increased until either (1) a significant reduction in IV cocaine self-administration is observed or (2) responding during the first food component is substantially decreased, e.g., to <50% of control values. These initial studies will be used to identify a dose of the test compound that is behaviorally active in the drug self-administration procedure. Whenever possible, the doses of compound that decrease self-administration of the peak unit dose of cocaine and that do not markedly alter food-maintained behavior shall be studied further. If significant reductions in IV cocaine self-administration are observed following more than one dose of test compound, the dose showing greatest “selectivity” (reductions in cocaine self-administration relative to reductions in responding for food) shall be studied further in a follow-up study.

In the second stage of the pretreatment procedure, test sessions shall be conducted to determine the effects of one or more doses of the treatment compound on responding maintained by a range of unit doses of cocaine. In addition to dose ranging results, data shall be obtained for effects of the selected dose(s) of test

NIHDA-2018-00198 Page 15 of 14 compound during access to saline and during access to lower and higher cocaine doses. In this way, the effect of a behaviorally active dose of the test drug on both the ascending and descending limbs of the cocaine dose-effect curve shall be studied. Cocaine dose-effect curves (control and following test compound) shall include enough points to fully delineate the ascending limb and the peak; at least one point beyond the peak (on the descending limb) shall be included in each curve.

7. Data Analysis: The principal dependent variables for these studies shall be the number of reinforcers (food pellets or injections) delivered during each component of the test session and response rate (response key presses per second). For individual monkeys, the number of reinforcers per session shall be closely correlated to response rates under this procedure because monkeys respond under a fixed ratio schedule, the duration of the post-reinforcer timeout period is short (10 or 60 sec), and, following training, the number of reinforcers per component is not limited. Response rates and number of reinforcers will be tabulated in reports, and the number of infusions of cocaine as a function of unit dose and the number of food reinforcer deliveries before and following sessions of cocaine self-administration shall be graphed for individual monkeys and for the group of subjects.

8. DRUGS: Cocaine HCl, provided by NIDA, will be dissolved in sterile saline and delivered intravenously. Instructions regarding preparation of test compounds, starting doses, and pretreatment times for study will be provided by the Project Officer.

ALL OTHER TERMS AND CONDITIONS OF THE RFP REMAIN UNCHANGED AND IN

FULL FORCE AND EFFECT.